An insufficient decrease in nocturnal pulse rate (PR), non-dipping PR, reflects autonomic imbalance and is associated with cardiovascular events and all-cause mortality. We aimed to investigate the clinical and microanatomical structural findings associated with the non-dipping PR status in patients with chronic kidney disease (CKD).This cross-sectional study included 135 patients who underwent ambulatory blood pressure monitoring and kidney biopsy concurrently at our institution between 2016 and 2019. Non-dipping PR status was defined as (daytime PR-nighttime PR)/daytime PR <0.1. We compared clinical parameters and microstructural changes in the kidney between patients with and without non-dipping PR, including 24 h proteinuria, glomerular volume, and Mayo Clinic/Renal Pathology Society Chronicity Score.2. Non-dipping PR status was observed in 39 patients. Patients with non-dipping PR were older and had worse kidney function, higher blood pressure, greater prevalence of dyslipidemia, lower hemoglobin levels, and a larger amount of urinary protein excretion than patients with dipping PR. Patients with non-dipping PR had more severe glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arteriosclerosis. In the multivariable analysis, the severe chronic changes of the kidney were associated with non-dipping PR status after adjusting for age, sex, and other clinical parameters .The median age was 51 years (interquartile range: 35–63), 54% of which were male, and the median estimated glomerular filtration rate was 53.0 (30.0–75.0) mL/min/1.73 mThis study is the first to indicate that non-dipping PR is significantly associated with chronic microanatomical changes in the kidneys of patients with CKD. Blood pressure (BP) and pulse rate (PR) physiologically decrease by 10–20% at night due to the relative dominance of the parasympathetic nervous system  and was carried out according to the Declaration of Helsinki. Because this was a cross-sectional study, information on the research plan was proposed and an opportunity to opt out was provided; therefore, individual informed consent was waived for this study. All patients provided their written informed consent for kidney biopsy.2, as previously reported , uric acid, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), urinary β2-microglobulin, and 24 h proteinuria. Urine was collected for 24 h, and dietary sodium intake was assessed using 24 h urinary sodium excretion. Estimated protein intake was estimated from 24 h urinary urea excretion according to Maroni’s formula , normalireported .2) = 194 × Cr–1.094 × age–0.287 (× 0.739 for women)  or the use of antidiabetic medications. Dyslipidemia was defined as LDL-C ≥ 140 mg/dL, HDL-C < 40 mg/dL, TG ≥ 150 mg/dL, or the use of antihyperlipidemic agents . BMI wasr women) .In addition, patients were classified into four CKD prognostic groups  by glomerular filtration rate (GFR) and proteinuria categories according to the KDIGO  2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease  25)..25).Ambulatory blood pressure monitoring analyses were performed using a TM-243 device . Measurements were taken at 30-min intervals from 06:00 to 22:00, whereas measurements were taken at 1-h intervals from 22:00 to 06:00. The daytime and nighttime were defined as the awake and sleeping periods, respectively, which were determined by the activity records of the patients . Accordi3/2 × β/d, where β is a dimensionless shape coefficient (β = 1.382 for spheres), and d is the size distribution coefficient used to adjust for variations in glomerular size (d = 1.01)  was estimated from the measured mean glomerular tuft area as follows: GV = (glomerular tuft area) = 1.01) . The sev = 1.01) . The per = 1.01)  to grade = 1.01) . IF and post hoc analysis for the Kruskal–Wallis test. Spearman’s correlation analysis was used to analyze the correlations among the variables. Multivariable logistic regression analysis was performed to identify independent determinants of non-dipping PR status in patients with CKD. All covariates except sex, the presence of DM, the renal chronicity score grades and the use of antihypertensive medications were treated as continuous variables in the multivariable analyses. Missing values are excluded and addressed for each variable. Statistical significance was defined as a two-sided P < 0.05. All statistical analyses were performed with SPSS v.25.0 .Continuous variables are presented as medians and interquartile ranges (IQRs) or numbers with percentages in parentheses. Differences in continuous variables were analyzed using the Mann–Whitney U test or Kruskal–Wallis test, as appropriate, and those in categorical variables were analyzed using the chi-square test or Fisher’s exact test according to the sample size. The Dunn–Bonferroni test was used as a A total of 172 patients aged ≥20 years underwent both ABPM and kidney biopsy at our institution between March 2016 and March 2019. Of these patients, 37 were excluded from this study due to the following exclusion criteria: kidney transplant recipients, taking β-blockers, inadequate glomerular number or unavailable kidney biopsy specimens. After exclusion, 135 patients were enrolled, of which 39 (28.9%) patients were in the non-dipping PR group and 96 (71.1%) patients were in the dipping PR group .2. The proportions of each GFR category were as follows: G1 7.4%, G2 32.6%, G3a 16.3%, G3b 20.0%, G4 13.3%, and G5 10.4%.P = 0.24, Patients with non-dipping PR were significantly older and had worse kidney function at baseline. Dyslipidemia was more prevalent among patients with non-dipping PR than among those with dipping PR. Patients with non-dipping PR had significantly lower levels of hemoglobin, a greater amount of urinary protein excretion, and a greater amount of urinary β2-microglobulin than patients with dipping PR. Twenty-nine out of 39 (74%) patients with non-dipping PR were classified as “very high risk” in the CKD prognostic categories, whereas 42 out of 96 (44%) patients with dipping PR were classified in the same category. Of note, other characteristics, including sex, frequencies of DM, BMI, serum uric acid, cholesterol levels, estimated protein intake, and sodium intake were not statistically different between the two groups . Patients = 0.40, P < 0.001, s = 0.04, P = 0.67, As shown in P < 0.001, P < 0.001, and P = 0.02, respectively) than patients with dipping PR; therefore, patients with non-dipping PR had a higher renal chronicity score than those without it (P < 0.001). GV was not significantly different between the groups. The proportion of the histopathological diagnosis was as follows: IgA nephropathy, 54 patients (40%); nephrosclerosis, 13 patients (9.6%); focal segmental glomerulosclerosis, 13 patients (9.6%); membranous nephropathy, 10 patients (7.4%); minimal change disease, 8 patients (5.9%); diabetic nephropathy, 7 patients (5.2%); tubulointerstitial nephritis, 6 patients (4.5%); membranoproliferative glomerulonephritis, 3 patients (2.2%); and others, 21 patients (15.6%) ( (15.6%) .P = 0.004 and P = 0.002, respectively). The GS% was significantly higher in the BP/PR non-dipping group than in the BP/PR dipping and BP non-dipping/PR dipping groups . The IF/TA ratio was significantly higher in the BP/PR non-dipping group than in the BP/PR dipping group (adjusted P = 0.02).When we classified subjects as having or not having BP and/or PR non-dipping into four categories , the proP = 0.003). Moreover, we added the use of antihypertensive agents to the age/sex-adjusted multivariable model to adjust for each effect of antihypertensive agents, which did not change the association between the renal chronicity score and non-dipping PR status  activation may be one of the underlying mechanisms of the association between non-dipping PR and chronic changes (GS% and IF/TA) in this study. Urinary angiotensinogen is an established surrogate marker for intrarenal RAS activity, and a previous pathological study showed that urinary angiotensinogen levels were correlated with the severity of GS% and IF/TA . AnotherThe renal chronicity score, which is derived from the sum of semiquantitative assessments of chronic changes, has been proposed as a uniform approach to grade chronic changes in kidney biopsy specimens . ChronicNotably, there was no association between non-dipping PR and non-dipping BP, which is consistent with previous studies , 14, 15.This study had several limitations. First, the study design was cross-sectional, and the causal relationship between non-dipping PR and microanatomical parameters could not be proven. In this regard, we assessed non-dipping PR status in relation to CKD prognostic categories by KDIGO and renal chronicity score, as these parameters are established prognostic factors. Second, ABPM was performed once during the hospitalization period, and these results might be different from ABPM performed in outpatient clinics; however, restricted diet and physical activity during hospitalization can minimize the effect of interpersonal differences, which could be an advantage at the same time. Third, we did not consider the physical activity of the patients, smoking habits, food intake, and sleep quality. Finally, the present study was limited to a single center with Japanese patients with CKD who underwent kidney biopsies, making it difficult to generalize these results to all patients with CKD.Despite these limitations, this study is the first to investigate the association between a flattened PR circadian rhythm and microanatomical structural findings of the kidney. This study supported the hypothesis that the bidirectional interactions between chronic changes in the kidney and circadian disruption fall into a vicious cycle in patients with CKD. We speculate that patients with CKD and non-dipping PR have an additional risk of cardiovascular events and poor kidney outcomes compared to patients with CKD and dipping PR. Non-dipping PR is an important but neglected parameter, and only limited studies focusing on this topic have emerged in recent decades . A new aNon-dipping PR status was observed in 28.9% of patients with CKD, and the majority of patients with non-dipping PR belonged to the “very high risk” category by the KDIGO GFR and proteinuria categories. In conclusion, this study indicates that a flattened PR circadian rhythm is associated with chronic changes in kidney microanatomical structure.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Review Board of The Jikei University School of Medicine . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.RO and GK: conceptualization, formal analysis, investigation, data curation, and writing—original draft preparation. RO, KH, and GK: methodology. TY: resources and supervision. RO, GK, KH, TS, YO, KK, NT, and TY: writing—review and editing. RO: visualization. GK: project administration. All authors contributed to data interpretation and approved the final version of the manuscript.


