In morbidly obese patients undergoing laparoscopic bariatric surgery, the combination of obesity-related comorbidities, pneumoperitoneum and extreme posture changes constitutes a high risk of perioperative hemodynamic complications. Thus, an advanced hemodynamic monitoring including continuous cardiac index (CI) assessment is desirable. While invasive catheterization may bear technical difficulties, transesophageal echocardiography is contraindicated due to the surgical procedure. Evidence on the clinical reliability of alternative semi- or non-invasive cardiac monitoring devices is limited. The aim was to compare the non-invasive vascular unloading to a semi-invasive pulse contour analysis reference technique for continuous CI measurements in bariatric surgical patients.This prospective observational study included adult patients scheduled for elective, laparoscopic bariatric surgery after obtained institutional ethics approval and written informed consent. CI measurements were performed using the vascular unloading technique (Nexfin®) and semi-invasive reference method (FloTrac™). At 10 defined measurement time points, the influence of clinically indicated body posture changes, passive leg raising, fluid bolus administration and pneumoperitoneum was evaluated pre- and intraoperatively. Correlation, Bland-Altman and concordance analyses were performed.2) were enrolled into the study and data from 54 patients could be entered in the final analysis. Baseline CI was 3.2 ± 0.9 and 3.3 ± 0.8 l/min/m2, respectively. Pooled absolute CI values showed a positive correlation  and mean bias of of − 0.16 l/min/m2 (limits of agreement: − 1.48 to 1.15 l/min/m2) between the two methods. Pooled percentage error was 56.51%, missing the criteria of interchangeability (< 30%). Preoperatively, bias ranged from − 0.33 to 0.08 l/min/m2 with wide limits of agreement. Correlation of CI was best  and percentage error lowest (46.34%) during anesthesia and after fluid bolus administration. Intraoperatively, bias ranged from − 0.34 to − 0.03 l/min/m2 with wide limits of agreement. CI measurements correlated best during pneumoperitoneum and after fluid bolus administration . Trending ability for all 10 measurement points showed a concordance rate of 85.12%, not reaching the predefined Critchley criterion (> 92%).Sixty patients (mean BMI 49.2 kg/mNon-invasive as compared to semi-invasive CI measurements did not reach criteria of interchangeability for monitoring absolute and trending values of CI in morbidly obese patients undergoing bariatric surgery.NCT03184272.The study was registered retrospectively on June 12, 2017 with the registration number  Furtemission . Nowadayemission . Howeveremission .In contrast, non-invasive devices based on the vascular unloading technique first described by Penaz  offer thThus, the aim of our study was to compare perioperative CI measurements between the non-invasive vascular unloading technique  to a semi-invasive pulse contour technique, the FloTrac™ system in a larger cohort of patients undergoing bariatric surgery. In particular, we sought to track clinical steps including PP and extreme posture changes with a likelihood of hemodynamic instability.2, an ASA (American Society of Anesthesiologists) class ≥ II, and written informed consent for study participation. A BMI ≥ 30 kg/m2 was chosen as not only morbid obese patients defined as a BMI ≥ 40.0 kg/m2 or 35.0 and 39.9 kg/m2 and comorbidities but also obese patients with BMI > 30 and < 35 kg/m2 and type 2 diabetes may have been scheduled for bariatric surgery [https://clinicaltrials.gov/ct2/show/NCT03184272.This was a single-center prospective observational cohort study conducted at the Department of Anaesthesiology and Intensive Care Medicine and General Surgery, University Medical Center, Schleswig-Holstein, Campus Kiel. Inclusion criteria were defined as adult patients with an indication for elective laparoscopic bariatric surgery, a BMI ≥ 30 kg/mThe individual risk for postoperative nausea and vomiting was evaluated at the time of study inclusion. In patients with more than 3 independent risk factors according to the score by Apfel and coworkers , generalThe Nexfin® system  is a finger cuff device combining the vascular-unloading technique with the principle of physiological calibration in order to reconstruct the brachial arterial pressure waveform from the finger arterial pressure waveform . CardiacIn the run up, a non-invasive blood pressure measurement using a forearm cuff on both arms was used for all patients in order to detect physiological as well as pathological blood pressure differences. Standard clinical monitoring with non-invasive blood pressure monitoring, relaxometry and pulse oxymetrically measured oxygen saturation was performed on the right arm. In accordance to previous study protocols , 19, theThe Nexfin® system was connected to the wrist unit as well as the heart reference system. This system adjusts the blood pressure to hydrostatic differences between the sensor and the heart level. The instruments were hold next to each other at the same level to adjust them to zero. After this procedure was completed, the heart reference system detectors were placed at finger and heart level. The correct size of the finger cuff was choosen and placed at the middle phalanx of the index finger. Finally, biometric patient data were entered as applicable in both the Vigileo™ and Nexfin® monitors and measurements of CI started.Figure The first measurement was performed in the awake, spontaneously breathing patient in neutral position (baseline). Directly before the induction of general anesthesia, the patients were placed in ATP (30° bottom low position) as per clinical standard to improve a better oxygenation and to provide an aspiration prophylaxis (measurement time point 2). The next measurement was taken in neutral position under general anesthesia . The following two measurement pairs (time points 4 and 5) were taken after a PLR maneuver (raising the legs by 30°) and - in neutral position - after administration of a 500 ml fluid bolus of a balanced crystalloid solution . After this preoperative period the patients were delivered to the operating room, where the measurement tools were reconnected and a new zero balance was performed. Further measurements were taken after PP had been applied to 15 mbar , after the ATP positioning during surgery (measurement time point 7) and in that position after another fluid bolus of 500 ml crystalloid solution (measurement time point 8). The last two intraoperative measurements (time points 9 and 10) were carried out after termination of PP in neutral position, and again in ATP by the end of general anesthesia.n = 60 patients, followed by an intermediate evaluation. For a Bland-Altman analysis, the width w of the confidence interval for the limits of agreement (LOA) is calculated as w = 6.79 • σ • 1 / √n, where n is number of cases and σ is the standard deviation. For a case count of n = 60, the result is w = 0.88 • σ and thus considered a sufficiently large number.The primary endpoint of this study was the analysis of the CI differences between the test and reference method. Sample size evaluation was based on the method by Bland and Altmann for calculating the mean measurement deviation (bias) and the precision  , 21. In P value of < 0.05 was considered as statistically significant. Statistical analysis was performed using SPSS Statistics 21 for Windows .A Spearman’s correlation analysis of measurement pairs for CI between the two monitoring devices was performed followed by a Bland-Altman analysis with calculation of the mean bias and LOA defined as the standard deviation (SD) of the mean bias times 1.96 as described above . In addi2, all patients met the definition for morbid obesity. Table 2, respectively. Of the 10 measurement time points pre- and intraoperatively, a total of 580 pairs of measured values were computed. Six patients had to be excluded from further correlation analyses as no valid CI measurement data sets could be derived for all measurement points leaving 54 patients for the final analysis. Missing individual data points are indicated, if applicable for each of the subsequent analyses.Sixty patients were included in the study with a mean age of 46,5 years. As the BMI was 49.2 ± 5.7 kg/ms = 0.76 (P < 0.001). The Bland-Altman analysis revealed a bias of − 0.16 l/min/m2 (LOA: − 1.48 - 1.15 l/min/m2). The criterion of interchangeability could not be reached with a PE of 56.51%. Table s = 0.82, P < 0.001) with the lowest PE (46.34%). Bias (SD) ranged from − 0.33 (0.42) to 0.08 (0.60) l/min/m2 indicating a slight overestimation of the Nexfin® system at measurement time point 5 and a slight underestimation at measurement time point 2, respectively with overall wide LOA.Figure Figure 2 undergoing bariatric surgery, perioperative measurements of CI by the non-invasive Nexfin® system were compared to the semi-invasive FloTrac™ device defined as the reference method at the ispsilateral arm. Overall, interchangeability for absolute CI values from 54 patients that could be entered into the final analysis, could not be shown between the two devices with a correlation coefficient of rs = 0.76 (P < 0.001), a bias of − 0.164 l/min/m2 (LOA: − 1.478 - 1.150 l/min/m2) and a high PE (56.61%). Although a high overall concordance rate of 85.12% was found, trending capability of the vascular unloading technique in the pre- and intraoperative phase did not reach the predefined Critchley criterion of 92%.In this prospective observational cohort study in 60 patients with a mean BMI of 49.2 kg/mMorbidly obese patients are prone to an increased cardiovascular risk with impaired cardiac performance, including impaired relaxation ability and myocardial hypertrophy in addition to other pre-existing comorbidities , 24, 25.The validity of non-invasive or semi-invasive CO measurements has been demonstrated in previous studies in different populations including normal-weight patient groups and surgical settings , 33–35. Thus far, evidence on non- or semi-invasive CI measurements in the perioperative setting of bariatric surgery is limited to one case series and one prospective observational study , 40. In 2) undergoing gastric bypass surgery, Boly et al. investigated whether different body weight formulas play a role in possible differences of CO measurements using Nexfin® as compared to invasive thermodilution (PiCCO® system) [2). However, the evaluation of the CI (ratio of CO to body surface area) in our study most likely minimized the possible influence of body weight as one of the underlying calibration variables. Moreover, body weight per se is not the only factor to adequately reflect individual vascular compliance. Especially in the morbidly obese patient cohort arterial compliance can be altered in the presence of obesity-associated comorbidities [The two measurement systems analysed in our study estimate individual vascular compliance by computer-assisted databases using the body weight besides other biometric data including sex, age and height –16. In a system) . Using abidities . The CO-bidities . Thus, tWith regard to preexisting vasculopathies likely invalidating measurements with the finger-cuff method used, the presence of peripheral arterial occlusive disease or advanced secondary damage from diabetes mellitus or arterial hypertension encompassed in the metabolic syndrome also play a role as comorbidities in the investigated patient population . HoweverBesides the observational nature of our study, the main limitation is that we did not use an invasive gold standard, i.e. thermodilution method as a reference for CO determination. In consideration of the high invasiveness and associated risk in particular with pulmonary artery catheters the risk-benefit ratio was considered to be not justified . Since nA strength of our study is that it provides – to our best knowledge - the largest sample size of morbidly obese patients with continuous CI measurements during bariatric surgery to date. Furthermore, this study thoroughly reflected the clinical scenarios patients undergo in the perioperative setting including different postures, induction of anesthesia and fluid bolus administration as well as on- and off-set of PP.In conclusion, non-invasive CI measurements using the vascular unloading technique based Nexfin® system in the perioperative phase of morbidly obese patients was not interchangeable with the semi-invasive reference method, neither with respect to absolute nor relative (trending) values. However, we have observed a strong trending ability in non-invasive CI measurements during the sensitive period of induction of anesthesia. Our findings underline further demand of larger trials to better evaluate the clinical useability of non- and semi-invasive devices for continuous CI measurements in the growing field of bariatric perioperative medicine.


