While baseline eAoPWV (9.25 ± 0.80 m/s) did not significantly change during hemodialysis, cerebral PAT increased significantly  and was associated with reduced pulsatile components of MCAv. This study shows that hemodialysis acutely reduces stiffness of arteries perfusing the brain along with pulsatile components of blood velocity.End‐stage kidney disease (ESKD) is associated with increased arterial stiffness and cognitive impairment. Cognitive decline is accelerated in ESKD patients on hemodialysis and may result from repeatedly inappropriate cerebral blood flow (CBF). The aim of this study was to examine the acute effect of hemodialysis on pulsatile components of CBF and their relation to acute changes in arterial stiffness. In eight participants , CBF was estimated using middle cerebral artery blood velocity (MCAv) assessed with transcranial Doppler ultrasound before, during, and after a single hemodialysis session. Brachial and central blood pressure, along with estimated aortic stiffness (eAoPWV) were measured using an oscillometric device. Arterial stiffness from heart to MCA was measured as the pulse arrival time (PAT) between electrocardiogram (ECG) and transcranial Doppler ultrasound waveforms . During hemodialysis, there was a significant reduction in mean MCAv (−3.2 cm/s,  This study assesses changes in cerebral blood velocity and regional arterial stiffness during hemodialysis. It shows an acute reduction of mean and pulsatile components of cerebral blood velocity, along with a reduction in the stiffness of arteries supplying the middle cerebral artery. This is the first study to assess cerebral artery stiffness in the setting of hemodialysis. We hypothesized that (1) mean MCAv decreases while pulsatile components of blood velocity increase during hemodialysis, (2) indices of aortic and cerebral stiffness decrease during hemodialysis while peripheral stiffness increases, and (3) during hemodialysis, pulsatile components of blood velocity are associated with regional markers of arterial stiffness.22.1All participants provided written informed consent prior to participating in the investigation, and the study was approved by the Comité d'éthique de la recherche du Centre Hospitalier Universitaire de Québec (CHUQ) – Université Laval (CER: 21180) according to the principles established in the Declaration of Helsinki (except for registration in a database) and the Canadian Government Tri‐Council Policy Statement (TCPS2) for integrity in research.2.22, and prevalent hemodialysis >3 months, with a single pooled Kt/V ≥ 1.3 indicating effective hemodialysis, as calculated from urea clearance. Patients with severe carotid artery stenosis  <15 mL/min/1.73mN = 2), hypertensive nephroangiosclerosis (N = 2), glomerulonephritis (N = 1), polycystic kidney disease (N = 1), tuberous sclerosis (N = 1), and unknown origin (N = 1). Arterial hypertension was defined as either documented prevalent arterial hypertension or patients taking antihypertensive medication. Cardiovascular disease was defined as either a past cardiovascular event or documented coronary obstruction.Baseline demographic and clinical patient characteristics were collected from patient medical charts and are presented in Table 2.32 (m). Participants were then instrumented with an electrocardiogram (ECG), a continuous blood pressure (BP) monitoring finger cuff, a brachial ambulatory BP monitoring system, and the TCD prior to hemodialysis onset. The participants remained connected to the probes and sat in a semi‐recumbent position throughout hemodialysis.The experimental protocol for this study is graphically presented in Figure N = 4), LO‐20 (N = 2), and Evodial 1.6 (N = 2). Vascular access was achieved through an arteriovenous fistula in half (N = 4) of the participants, while the other half had central venous (right jugular vein) catheters. A bicarbonate‐based buffer dialysis solution was used, with sodium concentrations [Na+] of 135–146 mmol/L, potassium concentrations of 2–3 mmol/L, a bicarbonate concentration of 31 or 34 mmol/L, a calcium concentration of 1.25–1.5 mmol/L, dextrose 5.5 mmol/L, blood flow of 350–400 mL/min, and dialysate flow rate of 500–800 mL/min.For the study, each participant underwent their regular 4 h hemodialysis session, as prescribed by their nephrologist. Hemodialysis was performed using FX‐100 membranes , and ECG activity were performed. These periodic assessments were completed within 30 min prior to hemodialysis start , after 1 h, 2 h, and 3 h of hemodialysis, and finally within 15 min of hemodialysis completion . Immediately before and after each 5 min monitoring period, central hemodynamic parameters of interest , as well as blood gases were measured. Given that these values did not significantly differ, they were averaged for each hour of hemodialysis. Finally, participants remained awake with their eyes opened and refrained from talking, or coughing, as to minimize the impact of increased intra‐abdominal pressure on physiological measurements.33.1Cerebral blood flow was estimated by monitoring MCAv using standardized procedures to identify the MCA . While systolic and diastolic finger BP were defined as peak and minimum of the pressure waveform, respectively, MAP was obtained by integration of the pressure waveform divided by the duration of the cardiac cycle.Continuous MCAv, BP, and ECG signals were analog‐to‐digital converted at 1000 Hz via an analog‐to‐digital converter  and stored for subsequent analysis using commercially available software . A representative 1 min sequence was selected from the continuous raw ECG, finger photoplethysmography (PPG), and MCAv data at each time point of interest, that is, pre‐hemodialysis, every hour during hemodialysis, and post‐hemodialysis.Using MATLAB , the net signals were filtered to obtain a clear signal. The recorded signal sequences were passed through a low‐pass filter characterized by a straight‐line phase. The same procedure of filtering and smoothing was applied to both MCAv and PPG signals, given that differences in signal treatment might have otherwise induced phase shifts. Setting the cut‐off frequencies of the filter requires prior knowledge of the signal and noise frequency spectra so that the filter's frequency response can be determined. This information was obtained through fast‐Fourier transform, where the raw signals were transformed from the time domain to the frequency domain, in order to determine the frequency of the noisy part to be eliminated by the filter. A 45 Hz threshold was selected.3.2Indices of arterial stiffness included brachial pulse pressure (bPP), where bPP was the difference between brachial systolic (bSBP) and brachial diastolic BP (bDBP) and central pulse pressure (cPP), where cPP was the difference between central systolic blood pressure (cSBP) and central diastolic blood pressure (cDBP). Estimated aortic pulse wave velocity (eAoPWV) using Mobile‐O‐Graph (I.E.M. GmbH) provides an estimate of aortic stiffness, as previously described and validated  and was drawn each hour during hemodialysis. In those with a central venous catheter, intra‐hemodialysis capillary blood was drawn at the 2 h within hemodialysis time point, to limit uncomfortable fingertip blood draws.In all participants, capillary blood samples were drawn before and after hemodialysis. During hemodialysis, arterial blood was accessible through the patient's arteriovenous fistula (2 (Torr), where [HCO3−] is calculated from measured PaCO2 and pH, using the Henderson–Hasselbalch equation  at 37.0°C in plasma of 0.0314 mEq × L−1 per Torr PaCO2 were used: pH = 6.1 + log [HCO3−]/(0.0314 × PaCO2).Blood samples were analyzed using a blood gas analysis system . Briefly, this blood gas analysis system provides reliable readings of pH and PCOhere HCO3− is calc3.4n (%) or median (25th–75th percentiles), and mean (95% CI). To account for intraindividual changes and repeated measures analysis, we used generalized estimating equations (GEE) using three time levels: before hemodialysis, during hemodialysis, and after hemodialysis. A robust estimator of covariance matrix was used. Values of the estimates are reported ± standard errors whenever a GEE was used. The p‐values were corrected using sequential Bonferroni for multiple comparisons. Using this approach, we examined the changes in hemodynamic variables in response to hemodialysis. We then examined the relationship between MCAv parameters and clinical, hemoglobin, PCO2, and arterial stiffness indices. Data analysis were performed using SPSS software . Statistical significance was set a priori to an alpha value <0.05.Data are reported as mean ± standard deviation, 44.12, and had been on hemodialysis for a median period of 28 (7–46) months, with the expected high frequency of diabetes, arterial hypertension, cardiovascular disease, and cardiovascular medication. All patients suffered from anemia with a mean hemoglobin concentration of 108 ± 19 (g/L), ranging from 78 to 116 g/L. Other biological parameters are presented in Table Demographic and clinical characteristics of participants are summarized in Table Baseline cerebral hemodynamics along with central and peripheral BP are reported in Table 4.2p = 0.051) of borderline statistical significance during hemodialysis, cSBP  did not significantly decrease. Changes in bDBP, cDBP, bPP, and cPP were not statistically significant.Table p < 0.001), and remained lower after hemodialysis . Syst MCAv was significantly reduced during hemodialysis  and remained so following the end of hemodialysis . Diast MCAv remained relatively unchanged during hemodialysis  and after hemodialysis , which resulted in a reduction of P‐MCAv during  and after hemodialysis . When adjusting for bSBP and cSBP, the reduction in syst MCAv was no longer statistically significant during hemodialysis  or after hemodialysis . However, there was a stronger association between mean MCAv with cSBP  than bSBP .As presented in Table p < 0.001), it returned to baseline levels by the end of hemodialysis . On the other hand, the cerebral PI, CVCi, and CVRi remained unchanged during the intervention , but this was no longer significant by the end of hemodialysis .Finally, Table 4.3p = 0.596) or after hemodialysis . However, the cerebral PAT was significantly increased during hemodialysis , and remained elevated by the end of hemodialysis , suggesting a reduction of vascular stiffness in the segment from the heart to the MCA. This intradialytic increase in cerebral PAT remained significant after controlling for potential covariates including MAP, total fluid removal, and heart rate.Table p < 0.001), but there was no difference after hemodialysis . This observation also suggests a transient reduction of vascular stiffness along the arterial path from the heart to the digital arteries.During hemodialysis, there was also an increase in finger PAT relative to baseline . However, hemoglobin levels were not associated with the mean MCAv response to hemodialysis treatment (p = 0.405 for hemoglobin‐time interaction). Patients with diabetes had a higher mean MCAv by 20.1 cm/s , but diabetes did not affect mean MCAv response to hemodialysis treatment (p = 0.984 for diabetes–time interaction). Furthermore, the impact of diabetes on mean MCAv was attenuated and no longer significant after correction for hemoglobin level (p = 0.081). Age, cardiovascular disease, sex, fluid removal, and PCO2 levels were not associated with baseline mean MCAv and its changes during or after hemodialysis treatment.At baseline, we found that for each reduction of 10 g/L of hemoglobin, the mean MCAv increased by 4.5 cm/s , and was higher by 4 cm/s (p = 0.023) and 4 cm/s (p = 0.015) for every 10 mm Hg increase in cPP and bPP, respectively. Syst MCAv was higher by 1 cm/s (p = 0.002) and 0.3 cm/s (p = 0.006) for every 0.01 s decrease in cerebral PAT and finger PAT, respectively. However, there were no associations between mean MCAv and any of the vascular stiffness indices.The relationships between indices of vascular stiffness and syst MCAv were further explored, along with their relationship to mean MCAv Table . Syst MCWe also examined the relationship between pulsatile components of MCAv and indices of vascular stiffness. The results are shown in Table 5This study shows that mean MCAv acutely decreases during hemodialysis, a finding that is largely due to decreased intradialytic cSBP. It also demonstrates that arterial stiffness assessed between the heart and the MCA, acutely decreases during hemodialysis, and is significantly associated with pulsatile components of cerebral blood velocity. Regional arterial stiffness between the heart and the MCA was calculated using a novel method, based on physiological signals readily available at the bedside, which opens the door for use in future large‐scale studies.5.12, a mechanism called cerebrovascular reactivity to CO2 (CVRCO2). Arterial bicarbonate concentration and pH also affect CBF, however, to a lesser degree than PCO2 . Central systolic BP, however, was more strongly associated with syst MCAv than bSBP. Previous studies have suggested that cerebral autoregulation is impaired in CKD patients when evaluated after a stroke or during hemodialysis  to obtain a segmental PWV. Increased PWV corresponds to increased stiffness . L.L. received a doctoral training scholarship from the Société québécoise d'hypertension artérielle (SQHA).None.


N = 24) diagnosed with TMD according to Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were included. Cone beam computed tomography (CBCT) images were taken before and after treatment. The anterior, superior, posterior, and medial joint spaces were measured on the CBCT images, and the condylar ratio was calculated using Pullinger and Hollender’s formula. Additionally, the thickness of the glenoid fossa (GFT), condylar medio-lateral widths (MLW), and condylar height (HCo) were measured. The condylar ratio was significantly higher after treatment (p = 0.049). The changes in dimensions of the anterior, superior, posterior and medial joint spaces were not statistically significant after treatment. No statistically significant differences were found in the dimensions of the GFT, MLW, and HCo post treatment. The condylar position did not shift anteriorly in a statistically significant way after occlusal splint therapy combined with cranio-temporomandibular kinesiotherapy in TMD patients.Occlusal splints are used as a non-invasive treatment for patients diagnosed with temporomandibular disorders (TMD). Another non-invasive treatment option for TMD patients is kinesiotherapy, which may be used alone or in conjunction with occlusal splint therapy. The aim of this study was to evaluate the changes in the intra-articular spaces of the temporomandibular joint (TMJ) after occlusal splint therapy combined with cranio-temporomandibular kinesiotherapy in TMD patients. Twenty-four patients ( For both volumetric and linear measurements of temporomandibular joint (TMJ) structures, cone beam computed tomography (CBCT) has been demonstrated to be accurate and reliable, specifically designed for imaging in the oral and maxillofacial fields . MoreoveOcclusal splints are indicated as a viable non-invasive treatment for patients diagnosed with temporomandibular disorders (TMD). Occlusal splints allow the lateral pterygoid muscle to relax and thus to center the condyles into glenoid fossa (GF). Together with the anterior deprogrammer and the leaf gauge, occlusal splints are frequently used for the treatment of dysfunction signs and symptoms such as muscle pain, TMJ pain, clicking, crepitus and restricted mandibular movement ,6. AlthoAnother non-invasive therapeutic approach for TMD patients is kinesiotherapy. Treatment of TMD has been found to be beneficial using manual therapy. It can be utilized independently or in addition to occlusal splint therapy . RocabadThe position of the condyles in the GF, meaning the concept of centric relation (CR), was introduced in dental literature almost one century ago and its definition has changed over the years. The original definition changed as a result of several, frequently conflicting research findings . This haAnother study suggested that position of condyles within the GF has been associated with TMD and, consequently, the optimization of condylar position is indicated using therapeutic procedures such as muscular deprogramming and occlusal equilibration . AccordiThe aim of this study was to evaluate the changes of intra-articular spaces post occlusal splint therapy used in conjunction with cranio-temporomandibular kinesiotherapy in TMD patients.This retrospective observational study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Iuliu Hațieganu University of Medicine and Pharmacy (no. 403/02.07.2015). Informed written consent was obtained from all subjects involved in the study.N = 24) diagnosed with TMD, according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) [Twenty-four patients N =  diagnoseAll the participants underwent occlusal splint therapy and cranio-temporomandibular kinesiotherapy targeting the TMJ and masticatory muscles. Based on facebow mounting  and bite registration , hard acrylic full coverage occlusal splints with flat occlusal surfaces were manufactured in semi-adjustable articulator  in patient’s arc of closure. Heat cured acrylic  maxillary occlusal splints divided into three parts  were designed. Equal contacts of all mandibular buccal cusps and incisal edges in centric relation and anterior guidance with immediate posterior disocclusion were obtained. Occlusal splints were delivered to all patients. They were advised to wear occlusal splint 24 h/day except for eating and cleaning procedures. Kinesiotherapy was performed by a physiotherapist who specialized in muscles and TMJ manual therapy, including joint mobilization and manipulation and manual therapy of the soft tissues. Kinesiotherapy was indicated to reduce local ischemia, to stimulate proprioception and synovial fluid production and to reduce pain. Additionally, all the patients were trained in and advised to perform Rocabado’s 6 × 6 exercises at home daily. The occlusal splint check-ups and kinesiotherapy took place on a weekly basis until the disappearance of the chief complaint.All patients underwent a CBCT examination of TMJs before and after the treatment. The primary acquisition was performed using a CBCT device  which was set at 6.0–8.0 milliamperage (mA) and 80 kilovoltage (kV); the exposition time was 15 s (s), with a field of view (FOV) of 8 × 5 cm and a slice thickness of 0.3 mm. The scans were performed by the same operator, with patients in sitting positions, holding their heads straight, with Frankfort plane parallel to the ground and the teeth closed in maximum intercuspation. All the examinations respected the ALARA principle (As Low As Reasonably Achievable).The primary outcome was the assessment of the antero-posterior position of mandibular condyles (MC) within the GF post therapy. The patients with TMD were treated with occlusal splints in conjunction with cranio-temporomandibular kinesiotherapy. The secondary outcomes were to evaluate the changes within the distance between the MC and the medial wall of the GF, the glenoid fossa thickness (GFT), the condylar mediolateral width (MLW), and the condylar height (HCo).Sagittal and coronal slices were used on reconstructed CBCT to measure the intra-articular spaces before and after therapy.The images were analyzed with OnDemand3DViewer version 1.0 , by two experienced examiners  trained to perform TMJ linear measurements on the oblique sagittal and coronal reformatted images. All measurements were performed twice with a two-week washout interval, with images being randomly analyzed without access to previous measurements.The examiners chose the axial view with the largest mediolateral dimension of the condylar head. Next, a sagittal slice crossing in the middle of the distance between the most prominent points on medial and lateral mandibular condylar poles, and perpendicular to the coronal axis, was selected .All measurements were performed on the oblique sagittal and coronal reformatted images. The following data were recorded for both TMJs, before and after occlusal splint therapy: anterior joint space (AJS), superior joint space (SJS), posterior joint space (PJS), medial joint space (MJS), condylar medio-lateral width (MLW), glenoid fossae thickness (GFT), and condylar height (HCo) A–D.The assessment of antero-posterior position of the MC within the GF was performed using Pullinger and Hollender’s formula : CondylaThe interpretation of Pullinger and Hollender’s formula according to literature is presented in Based on the condylar ratio changes, the treatment efficacy was assessed. Five percent or more condylar ratio changes were arbitrarily accepted as successful results. A decrease of condylar ratio of 5% or more was considered a negative result. Changes in the condylar ratio of less than 5%, whether they were positive or negative, were considered neutral results according to Derwich et al. .