Characterized by cardiovascular disease and diabetes, cardiometabolic diseases are a major cause of mortality around the world. As such, there is an urgent need to understand the pathogenesis of cardiometabolic diseases. Increasing evidence suggests that most of the mammalian genome are transcribed as RNA, but only a few percent of them encode for proteins. All of the RNAs that do not encode for proteins are collectively called non-protein-coding RNAs (ncRNAs). Among these ncRNAs, long ncRNAs (lncRNAs) are considered as missing keys to understand the pathogeneses of various diseases, including cardiometabolic diseases. Given the increased interest in lncRNAs, in this study, we will summarize the latest trend in the lncRNA research from the perspective of cardiometabolism and disease by focusing on the major risk factors of cardiometabolic diseases: obesity, cholesterol, diabetes, and hypertension. Because genetic inheritance is unavoidable in cardiometabolic diseases, we paid special attention to the genetic factors of lncRNAs that may influence cardiometabolic diseases. Cardiometabolic diseases (CMD) account for 31% of all global deaths , and morANRIL [official gene symbol: CDKN2B-AS1 (CDKN2B antisense RNA 1)], which corresponds to the Chr9p21 risk locus for coronary artery disease based on GWAS studies  is shown to be induced by the growth factors AngII and platelet-derived growth factor (PDGF) and the inflammatory cytokine tumor necrosis factor α (TNF-α) via the action of the transcription factor SRY-box transcription factor 9 (Sox9) in rat VSMCs [Alivec binds tropomyosin 3 (Tpm3) and heterogeneous nuclear ribonucleoprotein A2/B1 (Hnrnpa2b1) to regulate chondrogenic transformation of VSMCs implicated in vascular dysfunction and hypertension.Hypertension (high blood pressure) is a condition in which blood pressure is higher than normal. According to the current guideline by the American College of Cardiology/American Heart Association, hypertension is defined as a cut point of systolic blood pressure (SBP) ≥130 mm Hg and/or diastolic blood pressure (DBP) ≥80 mm Hg . As the at VSMCs   [HIF1A-AS1 acts as an adapter for the repressive human silencing hub complex (HUSH). Originally identified as an essential lncRNA gene for the normal development of the heart and body wall in mice [FENDRR) is recently shown to act in a similar mechanism as HIF1A-AS1 by forming triplex structure in the promoter region of dynamin 1 like  [Pulmonary hypertension is caused by high pressure in the blood vessels from the heart to the lungs, which affects both the lungs and the heart ,107. It F1A-AS1) . HIF1A-A in mice , FOXF1 aas DRP1) . These thttps://www.ebi.ac.uk/gwas/search?query=BMI) (accessed on 5 December 2022). Although there are several clinical trials underway to investigate the correlation of lncRNA expression to different diseases as potential diagnostic biomarkers [As summarized above, lncRNAs can be the key to unravel the pathogeneses of CMD, which may lead to the potential cures for CMD . As incromarkers ,122,123,omarkers . Thus, t


Autonomic dysfunction, such as reduced vagally mediated heart rate variability, has been suggested in headache patients but is still uncertain when considering primary headache disorders. This study aims to compare the heart rate and blood pressure variability and baroreflex sensitivity between women with migraine and controls. A migraine (n = 20) and a control group (n = 20) of age-matched women without headache were evaluated. Heart rate variability was analyzed through frequency-domain using spectral analysis presenting variance, low-frequency  and high-frequency  bands and by time domain . Blood pressure variability was analyzed with spectral analysis and baroreflex sensitivity with the sequence method. Migraine group had lower heart rate variability characterized by a reduction in total variance, LF oscillations  and HF oscillations , and a reduction in SD and RMSSD compared to control group. No difference was found in the blood pressure variability analysis. Regarding baroreflex sensitivity, migraine group had decreased values of total gain, gain down and up compared to control group. Women with migraine exhibited autonomic modulation alterations, expressed by decreased values of heart rate variability and baroreflex sensitivity, but not by differences in blood pressure variability. Autonomic nervous system dysfunction has been linked to common headache disorders, including migraine, which plays an important role in the understanding of many characteristic symptoms and signs of this disease with complex pathophysiology ,2,3. TheIn migraine patients, a systematic review with meta-analysis  suggesteAdditionally, baroreflex sensitivity is considered a robust and interpretable measure of balance  and the effectiveness of cardiovascular autonomic control . ImpairmThe current knowledge is still unable to determine the altered autonomic modulation when considering different diagnoses of primary headache disorders based on well-established criteria, such as migraine, and by considering homogenous samples by age and sex . Thus, tThe study sample involved 42 women, including a migraine group  and a control group , age-matched at 29.6 (9.4) years. All migraine patients involved in this study were recruited from a tertiary headache clinic and were included following the International Classification of Headache Disorders (ICHD-III) criteria for migraine by an experienced neurologist. Patients with other secondary headaches were excluded. Women included in the CG had no history of current or past primary headache diagnosis and no history of recurrent secondary headaches in the last 6 months that required treatment. All participants, patients, and health volunteers were between 18 and 50 years old and were excluded in the case of pregnancy, diabetes mellitus, arterial hypertension, cardiovascular diseases, habitual use of corticosteroids, and history of alcohol abuse in the last 6 months. We also excluded patients in menopause  and thosAnthropometric characteristics and basic clinical data were gathered from both groups using validated scales such as the Pain Catastrophizing Scale , CentralThe Institutional Ethics Committee approved the study (protocol number: 1278/2019), and written informed consent was obtained from all participants prior to data collection.Autonomic function tests were carried out in the Exercise Physiology and Cardiovascular Physiotherapy Laboratory, Department of Health Sciences, Ribeirão Preto Medicine School University, under standardized conditions. All women were evaluated in the follicular phase of the regular menstrual cycle and during the afternoon. They were instructed to avoid intense exercise a day before the test and to avoid drinking alcohol and caffeine. Volunteers were instructed to remain in the supine position for approximately 10 min to stabilize cardiovascular parameters. After this period, the ECG and arterial pulse pressure were recorded simultaneously for another 10 min.The heart rate data were obtained with an ECG digital recorder  through the modified MC5 shunt at a sampling frequency of 1000 Hz. The systolic blood pressure was obtained using digital plethysmography recording equipment  using a cuff positioned on the finger of the right upper limb. The data were recorded with an interface to the microcomputer using the PowerLab, LabChart version 8 .http://sites.google.com/site/cardioseries (accessed on 20 January 2022)) developed by Dias, DPM of the University of São Paulo, Brazil [The heart rate variability and the blood pressure variability analyses were performed with custom computer software  and normalized units (nu), whereas the SBP time series were integrated only in the low-frequency band , and the results were expressed in absolute values (mmHg2).For spectral analysis, the values of R-R intervals (RRi) were redesigned in a 3 Hz cubic spline interpolation to normalize the time interval between the beats. The series of interpolated RRi and SBP were divided into half-overlapping sets of 256 data points, overlapping 50% (Welch Protocol). The stationary segment was visually inspected, and those with artifacts or transients were excluded. Each RRi and SBP stationary segment was subjected to spectral analysis using Fast Fourier Transform after the Hanning window. RRi time series were integrated with bands of low-frequency  and high-frequency , and the results were expressed in absolute . In addition, the normalization procedure was performed to minimize the total power variations in the absolute values of LF and HF . To assess the sympathovagal balance, the LF/HF ratio of RRi variability was also calculated .Baroreflex sensitivity was assessed in the time domain using the sequence technique . The comThe sample size was based on a pilot study with 10 participants in each group considering the RMSSD difference between the migraine group  and control group  and an effect size of 0.88.The power and the alpha level were set at 85% and 5%, respectively, resulting in a minimum of 20 participants in each group.t-test. All between-group comparisons were performed using the independent Student’s t-test after log transformation when normal distribution was not verified (Shapiro–Wilk p > 0.05). The effect sizes (Cohen’s d) were calculated by dividing the difference between the means of the two groups by their pooled standard deviation [Age, body mass index, and total score of the pain catastrophizing, central sensitization, and depression questionnaires were compared between groups by using the independent sample eviation  and intep < 0.01, t = 3.963), central sensitization , and depression  questionnaires (Women with migraine had a headache frequency of 14.2 (6.8) days per month being of high frequency   and chroonnaires . RegardiCompared to controls, women with migraine had reduced heart rate variability and baroreflex sensitivity with a moderate effect size .p = 0.007, t = −2.85), reduced vagal autonomic influence evidenced by the lower HF band , and a decrease in sympathetic autonomic influence evidenced by the lower LF band  in the migraine group compared to the control group. Frequency domain analysis using spectral analysis  decomposes heart rate variability into fundamental oscillatory components, the main ones being the high-frequency (HF) band, which is associated with vagal autonomic modulation, and the low-frequency (LF) band, which is associated with both sympathetic and vagal modulation [Analysis of heart rate variability in the frequency domain showed lower variance  and RMSSD  with a large effect size in women with migraine compared to controls. The variables analyzed in the time domain, such as RMSSD, when reduced, are correlated with generalized autonomic impairment and increased morbidity and mortality [Additionally, heart rate variability analysis in the time domain showed decreased vagal modulation expressed by SD , gain down , and gain up  compared to controls.In blood pressure variability, variance and absolute values of LF oscillations were not different between groups. Regarding baroreflex sensitivity, the migraine group had decreased values of total gain . These inflammatory processes can cause continuous and prolonged excitation of primary nociceptive neurons, leading to chronic painful conditions (5). Additionally, decreased parasympathetic tone results in greater somatic and visceral input through the spinothalamic pathway, lowering the pain threshold in those with chronic pain (6). However, the participation of calcitonin gene-related peptide (cGRP) in this process cannot be ruled out. cGRP is a 37 amino acid neuropeptide known to be a vasodilator  expresseA more pronounced heart rate variability reduction was suggested in episodic migraine patients during the ictal period with a reduced LF . On the The present study has some limitations. Our study did not use autonomic cardiovascular reflex tests to assess the autonomic nervous system; however, the analysis of the variability of heart rate, blood pressure, and baroreflex sensitivity has been considered an effective, sensitive, and non-invasive method of measuring autonomic impulses. In addition, the sample size of our study may not have power for all variables, as it was previously calculated based on RMSSD. Moreover, our results should be restricted to patients with migraine headache more than 8 days per month with or without aura since we could not conduct separate sub-analyzes considering the effect of the presence of aura and possible differences between patients with chronic and episodic migraine.The women with migraine in our study had increased pain catastrophizing, central sensitization, and depression which is in accordance with a recent meta-analysis from Caponnetto et al. (2021) showing the high prevalence of depressive disorders, fibromyalgia, and musculoskeletal pain, mainly in women . AlthougThe decrease in vagal influence is a risk factor for all-cause mortality and for cardiovascular diseases and is related to greater inflammation and less inhibitory control of pain ,5. In thWomen with migraine exhibit autonomic modulation alterations, expressed by decreased values of heart rate variability and baroreflex sensitivity, but not by differences in blood pressure variability. Our results should be restricted to patients with migraine headache more than 8 days per month with or without aura since we could not conduct a separate sub-analysis.