Some cross-sectional studies associated CAN with low 25-hydroxyvitamin D levels. The aim of our study was to evaluate the effect of high-dose vitamin D (VD) supplementation on CAN in Type 1 Diabetes Mellitus (T1DM) patients.Cardiovascular autonomic neuropathy (CAN) is associated with diabetes We performed a prospective study with 23 patients diagnosed with T1DM and CAN. Subjects with VD levels <30 ng/ml received 10,000 IU/day; the ones with VD levels between 30–60 ng/ml were given 4,000 IU/day for 12 weeks.There was an improvement in CAN parameters related to resting heart rate variability, such as time domain parameters  and frequency domain parameters . In addition, there was a correlation between absolute VD level variation and posttreatment High Frequency (%), as well as among percent variation in VD level and end-of-study Low Frequency/High Frequency ratio .Our pilot study is the first to suggest a strong association between high-dose vitamin D supplementation and improved cardiovascular autonomic neuropathy in T1DM patients. It occurred without any variation in HbA1C, blood pressure levels, lipids, and insulin dose.http://www.isrctn.com/ISRCTN32601947, identifier ISRCTN32601947. Autonomic diabetic neuropathy is a degenerative condition that affects 16.7%–34.3% of DM patients . It is rCardiovascular autonomic neuropathy (CAN) is characterized by autonomic denervation of the cardiovascular system, causing hemodynamic changes and increasing morbidity and mortality in patients with diabetes , 5. It iFew cross-sectional studies suggest an association between 25(OH)D level, presence and severity of peripheral neuropathies –11 and CThere are few therapeutics options for CAN currently. In this context, Vitamin D (VD) could be a potential option to be evaluated in patients with diabetes with CAN. Thus, the aim of this study is to evaluate the effects of high-dose VD supplementation on CAN parameters in patients with T1DM.We performed a prospective study to evaluate the effect of vitamin D supplementation on CAN in T1DM patients as part of a research protocol (ISRCTN32601947) that has already provided evidence on other aspects of VD supplementation outcomes –20.A total of 68 subjects were recruited from the endocrinology ambulatory but only 23 had CAN diagnosis according to Toronto consensus  and wereThis study was developed according to the Declaration of Helsinki and the Nuremberg Code and was approved by the University Hospital João de Barros Barreto ethics committee, reference number 0122.0.071.000-12. Signed consent was obtained from all patients.Inclusion criteria consisted in: a) patients with T1DM diagnosis in at least a 1-year follow-up; b) age between 12 and 50 years in regular treatment with an endocrinologist; c) CAN diagnosis according to Toronto consensus ; d) insuData collection occurred during scheduled visits, during pre-treatment (baseline) and post-treatment (end of study) phases. Analysis of medical records  and physical examination were carried out. Laboratory tests and CAN evaluation were performed before and after 12 weeks.Serum 25(OH)D was measured quantitatively by the following kit: DiaSorin LIAISON 25-OH-Vitamin D TOTAL chemiluminescence immunoassay  . DiaSoriCAN research was always made in the morning, with fasting capillary glycemia levels between 70–250 mg/dl. Subjects were instructed not to use alcohol, caffeine beverages and tobacco for at least 8 h before the test, and not to perform vigorous physical exercises 24 h before examination.Parameters used to diagnose CAN were Very Low Frequency, Low Frequency, High Frequency, respiratory coefficient, 30/15 coefficient and Valsalva coefficient, as well as systolic blood pressure (SBP) reduction in orthostasis. Subjects were considered not to have CAN when presenting up to 1 abnormal parameter. The presence of two abnormal parameters was defined as criteria to diagnose incipient CAN; for established CAN, three parameters were necessary . Severe The VNS-MICRO software  was used to analyze data of seven heart rate variability (HRV) parameters: three of them in rest and four while performing maneuvers of vagal and sympathetic stimulations . The tesThe stimulatory maneuvers used were deep breathing, Valsalva and orthostasis (blood pressure and HRV). In each test the relation between the largest and smallest RR interval is assessed and, then, a coefficient is obtained .Beside seven diagnostic items, software provided another data about rest HRV called time domain parameters. Total Power (TP) is a set of three combined spectral bands, including: LF/HF ratio, which reflects balance between sympathetic and parasympathetic systems; RRmin , RRmax ; RRNN ; and SDNN . Despite it is not a diagnostic criteria, it provides additional information in sympathetic and parasympathetic performance in heartbeat. The frequency domain parameters were expressed in logarithm with base 10.To compare variables before and after VD supplementation Wilcoxon and paired T test were applied, and Chi-square test was run for categorical variables.®  e Statistical Package for Social Sciences .To establish correlations between variables, Pearson’s or Spearman’s test was used. The level of statistical significance was set at p<0,05. Statistical analysis was performed using SigmaStat 3.5Our sample size was calculated based on an expected difference of 0.01 in SDNN (SD=0.015) to achieve a power of 0.8 and alpha of <0.05, the sample size necessary was 20. In addition, the sample was enough to obtain the same power in all variables evaluated. 0.2 between means in TP (SD=0.3); 0.6 in LF (SD=0.4); 0.5 in HF (SD=0.7); 0.3 in VLF (SD=0.4); and 0.3 in Valsalva coefficient (SD=0.4). The sample size necessary was 20, 20, 18, 16, and 16, respectively.Baseline characteristics of all patients recruited and enrolled are described in Cardiovascular Autonomic Neuropathy test results are described in When analyzing just CAN criteria, we noticed a reduction in the number of altered rest parameters  after VD supplementation Figure 4We found correlations between VD variations with percentage of HF and LF/HF ratio 7, suggeOur study found a strong association between high-dose vitamin D supplementation and improvement in CAN parameters in patients with type 1 diabetes mellitus and autonomic neuropathy. There were no changes in HbA1C, blood pressure, lipid profile and insulin dose. In addition, we observed that percentage variation of serum VD level correlated with improvement in CAN rest parameters.Resting heart rate variability was advocated by some authors as a sensitive and specific method for diagnosis of cardiovascular dysautonomia. Besides that, it is easier to be performed than dynamic tests and does not need patient collaboration –35. TakaSome cross-sectional studies and a recent systematic review suggest an association between vitamin D serum level, presence and severity of peripheral neuropathies in patients with diabetes –11. In aThere are several major factors associated with CAN onset and progression. For instance, poor glycemic control and variability seem to be enrolled in this complication, as intensive glycemic control reduced CAN incidence after 14 years of follow-up , 39, 40.We have not evaluated genetic and epigenetic factors that could influence our results. It has been described that, among epigenetic factors, some miRNAs polymorphisms have been studied in this context. Presence of rs2910164 (G>C) MIR146A variant seems to have a beneficial effect in CAN, whereas the variant allele of rs895819 SNP in MIR27A was associated with a higher risk of developing this condition earlier. In addition, polymorphisms in vitamin D receptor (VDR) gene were described in association with type 1 and 2 diabetes mellitus, although there are no data about its correlation with diabetic neuropathy susceptibility (A hypothesis that may explain improvement of NAC parameters in present study is action of VD in regulation of neurotrophin . This meThe effect of vitamin D on diabetes microvascular complications has been studied for some authors , 50, 51.Since it is a pilot study, our results are insufficient to clarify the real effect of vitamin D supplementation on cardiovascular neuropathy of these patients. Small number of participants, short period of VD supplementation and absence of a placebo-controlled group with CAN suggest that our results are limited in understanding the real utility of vitamin D as a therapeutic option for this complication. Prospective studies with this specific methodology are required to get this answer.Our data suggest a strong association between high dose vitamin D supplementation and improvement of resting heart rate variability parameters in patients with type 1 diabetes and previous diagnosis of autonomic neuropathy. In addition, correlation between variation of serum vitamin D level and CAN parameters was observed.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by University Hospital Joao de Barros Barreto ethics committee. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. LS, JF, KF, and NQ took part in conception and design of study. AM, PF, FM, MR, IL, MS, and AC were responsible for acquisition of data, while NMS, ÍS, WS, LJ, NJKS, and JA have done the analysis and interpretation of data. ML, MO, AA, LM, GL, and PP have drafted the manuscript together. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cerebral autoregulation was preserved. The neurovascular unit of subjects with chronically reduced heart pumping capability is severely dysfunctional. Dynamic testing with transcranial Doppler could be useful in these patients, but whether it helps in predicting cognitive impairment must be addressed in future prospective studies.The hemodynamic consequences of a persistent reduced ejection fraction and unknown cardiac output on the brain have not been thoroughly studied. We sought to explore the status of the mechanisms of cerebrovascular regulation in patients with heart failure with reduced (HFrEF) and recovered (HFrecEF) ejection fraction. We monitored cerebral blood flow velocity (CBFV) with transcranial Doppler and blood pressure. Cerebral autoregulation, assessed by transfer function from the spontaneous oscillations of blood pressure to CBFV and neurovascular coupling (NVC) with visual stimulation were compared between groups of HFrEF, HFrecEF and healthy controls. NVC was significantly impaired in HFrEF patients with reduced augmentation of CBFV during stimulation (overshoot systolic CBFV 19.11 ± 6.92 vs. 22.61 ± 7.78 vs. 27.92 ± 6.84,  Increased rates of cognitive decline and dementia have been documented in patients with heart failure (HF) . From a A major regulatory mechanism of cerebral blood flow is cerebral autoregulation (CA), the ability to maintain a stable cerebral blood flow despite changes in systemic blood pressure . ImpairmFortunately, all cerebral hemodynamic regulation mechanisms, including NVC, can be studied non-invasively with transcranial Doppler  and EF cA total of 23 patients from the HF outpatient clinic at our center were invited to participate in the study from October 2017 to March 2020.Patients were considered appropriate to participate in the study if they fulfilled the inclusion criteria: (1) able to contribute throughout the entire duration of the study, (2) age >18 y, (3) diagnosed with systolic heart failure, (4) followed in expert outpatient clinic.Exclusion criteria were previous history of stroke, dementia or other central nervous system disease that led to cognitive sequels, inadequate temporal window for transcranial Doppler (TCD), significant stenosis ≥50% in carotid or main cerebral arteries, atrial fibrillation, severe aortic stenosis (mean gradient ≥40 mmHg), mechanic or biologic aortic valvular prothesis and other severe valvular diseases capable of interfering significantly with ejection fraction or associated with high risk of cerebral embolization and an expected survival of less than a year.We recruited two control groups from the institution with similar age and sex to the HFrEF patients: patients with heart failure with recovered ejection fraction (HFrecEF) and healthy controls without heart or cerebral disease and without vascular risk factors.The study was approved by the local medical ethics committee and all subjects gave their written informed consent.Medical history and physical examination were performed in all participants, including measurement of weight and height. Systolic and diastolic blood pressure (BP) was averaged from three measurements in the sitting position with an oscillometric cuff . Heart rate was determined (HR). Orthostatic hypotension was determined by assessing blood pressure over a 2-min period after standing and was defined as a 20 mm Hg fall in systolic blood pressure or a 10 mm Hg fall in diastolic blood pressure. Participants underwent cervical and transcranial Doppler ultrasound examinations  to exclude hemodynamically significant cervical or intracranial arterial stenosis.All heart failure patients underwent a transthoracic echocardiogram within 3 months of cerebral hemodynamic evaluation. Left ventricular ejection fraction was evaluated according to guidelines ,10, as wNeuropsychological evaluation of all participants was obtained with the Portuguese version of Montreal Cognitive Assessment (MoCA), performed by certified medical staff. It has been validated in the Portuguese population .Evaluations were carried according to the previously described protocol . We usedTo analyze cerebral dynamic autoregulation, a 7-min period of resting data was recorded. Transfer function analysis was used to calculate the gain and phase parameters between the mean BP spectrum and CBFV of MCA and PCA .NVC was determined by a visual paradigm that consisted of 10 cycles, each with a resting phase of 20 s (eyes closed) and a stimulating phase with a flickering checkerboard at 10 Hz for 40 s . All cycere used . Afterwa ξ∗sω+ 1 . Gain re ξ∗sω+ 1 .p-value of <0.05 (two-sided) was considered statistically significant.Kolmogorov–Smirnov test was used to assess the normality of the continuous variables. Categorical variables were presented as absolute values and percentages and continuous variables as median (interquartile range) or means (±SD) as indicated. Categorical variables were presented as absolute values and percentages and continuous variables as median (interquartile range) or means (±SD) as indicated. Statistical significance for intergroup differences was assessed by Pearson χ2 test for categorical variables and by Mann–Whitney U test or Student t test as indicated for continuous variables. Repeated-measures ANOVA test was used to compare the cerebral hemodynamic data by group  and arterial territory (PCA vs. MCA). A linear regression analysis was employed to detect an association between NVC parameters and absolute values of MoCA score. Multivariable logistic regression analyses were used to determine which of these parameters could be considered as independent predictors of cognitive decline. Statistical analyses were executed using SPSS Statistics, version 25 . A p = 0.022). Vascular risk factors were equally distributed in HFrEF patients and HFrecEF controls. Mean MoCA scores were also similar in both groups of HF subjects, although 3 out of 20 patients with HFrEF had a MoCA score compatible with cognitive deficit, with 2 SD below appropriate norms, adjusted to age and education level, but without criteria for dementia [We recruited 23 patients with HFrEF, 8 patients with HFrecEF and 13 healthy controls. Baseline characteristics of the study groups are compared in dementia . p = 0.04), slower upright of CBFV (Rate time to overshoot: 1.19 (3.0) vs. 3.06 (4.30) vs. 2.90 (3.84); p = 0.02) and reduced arterial oscillatory properties  vs. 0.20 (0.09) vs. 0.24 (0.07); p = 0.03; attenuation 0.34 ± 0.24 vs. 0.48 ± 0.35 vs. 0.50 ± 0.23, p = 0.05). Cerebral autoregulation was preserved. Although not statistically significant, HFrecEF subjects tend to perform worse in NVC task, with reduced overshot, gain and natural frequency comparing to healthy controls.Cerebral hemodynamic parameters are compared between HFrEF patients and healthy controls in p > 0.05) (There was no correlation of HF etiology with the various parameters of NVC ( > 0.05) .Our study examined the status of the cerebral hemodynamics regulatory mechanisms with transcranial Doppler in 23 HFrEF patients, 8 HFrecEF patients and 13 healthy controls and found that patients with HFrEF have significant NVC impairment, while CA seems to remain preserved.Brain injury in HF results from the interaction of multiple factors and is not well established. Reduced CBF is one of the main mechanisms, but other aspects contribute, as elevated levels of neurohormones and inflammatory reaction. In previous studies with hypotensive patients, insufficient cerebral perfusion led to NVC impairment ,18, sincOur HFrEF group showed no differences in CA indexes as compared to healthy controls, which is not in agreement with the study of Caldas et al. that states a reduced dynamic CA in ischemic HF patients with EF ≤45% . HoweverThis pilot study has some limitations. A noticeable limitation of this study is its small sample size and cross-sectional design. A prospective design could help to depict more accurately the differences between groups, namely in what concerns to CA.We tried to assess cognitive status using MoCA score, which is validated in Portuguese population . HoweverAnother limitation refers to the absence of assessment of cardiac output (CO), since we only measured ejection fraction with transthoracic echocardiogram. Determining CO and its variations at rest and with exercise would help to clarify the impact of CO on cerebral hemodynamics and needs to be clarified in further studies.Additionally, we need to consider the influence of drugs on cerebral hemodynamics, but we need a larger population to extract solid conclusions about their effects.Our work shows that NCV, assessed with transcranial Doppler, may be impaired in patients with HFrEF. However, this technique only evaluates large vessels , impedinFinally, HF is a multifaceted disease with a large spectrum of severity and comorbidities. Each factor has a specific burden in the cerebrovascular hemodynamics regulation which makes more difficult the analyses of data and the achievement of clear-cut conclusions.This study shows that NVC impairment seems to be selectively impaired in HFrEF patients. Other mechanisms of cerebrovascular control are preserved in the first stages of disease, like CA. Future research is warranted to understand how HFrEF development could lead to the dysfunction at the neurovascular unit, which could have an impact on the prevention of cognitive impairment. Moreover, it needs to be clarified if the evolution of HF impairs other cerebrovascular regulatory mechanisms.