∆ Condt-test , Wilcoxon’s signed rank test , and Stuart-Maxwell . To assess intra-observer reliability, the interclass correlation coefficient was computed, along with a 95% confidence interval. The statistical significance level was set at p ≤ 0.05. For all the statistical tests we used two-tailed p values.The software used for statistical analysis was R environment for statistical computing and graphics , version 4.1.2 . The folThere were 24 patients diagnosed with TMD included in this study. All the participants (22 women and two men) completed the protocol of treatment. The average age of the participants was 23.88 ± 4.66 years old, with a range between 18 and 33 years old. The main sign was pain in palpation : muscle pain, joint pain or both. Out of the above mentioned 21 patients, 14 patients  had associated arthralgia and myalgia pain in palpation. From those 14 patients, eight patients presented disk displacement with reduction  and one subject presented disk displacement without reduction and crepitus . Additionally, four subjects  had arthralgia in palpation alone, and it was associated with disk displacement with reduction in all subjects . Three subjects  had myalgia in palpation alone, and only one subject presented disk displacement with reduction . Additionally, three patients showed no signs of muscle or joint discomfort, although disk displacement with reduction was found . The main signs and symptoms for the study group are presented in The average number for occlusal splint adjustments was 8.83 times +/− 2.51 with a range between 4 and 14 times. The median time of wearing the occlusal splint was 7 months with an interquartile range between 4.75–10 months. The median kinesiotherapy appointments were 8.5 times with an interquartile range between 6–12.25 times.Using intraclass-interclass correlation coefficients (ICC) with 95% confidence intervals, Intra-observer reliability for each individual measurement had a range between 0.924 (95% CI: 0.821–0.969) and 0.974 (95% CI: 0.936–0.99). Inter-observer reliability for each individual measurement had a range between 0.826 (95% CI: 0.747–0.881) and 0.981 (95% CI: 0.966–0.989).Pre- and post-therapy, there were no statistically significant changes in the dimensions of anterior, posterior, superior and medial joint spaces.p = 0.049).Post-therapy, the condylar ratio’s average value increased in a statistically significant manner , mediolateral width (MLW) and condylar height (HCo).t-test results.p = 0.649).Prior to treatment, 24 TMJs were in a posterior position, 18 TMJs were in a central position, and 6 TMJs were in an anterior position within the GF. Post-treatment, 21 TMJs remained posteriorly positioned, 19 TMJs were in a central position and 8 TMJs were in an anterior position. The number of condyles anteriorly positioned increased from 6 (12.5%) to 8 (16.6%). However, the condylar sagittal position pre- and post-treatment had not changed in a statistically significant manner  and magnetic resonance imaging (MRI) . HoweverOcclusal splint therapy combined with cranio-temporomandibular kinesiotherapy appeared to be effective in pain reduction for TMD patients. Similar results were found by Derwich et al.  in a proIn order to evaluate the antero-posterior position of MC within the GF post-treatment, the anterior, posterior and superior joint spaces were measured on oblique sagittal reformatted images. After treatment, we did not find significant changes in the anterior, posterior, and superior joint spaces in patients with TMD. Furthermore, no significant changes were found in the dimension of the medial joint spaces on the coronal CBCT images. Similar results were found by Derwich et al. , even ifThe efficacy of occlusal splint therapy combined with kinesiotherapy was assessed based on ∆condylar ratio. According to Derwich et al. , an arbiMoreover, asymmetrical TMJ changes were observed in nine patients (37.5%): five patients had an increase in the condylar ratio on the right side and a decrease in the condylar ratio on the left side, respectively, and four subjects had an increase in the condylar ratio on the left side and a decrease in the condylar ratio on the right side. These asymmetrical changes might be correlated with the heterogeneous group of pathologies affecting TMJ, the masticator muscles, or both in TMD patients . Howeverp = 0.049). The condylar ratio increased from an average value of −11.38 to −5.72. Even the difference was statistically significant; both values corresponded to a concentric condylar position, with a tendency, however, to slide anteriorly. The same results were observed by Derwich et al. [p = 0.649).Based on Pullinger and Hollender’s formula , the conh et al. . This foh et al. , before In order to assess osseous structural changes (condylar bone and GF), the thickness of glenoid fossa, the condylar height, and the condyle medio-lateral width all were measured before and after treatment. We did not find any significant changes in the above-mentioned structures. It can be hypothesized that the occlusal splint therapy produced neither condylar remodeling, nor additional degenerative bone changes. A CBCT study in a case–control design found that degenerative bone changes occurred in the subarticular surfaces of the condyle and fossa during TMJ disorders . In our A few limitations of this study can be listed. Firstly, the number of participants included in this study was limited. Multicenter studies based on larger groups of patients would be valuable. Moreover, there was no a priori sample size computation for this study. The study group gender ratio  represented another limitation. According to a meta-analysis conducted by Bueno et al. , the preThe protocol of therapy involved the usage of the occlusal splint continuously, as we had observed that wearing time was correlated with effectiveness of the occlusal splint ,10.Even though the currently accepted definition of centric relation in which “condyles articulate in the anterior-superior position against the posterior slopes of the articular eminences” , the finFurther studies should focus on assessing other potential factors in the etiology and treatment of TMD, such as disk positioning, retro discal tissue and cervical spine pathology.Occlusal splints therapy combined with cranio-temporomandibular kinesiotherapy in patients with TMD do not change the dimensions of anterior, superior, posterior, and medial TMJ spaces. The sagittal position of the condyle does not change into an anterior-superior position against the posterior slope of articular eminence after treatment. Successful results in terms of pain resolution in TMD patients do not appear to require central condylar positioning.


Bone-modifying agents (BMA) such as bisphosphonates and denosumab are frequently used for the treatment of bone metastases, osteoporosis, and multiple myeloma. BMA may lead to anti-resorptive agent-related osteonecrosis of the jaw (ARONJ). This study aimed to clarify the risk factors for and probabilities of developing ARONJ after tooth extraction in patients undergoing BMA therapy. In this study, the records of 505 target sites of 302 patients undergoing BMA who presented with mandibular fractures at the Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, from March 2014 to January 2022, were retrospectively analyzed for the onset of ARONJ after tooth extraction. The following variables were investigated as attributes: anatomy, health status, and dental treatment. The correlation coefficient was calculated for the success or failure of endodontic surgery for each variable, the odds ratio was calculated for the upper variable, and the factors related to the onset of ARONJ were identified. The incidence rate of ARONJ was found to be 3.2%. Hypoparathyroidism was an important factor associated with ARONJ development. Thus, systemic factors are more strongly related to the onset of ARONJ after tooth extraction than local factors. Bone-modifying agents (BMA) such as bisphosphonates (BP) and denosumab (DMAb) are used to prevent osteoporotic fractures, bone metastases, and bone-related events in multiple myeloma. However, since the first case of BP-related osteonecrosis of the jaw was described by Marx in 2003 , cases oIn Japan, a position paper was published in 2016 by six related academic societies , which identified several known risk factors for the onset of ARONJ . FactorsThe purpose of this study was to clarify the risk factors and probability of developing ARONJ after tooth extraction in patients undergoing BMA.A retrospective clinical study was conducted on the incidence and risk factors of osteonecrosis of the jaw in patients who underwent tooth extraction at the Oral and Maxillofacial Surgery Department of Kagawa Prefectural Central Hospital between March 2014 and January 2022.This study was approved by the Institutional Review Committee of Kagawa Prefectural Central Hospital . Informed consent was obtained from all patients in this study. All data were anonymized and analyzed.The following criteria were used to select target patient cases: among patients taking BMAs, including BP and DMAb, an antibody-targeting receptor activator of nuclear factor kappa-b ligand (RANKL) therapy, those who had “hopeless” teeth, a good general condition, and a sufficient prognosis for life were included. All tooth extractions were performed under local anesthesia with the consent of the patient.Exclusion criteria were patients who had consented to surgery other than tooth extraction, such as dental implant placement surgery and bone ridge resection, patients who could not be followed up for 1 month or more, and those who had a history or ongoing radiation treatment in the facial area.According to the above criteria, 302 patients (505 tooth extraction sites) with BMAs were treated during the study period.All tooth extraction procedures were performed under local anesthesia, with or without intravenous sedation. A single surgical team of seven, under the guidance of two professional oral and maxillofacial surgeons (YF and SS), performed tooth extractions. In all cases, 4–0 absorbent silk was used for sutures, and the sutures were removed 10–14 days after surgery  The postoperative clinical management was performed in routine care. Patients received antibiotics  for 2 days postoperatively, as well as non-steroidal anti-inflammatory drugs .The resulting variable was the incidence of ARONJ after tooth extraction. ARONJ was diagnosed according to the contents of the position paper  of the AThe predictor variables for this study consisted of sets of exposures considered to be convincingly related to ARONJ and were classified as attribute, anatomical, health status, and dental treatment variables. Attribute variables included age and sex. Health status variables included body mass index (BMI), height, weight, alcohol consumption, smoking, anemia, diabetes, hypocalcemia, hemodialysis, hypoparathyroidism, hyperthyroidism, rheumatoid arthritis, steroid intake, molecular-targeted drugs, hormone therapy, chemotherapy, radiotherapy, malignant tumor, breast cancer, lung cancer, prostate cancer, colorectal cancer, and multimyeloma. Anemia was defined as hemoglobin levels <12 g/dL for women and <13 g/dL for men, according to the World Health Organization guidelines . Diabetep-value < 0.05. Any association in bivariate analyses (p < 0.05) was included in a multiple logistic regression analysis, which was subsequently used to provide adjusted odds ratios (ORs) to control the simultaneous effects of multiple covariates. Statistical significance was set at p < 0.05.Data were recorded in an electronic database throughout the study using Microsoft Excel . For statistical analysis, the digital database used was JMP version 14.2.0 for Macintosh . Categorical variables are presented as numbers and percentages, while continuous