Purpose: When dexmedetomidine is used in elderly patients, high incidence of bradycardia is reported. Given age-related physiological changes in this population, it is necessary to know the safety margin between the loading dose of dexmedetomidine and bradycardia. Therefore, we conducted this study to investigate the median effective dose (ED50) of dexmedetomidine causing bradycardia in elderly patients.Methods: Thirty patients with ages over 65 years undergoing elective general surgery were enrolled. The Dixon and Massay sequential method were applied to determine the loading dose of dexmedetomidine, starting from 1.0 µg/kg. The dose for the follow-up subjects increased or decreased according to the geometric sequence with the common ratio 1.2, based on the 'negative' or 'positive' response of the previous subject. Positive mean that the subject developed bradycardia during the test. Hemodynamic data including heart rate and systolic blood pressure were recorded. The level of sedation was assessed with the Observer Assessment of Alertness and Sedation Scale (OAA/S).Results: Bradycardia occurred in 13 patients (43.3%). The ED50 of dexmedetomidine causing bradycardia was 1.97 µg/kg . OAA/S scores at 10 min after the beginning of the dexmedetomidine infusion and 10 min after the termination of dexmedetomidine administration showed no significant differences between the positive and negative groups (P > 0.05).Conclusion: The ED50 of dexmedetomidine causing bradycardia in our cohort was higher than clinical recommended dose. A higher loading dose appears acceptable for a faster onset of sedation under careful hemodynamic monitoring.Trial registration: ChiCTR 15006368. Dexmedetomidine is a potent and highly selective α2-adrenoceptor agonist displaying anxiolytic, sedative, sympatholytic, and analgesic effects with minimum cardiovascular and respiratory depression The cardiovascular effects of dexmedetomidine begin with transitory hypertension after the administration of a loading dose, owing to the activation of α2B receptors, with consequent hypotension and bradycardia because of the reduction of sympathetic tone The hemodynamic effects of dexmedetomidine after short-term  infusions have been described and summarized at doses ranged from 0.25 to 4 μg/kg The aim of this study was to determine the ED50 values of intravenous dexmedetomidine causing bradycardia in elderly patients (aged >65 years) by Dixon's up-and-down sequential allocation method.2, (4) taking hypnotics, opioid analgesic or antianxiety agents, (5) known or suspected heart failure (ejection fraction <40%), severe respiratory disease, renal or metabolic diseases, (6) heart rate (HR) < 60 bpm, sick sinus syndrome, atrioventricular block, arrhythmia or atrial fibrillation, (7) electrolyte disturbances, (8) could not complete the informed consent procedure independently. A total of 30 elderly patients undergoing general surgery from July to August in 2020 were enrolled in the study and written informed consent was obtained from each patient.This study was approved by the Institutional Research Ethics Committee of Shidong Hospital Affiliated to University of Shanghai for Science and Technology. The trial was registered at Chinese Clinical Trial Registry (ChiCTR 15006368). Patients aged 65 years and over scheduled for general surgery under general anesthesia were considered eligible. Patients were excluded if they: (1) American Society of Anesthesiologists (ASA) physical status score ≥3, (2) allergies to any of the drugs used for anesthesia, (3) body mass index (BMI) ≤20 or ≥30 kg/m2), and non-invasive blood pressure (BP).After overnight fasting, the patients without any pre-medication were brought to a quiet operating room where a 20-gauge intravenous cannula was placed in the peripheral vein for Ringer's lactate solution at 15-18 ml/kg/h. All patients were monitored with electrocardiogram (ECG), HR, pulse oximetry , diluted in 50 ml of saline 0.9% and delivered at an assigned rate by a Graseby 3500 syringe pump . The first patient was tested at a loading dose of 1.0 μg/kg in 10 min without maintenance dose, which was the recommended loading dose according to the instructions for dexmedetomidine. The dose for the follow-up subjects was determined by the response of the previous patient, using the modified Dixon's up-and-down method During 10 minutes after the termination of loading dose of dexmedetomidine infusion, early signs of hypotension, hypertension, bradycardia, respiratory depression, airway obstruction, apnoea, dyspnoea and/or oxygen desaturation were monitored continuously. At 10 minutes after the termination of the loading dose of dexmedetomidine administration, anaesthesia was induced with propofol (0.7-1.0 mg/kg), cisatracurium (0.2 mg/kg) and sufentanil (0.4-0.5 ug/kg). Endotracheal intubation was performed and mechanical ventilation began. Anesthesia maintenance was provided by sevoflurane.0) of BP and HR were defined as the average of three consecutive measurements at the time when patients arrived in the operating room with supine position. Haemodynamic data were also measured at 3 min (T1), 6 min (T2) and 10 min (T3) after the beginning of the dexmedetomidine infusion, 3min (T4), 6 min (T5) and 10 min (T6) after the termination of dexmedetomidine administration and immediately before anesthesia induction (T7). Bradycardia was defined as HR less than 50 beats/min. Hypotension was defined as decrease in systolic blood pressure by more than 30% of the baseline value. Hypertension is defined as an increase in systolic blood pressure more than 30% of the baseline value. Other types of arrhythmia and hypoxemia were also recorded. The level of sedation was assessed at T3 and T6 using the Observer Assessment of Alertness and Sedation Scale (OAA/S) score The baseline . Data are expressed as mean  for continuous variables, frequency (percentage) for categorical variables, or median  for continuous variables with skewed distribution, as appropriate. Nominal data were analyzed using the Chi-square test, normally distributed continuous data were analyzed using Student's t-test and non-normally distributed continuous data were analyzed using nonparametric Mann Whitney U test. For within-group comparison, the repeated-measures ANOVA with adjustment for multiple comparisons to control the type I error with Bonferroni test was used for normal data. Statistical significance was defined as P < 0.05.Fig. 1. The study was stopped after the enrolment of 30 consecutive patients. Patients' characteristics are presented in Table 1.The study flow diagram is presented in P > 0.05).The defined positive outcomes took place in 13 patients, 11 of which had positive results during the dexmedetomidine infusion, and 2 of which had positive results after the infusion within 10 minutes. There was no significant difference in demographic data between the positive and negative groups  . The percentages of different doses of dexmedetomidine inducing bradycardia are shown in Fig. 3.The sequence of the dose of dexmedetomidine is illustrated in 3 and T6 showed no significant differences between the 2 groups (P > 0.05). After dexmedetomidine administration, OAA/S scores of both groups at T6 were lower than those at T3 (P < 0.05) (Table 2).OAA/S scores at TFig. ). However, negative group showed significant increase in HR than positive group at T1-7 (P < 0.05). In addition, Comparing HR to baseline within positive group, HR was significantly lower at T1-7 (P < 0.05). Comparing HR to baseline within negative group, HR was only significantly lower at T3 (P < 0.05). Data regarding SBP are shown in Fig. . SBP showed no significant difference in each comparison at the same period between the groups (P > 0.05). Comparing SBP to baseline within both groups, there were also no significant difference at each time point (P > 0.05).The HRs were similar in all two groups at baseline , hypoxemia, or respiratory depression occurred during the study. The systolic blood pressure increased over 200 mmHg in 2 patients, but they were under 30% the baseline value. No patients needed atropine or ephedrine.Bradycardia is a common adverse reaction of dexmedetomidine, which incidence varying from 10% to 30% depending on the dose of dexmedetomidine It is likely that a lower dose might have prevented such an event, but which may not achieve the level of sedation required. For sedation in the operating room, a faster onset of effect from dexmedetomidine is often desired such as awake fibreoptic intubation The first question in this study sought to determine the ED50 values of intravenous dexmedetomidine causing bradycardia in elderly patients (aged >65 years). Studies have shown that loading doses of 0.5-1.0 µg/kg dexmedetomidine in 10 min, followed by an infusion at a rate of 0.2-0.7 µg/kg/h, provide effective sedation and be well-tolerated for elderly patients In the current study, the observation and recording of bradycardia is set before anesthesia induction, which advantage is the absence of other pharmacologic confounding factors, such as opioids and sevoflurane may have played the synergistic roles with dexmedetomidine. Previous studies Dexmedetomidine exerts sedative and anti-anxiety effects since acting on central pre- and postsynaptic a2-receptors in the locus coeruleus. After sedation, dexmedetomidine may also induce physiological sleep without obvious respiratory suppression Dexmedetomidine produces a typical biphasic effect on blood pressure, a transient increase followed by a longer lasting decrease in blood pressure Generally speaking, this study was an exploratory trial under the safety of all patients. All subjects had normal liver and kidney function without co-morbidities before enrollment. During dexmedetomidine infusion, all patients had continuous cardiac and respiration monitoring. In addition, the trial was conducted under the close supervision of experienced doctors. Finally, all subjects did not suffer further sequelae related to the dexmedetomidine in the recovery and postoperative periods.There were several limitations in the current study. First, we did not record the hemodynamics data after anesthesia induction, which could be theoretically influenced by dexmedetomidine. Second, sedation in this study was only measured subjectively using OAA/S, lacking the bispectral index (BIS) monitoring during the infusion of dexmedetomidine. Third, the up-and-down method was used to determine the ED50 in the current study, which premise is that the dose-effect relationship is the traditional S-shaped curve, and often depended on a small sample size. But this did not provide reliable insight into the upper tail of the distribution, which may be imprecise In conclusion, the ED50 of intravenous dexmedetomidine causing bradycardia in elderly patients was 1.97 μg/kg. A slightly higher loading dose appears to be accepted for a faster onset of sedation under careful hemodynamic monitoring. Moreover, the use of dexmedetomidine during daily practice should be cautiously evaluated for each patient.