Acute canine idiopathic polyradiculoneuritis (ACIP) is one of the most common generalised neuromuscular diseases affecting dogs. In this report, we describe a 5-year-old, 25-kg, male, intact, Siberian Husky dog with ACIP with secondary induced arterial hypertension {systolic blood pressure [mean (m) ± standard deviation (sd)], 214 ± 19 mmHg; mean blood pressure (m ± sd), 164 ± 6.36 mmHg; and diastolic blood pressure (m ± sd), 137 ± 0.7 mmHg} and sinus tachycardia. Heart rate variability analysis indicated decreased vagal activity  and predominance of sympathetic activity. Arterial hypertension was treated with amlodipine but remained greater than the upper limit for 51 days until the dog recovered ambulation. This is the first case report of ACIP and secondary arterial hypertension in a dog. Routine blood pressure measurements should be included in the monitoring of patients with ACIP if arterial hypertension might interfere with patient prognosis. A 5-year old, 25-kg, male, intact, Siberian Husky dog was presented to the neurology service in the Veterinary Teaching Hospital Iași with acute non-ambulatory tetraparesis. The clinical signs occurred five days prior to presentation and consisted of progressive symmetrical weakness with onset from the posterior limbs that advanced to the anterior limbs. At presentation, neurological examination revealed areflexia and atonia in all four limbs with preserved perineal reflex, urinary continence, voluntary movements of the tail, and intact nociception. No signs of impaired cranial nerves were observed, but vocal changes over the last three days, suggesting dysphonia, were described by his owner. The dog could hold up his head and was able to eat and drink voluntarily. The rectal temperature was 38.6 °C, heart rate (HR) was 80 beats/min, and respiratory rate was 32 breaths/min. No recent illness, trauma, exposure to toxins, exposure to raccoon bites, or previous episodes of weakness prior to presentation were reported by the owner. Blood work revealed left-shift mild leukocytosis , an increased activity of creatine kinase , and a modified albumin/globulin ratio . No blood gas analyses were performed.The neuroanatomical localisation was consistent with a generalised lower motor neuron condition.Cerebrospinal fluid tap, electrodiagnostic examination, and muscle biopsy (the owner declined nerve biopsy) were scheduled for the next day. Overnight, the dog developed tachycardia (140 beats/min) with short episodes of tachypnoea (up to 60 breaths/min) and was unable to hold up his head. The next day, the dog underwent abdominal ultrasonography and a complete cardiologic examination, which consisted of 5-min 10-lead electrocardiography , trans-thoracic echocardiography , thoracic radiography, and arterial blood pressure measurement Thrall .The blood pressure was assessed noninvasively in the coccygeal artery with the dog positioned in lateral recumbency, using an oscillometric veterinary device equipped with a size-suitable cuff . The mean value of five artefact-free measurements evaluated through the dedicated arterial pulse graphic was used for analyses  and did not change between the two ECG recordings.Echocardiography revealed a normal left ventricular dimension, with a mildly decreased left ventricular internal diameter in diastole  and normal value of left ventricular internal diameter in systole   tap, muscle biopsy, and electrophysiological tests were carried out under sedation with 0.03 mg/kg BW of medetomidine  and 0.1 mg/kg BW IV of ketamine . The electrophysiological tests were performed using the Neuropack S, MEB 9400 K electrodiagnostic System . The CSF was considered normal in terms of the number of cells   using the same technique and device used previously. The voluntary movements of the limbs appeared after 28 days, and the dog became ambulatory without support 51 days after initial presentation. The SAP was in the normal range from that day, and the amlodipine dosage was reduced for another 14 days to 0.1 mg/kg BW/day and then discontinued. Complete recovery in the dog was noticed 9 weeks after initial presentation. Further follow-ups were scheduled , and no signs of arterial hypertension were noted. The changes in blood pressure from presentation to day 80 are presented in ab ingestis pneumonia. Both patients reported with intercostal muscle malfunction and ab ingestis pneumonia needed specific intensive care procedures [19]. In the present case, during the first night of hospitalisation, the patient developed episodes of tachypnoea, but no signs of bronchopneumonia were noticed on radiological examination, and no intercostal muscle impairment (such as visible chest movements during breathing) was observed.Acute idiopathic polyradiculoneuritis (ACIP) is the most common generalised polyneuropathy to occur in dogs. The clinical presentation is usually characterised by acute onset of progressive symmetrical ascending weakness expressed by hypo- or areflexia associated with normal sensory function  that disappeared once the neuropathy was resolved. The HRV analysis was proven to be reliable to assess ANS imbalance associated with ACIP in dogs. Routine blood pressure measurements should be included in the monitoring of patients with ACIP if the complications  might interfere with patient prognosis.


Little is known about age-specific target blood pressure (BP) in hypertensive patients with diabetes mellitus (DM). The aim of this study was to determine the BP level at the lowest cardiovascular risk of hypertensive patients with DM according to age.Using the Korean National Health Insurance Service database, we analyzed patients without cardiovascular disease diagnosed with both hypertension and DM from January 2002 to December 2011. Primary end-point was composite cardiovascular events including cardiovascular death, myocardial infarction and stroke.Of 241,148 study patients, 35,396 had cardiovascular events during a median follow-up period of 10 years. At the age of < 70 years, the risk of cardiovascular events was lower in patients with BP < 120/70 mmHg than in those with BP 130–139/80–89 mmHg. At the age of ≥ 70, however, there were no significant differences in the risk of cardiovascular events between patients with BP 130–139/80–89 mmHg and BP < 120/70 mmHg. The risk of cardiovascular events was similar between patients with BP 130–139/80–89 mmHg and BP 120–129/70–79 mmHg, and it was significantly higher in those with BP ≥ 140/90 mmHg than in those with BP 130–139/80–89 mmHg at all ages.In a cohort of hypertensive patients who had DM but no history of cardiovascular disease, lower BP was associated with lower risk of cardiovascular events especially at the age of < 70. However, low BP < 130–139/80–89 mmHg was not associated with decreased cardiovascular risk, it may be better to keep the BP of 130–139/80–89 mmHg at the age of ≥ 70. Hypertension and diabetes mellitus (DM), 2 major cardiovascular risk factors, have emerged as major medical and public health issues globally. There has been a continued growth in the prevalence of hypertension  and DM –6. HyperBecause blood pressure (BP) rises with age, hypertension is one of the main medical problem with high prevalence in the elderly . Even inThis study used a database provided by the National Health Insurance Services-Health Screening (NIHS-HEALS) cohort in Korea. NHIS is a single insurance provider in Korea and covers 97.2% of the Korean population; enrollees aged 40 years or older are entitled to a general health screening program every 2 years. A database includes data regarding sociodemographics, use of inpatient and outpatient services, diagnoses, prescriptions, death, and health screening examination data . The cohort details have been previously described . The stuA total of 314,293 subjects who were diagnosed with both hypertension and DM from January 2002 to December 2011 were extracted from the NIHS-HEALS cohort. Subjects were considered as having hypertension if: (1) hypertension was diagnosed before health screening examination, or (2) anti-hypertensive medications were prescribed before. Having DM was defined if: (1) DM was diagnosed before health screening examination, (2) hypoglycemic agents were prescribed before, or (3) fasting glucose ≥ 126 mg/dL. Among them, patients with the following were excluded: prior history of myocardial infarction or stroke , death before second screening (n = 623), diagnosis of malignancy , and unavailable data (n = 7400). Therefore, a total of 241,148 patients were finally analyzed. Flow chart for study enrollment is shown in Fig. The data on BP records were extracted from the NIHS-HEALS cohort. Considering BP variability, 2 BP records within 4 years were averaged. BP measured using a sphygmomanometer or an oscillometric device. BP measurements were recommended twice at 2 min intervals after 5 min of stabilization.The collection of information on the occurrence of cardiovascular events began the day after second check-up, and patients with cardiovascular events between 2 check-ups were excluded from the study. Baseline clinical data used in this study was obtained from the second check-up. The primary study endpoint was major cardiovascular events including cardiovascular death, myocardial infarction and stroke. A diagnosis of myocardial infarction was made based on discharge diagnosis after a hospitalization (ICD-10 codes: I21-23). A diagnosis of stroke was made based on discharge diagnosis (ICD-10 codes: I60-69) in patients who had been hospitalized and undergone brain imaging . The cauP value < 0.05 was considered statistically significant. Statistical analyses were performed using SAS Statistical Software  and R Statistical Software .Continuous variables are expressed as mean (standard deviation) and categorical variables as percentages. The mean values of continuous variables were compared using analysis of variance, and the frequencies of categorical variable were compared using