variables are presented as mean and standard deviation (SD). For the two-group comparison, we used the Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Statistical significance was set at a two-tailed The correlation coefficient is a measure of the strength of the linear relationship between two data points or a random variable. In the range of 0 to 1, the onset rate of ARONJ increases with the increasing index. Conversely, in the range of 0 to −1, as the index decreases, the likelihood of ARONJ occurrence decreases. Thus, the correlation coefficient chart was plotted according to the variable data based on the number of occurrences of ARONJ. Further, an algorithm for calculating statistical properties was implemented in Python (version 3.7.13) using NumPy (version 1.21.5) and the Pandas library (version 1.3.5).p < 0.05) included age (p = 0.004) for demographic variables, hypoparathyroidism (p <0.001), hormone therapy (p = 0.002), chemotherapy (p <0.001), radiotherapy (p <0.001), and breast cancer (p = 0.01) for health status variables.When examining the correlation coefficient accounting for the prognosis of ONJ onset after tooth extraction, the top five factors were hypoparathyroidism, chemotherapy, radiotherapy, hormone therapy, and age . Among tFor further statistical exploration, we used a multivariate logistic regression model for the occurrence of ONJ after tooth extraction, using significant variables in the bivariate analysis and variables with higher correlation coefficients. The selected items were hypoparathyroidism, chemotherapy, radiotherapy, hormone therapy, and age .In multivariate logistic regression analysis, hypoparathyroidism was a significant factor in the onset of ONJ. Chemotherapy showed a high OR for the extracted variables (OR = 3.617). It was also suggested that hypoparathyroidism is most involved in the onset of ONJ. However, it was difficult to properly calculate the OR because ONJ occurred in almost all patients with hypoparathyroidism.This retrospective study investigated the prevalence of and risk factors for ARONJ. The incidence of ARONJ in the present study was 3.2%, while the reported incidence of ARONJ is 17.8%, which is higher than the estimated value of 0.001–0.01%  reportedThe risk of ARONJ onset in hypoparathyroidism has not yet been explored. Hypoparathyroidism is an endocrine disorder in which parathyroid hormone (PTH) production is abnormally low or absent . It is aIn addition, breast cancer had a high correlation with ARONJ; however, in patients with metastases, intravenous BPs or RANKL inhibitors were used, which reduced bone metabolism and turnover and resulted in ARONJ. The risk was therefore considered to be high in such cases. Moreover, radiation therapy to organs other than the jawbone is often administered to such cancer patients, and the risk factors are thus inevitably increased. Chemotherapy, such as BMA, suppresses bone metabolism and causes immune changes; hence, it is also considered a risk factor for ARONJ ,15,16. TRegarding the BMA drug holiday and administration period, the AAOMS position paper (2014) advocates a 2-month drug holiday given the risk of ARONJ in those treated with BP for 4 years or more . HoweverWe used the correlation coefficient as a statistical tool to identify the risk factors responsible for the onset of ARONJ due to tooth extraction. Although most ranks of the correlation coefficient were similar to those of odds ratios obtained by multivariate analysis, some ranks were distinct. The correlation coefficient is an ordinal scale, and it is not possible to compare the strengths of causality. Therefore, it is necessary to identify risk factors using odds ratios by multivariate analysis. The advantage of calculating the correlation coefficient is that one can quickly and visually evaluate the correlation between two factors . Our stuThis retrospective study has two limitations. The first limitation is that the sample composition is biased. Since there are many referrals of patients with ARONJ to our department, the incidence of bone resorption inhibitor-related osteonecrosis of the jaw is higher than the value estimated by the International Task Force on Osteonecrosis of the Jaw. Therefore, future studies with a larger number of cases are necessary. Second, we could not confirm the treatment for comorbidities without treatment at our hospital. Therefore, confirmation of the treatment of comorbidities may be necessary for more accurate estimates in future studies. Despite the above limitations, to the best of our knowledge, multifactorial factors such as comorbidities and associated treatments were detected as risk factors for ARONJ in this study. In the future, for patients with comorbid diseases that are risk factors, active dental intervention should be performed on teeth that are the source of infection before BMA administration.This retrospective study investigated the prevalence and risk factors for ARONJ after tooth extraction. The incidence of ARONJ was 3.2%, and we found that hypoparathyroidism was a strong risk factor for ARONJ after tooth extraction. Thus, systemic factors are more strongly related to the onset of ARONJ after tooth extraction than local factors.


Background: The present study aimed to assess the determinants of arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2) in the early phase of veno-arterial extracorporeal membrane oxygenation (VA ECMO) support. Even though the guidelines considered both the risks of hypoxemia and hyperoxemia during ECMO support, there are a lack of data concerning the patients supported by VA ECMO. Methods: This is a retrospective, monocentric, observational cohort study in a university-affiliated cardiac intensive care unit. Hemodynamic parameters, ECMO parameters, ventilator settings, and blood gas analyses were collected at several time points during the first 48 h of VA ECMO support. For each timepoint, the blood samples were drawn simultaneously from the right radial artery catheter, VA ECMO venous line (before the oxygenator), and from VA ECMO arterial line (after the oxygenator). Univariate followed by multivariate mixed-model analyses were performed for longitudinal data analyses. Results: Forty-five patients with femoro-femoral peripheral VA ECMO were included. In multivariate analysis, the patients’ PaO2 was independently associated with QEC, FDO2, and time of measurement. The patients’ PaCO2 was associated with the sweep rate flow and the PpreCO2. Conclusions: During acute VA ECMO support, the main determinants of patient oxygenation are determined by VA ECMO parameters. The use of veno-arterial extracorporeal membrane oxygenation (VA ECMO) has improved refractory cardiogenic shock mortality ,2. VA EC2 and PaCO2) have never been evaluated in patients on VA ECMO support. Several studies have evaluated the determinants of oxygenation and carbon dioxide clearance in the setting of veno-venous ECMO (VV ECMO), as it is used for respiratory indications [Firstly, the determinants of patient’s blood gases . A clear answer is difficult, considering that the maintaining of an optimal equilibrium between VA ECMO and the patient’s native heart and lung function is challenging, according to the medical conditions evolution and illness phase [Secondly, this hemodynamic phenomenon brings into question whether the oxygenated VA ECMO flow can reach the proximal aortic arch during the first hours of support, altering the difference between the Pss phase .postO2 value of 150 mmHg to counterbalance the risk of hyperoxemia and to minimize the risk of hypoxemia [postO2 cutoff value of 150 mmHg proposed by ELSO guidelines can prevent hyperoxemia or hypoxemia.Recently, the Extracorporeal Life Support Organization (ELSO) published guidelines that consider the risks of both hypoxemia and hyperoxemia during ECMO support . The ELSypoxemia . In the 2 and PaCO2) and determinants of and delta-PaO2 in patients supported by VA ECMO. The secondary aim was to evaluate the concordance with the actual ELSO guidelines.The present study was designed to assess the determinants of blood gases . Because all data were collected retrospectively from the standard medical chart, this study was not considered as involving human participants (according to French law). Nevertheless, this study was approved by the institutional review board . Inclusion criteria were: (i) patients supported by peripheral femoro-femoral VA ECMO, (ii) right radial arterial cannula, and (iii) available pre/post membrane blood gas measurements. We excluded (i) pediatric patients and (ii) patients with femoral arterial catheter for invasive blood pressure monitoring. The patients with femoral arterial catheter for invasive blood pressure monitoring were excluded in order to have a homogenous cohort with the same site for arterial blood measurements.EC) is gradually increased until it corresponds to a cardiac index above 2.5 L min−1 m−2. Then, QEC is adapted to blood pressure, arterial lactate clearance, echocardiographic parameters, native heart function, and arterio-venous CO2 difference [EC, and then adjusted according to blood gases. All patients were mechanically ventilated during the study period. Patients were ventilated in the controlled volume mode with tidal volume of 5 to 8 mL kg−1 , respiratory rate between 5 and 12 respiratory rate per minute, and positive end-expiratory pressure (PEEP) between 5 and 12 cm H2O, in order to obtain plateau pressure below 25 cm H2O. All patients were continuously administered unfractionated heparin 4 h after VA ECMO initiation. The heparin dose was adjusted at least twice daily according to heparinemia, targeting an anti-factor Xa activity between 0.15 and 0.3 UI mL−1. Packed red blood cells were transfused to maintain hemoglobin level between 8 and 10 g dL−1.All patients underwent femoro-femoral peripheral VA ECMO. The indications, protocols for implementation, VA ECMO management, and patient management have been described elsewhere ,18,19. Bfference . The fraDO2), sweep flow rate), ventilator settings , vasopressor and inotropic therapy, blood gas analysis, ICU length of stay, hospital length of stay, and death. Blood gas analysis was noted at baseline (immediately after ECMO initiation), and at 12 h, 24 h, and 48 h after the initiation of VA ECMO support. For each time point, the blood samples were drawn simultaneously from the radial artery catheter, from the VA ECMO venous line (before the oxygenator), and from the VA ECMO arterial line (after the oxygenator). The arterial line pulsatility was defined as a pulse pressure ≥ 20 mmHg [postO2 and radial artery partial pressure (delta-PaO2) as the absolute difference between PpostO2 and patient’s radial artery PaO2.All of the data were collected from the patient medical charts. These included demographic data, comorbidities, medical aetiology, circulatory parameters , VA ECMO parameters , or as means ± standard deviation (SD), as appropriate. Categorical variables were expressed