High blood pressure (BP) and type 2 diabetes mellitus (T2DM) are major causes of atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Central blood pressure (CBP) is more predictive of ASCVD than is brachial BP; however, an association of CBP with ASCVD has not been found in T2DM patients. We evaluated the impact of CBP and the association between optimal level of noninvasively measured CBP and office BP in T2DM patients based on composite outcome of ASCVD, HF, and complications of hypertension.Patients were enrolled from June 2011 to December 2015 and were followed up through December 2019. CBP was measured using radial tonometry. The primary endpoints were composite outcome of ASCVD, HF, and hypertension-induced complications such as left ventricular hypertrophy, retinopathy, and proteinuria.n = 283) were male. Patients who developed primary endpoints were older (65.3 ± 9.5 years vs. 60.5 ± 12.4 years) and had lower high-density lipoprotein (36.6 ± 9.4 mg/dL vs. 41.8 ± 11.1 mg/dL), higher CBP (123.6 ± 20.6 mmHg vs. 118.0 ± 20.6 mmHg), and higher pulse pressure (61.3 ± 16.6 mmHg vs. 56.5 ± 15.1 mmHg) than subjects without primary endpoint development. After adjustment for various risk factors, CBP was an independent predictor for primary endpoints . In addition, the association of CBP and primary endpoints showed a U-shaped curve with the lowest incidence at CBP 118 mmHg and systolic BP about 128 mmHg.During the 6.5-year follow-up period, 515 patients were enrolled in the study. A total of 92 patients (17.9%) developed primary endpoints. The mean age of subjects was 61.3 ± 12.1 years and 55% (We show the importance of CBP measurements in T2DM patients and present a cutoff value for ASCVD events and hypertension-induced complications. The number of people with hypertension has increased worldwide from 650 million to 1.28 billion in the last 30 years [HBP is a strong risk factor for ASCVD in patients with type 2 diabetes mellitus (T2DM) . In a reSeveral studies have shown that central BP (CBP) , 11, whiAn initial cohort of participants with T2DM who presented with or without concomitant CV risk factors or target organ damage was selected from the Department of Internal Medicine, St. Vincent’s Hospital, from July 2011 to December 2015. Among the patients who underwent noninvasive, semiautomated, radial artery applanation tonometry  and were eligible for our study, 515  were enrolled in this study. Based on self-reported menopause state, female patients were classified as premenopausal or postmenopausal. Exclusion criteria were clinical or laboratory findings of acute CV events within 3 months prior to enrollment. Subjects who had an irregular cardiac rhythm or brachial artery stenosis were excluded due to the method used to measure radial PWV.There was no industry involvement in the design, implementation, or data analysis of this study. The present study was a single-center retrospective study and was approved by the Institutional Review Board of St. Vincent’s Hospital (VC21RISI0202).Participants rested for at least 5 min in a quiet room and were seated comfortably with their legs uncrossed and their back and arms supported. BBP was measured using an automatic cuff oscillometric device . The average of three readings was used to determine SBP mean arterial pressure, and pulse pressure (PP) . Next, tBlood specimens were obtained after a 12- to 14-h fast (8:00 PM to 9:30 AM) to reduce the influence of circadian variation. Total cholesterol  and trigThe primary endpoints were composite outcome of ASCVD events or death from ASCVD and hypertension-induced complications, including newly diagnosed atrial fibrillation (AF), heart failure (HF), and HBP complication such as LVH, retinopathy, and proteinuria. ASCVD was defined as the presence of acute coronary syndrome  or a history of MI, stable or unstable angina, coronary or other arterial revascularization, cardiorovascular disease (CVD) including stroke or transient ischemic attack, or peripheral arterial disease (PAD) defined as an ankle-brachial index < 0.9 measured using an Omron VP-1000 Vascular Profiler  presumed to be of atherosclerotic origin. Medical records were obtained from ASCVD-related physician visits during follow-up and were reviewed by cardiologists.https://www.r-project.org/).Continuous variables are presented as mean ± standard deviation, and categorical variables are presented as absolute and relative frequencies (%). A t-test was used to compare the means between two groups. Proportions were compared using two-way tables and chi-square tests. To identify the independent predictors of primary endpoints, multivariate analyses using the Cox proportional hazard regression model were applied to the variables that were significant in univariate analysis and were known important risk factors for primary endpoints. Two-sided ≤ 0.05 indicate statistical significance. Multivariate analyses were schematized using a restricted cubic spline curve. All statistical analyses were conducted using R ver. 3.6.3  developed primary endpoints during the follow-up period. Of the 92 events, 52 were ACS (57%), 14 were CVA (15%), 3 were PAD (3%), 8 were HF events (9%), hypertension complications were found in 12 cases (13%), and AF were cases (3%). Table P = 0.002), HDL , and longer diabetes duration  showed a significant increase of primary endpoints. In the incidence of primary endpoints, there was no significant difference according to sex; however, postmenopausal women were significantly more frequent than men . In multivariate analysis, CBP was a significant predictor for primary endpoints  after adjustment for age, sex, smoking, BMI, and T2DM complications (Table P = 0.002) and HR was 1.14  even when age, gender, smoking, and diabetes complications were adjusted.In Table As shown in Fig. This study found that CBP is a clinically significant predictor for primary endpoints, showing a U-shaped association of CBP and risk of CV events in T2DM. The lowest incidence of primary endpoints was seen at CBP of 118 mmHg and SBP of about 128 mmHg.A previous large cohort study reported an association of SBP and risk of CV events and mortality, with a U-shaped curve pattern in T2DM , and SBPP = 0.016).In the result, risk ratio to an increase in CBP of 10 mmHg. As a result, this study suggests that after 6.5 years of follow-up, the risk of CVA increases by 14% for every 10 mmHg increase in CBP (HR, 1.14 In addition, previous studies suggested that there is a limitation in providing accurate information about the patient's BP status due to the problem of variability in peripheral BP. Although somewhat cumbersome, noninvasively measured central pulse pressure is more strongly associated with vasoconstriction, severity of atherosclerosis, and CV events than BBP as is known from the Strong Heart Study. Therefore, it is thought that measuring CBP may be important in assessing each patient's CV risk in order to more accurately determine the patient's BP status. So optimal CBP setting is more important in T2DM patients than general population.A previous study conducted in the general population confirmed an increase in SBP in a cascading manner as CBP increased  and showPostmenopausal female patients showed a greater risk of study end point than male patients. These findings were similar to a study conducted in the Korean population, confirming that central PP tended to be higher in men before 3847 years of age, but the slope was steeper in women than in men at later ages . This isThis study has several limitations. First, the study design is observational and retrospective; consequently, we could not control all confounding factors that affect ASCVD events or hypertension-induced complications. We attempted to adjust confounding factors to reduce this effect. Second, this study included only Korean subjects. In addition, the normal range or cutoff value of CBP has not been confirmed. This study also has plausible strengths in that it is the largest study of CBP measurement, CV events, and hypertension-induced complications and was conducted with long-term follow-up in patients with T2DM.With the logic that CBP may be more efficient than peripheral BP in predicting ASCVD, this study evaluated the risk of ASCVD in diabetic patients through CBP measurements. Accordingly, as confirmed in previous studies, the U-shape pattern, which increases the risk when BP increases and decreases, was confirmed, and the lowest HR was suggested as cutoff of 118 mmHg in CBP and 128 mmHg in SBP. In addition, it is thought that this will require research on the clinical importance and cutoff of CBP and SBP in various populations, and clinical application thereof may be necessary.