chi-square test among BP category groups. The incidence of endpoints was calculated using the total number of outcomes during the follow-up period divided by 100,000 person-years. Multivariable analysis was performed using the Cox proportional hazard model to evaluate the relationship of BP with the cardiovascular events and mortality. Hazard ration (HR) and 95% confidence interval (CI) were calculated and adjusted for age, income level, history of smoking, physical activity, alcohol consumption, body mass index, fasting glucose, total cholesterol, and use of aspirin or statin. Subgroup analyses were performed by dividing the patients into those aged < 50 years, 50–59 years, 60–69 years, and ≥ 70 years to determine the appropriate target BP according to age. Restricted cubic splines were fitted to evaluate the non-linear relationship between BP and outcomes. The baseline characteristics of the study subjects according to BP categories are shown in Table A total of 35,396 events occurred during a median follow-up period of 10.0 years. Cardiovascular events according to BP and age categories are shown in Table P < 0.001).At the age of < 70 years, the risk of cardiovascular events was significantly lower in patients with BP < 120/70 mmHg than in those with BP 130–139/80–89 mmHg. The risk reduction was stronger at younger ages: HRs (95% CIs) were 0.74 (0.61–0.90), 0.87 (0.77–0.99), and 0.86 (0.78–0.95), in patients with < 50 years, 50–59 years, and 60–69 years, respectively. At the age of ≥ 70 years, however, there were no significant differences in the risk of cardiovascular events between patients with BP 130–139/80–89 mmHg and BP < 120/70 mmHg with HR of 0.99 (95% CI 088–1.11). The risk of cardiovascular events was similar between patients with BP 130–139/80–89 mmHg and BP 120–129/70–79 mmHg at all ages. The risk of cardiovascular events was significantly higher in patients with BP ≥ 140/90 mmHg than those with BP 130–139/80–89 mmHg at all ages. The younger the patients, the higher the risk. Adjusted HRs for the risk of cardiovascular events according to BP and age categories are also demonstrated in Fig. Similar results were obtained in sex-specific analysis  patients were taking anti-hypertensive medications. In these patients with anti-hypertensive medications, the risk of cardiovascular events was not different among those with BP < 120/70, 120–129/70–79, and 130–139/80–89 mmHg, and it was significantly higher in patients with BP ≥ 140/90 mmHg than in those with BP 130–139/80–89 mmHg at the age of < 70 years. At the age of ≥ 70 years, the risk of cardiovascular events was not different among patients with BP < 120/70, 120–129/70–79, 130–139/80–89, and 140–149/90–99 mmHg, and it was significantly higher in those with BP ≥ 150/100 mmHg than in those with BP 130–139/80–89 mmHg  there might be coding errors which have always been an issue when using claim data. Nevertheless, it is reported that the diagnosis accuracy of hypertension is relatively high in claim data  , (2) pat there miIn a cohort of hypertensive patients who had DM but no history of CVD, lower BP was associated with lower risk of cardiovascular events especially at the age of < 70 years. Effort to lower BP of < 130/80 mmHg may be justified in patients at the age of < 70 years; however, the intensive BP lowering strategy is less beneficial in those at the age of ≥ 70 years, and lowering BP to 130–139/80–89 mmHg would be appropriate at the age of ≥ 70. In patients on anti-hypertensive medications, target BP should be < 140/90 mmHg, but not BP < 120/70 mmHg. Well-designed prospective studies are needed to verify our findings.Additional file 1: Table S1. Incidence of primary end-point* according to BP and age categories in men. Table S2. Incidence of primary end-point* according to BP and age categories in women. Table S3. Incidence of primary end-point* according to BP and age categories in patients with body mass index ≥ 25 kg/m2. Table S4. Incidence of primary end-point* according to BP and age categories in patients with body mass index < 25 kg/m2. Table S5. All-cause mortality according BP and age categories. Table S6. Cardiovascular mortality according to BP and age categories. Table S7. Incidence of myocardial infarction according to BP and age categories. Table S8. Incidence of stroke according to BP and age categories. Table S9. All-cause mortality of study subjects with anti-hypertensive medications according to BP and age categories. Table S10. Cardiovascular mortality of study subjects with anti-hypertensive medications according to BP and age categories. Table S11. Incidence of myocardial infarction of study subjects with anti-hypertensive medications according to BP and age categories. Table S12. Incidence of stroke of study subjects with anti-hypertensive medications according to BP and age categories.


Severe asthma affects a small population but carries a high psychopathological risk. Therefore, the psychodemographic profile of these patients is of interest. A substantial prevalence of anxiety, depression, alexithymia and hyperventilation syndrome in severe asthma is known, but contradictory results have been observed. These factors can also affect patients’ quality of life. For this reasons, our purpose is to evaluate the psychodemographic profile of patients with severe asthma and assess the prevalence of anxiety, depression, alexithymia and hyperventilation syndrome and their impact on the quality of life of patients with severe asthma.A cross-sectional study of 63 patients with severe asthma. Their psychodemographic profile was evaluated using the Hospital Anxiety and Depression Scale (HADS), Toronto Alexithymia Scale (TAS-20), Nijmegen questionnaire and Asthma Control Test (ACT) to determine the state of anxiety and depression, alexithymia, hyperventilation syndrome and control of asthma, respectively. Quality of life was assessed with the Mini Asthma Quality of Life Questionnaire (Mini-AQLQ).The mean age was 60 ± 13.6 years. Personal psychopathological histories were found in 65.1% of participants, and 8% reported previous suicidal attempts. The rate of anxiety and/or depression (HADS ≥ 11) was 68.3%. These patients present higher scores on the TAS-20 (p < 0.001) for the level of dyspnea (p = 0.021), and for emotional function (p = 0.017) on the Mini-AQLQ, compared with patients without anxiety or depression. Alexithymia (TAS-20 ≥ 61) was observed in 42.9% of patients; these patients were older (p = 0.037) and had a higher HADS score (p = 0.019) than patients with asthma without alexithymia. On the other hand, patients with hyperventilation syndrome (Nijmegen ≥ 23) scored higher on the HADS (p < 0.05), on the Mini-AQLQ (p = 0.002) and on the TAS-20 (p = 0.044) than the group without hyperventilation syndrome. Quality of life was related to anxiety-depression symptomatology  and alexithymia . Finally, the Mini-AQLQ total score was associated with the Nijmegen questionnaire total score , and the activity limitation domain of the Mini-AQLQ correlated with the ACT total score ..The rate of anxiety, depression, alexithymia and hyperventilation syndrome is high in patients with severe asthma. Each of these factors is associated with a poor quality of life Asthma is a chronic respiratory disease with a high prevalence and incidence. In Spain, its prevalence is approximately 5% –3. WithiSevere asthma is a multifactorial disorder involving, among others, ambient and psychological factors. The Global Initiative for Asthma defines severe asthma as that which remains uncontrolled despite proper use of the recommended treatment and with maximal optimised adherence . HoweverThe anxiety and depression combination has a high prevalence in severe asthma , 6 and aFurthermore, anxiety and depression are closely linked to misperception, an implicit concept in the psychological construct of alexithymia , 18. AleAnother factor to consider in relation to anxiety and alexithymia is hyperventilation syndrome , a condiDespite the apparent robustness of the relationship between severe asthma and various psychological aspects inherent to the disease and to quality of life, there has been little research evaluating the psychodemographic profile of this disease in detail, and the results have been heterogeneous.For this reason, the aim of this study was to evaluate the psychodemographic profile, the rate of anxiety, depression, alexithymia and hyperventilation syndrome, and their association with quality of life in patients with severe asthma.A descriptive, cross-sectional and observational study was designed. A total of 63 patients diagnosed with severe asthma were consecutively included in the study.Patients were recruited from the Severe Asthma Clinic in the Pneumology and Allergology Department of a Tertiary Referral University Hospital in the Community of Madrid from January to April 2014. Of the 160 patients initially selected, 97 were excluded for the following reasons: 28 did not wish to participate, 29 did not meet the criteria for being diagnosed with severe asthma, 30 answered the questionnaire incompletely and 10 had incomplete medical records.The inclusion criteria were as follows: a diagnosis of severe asthma according to the criteria established by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR)  and age Comité de Ética de la Investigación con Medicamentos). The committee’s reference number of the study is PI-2553. This investigation was developed according to the principles of the Declaration of Helsinki and its subsequent amendments [After checking the inclusion and exclusion criteria, the study procedures were explained to the patients. Those patients who agreed to the procedures signed the informed consent. All participants were allowed to withdraw their informed consent at any point during the process. The research was approved by the Clinical Research Ethics Committee , Hospital Anxiety and Depression Scale (HADS), Toronto Alexithymia Scale (TAS-20), Nijmegen questionnaire and Asthma Control Test (ACT) were completed.The interview was based on the Mini-International Neuropsychiatric Interview (MINI) for the evaluation of the patient’s psychopathology , 29. TheSex, age, civil status, level of studies and professionFamily and personal psychopathological historySocial and family support to cope with the diseaseSuicide attemptsEmployment situation: active employment, unemployment, retirement, leave or unable to workExacerbating factors explained by the patient: Patients were asked an open question about the exacerbating factors perceived as causes of asthmatic crisis in the last 2 years, including respiratory infection, allergy and emotional stress .The information collected was related to the following aspects:The Mini-AQLQ questionnaire was used to evaluate quality of life in asthmatic adult patients with asthma. It was developed by Juniper,  et al. aThe questionnaire provides an overall score, which is the mean for all the items, and a score for each dimension, which is the mean of the corresponding items. It is divided into 4 dimensions: symptoms, limitation of activities, emotional function and environmental stimuli , 31. It The HADS questionnaire was used to evaluate anxiety and depression . This inAlexithymia was evaluated using the TAS-20 scale. The instrument was originally developed by Taylor et al.  with 26 The Nijmegen questionnaire is a screening method for the early identification of hyperventilation syndrome . This inAsthma control was assessed through the self-administered ACT questionnaire, which assesses asthma symptoms and activity limitations , 41. It The minimal sample size was calculated for detection, in asthmatic patients, a correlation coefficient of 0.45 between anxiety scores and emotion scores in the Mini-AQLQ . AcceptiData were expressed as means (standard deviation) or as number of subjects (percentage), depending on whether they corresponded to quantitative or qualitative variables, respectively. To compare quantitative variables, an analysis of variance or Student’s t-test was used for independent groups and, in the case of qualitative variables, the chi-squared test or Fisher’s test was used. For cases in which normality criteria were not fulfilled, nonparametric tests were used. We used the chi-squared test for quantitative variables and the Mann–Whitney U test and Kruskal–Wallis test for qualitative variables. The correlation between variables was analysed using Pearson’s correlation coefficient. Finally, to investigate variables related to the dependent variable, the quality of life, firstly we categorized this variable in two categories, accordingly to the Mini-AQLQ scores ≤ 3 points  and ≥ 4 points . After that, an univariate regression was used to test each variable separately, aiming to select those to be integrated into the multiple model. Those with p > 0.20 were selected. The SPSS (IBM SPSS Statistic version 19.0.) programme was used to analyse the data, and differences with p < 0.05 were considered to be statistically significant.The mean age of the included participants was 60 ± 13.6 years; 53 (84.1%) were women. In terms of civil status, 36 (57.1%) were married or lived with a partner. Furthermore, 2 (3.2%) patients had had no academic studies and 19 (30.2%) were in active employment. Personal psychopathological histories were found in 41 (65.1%) patients, and 34 (54%) patients were observed to have no socio-family support to cope with asthma. Five (8%) patients reported previous suicide attempts , respiratory infections (52.6%) and changes in environmental conditions (33.3%) as principal exacerbating factors Table .The total mean score in the Mini-AQLQ questionnaire was 3.8 ± 1.4, and the scores in the various dimensions were as follows: symptoms 3.7 ± 1.5; limitation of activities 3.7 ± 1.6; emotional function 3.9 ± 1.7; and environmental stimuli 3.6 ± 1.7. No significant differences were found when comparing the quality of life of the various subgroups after classifying the population according to sex, obesity, civil status, level of studies, employment situation and profession . It was also observed that 43 (68.3%) asthmatics presented total scores ≥ 11, compatible with the diagnosis of anxiety-depression disorder , in the TAS-20 score  and in the level of dyspnea  . When comparing the group of patients with ≥ 61 vs. < 61 points on the questionnaire, significant differences were found in age , civil status (p = 0.024) and the HADS questionnaire score   patients had a score ≥ 23 on the questionnaire, which indicated hyperventilation syndrome. When comparing those with ≥ 23 vs. < 23 points, it was observed that patients with hyperventilation syndrome had a higher total score on the HADS scale (p < 0.001) and on the anxiety subscale (p = 0.002); as well as in the total score on the Mini-AQLQ (p = 0.002) and in the dimensions of symptoms (p = 0.009), limitation of activities (p = 0.027), emotional function (p = 0.003) and environmental stimuli (p = 0.001). Furthermore, this group of patients recorded a higher score on the TAS-20 scale (p = 0.044) than the group without hyperventilation syndrome. In addition, significant differences were observed in civil status  Table .Table 5CFurthermore, alexithymia correlated with a poorer quality of life  Table . FinallyIn the logistic regression model, hyperventilation syndrome (p = 0.012), TAS-20 scores (p = 0.043), subscales of anxiety and depression scores (p = 0.077) and ACT scores (p = 0.091) were selected for the multivariate model. Hyperventilation syndrome was found to be independently associated with quality of life .Our study corroborates high rates, close to 60% and 40%, of anxiety-depression symptomatology and alexithymia, respectively. Similarly, it reveals that almost one-third of patients with severe asthma present an associated hyperventilation syndrome. Finally, the anxiety-depression combination, alexithymia and hyperventilation syndrome are associated with a poorer quality of life in these patients.Asthma impacts negatively on the quality of life of a high percentage of patients . FactorsWith regard to the association between alexithymia and quality of life, we found that patients with alexithymia presented a poorer quality of life than those who did not have it. Several studies that have evaluated this relationship have been performed on small samples of patients with various severities of asthma and have used generic questionnaires to evaluate quality of life , 24, 25.Psychomorbidity in asthma has been highlighted in several studies –7, 49. RFinally, we observed that 54% of our patients did not receive any socio-family support for their disease, which some studies have related to anxiety-depression symptoms and also with poorer control of the disease .Emotional disorders, especially depression, can in the long term manifest themselves as suicide attempts. In our series, 8% of patients had made one or more attempt. Chung et al.  and ClarThe prevalence rate of alexithymia in the general population is between 5 and 10% , 21. In These neuroanatomical structures are related to affective flattening, perceptive distortions, emotional regulation and empathy. Similarly, old age can increase the characteristics of the alexithymic personality, given the cognitive deterioration inherent to the natural evolution of humans. As we age, cognitive ability declines and consequently generates a reduction in expressive ability and abstract thinking .We observed that 34% of patients presented hyperventilation syndrome. This finding is consistent with the literature that describes a prevalence of hyperventilation syndrome of 5%–10% in the general population and between 29 and 42% of patients with bronchial asthma . AlthougChronic respiratory diseases, such as asthma, result in the development of personal and psychosocial characteristics with a high psychopathological risk, –9. FurthAlong the same lines, some years ago, Wamboldt et al.  recordedOur study is characterised by high levels of unemployment, primarily due to retirement, work-related disability or sick leave. These results could be influenced by the advanced age of the population, which is inherent to severe asthma. These findings could also be influenced by the high rate of anxiety-depression symptoms observed. Campbell et al.  revealedA key limitation of our study is the absence of a control group with mild asthma. Also, comparing our findings with those of a group with diagnosis of milder severity asthma would be interesting, and this comparison could increase the results’ degree of evidence. Another important limitation of this study is that we did not include the separate score of the 3 subscales that comprise the alexithymia questionnaire, TAS-20. We were only interested in whether patients had alexithymia as commonly as in the works of Baeza et al.  or PonceChronic respiratory diseases have an effect on the personality and emotional state of the individuals who experience them. Specifically, patients with severe asthma evidence a sociodemographic profile with personality traits  and specific levels of psychopathology (anxiety and/or depression). This profile can make it difficult to identify asthma symptoms and could overlap with other clinical conditions, such as hyperventilation syndrome, which can influence quality of life. Thus, our results could have clinical utility given they highlight the advantage of collaborating with a psychologist in multidisciplinary units for patients with severe asthma.In summary, the present results suggest that populations diagnosed with severe asthma present specific sociodemographic characteristics indicating a high burden of associated psychopathology. We also conclude that anxiety, depression, alexithymia and hyperventilation syndrome are present in a high percentage of patients with severe asthma and that these act as factors associated with a poorer quality of life for these individuals.