as numbers (percentage).2, PaCO2, and delta-PaO2 were evaluated using a mixed effects generalized linear model approach. A random “subject” effect was used in these longitudinal analyses. Firstly, each of the collected variables of interest was introduced as fixed effect variable in a univariate mixed effect model with patient artery measured PaO2, PaCO2, or delta-PaO2, as dependent variables. Secondly, the statistically significant and clinically pertinent variables in univariate analysis were included in multivariate mixed effects generalized linear model models with patient artery measured PaO2, PaCO2, or delta-PaO2, as dependent variables.The determinants of PaO2, because the ELSO experts recommend having a PpostO2 value of 150 mmHg and did not provide any cut-off value for post-membrane PCO2. Based on the PpostO2 the determinations were classified as ELSO concordant (<150 mmHg) or not. Furthermore, the patients’ PaO2 right radial artery determinations were classified as hyperoxemic (>120 mmHg) or as hypoxemic (<70 mmHg). The association the ELSO concordance (yes/no), hyperoxemia (yes/no), or hypoxemia (yes/no) was evaluated using an exploratory logistical regression model.The concordance with ELSO guidelines was evaluated based on the blood determinations of post-membrane POp < 0.05.The statistical analyses were performed using RStudio . The threshold for statistical significance was set at The patients’ characteristics are shown in Forty-five patients were included in the study analyses. The mean age was 59 ± 12 years, and they were mostly male (77%), with a baseline SOFA score of 13 ± 2. The main indications for VA ECMO support were cardiopulmonary resuscitation (CPR), post-acute myocardial infarction cardiogenic shock, and post-cardiotomy cardiogenic shock. The description of patients’ hemodynamic and respiratory characteristics at each timepoint of the study is presented in 2 was associated with the ventilator FiO2, QEC, sweep rate, FDO2, pre-ECMO-membrane pH and post-ECMO-membrane pH, PaO2, and HCO3. The multivariate analysis demonstrated that QEC, the FDO2, and the time point of the measurement were the only variables independently associated with patient PaO2 , according to the recent ELSO recommendations. Of these 59 determinations, 22 (37%) had a radial artery PaO2 over 120 mmHg (hyperoxemia) and 14 (24%) a radial artery PaO2 lower than 70 mmHg (hypoxemia).Fifty-nine (33%) blood determinations of Pp < 0.001), but it was also associated with a risk of patient hypoxemia .In all cohort, the concordance with ELSO guidelines was protective of patient hyperoxemia  the ventilator parameters had no significant clinical effect on oxygenation or CO2 removal during the acute phase of VA ECMO support, (iii) a patient’s pulsatile arterial flow pattern was associated with higher delta-PaO2, and (iv) maintaining a PpostO2 lower than 150 mmHg can be associated with an increased risk of hypoxemia.Our findings can be summarized as following: (i) VA ECMO settings were the main contributor to patient oxygenation and CODO2, sweep flow rate), are the main determinants of patients’ PaO2. These results are similar to those demonstrated in VV ECMO, where patients’ oxygenation was dependent on the ratio between VV ECMO QEC and patient cardiac output, and VV ECMO oxygenation parameters [2 might also suggest that the so-called oxygenshed phenomenon is not a very significant concern in the acute phase [EC which was high, thus maintaining oxygen delivery [Our study demonstrated that VA ECMO oxygenation parameters, and particularly ECMO membrane oxygenation parameters  between the ECMO PpostO2 and the patient’s PaO2 was influenced by ECMO FDO2 and arterial pulsatility. These results emphasize the main role of ECMO parameters, and particularly the residual cardiac function of the patient. A low pulse pressure during VA reflects a low native cardiac output [EC), particularly in the case of the commonly used peripheral femoro-femoral cannulation [2 measured from the radial artery is a sensitive tool that is readily available at bedside to detect oxygenation imbalance [The gradient of oxygenation  could provide information on competing flow. In addition, most patients supported by VA ECMO undergo early extubation [This approach becomes even more important during the weaning process, where the decrease in Qerfusion . In thistubation . In this2 removal, and clinical outcomes has been demonstrated [The study is limited by its retrospective, observational, exploratory design, and causality cannot be inferred. Considering the high complexity of the ICU clinical situations requiring VA ECMO support, our study design is limited. We included only patients on femoro-femoral VA ECMO. Some important cardio-respiratory parameters were not available for the analysis, such as the native cardiac output for all patients or the native respiratory function and pulmonary shunt . Furthernstrated ,40.EC and FDO2 are associated with patient oxygenation, whereas sweep gas flow and PpreCO2 are associated with PaCO2. Further studies in patients with varying QEC and during the weaning process may lead to a better understanding of the interactions between QEC and native flow.During the early VA ECMO support, the main determinants of patients’ oxygenation and carbon dioxide removal are the parameters the VA ECMO. Q


Blood pressure (BP) control rates among adult patients taking antihypertensive medications in the United States have not improved over the last decade. Many CKD adults require more than one class of antihypertensive agent to reach the BP target recommended by the guidelines. However, no study has quantified the proportion of adult CKD patients taking antihypertensive medication who are on monotherapy or combination therapy.n = 4,453). BP control rates were investigated under the BP targets recommended by the 2021 KDIGO, the 2012 KDIGO, and the 2017 ACC/AHA guidelines.National Health and Nutrition Examination Survey data during 2001-2018 was used, including adults with CKD taking antihypertensive medication (age ≥ 20 years, The percentages of uncontrolled BP among US adults with CKD taking antihypertensive medication were 81.4% in 2001-2006 and 78.2% in 2013-2018. The proportion of monotherapy of antihypertensive regimen were 38.6, 33.3, and 34.6% from 2001 to 2006, 2007-2012, and 2013-2018, with no obvious difference. Similarly, there was no significant change in percentages of dual-therapy, triple-therapy, and quadruple-therapy. Although proportion of CKD adults not treated with ACEi/ARB decreased from 43.5% in 2001-2006 to 32.7% in 2013-2018, treatment of ACEi/ARB among patients with ACR > 300 mg/g had no significant change.The BP control rates among US adult CKD patients taking antihypertensive medications have not improved from 2001 to 2018. Mono-therapy accounted for about one third of adult CKD patients taking antihypertensive medication and not changed. Increasing antihypertensive medication combination therapy may help improve BP control in CKD adults in the United States. The Systolic blood pressure (SBP) of < 120 mmHg reduced cardiovascular disease (CVD) risk by 25% and all-cause mortality by 27% when compared with SBP < 140 mmHg in participants with and without CKD in the Systolic Blood Pressure Intervention Trial (SPRINT) .The proportion of US adults with hypertension taking antihypertensive medication increased to 80.5% in 2015-2018 , 5. HoweAngiotensin-converting enzyme inhibitors (ACEi) or Angiotensin II-receptor blockers (ARB) were recommended by 2021, 2012 KDIGO guidelines and 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline for CKD patients with BP above the target , 8, 9. TSeveral previous studies have evaluated trends in antihypertensive agent use among US adults with CKD , 11. Moshttps://wwwn.cdc.gov/nchs/nhanes/default.aspx). NHANES uses a stratified, multi-stage probabilistic sampling approach to select participants. Consequently, the results can be used to estimate the health and nutrition status of the civilian, non-institutionalized population in the US. The survey in NHANES is cross-sectional and has been conducted in every two-year cycle. Therefore, we pooled data from 2001-2018, and grouped it into three separate groups: 2001-2006, 2007-2012, and 2013-2018.NHANES is a population-based survey conducted by the National Center for Health Statistics of the US Centers for Disease Control and Prevention (CDC), and the data used in this study were downloaded from the National Center for Health Statistics  ≥ 30 mg/g, and the serum creatine and urinary albumin and creatinine were from NHANES single measurement. For our analytic population, we included participants who had eGFR < 60 ml/min/1.73 m2, or those who had eGFR ≥ 60 ml/min/1.73 m2 and ACR ≥ 30 mg/g . We excluded 2,642 who were less than 20 years old or were pregnant. There were 7,163 participants have completed three times SBP and DBP measurements, and answered: “yes” to “Have you ever been told by a doctor that you had hypertension, also called high BP?”  were excluded. The final sample for the current analysis consisted of 4,453 participants with complete information on eGFR and three times blood pressure measurements, self-reported hypertension, and antihypertensive medication information   and clinical characteristics eGFR categories  , ACR catWe also calculated the proportions of antihypertensive agent use among adult CKD individuals with controlled and uncontrolled BP based on the 2021 KDIGO guideline. Furthermore, according to the 2021 KDIGO, 2012 KDIGO, and 2017 ACC/AHA BP guidelines, we estimated the proportions of adults with CKD using each antihypertensive agent and combinations of classes in uncontrolled BP groups. The distribution of antihypertensive medication classes in CKD G1/2 and G3, ACR < 30 mg/g and ACR ≥ 30 mg/g, CKD with or without diabetes, age 60-74 and ≥ 75 years old, and Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) were also analyzed. All analyses were conducted based on NHANES survey weights, strata, and complex sampling design units. R version 4.1.3  was used in all analyses, and p < 0.05 were accepted as statistically significant.2) taking antihypertensive medication had increased from 31.2% in 2001-2006 to 41.47% in 2013-2018, and the proportion decreased in CKD G3 (30 ≤ eGFR < 59 mL/min/1.73m2) and groups, while the proportion had not changed in CKD G4/5 from 2001-2018 . The diuretic with CCB or BB had slightly decreased. The triple-therapy regimen of an ACEi/ARB combined with CCB and BB increased from 1.3% to 3.8% (P < 0.001).The most commonly used hypertensive medication was ACEi/ARB, which increased in adult CKD G1/2 or G3, in CKD adults with ACR ≤ 300 mg/g, in CKD adults with or without diabetes, in CKD adults aged 60-74 or older than 75 years, in NHW or NHB adult CKD, from 2001-2006 through 2013-2018. The use of diuretics significantly decreased in adult CKD G3-G5, in CKD adults with ACR ≤ 300 mg/g, in CKD adults with or without diabetes, in