There is a significant correlation between the age of pregnant women (over 35 years of age) and the increase in the area of the genital hiatus . 3D ultrasound of the pelvic floor performed at week 20 of gestation can to be an effective, non-invasive, reproducible and cheap tool in the prognosis of the development of labor and of possible subsequent perineal dysfunctions.The objective of our study is to determine the thickness of the pubovisceral fasciculus of the levator ani muscle and the area of the genital hiatus by means of three-dimensional perineal ultrasound, in pregnant women in the 2nd trimester, and to analyze the related maternal, perinatal and postpartum clinical variables. Furthermore, to compare the results of our study with two similar series previously published. An observational, prospective study of pelvic floor ultrasound was carried out, performed at week 20, whose delivery was attended in the obstetrics service of the Hospital General Universitario Gregorio Marañón de Madrid (HGUGM), during the period of August from 2021 to June 2022. Maternal, ultrasound, perinatal and postpartum clinical variables were collected from each participant. During the study period, a total of 54 patients were included in it. The mean gestational age at which the ultrasound was performed was 19.81 ± 0.91 weeks. In relation to the ultrasound variables, the mean thickness of the pubovisceral muscle was 0.87 ± 0.13 cm , while, in the plane of minimum dimension of the genital hiatus, the hiatal area at rest was 13.41 ± 3.22  cm The relationship between the Levator ani muscle (LAM) and pelvic floor morbidity has been studied in different studies. In fact, De Lancey et al. have related LAM trauma or increased urogenital hiatus with loss of pelvic floor support ,2. PelviDuring childbirth, the LAM plays a fundamental role since it is the soft tissue that defines the biomechanical properties of the birth canal . In factLAM avulsion and consequently an increase in the genital hiatus are related to different pelvic floor dysfunctions (PFD), such as pelvic organ prolapse (POP) ,11,12,13Pelvic floor ultrasound has an increasing clinical application, for the measurement and visualization of different structures, such as the LAM, urogenital hiatus, LAM avulsions, etc. and its performance shows cheap, simple and very precise results, compared to MRI, in the visualization of the different perineal structures ,30,31,32Transperineal ultrasound is considered the gold standard for exploration through imaging of the pelvic floor, being a tool for detecting different dysfunctions of the anterior, central or posterior compartment of the female genital sphere .The LAM can elongate in very different ways in patients as a result of biomechanical stress or perineal trauma during childbirth, as well as having different morphological characteristics, among different patients that facilitate or slow down the second labor in childbirth , being aThe objective of our study is to determine the thickness of the pubovisceral fasciculus of the LAM and the area of the genital hiatus by means of three-dimensional perineal ultrasound in 2nd trimester pregnant women and to analyze the related maternal, perinatal and postpartum clinical variables. Furthermore, to compare the results of our study with two similar series previously published.A descriptive, observational and cross-sectional study has been carried out on a sample of pregnant women who attended the consultation for the routine ultrasound of week 20 at the Hospital General Universitario Gregorio Marañón, during the period between August and October 2021.Among the inclusion criteria were a pregnant woman over 18 years of age, a singleton pregnancy without serious gestational pathology, a visit to perform a morphological ultrasound at week 20, and acceptance of informed consent. Exclusion criteria were delivery in another center and fetal death during pregnancy. Patients who did not respond to the postpartum questionnaire were excluded from the comparative analysis.During the ultrasound examination, in addition to the obstetric ultrasound, measurements of the thickness of the pubovisceral fasciculus of the LAM and the area of the genital hiatus were made by three-dimensional transperineal ultrasound.Images were obtained by 3D translabial ultrasound in the supine position, using a SAMSUNG ultrasound machine, model WS80A, with a 3D-4D volumetric probe (4–7 MHz). The method used to obtain the anatomical dimensions of the thickness of the pubovisceral muscle and the genital hiatus is that described in the study published by Dietz et al.  after beIn In addition to the ultrasound examination, patients were offered to participate in a postpartum health questionnaire that assessed symptoms of perineal dysfunction. Those who accepted received a copy of the questionnaire to be completed so that they knew the questions beforehand. A non-standardized questionnaire was defined  and the statistical analysis was performed with SPSS version 25 programs  and Epidat 3.1 program for epidemiological data analysis. Version 3.1, Conselleria de Sanidade, Xunta de Galicia, Santiago, Spain; Pan American Health Organization (PAHO-WHO); CES University, Colombia. For each group, the descriptive parameters mean, standard deviation and 95% confidence interval were calculated for all the quantitative variables, and the percentage relative frequencies were calculated for the qualitative variables. A comparative analysis of the clinical variables of the patients was carried out based on the two groups of patients established according to presenting values of pubovisceral and hiatal thickness or equal to or less than the mean and above the mean. To calculate the effect correlation of each variable, a univariate logistic regression analysis was carried out to determine the value of the OR.Subsequently, of the most representative variables in the results of the comparison of the groups, a calculation of the correlation between these ultrasound measurements and the most representative variables in the results of the comparison of the two groups was carried out.t-test. A p < 0.05 has been defined for statistical significance.To compare differences in anatomical measurements, statistical differences were calculated from the summary data  using Student’s The study protocol received the approval of the Ethics Committee for Medical Research of our center .During the study period, 54 patients from our center who met the inclusion criteria were recruited. Maternal and ultrasound variables could be collected in all recruited patients.No cases of LAM injury were detected in the ultrasounds performed, not even in patients with previous deliveries.Nine (16.67%) patients were excluded due to delivery in another center and 1 (1.85%) patient due to fetal death, therefore 44 patients were included for the study of perinatal and postpartum variables.2.In relation to the ultrasound variables, the mean thickness of the pubovisceral muscle was 0.87 ± 0.13 cm , while, in the plane of minimum dimension of the genital hiatus, the hiatal area at rest was 13.41 ± 3.22  cm55.8% of deliveries were induced, with a frequency of 4.5% instrumental delivery and 9.1% cesarean section. 43.2% of perineal tears have been described in vaginal deliveries.2 and greater than the mean).In order to analyze the results in the different variables, the patients have been classified into two groups based on the measurement of the pubovisceral muscle, classifying them into those with a measurement equal to or less than the mean (0.87 cm) and above the mean. In addition, they have been classified into two groups in relation to the size of the genital hiatus, also taking the mean of its area as the cut-off point , however, this association has been established with the increase in the genital hiatus . None of the other variables studied have shown statistical significance, including parity, labor induction, or the presence of IU or POP postpartum. Only the frequency of labor induction is close to statistical significance, although its clinical etiological relationship is not clear.p = 0.51), labor induction  and urinary incontinence . While the main variables with greater relevance to the genital hiatus area are maternal age , multiparity , urinary incontinence  and pelvic organ prolapse .In addition, it describes the degree of association through odds ratio. The variables with the greatest difference in cases, in the comparison between groups in As previously mentioned, a comparison of the measurements obtained in our study with those published in the works of Dietz et al. and Yang et al. has been incorporated into the analysis. in non-pregnant women. The results of this comparison are shown in p < 0.001). However, these differences do exist in the area of the genital hiatus, which is higher in our study (p = 0.002). The age of the patients also differs between these studies, being higher in our sample, which could justify this second point.It can be noted that, in our study on pregnant women, the pubovisceral muscle is thicker than in the aforementioned studies . It is widely described in other studies that age has an impact on the increase in different PFDs [The mean area of the genital hiatus appears to be related to age, being higher in the group of women older than 35 years .POP occurs when there is a defect in the support mechanism of the different levels of suspension that Delancey et al. already described, in order to even be able to support normal intra-abdominal pressure ,44. In fIn addition, we have been able to determine that in our study the measurement of the thickness of the pubovisceral muscle and the genital hiatus does not seem to be related to age or other clinical parameters such as parity. The only aspect related to thickness, in a significant way, has turned out to be the probability of labor induction, however, we do not know the underlying pathophysiological relationship if it exists. We have also not been able to find a significant association between variables related to childbirth and muscle thickness or hiatal area, despite the fact that they seem to be biologically related, such as the total duration of labor, the frequency of eutocic or instrumental vaginal delivery, or the of soft canal tears. This may be due to the low power due to the end of the study or to the fact that the examination during pregnancy around week 20 does not allow an association to be established with different events that may take place during childbirth.p of 0.26. A higher n is likely to be needed to assess these outcomes, which are known risk factors for pelvic floor pathology. We must also take