Cardiovascular disease is one of the leading causes of death in the United States and obesity significantly increases the risk of cardiovascular disease. The measurement of blood pressure (BP) is critical in monitoring and managing cardiovascular disease hence new wearable devices are being developed to make BP more accessible to physicians and patients. Several wearables utilize photoplethysmography from the wrist vasculature to derive BP assessment although many of these devices are still at the experimental stage. With the ultimate goal of supporting instrument development, we have developed a model of the photoplethysmographic waveform derived from the radial artery at the volar surface of the wrist. To do so we have utilized the relation between vessel biomechanics through Finite Element Method and Monte Carlo light transport model. The model shows similar features to that seen in PPG waveform captured using an off the shelf device. We observe the influence of body mass index on the PPG signal. A degradation the PPG signal of up to 40% in AC to DC signal ratio was thus observed. BP is less than 120/80 mmHg in normotensive individuals, between 120 and 129/80 mmHg in prehypertensive individuals, between 130–139/80–89 mmHg in hypertensive stage 1, above 140/90 mmHg in hypertensive stage 2, and above 180/120 mmHg in hypertensive2.Elevated blood pressure (BP) is considered one of the highest risk factors for cardiovascular disease. In fact, it has been estimated that 47% of all coronary heart disease worldwide is attributable to high BP5, defined as having a body mass index (BMI) of over 30 kg/m29. BMI is found to correlate strongly with increased 24 h blood pressure as well as non-dipping nocturnal blood pressure11. Physiological changes that occur in individuals with obesity may increase the measurement uncertainties, and optical means for monitoring blood pressure will have to account for obesity-related changes to the skin optical properties12 and increased subcutaneous tissue thickness.In adults, the risk of cardiovascular disease is significantly increased with obesity13, and the most common clinical method of measuring blood pressure is through auscultations using a sphygmomanometer with the arm maintained at heart level14. Invasive arterial line blood pressure measurement is often used in the Intensive Care Unit (ICU), where an arterial catheter is placed inside the radial artery of a patient to directly measure vessel internal pressure16.There are several ways to evaluate BP. Sphygmomanometers and oscillometric devices are standard techniques10 a condition strongly associated with cardiovascular events and organ damage. The PPG waveform can provide information such as pulse wave velocity, the relative change in blood volume and pressure wave reflection17. The systolic peak and diastolic peak are the primary and secondary features respectively as seen in Fig. 18. The vessel dilates due to the pressure wave generated by ventricular contraction. The pressure profile inside the arteries changes as the pressure wave propagates downstream from the heart to peripheral vasculature21. This is due to vessel compliance, vessel branch and bifurcations, and wave reflections encountered by the pulse during its journey from the heart. The dicrotic notch moves further away from the systolic peak as arterial line measurement location moves further down the arterial tree. Another mechanism which has been noted to influence PPG signals is optical scattering caused by time-variant red blood cell (RBC) aggregation23. Shvartsman et al. show through theoretical and experimental approaches that the pulsatile nature of the PPG signal can be described through RBC aggregation22 using a PPG monitoring device. It is to be noted though that the RBC aggregation effect is dominant in thin blood layers24 specifically microvasculature of the upper dermis. In our work, we have focused on dynamics and biomechanical behavior of a large vessel, specifically the radial artery, deeper and larger in physiology past thin blood layer contained in the dermis. The vessel under observation is 2.5 mm in diameter. In vessels of this size, the vessel diameter is large compared to cell size and fluid can be approximated as a Newtonian fluid26 and flow can be modeled as a homogenous fluid27 flow.Research into cuff-less and continuous BP devices based on photoplethysmography (PPG) is rapidly expanding. These systems provide unique diagnostic opportunities, such as monitoring of nocturnal hypertension28.Measurement of blood pressure at the radial artery located at the wrist is desirable since it is easily accessible, and instrumentation can be developed for a wearable device. The blood pressure in the radial artery at the volar surface of the wrist is more representative of blood pressure in the main arterial network as opposed to pressure in superficial vasculature of the skin31. Yet to our knowledge, these studies have not attempted to capture the PPG waveform in its entirety and have focused on an idealized skin model.In order to derive a better understanding of devices based on PPG, several groups have conducted light propagation models using Monte Carlo (MC) simulations34 as well as skin tones.The design of wearable devices must account for the population diversity, including physiological changes due to obesityOur study has two main goals. First, we develop a more realistic representation of light interaction with the radial artery during a pulse as seen by a commercially available photoplethysmographer (Nellcor by Covidien). This location and instrumentation are the focus of our experimental efforts toward developing low-cost cuffless BP sensors. Second, we use our model to study the influence of increased BMI on the PPG waveform.38. These changes include but are not limited to skin barrier function, epidermal changes, dermal changes, and changes to the vascular and capillary recruitment function. In our model, both skin tone and BMI diversity will be considered.Recent studies have shown that obesity creates variations in skin physiology19. The key distinction between rigid versus elastic walled flow is the fluid streamline velocity profile  to model the mechanical behavior of an arterial vessel. Our model allows us to visualize the motion of an arterial wall under an applied internal pressure. The artery is modeled in Solidworks computer-aided design (CAD) software.We have chosen the volar surface of the distal forearm as the location of our virtual PPG instrument. This choice is governed by our interest in the development of wrist-based wearable devices targeting that vessel.48. Vessel wall mass density and Poisson’s ratio were set to 1160 kg/m3 and 0.4949 respectively. A radial artery wall Young’s modulus of 0.70 MPa was used46. Arterial mechanical stiffness ranges between 0.70 and 1.10MPa46. Mechanical properties are highlighted in Table A drawing of the vessel with associated dimensions is shown in Fig. 50 higher than the brachial artery, where blood pressure is often measured using the sphygmomanometer. An internal pressure of 130 mmHg50 was imposed to the vessel representing the radial artery. The result of the FEM model at peak applied force is shown in Fig. Radial artery pressure has been shown to be 5 to 15 mmHg51, pressure changes applied internally translates to vessel wall dilation, but the total wall volume is conserved. This incompressibility estimation is seen in the FEM model. Changes to the inner wall and outer wall radii are relatively small in comparison to total vessel dilation. Vessel walls have been reported to experience 10–20% diametral strain53. Applying 0.70 MPa stiffness, vessel wall shows total dilation of 0.4 mm in diameter. The mechanical behavior of the artery during pulse propagation is integrated into the light transport model (Monte Carlo) through changes in the vessel geometry.The arterial wall is often treated as incompressiblea, b, and c represent the radii of each respective axis of the ellipsoid in the x, y, and z direction, respectively. The dilation of the vessel under pressure is directly applied to the radii of the ellipsoid in the x and z directions. Whereas the y direction axis controls the elongation of the wave along the length of the artery. Note that the pulse wave propagates in the y direction.Through observation of the dilated shape of the finite element model, a set of equations is created to represent this shape in the Monte Carlo framework. This shape function is defined as an ellipsoid in three-dimensional space. The basic ellipsoid equation is shown in Eq. .1\documeThe development of the mathematical ellipsoid envelope of the FEA derived pulse geometry using a double ellipsoid shown in Eqs. –4.2\docux, y, and z represent each direction in the frame, z, direction in the media. In Eq. ,,3), x, yentclass1pt{minimaEquation  defines 29. MCMatlab converts S. Jacques’ “mcxyz.c”30 from C-based code to a compact tool usable through Matlab interface. Monte Carlo framework simulates a 3-layer model to include epidermis, dermis and subcutaneous tissue with the radial artery inserted into the adipose tissue layer. The epidermis consists of multiple sublayers with various components, including melanin and melanocytes54. The dermis is comprised of connective tissue along with blood vessels (capillaries and arterioles) with blood volume ratios ranging from 0.2 to 7% and water volume concentration around 65%56. The subcutis consists of subcutaneous adipose tissue and other connective tissue57.Aside from the radial artery, the Monte Carlo simulation also considered three skin layers: epidermis, dermis and subcutaneous tissue with the radial artery inserted into the adipose tissue layer. The Monte Carlo model used in this work is an adaptation of MCMatlab developed by Marti et al.2 with numerical aperture of 0.866. The sensor schematic is shown in Fig. In this work, we modeled a commercial PPG . This is a clinical system that incorporates two wavelength sources at 660 nm peak 22 nm FWHM and 890 nm peak 54 nm FWHM. The sensor provides and effective beam waist radius of 0.06 cm. The detector is located 0.97 cm away from the sources providing reflectance PPG signal. Light collector area is measured to be 0.35 cm × 0.35 cm which is an effective collector area of 0.1225 