CKD adults aged more than 75 years, and in NHW CKD adults. BB increased in CKD adults aged more than 75 years, and in NHW or NHB CKD adults –6.Between 2001-2006 and 2013-2018, there was no apparent difference in the proportion of monotherapy, dual-therapy, triple therapy, quadruple therapy or more antihypertensive medication combination among US adult CKD patients with uncontrolled BP based on the 2021 KDIGO , the 201We also compared the proportion of antihypertensive agents taken among CKD adults between BP controlled and uncontrolled groups (based on 2021 KDIGO). As presented in Resistant hypertension is defined as above BP target despite 3 or more antihypertensive agents, including a diuretic, administered at maximally tolerated doses and appropriate dosing frequency . In thispost hoc analysis showed that the intensive SBP control reduced CVD events and mortality independent of albuminuria  was associated with a reduction of CVD and all-cause mortality risk for patients with and without CKD 20 mmHg w. The SPRuminuria . Anotheruminuria . The extuminuria . Based ouminuria . HoweverThere were several gaps in the antihypertensive medication regimen between practice patterns and clinical practice guideline recommendations for adult CKD patients. For example, this analysis showed that about one-third of US adults with CKD take a single antihypertensive regimen class, even those with uncontrolled blood pressure. In addition, it has been demonstrated that monotherapy has less BP-lowering ability than dual-therapy and triple-therapy regimens –26. In lThe 2003 JNC 7 guideline recommended ACEi/ARB treatment for adults with urine ACR ≥ 300 mg/g . The 201Both 2017 ACC/AHA and 2018 ESC-ESH guidelines recommended ACEi/ARB, CCB, and thiazide or thiazide-like diuretics as first-line antihypertensive agents . The patients/participants provided their written informed consent to participate in this study.FL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. DZ contributed to the concept and design. FL and AS drafted the manuscript and performed the administrative, technical, or material support. ZZ and DZ contributed to the critical revision of the manuscript for important intellectual content and performed the supervision. FL, AS, and FW performed the statistical analysis. All authors have data acquisition, analysis, or interpretation of data.


A complete echocardiographic examination was available in all athletes.In general, only few studies are dedicated to blood pressure behavior under physical stress in children and adolescents. Even less is published about the blood pressure behavior of young high-performance athletes on the ergometer. For this reason, we evaluated the blood pressure behavior under stress compared to non-athletes in a large collective (Regardless of gender, the young competitive athletes achieved significantly higher maximum blood pressure values than investastigated populations from previous studies. Based on the data obtained, blood pressure percentiles are now defined explicitly for junior athletes across sports as well as age- and gender-dependent, which did not exist in this form of normal values for the special clientele of young competitive athletes. The echocardiographic examinations demonstrated stress-induced cardiac adaptation adaptations in the majority of athletes, which thus correlate with the comparatively higher stress blood pressures compared to non-athletes.For the first time, blood pressure percentiles for exercise tests on the ergometer for age groups and gender in high performance athletes are defined based on a comparatively large collective of young competitive athletes. Upper limits were determined, in particular for systolic blood pressure under stress, and categorized according to gender and age. Performance diagnosticians and physicians are now enabled to make a more accurate assessment of the corresponding blood pressure regulation of young athletes under exercise conditions. Description of normative response to physical exercise in healthy children and adolescents in terms of percentiles was just recently given by Sasaki et al. and Clark and al. In the study by Clarke and collegues normative percentiles of blood pressure response on a treadmill for healthy children and adolescents were described  in Leipzig, mainly high-performance athletes, from different sports, are seen mostly for preparticipation screenings. A retrospective analysis of our database from 2010 to 2019 for exercise testing on a bicycle ergometer identified 4,899 athletes. After excluding athletes with an age of >20 years, 2,217 datasets remained. Since the exercise-induced blood pressure regulation was intended to be analyzed in contrast with echocardiographic findings, only exercise tests of athletes were included who had a complete echocardiographic examination within the same year. After data adjustments for doublings, 739 datasets of young athletes remained. Since most of the echocardiographic studies were performed on the day of exercise testing or within a few weeks relevant breaks from sport after injury or illness between exercise testing and echocardiography can ruled out in general. All athletes were highly trained elite athletes of their sports and members of the national team squad according to their age. Non of the tested pupils suffered from any kind of cardiovascular desease nor took any kind of medication that might have an effect on the intrinsic blood pressure reactionHeight and weight were measured using a scale with integrated straightedge , and body mass index (BMI) was calculated by dividing weight in kilograms through the square of height in meters. Body fat was determined by skinfold thickness using the ten-fold model introduced by Parizkova . Fat perTests were performed on cycle ergometers . The standard protocol for all females started with an initial workload of 50 Watt (W), increment 30 W; stage duration was 3 min. Only petite and lightweight girls started with an initial workload of 25 W. The initial workload for all male athletes was 100 W . Boys of little height or weight (<50 kg) could also be tested with the girl's protocol. The supervising physician decided the test protocol. All tests were supervised by experienced staff and were performed until subjective exhaustion. All participants were motivated to reach their maximal limits of work capacity by oral motivation. Sine all participants were experienced athletes, all participants were familiar with voluntary maximal exhaustion. Heart rates and BP were measured at the end of each stage, including maximal SBP and DBP . Heart rates were obtained automatically from 12-channel ECG  but were verified and corrected (if necessary) manually afterward. BP was measured manually using standard sphygmomanometers adjusted to the individual's arm circumference.Experienced echocardiographers performed two-dimensional echocardiography according to guidelines of the german society of cardiology valid for the study period . From 2010 to 2014, Philips IE 33 system  and after 2014 a Philips Epiq, both with a 3.5 MHz transducer. Left atrial diameters (anteroposterior) were assessed from either B-mode or M-mode parasternal long-axis views. LV end-diastolic diameter and septal wall thickness were measured in the parasternal long-axis at the level of the LV minor axis, approximately at the mitral valve leaflet tips. The absolute and relative mass of the heart was calculated using the formula established by  Pulsed DThe classification of sports by Schnabel and Thieß  subdividThe data obtained from the stress tests and echocardiographic examinations were processed in Microsoft Office Excel 2016 for Windows from Microsoft Corporation  and statistically calculated using IBM SPSS Statistics 25.r|. According to Cohen Guidelines (1988) data was interpreted as: |r| = 0.10 a weak |r| = 0.30 a moderate |r| = 0.50 describe a strong correlation. Associations of variables were analyzed using Pearson's correlation coefficients. Normative ranges were defined as the central 95% of all observations, and lower and upper limits were estimated assuming normality as means 2-fold SD. Additionally, 95% confidence intervals for limits of normative ranges are presented in squared brackets .Except for age, all data fulfilled criteria for normal statistical distribution as verified by previous authors  thus conn = 739 athletes  with a median age of 15.8 years  were analyzed. There was no significant difference in age and duration of training years between male and female athletes. The demographic and clinical characteristics of this population are summarized in A total of p < 0.001). The diameter of the left atrium 3.42 ± 0.43 (♂), bzw. 3.2 ± 0.41 cm (♀) was within the standard range. The values of male athletes were significantly higher than those of female athletes . The differences between the sexes in the left ventricular diameter's values during the diastole (LVEDD) and the interventricular septum thickness were significantly different, too (both with p.001). All subjects were in the standard range with their respective values. All relevant echocardiographid data are presented in relation to athletes age and sex in An overview of the echocardiographic data is shown in p < 0.001 for both sexes). whereas DBP remained almost unchanged in femal and male athletes. Male athletes absolved more exercise stages, started with a higher workload, attained higher peak workloads, and showed a more pronounced SBP response than female athletesIn the cohort of 10–12 year old junior athletes, the SBP at maximal effort was 159 mmHg (±18 mmHg). In the progression of the age of the athletes, the SBP increased continuously. 