into account that the development of these pathologies can present years of latency, so that a single evaluation at 3 months postpartum may not adequately represent the evolution in the more distant future.In the evaluation of the risk factors for UI and POP, the presence of a lower-than-average thickness in the pubovisceral muscle shows an OR of 1.97 for postpartum IU, although without reaching statistical significance. In the case of increased genital hiatus, the OR for POP is 2.25, although with a If we analyze our results by comparing them with the studies by Dietz et al. and Yang et al. the patients in our study present a larger area of the genital hiatus. This can be explained either by her gestational state in which the weight of the gravid uterus on this muscular diaphragm increases its diameter and is in turn related to the older average age of our population.p = 0.06). Therefore, an early detection of a thinner pubovisceral muscle (we can associate it with less muscle tone and strength), may indicate a higher risk of a perineal tear during childbirth, especially if it is an induced, long or instrumental delivery and its subsequent appearance of postpartum anal incontinence, due to the existing relationship already described in other studies [Another relevant aspect in the results of the study is the relationship that may exist between the decrease in thickness of the pubovisceral muscle and the performance of labor induction. In fact, labour induction has been studied as one of the important risk factors for pelvic floor tears ,46,47,48 studies ,52,53,54Ultrasound is currently the fundamental tool in the study of the pelvic floor muscles, given its accessibility and low cost compared to other radiological techniques ,56.The possibility of obtaining these images has been very high, being able to capture volumes in all the patients recruited, so in practice it is a technique that is easy to acquire, minimally invasive and of reasonable cost compared to MRI. In addition, its performance during pregnancy can be framed within the obstetric ultrasound study and contribute to detecting and informing those patients with risk factors for pelvic floor pathology in the future and designing both primary prevention strategies  as secondary if there are postpartum symptoms.It is necessary to carry out more studies in pregnant patients, with more numerous samples that improve the statistical power and thus be able to determine which are the main risk factors associated with pelvic floor dysfunction, especially those antepartum that can be influenced in primary prevention. Interobserver studies are also advisable in order to compare the agreement between different sonographers. Despite other methods to assess the biomechanical parameters of the pelvic floor muscles have been described, such a biochemical markers like elastin and collagen, ultrasound assessment seems to be the first line of study given its availability, innocuity (no histology is required) and reproducibility ,58.A future research line could include the performance of a combination of imaging and biochemical studies in second or third trimester in order to obtain a more complete information of the status of the pelvic floor musculature and its possible behaviour under the stress of childbirth.The timing of the 20-week examination was considered the optimal time for preventive action, in the case of high risk and as part of a complete examination that includes fetal morphological ultrasound, cervical measurement and second trimester analysis, although we can consider it a limitation of the study, not to have been able to perform measurements in the 32nd weeks to check for more significant associations. In fact, it would be interesting to be able to measure, biochemical parameters in the study population and combine them with the ultrasound study, to complete a pelvic floor examination.3D ultrasound of the pelvic floor performed at week 20 of gestation can be an effective, non-invasive, reproducible and cheap tool in the prognosis of the development of labor and possible subsequent perineal dysfunction.


To investigate the effect of sub-satisfactory stent recanalization on hemodynamic stresses for severe stenoses of the middle cerebral artery (MCA) M 1 segment.Patients with severe stenoses of the MCA M1 segment treated with endovascular stent angioplasty were retrospectively enrolled. Three-dimensional digital subtraction angiography before and after stenting was performed; the computational fluid dynamics (CFD) analysis of hemodynamic stresses at the stenosis and normal segments proximal and distal to the stenoses was analyzed.P < 0.05) decrease in MCA stenosis after comparison with before stenting (31.4 ±12.5% vs. 87.5 ± 9.6%), with residual stenosis of 15–30% (mean 22.4 ± 3.5%). Before stenting, the total pressure was significantly higher (P < 0.0001), while the WSS, velocity, and vorticity were all significantly decreased (P < 0.0001) at the normal arterial segment proximal to the stenosis, and the total pressure, WSS, velocity, and vorticity were all significantly decreased (P < 0.0001) at the normal arterial segment distal to the stenosis compared with those at the stenosis. After sub-satisfactory stenting recanalization, all the hemodynamic stresses proximal or distal to the stenosis and at the perforator root were improved compared with those before stenting and were similar to those after virtual stenosis removal.Fifty-one patients with severe stenosis at the MCA M1 segment were enrolled, with the stenosis length ranging from 5.1 to 12.8 mm (mean 9 ± 3.3 mm). Stent angioplasty was successful in all (100%) the patients. The angiography immediately after stenting demonstrated a significant (Sub-satisfactory recanalization of severe MCA stenoses can significantly improve the hemodynamic status for cerebral perfusion at the stenoses. Middle cerebral artery (MCA) atherosclerotic stenosis is an important cause of recurrent cerebral ischemic strokes –6, and sThis retrospective study was approved by the ethics committee of a tertiary hospital 2018-052), and all the patients had given their signed informed consent to participate. The inclusion criteria were similar to those in the SAMMPRIS trial , includi-052, andAll the patients underwent endovascular stent angioplasty under general anesthesia. Dual antiplatelet inhibition was performed with aspirin (100 mg/day) and clopidogrel (75 mg/day) 3 days before the procedure, and a weight-based intravenous heparin bolus injection was conducted to achieve an activated clotting time of 200–350 s before guide catheter placement. The Seldinger technique was used to puncture the femoral artery followed by insertion of an 8F arterial sheath in the artery. After a micro-guidewire was used to navigate through the stenosis, a Gateway balloon catheter  was placed on the stenosis and inflated slowly to dilate the stenosis. The diameter of the balloon selected for pre-dilatation was 1.5–2.75 mm (mean 1.7 ± 0.2), and the length was 9–20 mm (mean 13.5 ± 2.6), with the pre-dilatation pressure ranging from 2 to 8 atm (mean 5.3 ± 2.4) and the pre-dilatation time ranging from 30 to 75 s (mean 45.7 ± 34.8). Then, a Prowler micro-catheter  was used to navigate the stenosis for deployment of the Enterprise stent  according to instructions for use of the manufacturer. The stent selected for deployment was 6–10 mm longer than the stenosis, with 3–5 mm over each end of the stenosis. Angiography was performed to confirm the appropriate deployment of the stent, and the residual stenosis was assessed based on normal distal arterial diameter, and successful stenting was defined as residual stenosis < 30%.In this study, a Gateway balloon catheter  was used. The size of the balloon catheter was selected according to the measurement of MCA stenosis, and the balloon diameter was selected to be no more than 80% of that of normal blood vessels at the distal end of the lesion. Based on studies in the literature , 21, theIstituto di Scienza e Tecnologie dell'Informazione, Consiglio Nazionale delle Ricerche). Virtual removal of the arterial stenosis and virtual repair of the artery were performed with the Meshlab software. Sharc Harpoon V4.3a (http://www.sharc.co.uk/html/downloads.htm) was used for generation of high-resolution 3D polyhedral mesh at a count of 1,000,000 cells. Finite-volume solution was performed with the Ansys 12.0.16 software  using the laminar double-precision steady regimen, which assumed blood viscosity of 0.004 Pa S, rigid nonslip wall conditions, and density of 1,050 kg/m3  DICOM data of all the patients were collected for analysis, and the Amira software  was used for visualization and removal of small or unnecessary arteries. Surface smoothing of the 3D vascular datasets was conducted with the MeshLab software  and tested by the Mann Whitney U-test. Significant P was set at < 0.05.All the data were analyzed with the SPSS 17.0 software . Continuous measurement data in normal distribution were expressed as mean ± standard deviation and tested by the Fifty-one patients met the inclusion criteria and were enrolled, including 29 men and 22 women aged 36–71 years (mean 54.8 ± 8.3) . HyperteP < 0.05) decrease in MCA stenosis after comparison with before stenting (31.4 ± 12.5% vs. 87.5 ± 9.6%), with a residual stenosis of 15–30% (mean 22.4 ± 3.5%). Perforator infarction occurred in one (1.96%) patient after the procedure, but there were no deaths. At 3–12 month follow-up (mean 5.8 ± 0.4), one (1.96%) patient had an asymptomatic in-stent restenosis, and one (1.96%) patient presented with an ischemic event consistent with the blood supply area of the arterial stenosis.Stent angioplasty was successful in all (100%) the patients . The angP < 0.0001) elevated while the WSS, velocity, and vorticity were all significantly (P < 0.0001) decreased at the normal arterial segment proximal to the stenosis. The total pressure, WSS, velocity, and vorticity were all significantly (P < 0.0001) decreased at the normal arteries distal to the stenosis compared with those at the stenosis.A computational fluid dynamics analysis was performed before and after stenting and after virtual stenosis repair . In compP < 0.0001) decreased, while the velocity was insignificantly higher (P > 0.05) than that before the stenting. At the normal arterial segment proximal to the stenosis, the WSS, velocity, and vorticity were all significantly (P < 0.0001) higher, while the total pressure was significantly (P < 0.0001) decreased as compared with that before the stenting. At the normal arterial segment distal to the stenosis, the WSS, total pressure, velocity, and vorticity were all