cm59. To avoid using a very small voxel size in the simulation, we chose to scale the optical properties of the epidermis to match its optical thickness60.The geometry of our Monte Carlo simulation is shown in Fig. 48. The target radial artery is constructed with a vessel wall and the internal lumen is filled with blood. Optical properties used in Monte Carlo simulations are extracted from previous work65. Simulation parameters are highlighted in Table The dermis layer was 1.0 mm in thickness. Below the dermis, a subcutaneous adipose tissue layer was added. Within this layer, the radial artery is modeled as a cylinder situated at 2.5 mm depth from the top surface3 volume with 200 × 100 × 100 elements in each direction. Monte Carlo simulations were performed on Windows 10 64-bit Operating System with Intel Core i7-8700 CPU 3.20 GHz, NVIDIA GeForce GTX 1070 GPU, and 32 GB RAM, and Windows 10 64-bit Operating System with Intel Core i7-8750H CPU 2.20 GHz, NVIDIA GeForce GTX 1050 Ti GPU, and 16 GB RAM. Simulations speeds varied between two million photons per minute to 70 million photons per minute. Waveform simulations are conducted at 89 incremented pulse positions at 100 million to one billion photons each.Monte Carlo geometry frames a 1.4 × 1.4 × 0.8 cm34. The melanin content of the skin increases with darkening skin tone. Melanin volume fraction variation can be used to model the various pigmentation levels. Lightly pigmented skin adults have a melanin volume fraction of 1.3–6.3%, moderately pigmented skin adults have a 11–16% melanin volume fraction, and darkly pigmented skin adults have an 18–43% melanin volume fraction in the epidermis55.Analyses of the performance of commercial systems and functionality of arterial PPG must account for factors of skin tone and physiological changes with the development of obesity37 et al. studies the optical properties of breast tissue and discovered a positive correlation between BMI and lipid and total hemoglobin, and a negative correlation between BMI and water content. When studying the optical properties of adipose tissue, Lanka38 et al. results show that obese have lesser values for absorption and reduced scattering coefficients.Individuals with obesity experience changes to skin anatomy/physiology and thus optical properties. Previous authors have reported relationships between BMI and chromophore concentration in the skin as well as adipose tissue. For example, Spilenlli58. Along with changes to the skin, the artery itself is situated deeper in the subcutaneous adipose tissue as adipose tissue layer thickness with increasing level of obesity. The signal from the radial artery is discovered to vary in depth with different levels of obesity from 2.5 mm for non-obese individuals at BMI of 25 to 3.5 mm for BMI of 4548. Trans-epidermal water loss (TEWL) the process where water evaporates through the epidermis from the dermis is disruption in the obese36. As BMI increases so does TWEL66, and this effect directly contributed to dry skin and skin irritation often seen in the obese population. The significant changes to the skin which we have highlighted include changes to dermal water content66 and blood content content66 as well as dermal thickness and increased radial artery depth all with increasing levels of obesity58. A summary of all the parameters utilized in the modeling is shown in Table Dermal thickness variations with BMI is shown to range from 1.0 mm to over 2.5 mm thicknessChanges in Table Experimental PPG signals were gathered from four healthy volunteers utilizing the commercial PPG system described above. The protocol for the study was approved by the Institutional Review Board of Florida International University and followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. The radial artery was located by tactile exploration so that the PPG sensor could be located as in the geometry described in Fig. A power absorption map of our geometry is shown in Fig. Figure Figure Waveforms for different levels of obesity are generated through varying the combined dermal thickness and arterial depth to indicate corresponding physiological changes. Figure 2, the AC/DC signal ratio is 8.1% and at the maximum level calculated the ratio is 4.66%. This accumulates to the total percentage change of 43% between the Non-Obese waveform and Obese 3 waveform.The non-obese BMI of 25 kg/mThe degradation of the return signal gives an indication to the decrease in quality of the signal that will be received by the PPG device. A loss in signal quality is shown to increase as BMI and obesity level increase with changes in dermal thickness and arterial depth. PPG devices designed to periodically or continuously probe arterial blood pressure as a wearable device at the wrist must be designed to be mindful of the significant effects of obesity on optical performance. The advantage of the development of synthetic waveform is understanding these changes and the significance of their impact.We have demonstrated an approach to modeling PPG signals utilizing a combination of FEM and Monte Carlo modeling. Ultimately, our intent is to develop a wearable health device capable of assessing continuous cuff-less blood pressure with comparable level of performance across populations of varying body size. Cuff-less, continuous blood pressure monitoring can provide critical information concerning nocturnal cardiovascular function, which is a significant indicator of overall cardiac health. This work focuses on a commercial PPG sensor measurement of pulsatile flow in the radial artery.Our simulations demonstrate that with no changes to the underlying vessel mechanical behavior, an increase in BMI significantly impacts the PPG waveform. The AC/DC ratio changes from 14 to 41% as BMI increases from 20 to 40 for isolated changes attributed with increasing level of obesity and BMI. Increase to dermal thickness increases the total volume of absorbers and scatterers through which photons must traverse to reach the artery and return to the detector. Increased radial artery depth also increases the total travel distance for photons to reach the vessel wall as and return to detector.67, the presence of obesity degrades the quality of the signal even when the vessel mechanics remain unchanged. Synthetic waveform generation provides an insight and prediction of optical device functionality.Vessel expansion and contraction, under pressure changes of the cardiac cycle, is directly associated with the pulsatility of the PPG waveform68 and it may account for some of the errors experienced by dark skin individuals utilizing wearable based on PPG71. Here we propose a computational framework that could be used to design and develop better wearable that account for population diversity.Computational work from our group has shown that increasing melanin concentration in the epidermal layer yields a decrease in overall signal quality of up to 17%. This effect has been documented by other investigatorsThe changes associated to BMI are applied to evaluate their isolated effect on the captured PPG signal to compared differences across different BMI ranges according to each physiological effect. It is, however, clear that the development of obesity has other significant changes to total physiological changes to the body. We have chosen to isolate and characterize the impact of changers to the skin to observe changes to the PPG signal which are not attributed to vascular dynamic behavior.Future work will focus on the understanding of waveform morphology through connecting various cardiovascular conditions with the corresponding PPG. The addition of synthetic waveform generation can allow for the study of isolated effects from a variety of factors on the output PPG. Post-processing of the PPG such as first and second derivative and frequency domain information can be used as tools for feature extraction for desired information.Future developments of the model will approach the correlation of vascular physiological parameters to the shaping equations to help understand the relationship between the biomechanics and PPG output signal. The Finite Element Model is based on vascular mechanical stiffness and applied stress to observe vessel dilation. We propose that through the development of a robust method of analysis of a PPG signal, the relationship between optical signal and internal vessel blood pressure could be derived. Various methods of waveform analysis through neural networks have been used to attempt to derive blood pressure values from experimental PPG data sets. Unfortunately, the variability in individual anatomy and physiology makes this correlation very complex. Our synthetic framework offers a controlled approach to this very complex problem.This work is limited to the detection of the radial artery and does not consider the pulsatile effect of the superficial arterioles, this will be the focus of future addition to the present model. The model geometry is limited to the primary layers of the skin and an embedded dynamic blood vessel, however underlying structures around the radial artery such as the muscle or radial styloid process has not been included. The addition of these features will be explored in future model to evaluate their effects on generated signal.We have created a model to describe photoplethysmographic waveform and vascular behavior of the radial artery within a light propagation model (Monte Carlo). This was accomplished using Finite Element Modeling to view mechanical changes in the radial artery during a single pulse propagation cycle and translating the vessel dilation into a set of equation that could be adapted to a voxel-based Monte Carlo model. This modeling framework is necessary and useful when developing wearable devices for non-invasive continuous blood pressure monitoring systems. Specifically, our interest lies in the development of low-cost devices individuals experiencing obesity. We have focused our study on the changes to the PPG waveform for a single pulse cycle due to changes in physiology and optical properties of the skin in relation to BMI. Modeled AC to DC PPG signal ratio suggests that physiological changes due to BMI lower the ratio up to 40% this loss of signal amplitude could explain some of the errors observed by obese population.