13–15 year old athletes had an average SBP of 182 ± 20 mmHg, 16–17 year old athletes 192 ± 20 mmHg, and 18–20 year old athletes 196 ± 22 mmHg. There was a significant difference between male and female athletes in which male athletes gained higher values. Within the different age cohorts, the SBP was also significantly different between sexes. see F = 11.823, p < 0.001). The post-hoc comparison of the categories of these significant differences between the lowest training frequency of 1–5 h/week and 6–10 h/week  = 4.850, p = 0.001). The highest mSBP values were observed in the sprint/ strength athletes with an average value of 190 (±23) mmHg. The lowest values were recorded by athletes from technical-acrobatic sports with an average mSBP value of 178 (±21) mmHg. Significant differences were found in the maximum systolic blood pressure values between the technical-acrobatic and endurance sports  in technical-acrobatic sports, double-fight, endurance, sprint power/strength and game sports. The maximum systolic blood pressure values differed significantly in terms of the respective sports (r = 0.171). The thicker the interventricular septum during the junior athletes' diastole, the higher the systolic rest values were (r = 0.323). The effect can be interpreted as moderate. If one combines above two echo parameter with the maximum systolic blood pressure value, the effect (r = 0.490) strengthens and indicates that the higher the echocardiographic diameters, the higher the mSBD values during the load.The Pearson correlation coefficient shows a moderate positive correlation between the relative heart volume (g/kg BM) and the mSBD  = 27.552, p.001 effect strength high (η2 = 0.101) . It is noticeable that with increasing deviation from the mean, the diameters in the left ventricle also increase during the diastole. Those young athletes who had a maximum systolic blood pressure value >229 mmHg also showed the highest end-diastolic diameter. The differences were highly significant (F (3.738) = 28.134, p.001) with also high effect strength (η2 = 0.103). Both between the single and the double SD  and between the simple and the more than double SD, i.e., a systolic blood pressure development of more than 229 mmHg , the calculations showed highly significant results. Equally significant were the calculations of the left ventricular posterior wall thickness (p.001). Similar to the above results, significant differences between the single and the double SD  and between the simple SD and the classification >229 mmHg  were found. Concerning right ventricular function in the form of TAPSE, the groups do not differ significantly (p = 0.089). The left atrium diameter showed significant differences between the mSBD classifications, F (3. 727) = 12.308, p.001. The post-hoc testing significant differences between the group of athletes with single SD and double SD  and between single SD and the classification group “blood pressure >229 mg” .Finally, it was investigated whether those young athletes who had significantly higher systolic blood pressure levels during the stress test also showed corresponding abnormalities in cardiac ultrasound. see  SignificOf the 739 studied young athletes, percentiles of blood pressure levels were calculated. These were initially calculated jointly for both sexes and all age groups. Within the 95th percentile are blood pressure values diastolic of 95 mmHg and systolic of 230 mmHg. Across all age groups and separated by gender, 95% of young male athletes aged 10–20 years have a blood pressure below 230/95 mmHg. For female athletes, the 95th percentile is 206/90 mmHg.In addition to distinguishing blood pressure limits by sex, age-dependent distinctions are of particular interest. Thus, all subjects were additionally assigned to a corresponding age group. For each age group, blood pressure limits have now been determined by calculating the percentiles, which can quickly provide information about possible exercise-induced hypertonia see –8.This work aimed to investigate the blood pressure behavior of young athletes on the bicycle ergometer and to establish blood pressure limits that apply to young competitive athletes. In contrast to many exercise testing in international studies ergometry was conducted on the bicycle ergometer. Since the reason for exercise testing was focused on preparticipation screening in sports the quality of the exercise ECG to detect any cardiac pathology is essential. In terms of torso movement related ECG artefacts the ECG quality is much higher than during an exercise ECG testing on a treadmill.According to the guidelines of the European Society of Hypertension (ESH), the resting blood pressure values of the athletes are within the normal range . In thisThe sex, the age, the proportion of fat-free mass and the amount of training exercise influence the development of the maximum systolic blood pressure. Male athletes had higher mSBD levels and an equally higher fat-free mass than their female counterparts did. It is believed that the higher weight associated with increased muscle mass allows for higher performance on the ergometer. The extent of the increase in systolic blood pressure is also related to the mass of muscles involved . HoweverThat the age component has a decisive influence on the development of maximum systolic blood pressure under stress , was conThe training frequency parameter had a significant influence on the maximum systolic blood pressure development of young athletes. It confirmed the results of the meta-analysis of Berge et al. (2015). The research team around Berge classified the training amount into two categories: >10 h per week and 10 h of training effort per week. We were able to confirm the fact that those athletes who exercised more frequently (>10 h/week) had higher blood pressure development. With a four-part classification of the training frequency , a linear relationship between training frequency and mSBD development could be revealed across genders. However, what is striking about both sexes is that the mSBD forms a plateau from a training range of 6–10 h and then only increases minimally with increasing training scope. The maximum values are reached for both sexes with a training range of 16–20 h. These results suggest that from a training volume of 6 h per week, sports-related adjustment reactions of blood pressure occur.Influence of the sports type can be found as well. The technical-acrobatic sports results were significantly different compared to endurance athletes and sprint/strength and strength sports. In both cases, the technical-acrobatic athletes had a lower maximum systolic blood pressure level. This result differs from other study results , 28. We When looking at the subjects with the highest systolic blood pressure values in the exhaustion, significant abnormalities could be identified in single athletes. A canoeist and a cross-country skier had a maximum value of 260 and 250 mmHg, by far the highest systolic values. Both athletes also performed correspondingly high but not the highest relative workloads. However, it is also noticeable that in both athletes, the systolic resting blood pressure was above the age-appropriate limit. Excitement, but also cardiovascular regulation disorders, can be the cause of this.On the contrary, by looking at those athletes who stand out with a particularly good relative performance, it becomes clear that in these subjects, the maximum systolic blood pressure only assumes values of 200 mmHg. All these athletes are even in their 90th percentile of upper systolic blood pressure levels. As a result, no direct linear relationship can be determined between an excessive blood pressure reaction and a higher relative performance on the bicycle ergometer.n = 610, 82,5%) are in the range of the calculated mean value plus the simple standard deviation in terms of the maximum systolic blood pressure reaction (<206 mmHg). According to the calculated percentiles, this corresponds to the 90th and 95th percentiles in all age ranges. Ninety-one subjects had mSBD values above the mean up to twice the standard deviation (up to 229 mmHg).Overall, the majority of the athletes studied . Thirteen of the 38 athletes with excessive blood pressure reaction above systolic values of 229 mmHg correspondingly had norm-deviating systolic rest values of >140 mmHg. Whether these deviations are excitement-related increases, or already an indication of aterial hypertension, is to be discussed.Those young athletes who had a maximum systolic blood pressure value >229 mmHg showed significant different (higher) values for inner left ventricular dimension in the systolic and diastolic and the left ventricular posterior wall thickness. Therefore these athletes might need to be monitored more closely during their career, if both cardiac function and dimensions and blood pressure regulation show any signs of pathologic development.Due to the increase in blood pressure and the associated increase in intramyocardial pressure, there may be increased wall stress on the heart during a training career . EchocaHowever, since this work is only a cross-sectional analysis, the long-term effects of stress-induced hypertension are neglected. Mainly the long-standing competitive sport with numerous intensive training sessions and competitions provokes functional and structural changes to the musculoskeletal system and the cardiovascular system . To ruleThe presented blood pressure percentiles for children and adolescents are related to sex and age to simplify the graphic representation. The aspect of body hight, which is known to effect the age dependent resting blood pressure was not taken into account and might lead to misinterpreting the exercise blood pressure children and adoslescents.Another limitation of this work is that a pre-test activity, the nutritional status of the athletes, but also temporary emotional and psychological stress, such as in school or family, were not taken into account. However, all these factors can influence athletic performance and resulting blood pressure. The extent to which they have an impact remains debatable.To define cluster of paediatric subjects by age may not be appropriate when investigating the influence of physical maturity on parameters. Unfortunatly no data of puberty was gathered during the regular clinical assessment. Therefore the influence of pre- or late puberty on exercise related blood pressure regulation cannot be assessed in this study.In this study, the blood pressure behavior of young athletes aged 10–20 years was investigated and evaluated retrospectively. Overall, the young athletes show standard-compliant systolic and diastolic rest blood pressure values in the results of the examination. Only the level of maximum blood pressure values differs between athletes and non-athletes.For the first time, blood exercise related pressure percentiles were defined for junior athletes across sports. Competitive athletes in the junior field achieve higher blood pressure values due to physiological training adaptations and tolerate overall higher maximum blood pressure values than subjects who do not exercise.However, children and adolescents who are above these limits during exercise exposure may be at higher risk of cardiovascular disease.Overall, a large proportion of the athletes studied already show cardiac adaptation reactions that have a positive effect on performance. However, those subjects who had excessive BD reactions showed significantly higher chamber septum thicknesses during the diastole and higher left ventricular posterior wall thicknesses compared to their colleagues. Although these values are still within the range of the athlete-specific norm values, a tendency related to blood pressure is visible. Regular medical examinations should further be carried out to ensure the long-term health of all athletes.In general, there are only a few studies devoted to blood pressure behavior in childhood and adolescence. There is a need for research, especially to the question of what causes stress-induced hypertension in the long term. For this purpose, further longitudinal studies should be done examining children and adolescents from junior performance sports several times during their sporting careers for abnormalities.