significantly higher than those before the stenting. At the root of the perforating branch, the WSS, velocity, and vorticity were significantly decreased, while the total pressure was significantly higher (negatively) in the opposite direction than that before the stenting.After the stent angioplasty, the WSS, total pressure, and vorticity at the stenosis location were all significantly  M1 segment, it was found that stent angioplasty could significantly restore the atherosclerotic stentosis and that sub-satisfactory recanalization could significantly improve all the hemodynamic stresses proximal or distal to the stenosis and at the perforator root as compared with those before the stenting and were similar to those after virtual stenosis removal.The blood supply region of the MCA is extensive, and the area of the MCA blood supply contains important functions of the brain. Arterial stenosis of the MCA often results in ischemic stroke, because perforating arterial branches distal to the stenosis usually lack blood compensation from collateral circulation and are more sensitive to blood flow changes. Endovascular recanalization by stent angioplasty can effectively improve and correct the hemodynamic disorder distal to the stenosis, and the blood flow of the distal perforating arterial branches can also be improved , 24.Currently, three-dimensional imaging examinations, including magnetic resonance imaging angiography and DSA, can be performed to diagnose intracranial arterial atherosclerotic stenoses –27. WithArterial stenosis will limit blood flow from going through the stenosis, and a great deal of blood will be congested proximal to the stenosis, leading to increase in pressure and decrease in WSS, flow speed, and vorticity proximal to the stenosis, as proved by the findings of our study. Because of higher pressure proximal to the stenosis, the speed of blood flow at the stenosis is significantly accelerated, resulting in increase in WSS and flow vorticity but decrease in total pressure. Distal to the stenosis, the arterial diameter returns to normal, and the WSS, total pressure, flow velocity, and vorticity will all be decreased because of reduced amount of blood flow from the stenotic upstream area. These hemodynamic changes have been proved at the M1 stenosis and normal segments proximal to the stenosis in our study.After the sub-satisfactory recanalization of the stenosis by stent angioplasty, the stenotic arterial lumen is expanded to nearly normal. With increase in the amount of blood flow through the stented segment, the flow speed increases, the WSS and vorticity are enhanced, but the total pressure is decreased at the proximal segment. At arterial segments distal to the stented segment, all the hemodynamic stresses  are increased because of higher amount of blood flow and flow speed. The increase in the total pressure and velocity of blood flow, thus, significantly promotes cerebral blood perfusion, improving the ischemic status of the brain and subsequent ischemic symptoms. This is the hemodynamic effect of stent angioplasty on intracranial atherosclerotic stenosis as confirmed in our study. At the root of the perforating arterial branch, the total pressure is negatively enhanced, and the vorticity is significantly decreased, which will promote blood flow into the perforating artery even though the flow speed is decreased. With improvement in the hemodynamic stresses and parameters after sub-satisfactory recanalization, the pre-stenting poor blood perfusion in the brain distal to the stenosis will be significantly improved, and the clinical prognosis will consequently be improved. On the follow-up of the patients 3–12 months (mean 5.8 ± 0.4) later, one (1.96%) had an asymptomatic in-stent restenosis, and one (1.96%) presented with an ischemic event consistent with the blood supply area of the arterial stenosis. These clinical outcomes may prove the efficacy of sub-satisfactory recanalization of severe MCA stenosis.After the virtual removal of the arterial stenosis, the hemodynamic stresses are further improved, and even if the stresses have not completely recovered to the optimal status after the virtual removal, the sub-satisfactory stent recanalization has led to a significant improvement in the hemodynamic stresses, with improved cerebral perfusion pressure and blood flow speed.Current hemodynamic studies are mainly focused on the primary technique of simulating the stenosis itself and WSS and pressure at the stenosis without revealing more hemodynamic stresses proximal and distal to the stenosis and at the root of a perforating branch –32, and Some limitations may exist in this study, including the limited number of patients, only Chinese patients were enrolled, being a single-center study, and stenosis only at the middle cerebral artery, which may all affect the generalization of the outcome. Future studies will have to resolve all these issues for better outcomes.In conclusion, sub-satisfactory recanalization by stent angioplasty can significantly improve the hemodynamic status proximal and distal to the stenosis and at the perforator root as compared with that before stenting, similar to that after virtual stenosis removal, improving the hemodynamic status and cerebral hypoperfusion.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 Ethics Committee of Henan Provincial People's Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.KZ and B-LG: study design. KZ, WR, J-CX, H-LG, Y-FW, and J-JG: data collection. KZ, Z-LW, and B-LG: data analysis. J-JG: supervision. KZ: writing of the original article. B-LG: revision. All authors contributed to the article and approved the submitted version.This study was funded by Joint Construction Project of Henan Provincial Medical Science and Technology Research Plan (SBGJ202003006).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Alae nasi (EMGan).Dyspnea, a key symptom of acute respiratory failure, is not among the criteria for spontaneous breathing trial (SBT) failure. Here, we sought (1) to determine whether dyspnea is a reliable failure criterion for SBT failure; (2) to quantify the relationship between dyspnea and the respective electromyographic activity of the diaphragm (EMGdi), the parasternal (EMGpa) and the Mechanically ventilated patients undergoing an SBT were included. Dyspnea intensity was measured by the Dyspnea-Visual Analogic Scale (Dyspnea-VAS) at the initiation and end of the SBT. During the 30-min SBT or until SBT failure, the EMGdi was continuously measured with a multi-electrode nasogastric catheter and the EMGan and EMGpa with surface electrodes.p = 0.01). The area under the receiver operating characteristics curve for Dyspnea-VAS was 0.909 (0.786–1.032). The increase in Dyspnea-VAS was significantly correlated to the increase in EMGan , but not to the increase in EMGpa  and EMGdi .Thirty-one patients were included, SAPS 2 (median [interquartile range]) 53 (37‒74), mechanically ventilated for 6 (3‒10) days. Seventeen patients (45%) failed the SBT. The increase in Dyspnea-VAS along the SBT was higher in patients who failed (6 [4‒8] cm) than in those who passed (0 [0‒1] cm, Alae nasi than of the diaphragm.Dyspnea is a reliable criterion of SBT failure, suggesting that Dyspnea-VAS could be used as a monitoring tool of the SBT. In addition, dyspnea seems to be more closely related to the electromyographic activity of the The online version contains supplementary material available at 10.1186/s13613-022-01025-5. First, readiness-to-wean criteria should be searched for, at least on a daily basis . Second,Although dyspnea is a key symptom of acute respiratory failure, dyspnea is not listed among the criteria for SBT failure and is often not even collected and therefore ignored during the SBT. Yet, dyspnea is a self-reported symptom that is easy to collect and to quantify in communicative patients, and could be used as a criterion of SBT failure , 8. DyspAlae nasi.Here, we assessed dyspnea during an SBT. Our first objective was to determine whether dyspnea change is a reliable criterion of weaning failure and to compare dyspnea to other criteria for weaning failure to determine whether dyspnea collection should be part of the follow-up of all SBTs in an effort to improve the current MV weaning procedure. Our second objective was to establish the relationship between dyspnea and the respective electromyographic activity (EMG) of the diaphragm and two extradiaphragmatic inspiratory muscles, namely the parasternal intercostal and the This observational, single-center prospective study was conducted over a 1-year period in the 10-bed medical intensive care unit (ICU) of the respiratory and ICU Division of La Pitié-Salpêtrière Hospital, Paris, France.The study was approved by the Comité de Protection des Personnes Ile de France VI (No. 84-14). Informed consent was obtained from patients.2 > 90% with FiO2 ≤ 40% and positive end-expiratory pressure (PEEP) ≤  8 cm H2O, respiratory rate ≤ 40 breathes/min, a Ramsay sedation scale < 4 and stable cardiovascular status . Patients < 18 years, with neuromuscular diseases, those for whom life support would be withheld or withdrawn and patients for whom the repeated assessment of dyspnea was likely to be difficult  were not included in the study.Patients were eligible as soon as they met the following criteria: 1) intubation and mechanical ventilation for more than 24 h, and (2) the predefined readiness-to-wean criteria, adapted from the 2007 international consensus conference [ intubatiAll patients were ventilated using a Servo-i ventilator  equipped with the standard commercial version of the NAVA module.The standard nasogastric feeding tube was removed and replaced by an electromyography activity of the diaphragm catheter consisting of a 16-French gastric tube equipped with electrodes.2O and zero end-expiratory pressure. The FiO2 was adjusted during the SBT so as to obtain an SpO2 of between 90 and 95%. Electromyographic recording was performed during the whole time of the SBT. The endotracheal tube was suctioned before starting recording.As soon as the patients met the readiness-to-wean criteria, a 30-min SBT was performed with the patient connected to the ventilator with a pressure support level of 7 cm H2 < 90% with FiO2 ≥ 50%; (2) acute respiratory distress ; (3) systolic arterial blood pressure ≥ 180 mmHg; (4) sudden cardiac arrhythmias, and (5) respiratory acidosis  were present. The decision as to whether the SBT was passed or failed was based on the clinical judgment of the physician in charge of the patient, who was independent of the investigators.Based on the criteria adapted from the 2007 international consensus