This study examines the feasibility of using a robot-assisted therapy methodology based on the Bobath concept to perform exercises applied in conventional therapy for gait rehabilitation in stroke patients. The aim of the therapy is to improve postural control and movement through exercises based on repetitive active-assisted joint mobilization, which is expected to produce strength changes in the lower limbs. As therapy progresses, robotic assistance is gradually reduced and the patient's burden increases with the goal of achieving a certain degree of independence. The relationship between force and range of motion led to the analysis of both parameters of interest. The study included 23 volunteers who performed 24 sessions, 2 sessions per week for 12 weeks, each lasting about 1 h. The results showed a significant increase in hip abduction and knee flexion strength on both sides, although there was a general trend of increased strength in all joints. However, the range of motion at the hip and ankle joints was reduced. The usefulness of this platform for transferring exercises from conventional to robot-assisted therapies was demonstrated, as well as the benefits that can be obtained in muscle strength training. However, it is suggested to complement the applied therapy with exercises for the maintenance and improvement of the range of motion. Stroke is a leading cause of death and disability worldwide, with an incidence of nearly 14 million new cases each year , a resource provided by the U.S. National Library of Medicine. The protocol (Code: CRCS_UID_210619) was approved by the Institutional Review Board of the Rehabilitation Center Club de Leones Cruz del Sur.A total of 23 patients  with a mean age of 53.9 ± 9.7 years, mean weight of 77.7 ± 14.2 kg, and mean height of 163.8 ± 7.7 cm participated in this clinical study. All the participants were recruited from the Outpatient Rehabilitation Program of the Rehabilitation Center Club de Leones Cruz del Sur.All the patients included in the present study had unilateral lower extremity paresis resulting from a stroke occurring at least 6 months prior to the study. Furthermore, patients had full passive range of motion in the lower extremities or at least reached a neutral joint position; they were also able to stand freely and walk with or without assistance for at least 20 m in <2 min. Exclusion criteria were peripheral nervous system pathology, epilepsy, weight over 100 kg, difficulty following the study instructions, pregnancy, use of implanted devices, and unstable lower extremity joints or fixed contracture. The co-researchers obtained written informed consent from all participants. All enrolled participants were informed of their responsibility to attend all scheduled sessions.A rehabilitation platform was developed consisting of a powered lower limb exoskeleton , a control software and a weight-bearing system  was designed to control the position of each joint of the exoskeleton independently, adjust the assistance and record data from each rehabilitation session. The control diagram can be found in the supplementary material provided . This soThe assistance level can be set in percentage values between 50 and 100% , the latIn short, the new platform allows to control the movement of each joint, facilitating normal movement and avoiding the use of compensatory movement strategies that patients use due to muscle weakness. Additionally, the software allows the modification of variables such as speed, repetitions and rest time between each exercise, facilitating the application of adjustments in each session to personalize the therapy according to the patient's progress.Participants were assessed at baseline and after the robotic therapy through standardized clinical tests to measure the strength and PROM of each joint. Lower limbs PROM assessment was performed using a six-piece goniometer set . Strength assessment was carried out using a digital handheld dynamometer  in which maximum and average muscle strength of hip flexion, hip extension, hip abduction, knee extension, knee flexion, dorsiflexion and plantar flexion of the ankle were assessed. The assessment was performed using the evaluation protocols available in the literature to reach positions with higher reliability to test isometric strength  and then gradually decreased their assistance by 5% every 4 sessions based on clinical judgment. Each session was subdivided into preparatory activities, robotic therapy and post-therapy activities. Preparatory activities included securing the patient by installing a harness connected to a non-movable weight-bearing system whose sole purpose is to secure the patient and prevent falls, but without supporting a fixed percentage of weight; installing and adjusting the exoskeleton; connecting the software; selecting the exercise to be performed, and setting the percentage of assistance per joint. In addition, vital parameters as blood pressure and heart rate were measured before and after each session with the SureSingVS2+ multiparametric device  to ensure that the patient performed the training in perfect condition and that no adverse effects occurred after the session.The therapy design included 5 gait training exercises  based onOnce the training session was over, the system was switched off and the equipment was uninstalled. A skin inspection was carried out in the areas where pressure was applied with the exoskeleton and the patient was consulted about his or her comfort and experience during the session. In addition, at the end of each session the therapist monitored established criteria for discontinuing the study: (1) Participant requests to leave the study; (2) Follow-up assessment reveals evidence of unexpected contraindication to the intervention, such as skin problems or pain. In addition, participants' adherence to the program was monitored and encouraged throughout the trial. In addition, all patients were informed about permitted and prohibited concomitant interventions during the trial.After 12 weeks of training, assessment tests were repeated for comparison with the baseline condition. In addition, post-trial care of the study included: (1) All patients enrolled in the study were scheduled for clinical follow-up; (2) Implementation of a telephone line for patients in case of post-trial complications.Only institution employees, co-researchers, and ethics committees get access to the participants' records. Participants' identities are concealed in any research related publications.−1. The results presented in relation to the PROM are in degrees. Descriptive statistics, such as mean (M) and standard deviation (SD), were calculated. An analysis of the classical assumptions was performed, i.e., normality tests (Shapiro Wilks test). The results obtained from these tests conditioned the use of a parametric (Student's t-test) or non-parametric (Wilcoxon test) test for related samples at 5% confidence. In addition, a statistical power study was performed with GPower v3.1 software to confirm the reliability of the results obtained with the proposed statistical analysis. For this purpose, it was established that the statistical power should be equal to or >80%. Due to the multiple comparisons made to identify significant differences in the variables measured for strength and PROM, the familywise error rate increases. That is, the probability of making a type I error increases. To control this effect, a Holm-Bonferroni adjustment was applied to the strength and PROM family variables separately. This allowed us to identify the significant differences for each of the groups of variables studied.The data collected with the pre- and post-therapy assessments were analyzed with SPSS Statistics 26 software. The results obtained in the dynamometry tests were normalized by the weight of each subject in order to carry out the statistical study, so the units of the strength results presented in this study are kgf·kgFinally, to assess the possible relationships between the significant changes detected, the percentage of change that occurred between the pre- and post-variables was calculated. For this purpose, the following equation was applied:Subsequently, the relationships between these newly calculated variables were evaluated for two different scenarios. Variations of the variables on the paretic side and on the non-paretic side were analyzed separately. In a first scenario, the relationship was studied for the variations of the maximum strength measures. They were only examined for maximum strength, as maximum strength and average strength were considered to be linearly dependent. Furthermore, clinically, maximum strength is more relevant than average strength. This helps to simplify and interpret the results in the sense that the aim is to explore whether the strength variations experienced after therapy are in the same direction and with the same intensity. In a second scenario, the same analysis was performed with respect to PROM variations. Finally, the relationships between the variations of the variables that underwent significant changes on both sides were analyzed in order to study whether these changes were similar.For the statistical analysis of the last two hypotheses involving multiple comparisons, partial approximations have been made. A principal component analysis (PCA) was applied in order to reduce dimensionality and describe the dataset in terms of new uncorrelated variables that help to understand the main relationships between the study variables. Loadings allow us to interpret the distribution of our variables with respect to these principal components. A loading is large when its absolute value is >0.5. The sign will indicate whether the correlation between the variable and the component is positive or negative, resulting in a direct or inversely proportional relationship, respectively. As for the relationships of maximum strength and the relationships of the same variable comparing different sides, the comparisons were bivariate. Therefore, Pearson's or Spearman's correlation was applied depending on whether or not the normality criterion previously analyzed was met for the variables used to calculate the variation.p < 0.05) which seem to indicate that this training therapy promotes strength gain mainly at the hip and knee joint level . MCID is defined as “the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient's management”  and by the Rehabilitation Center “Club de Leones Cruz del Sur”, Punta Arenas, Chile. This work has been also partially funded by CSIC Interdisciplinary Thematic Platform (PTI+) NEURO-AGING+ (PTI-NEURO-AGING+).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.