conference , the SBTAnthropometric data and medical history were collected at inclusion.Heart rate, systemic blood pressure and dyspnea were collected at the initiation and end of the SBT. Presence of neuromuscular weakness, defined by MRC score < 48, was collected. Richmond Agitation Sedation Scale and Pain-Visual Analogue Scale (from 1 to 100 mm) were collected during the assessment that was the closest of the SBT. Medications received by the patient before and during the SBT were collected. Patients were considered able to consistently self-report dyspnea if the Dyspnea-Visual Analogue Scale (Dyspnea-VAS) variation did not exceed 1 cm for three consecutive measures . DyspneaAirway flow was measured with a pneumotachograph  inserted between the Y-piece and the endotracheal tube before being connected to a differential pressure transducer . Airway pressure was measured at the Y-piece by a differential pressure transducer .Alae nasi muscles, electrodes were placed on the lateral surfaces of the nose (nostrils) [The EMG signal was collected by self-adhesive surface electrodes such as those commonly used to record the electrocardiogram signal in critically ill patients, with an interval of 2 cm between the two electrodes. Electrode positions varied according to the muscle being recorded. For the EMG of the parasternal intercostal muscles, electrodes were placed next to the second intercostal space as close as possible to the sternum. For the EMG of the ostrils) . EMG sigThe EMG of the diaphragm was obtained from the multi-electrode nasogastric NAVA catheter, an esophageal probe that collects the EMG signal with bipolar electrodes in sequential order, after checking the correct positioning of the probe and the quality of the signal. An automated processing technique tracks the displacement of the diaphragm . A crossBlood gases were sampled at the initiation and end of the SBT or earlier in case of intolerance using an arterial catheter.Vt) were determined on a breath-by-breath basis and averaged for the first and last 5 min of the SBT recording .Respiratory rate (RR) and tidal volume (Maximum EMG (EMGmax) and the area under the curve of the EMG during inspiratory time (EMGauc) integrated from baseline to peak were calculated on a breath-by-breath basis. The first and last 5 min of the SBT were eventually averaged. Due to the variability of skin impedance , 17 and Alae Nasi to the EMG activity of the diaphragm. Categorical variables were expressed as absolute values and percentages. All analyses were performed with a type I error of 5%. Results were compared between the success and failure groups. Differences between groups were assessed with the Mann–Whitney test for continuous variables and the χ2 tests for categorical variables. Correlations between variables were evaluated using the Spearman rank correlation coefficient. receiver operating characteristic (ROC) curves were performed to evaluate the performance of indices to detect SBT failure.Statistical analysis was performed with Prism 8.0 software . Quantitative variables were described by their median and interquartile range. Changes in dyspnea, breathing pattern, hemodynamics and blood gas are expressed as the difference in variables between the initiation and end of the SBT. Change in EMG activity is expressed as the ratio of the EMG activity and the end of SBT to the EMG activity at the initiation of the SBT. Contribution of extradiaphragmatic recruitment to diaphragm activity is expressed as the ratio of the EMG activity of the On the basis of previous studies that our team has conducted on this subject and data from the literature, which estimate the probability of failure to wean at 40% , we predOne hundred and forty-five patients with invasive mechanical ventilation for more than 24 h and eligible for SBT were admitted during the study period. Two patients were less than 18 years old, three had auditory impairment, three had insufficient command of French, 26 refused to participate, and, a technical reason  could not allow inclusion in 61.Fifty patients were included in the study, of whom five were excluded because dyspnea could not be assessed reliably and 14 because the EMG signal was of poor quality and could not be process or interpreted. Overall, 31 patients were enrolled, of whom 14 (45%) failed the SBT; among them, three were due to cardiac failure.Patient characteristics are shown in Table p = 0.188). Systolic blood pressure (p = 0.233), PaCO2 (p = 0.406), pH (p = 0.212) and SaO2 (p = 0.462) were also no different between patients who passed the SBT and those who failed. Conversely, RR (p = 0.001), RR/Vt (p = 0.031) and heart rate (p = 0.014) were higher in patients who failed the SBT than in those who passed, while PaO2 was lower (p = 0.039). At the end of the SBT, dyspnea-VAS was higher in patients who failed the SBT than in those who passed (p = 0.003). Respiratory rate (p = 0.001), heart rate (p = 0.001) and systolic blood pressure (p = 0.016) at the end of the SBT were also higher in patients who failed the SBT than in those who passed, while SaO2 (p = 0.005) was lower.Dyspnea, breathing pattern, hemodynamics and blood gas at the initiation and end of the SBT are reported in Table p = 0.006), RR (p = 0.001), heart rate (p = 0.017), systolic blood pressure (p = 0.020) and SaO2 (p = 0.036) between the initiation and end of the SBT was higher in patients who failed the SBT than in those who passed. There was no difference between patients who failed the SBT and those who passed in terms of change in Vt (p = 0.844), RR/Vt (p = 1), PaO2 (p = 0.537), PaCO2 (p = 0.738) and pH (p = 0.785).The change in dyspnea, breathing pattern, hemodynamics and blood gas between the initiation and end of the SBT is shown in Table Vt, respiratory rate, PaO2, PaCO2, pH, SaO2, heart rate and systolic blood pressure.Figure 2, PaCO2, SaO2 and respiratory rate at the initiation and the end of spontaneous breathing trial is reported in Additional file 2, PaCO2, SaO2 and respiratory rate is reported in Additional file Correlation between the dyspnea-VAS and the PaOAlae nasi, parasternal intercostal muscles and diaphragm between the initiation and end of the SBT are reported in Table Changes in the EMG activity of the Alae nasi (p = 0.010 for EMGmax and p = 0.015 for EMGauc) and diaphragm (p = 0.008 for EMGmax and p = 0.125 for EMGauc) EMG activity between the initiation and end of the SBT was higher in patients who failed the SBT than in patients who passed. The change in parasternal intercostal EMG activity (p = 0.426 for EMGmax and p = 0.855 for EMGauc) was no different between patients who passed and those who failed the SBT. The contribution of extradiaphragmatic recruitment to the diaphragm (p = 0.039 for EMGmax and p = 0.812 for EMGauc) was lower in patients who failed the SBT than in patients who passed   or the diaphragm EMGauc . EMGmax gave similar results , between the change in Alae nasi EMG activity and in diaphragm EMG activity  and between the change in parasternal EMG activity and in diaphragm EMG activity .There was no significant correlation between the change in Our results can be summarized as follows. During SBT, (1) dyspnea is a reliable criterion of weaning success and failure, suggesting that dyspnea-VAS has the potential to become a useful clinical decision-making tool for SBT; (2) dyspnea seems to be more closely related to the EMG activity of the extradiaphragmatic inspiratory muscles than to the EMG activity of the diaphragm.Alae nasi was no different, which is consistent with a recent report that showed a similar increase in the EMG of various inspiratory muscles during a progressive decrease of pressure support in mechanically ventilated patients [These results confirm the link between increase in respiratory drive and dyspnea. Rapid increase in respiratory loading, which happens during the SBT, in turn increases the central respiratory drive to the inspiratory muscles . It has patients .Alae nasi EMG activity, but not with diaphragm EMG activity. It suggests that dyspnea is more closely linked to the central respiratory drive to extradiaphragmatic inspiratory muscles than to the central respiratory drive to the diaphragm. This result is consistent with previous reports of a significant correlation between dyspnea and extradiaphragmatic inspiratory muscle EMG activity [In our study, the increase in respiratory drive was associated with an increase in dyspnea. It is of note that dyspnea was correlated with activity , 24, 25.activity .Alae Nasi, it is possible that this absence of correlation results from a lack of power or a technical issue.In our study, the change in dyspnea was not correlated with the EMG of the parasternal muscle. If we cannot exclude that dyspnea is lesser closely linked to the central respiratory drive to the parasternal muscle than to the central respiratory drive to Although dyspnea is a key symptom of acute respiratory failure, it is not listed among the criteria for SBT failure . Our resIn our study, patients who failed the SBT reported an extremely high level of dyspnea. Dyspnea is a major cause of suffering for ICU patients, including anxiety; dyspnea could even contribute to the genesis of post-traumatic stress disorders , 32. It The use of EMG, due to its technical difficulties of acquisition and interpretation, is not a suitable tool for monitoring SBT. In the present study, we used this tool to establish a relationship between dyspnea and the respective electromyographic activity (EMG) of the diaphragm and the two extradiaphragmatic inspiratory muscles.This study presents limitations. First, the decision as to whether the SBT was passed or failed was based on the clinical judgment of the physician in charge of the patient; this leads to a potential inconsistency of decision criteria, even if they were based on the recommendations . Second,Alae nasi than to the EMG activity of the diaphragm. In addition, the intensity of dyspnea seems to be a reliable criterion of weaning success and failure. Subsequently, this suggests that change of dyspnea could be used as a simple monitoring tool of the SBT. The reliability of dyspnea in assessing SBT success now needs to be evaluated by a larger multicenter observational study.In conclusion, during an SBT, change of dyspnea is more closely related to the EMG activity of the Additional file 1: Figure S1. Correlation between the dyspnea-visual analog scale (VAS) and the PaO2, PaCO2, SaO2 and respiratory rate at the initiation and the end of spontaneous breathing trial. Figure S2. Correlation between the change of dyspnea-visual analog scale (VAS) and the change in PaO2, PaCO2, SaO2 and respiratory rate.