DHA) modulates atherosclerosis and hypertension, possibly via an inflammatory mechanism. IL‐1 (interleukin 1) has an established role in atherosclerosis and inflammation, although whether IL‐1 inhibition modulates blood pressure is unclear.Hypertension is a complex condition and a common cardiovascular risk factor. Dietary docosahexaenoic acid (−/− (apolipoprotein E–null) mice were fed either a high fat diet or a high fat diet plus DHA (300 mg/kg per day) for 12 weeks. Blood pressure and cardiac function were assessed, and effects of DHA on wall shear stress and atherosclerosis were determined. DHA supplementation improved left ventricular function, reduced wall shear stress and oscillatory shear at ostia in the descending aorta, and significantly lowered blood pressure compared with controls . Analysis of atheroma following DHA feeding in mice demonstrated a 4‐fold reduction in lesion burden in distal aortas and in brachiocephalic arteries . In addition, DHA treatment selectively decreased plaque endothelial IL‐1β (P<0.01).Male apoEIL‐1 indirectly by administration of DHA in the diet through a mechanism that involves a reduction in wall shear stress and local expression of the proinflammatory cytokine IL‐1β.Our findings revealed that raised blood pressure can be reduced by inhibiting  In a mouse model of atherosclerosis, supplementation of a Western diet with docosahexaenoic acid improved left ventricular function, reduced aberrant hemodynamic flow patterns in the aorta, and lowered blood pressure.Atheroma burden was reduced 4‐fold in the docosahexaenoic acid–supplemented group at 2 anatomic sites.IL‐1 (interleukin 1) is plausibly implicated in the mechanism for these effects because docosahexaenoic acid selectively decreased plaque endothelial IL‐1β.Regular supplementation of the diet with docosahexaenoic acid alters blood‐flow patterns in the vasculature, reducing local IL‐1–induced inflammation and atherosclerosis and, consequently, lowering blood pressure.Given the importance of the CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study), our data suggest that strategies that control local IL‐1β may also be useful in hypertension.Hypertension is a major healthcare concern, given its prevalence among the population and its devastating complications, namely, stroke and ischemic heart disease (IHD).Arterial inflammation has been shown in patients with systemic hypertension.Recent studies suggest that dietary fat, especially saturated fatty acids, are deleterious for atherosclerosis and hypertension.Epidemiological, case–control, and prospective clinical studies have demonstrated positive effects of n3FAs in the reduction of cardiovascular mortality rates among IHD patients.Consequently, it is clear that DHA has broad anti‐inflammatory effects, but whether it has inhibitory effects on IL‐1–dependent inflammation in the setting of hypertension and the mechanisms involved needs further elucidation.We aimed to investigate whether DHA supplementation in mice could alter vascular contractility via an IL‐1β–mediated mechanism, contributing to blood pressure reduction in experimental atherosclerosis. We showed that DHA reduces wall shear stress  in the descending aorta, especially at ostia, and that this is associated with significantly decreased arterial blood pressure, enhanced left ventricular (LV) function, and a reduction in intraplaque inflammation directed by IL‐1β.The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure; however, requests for specific elements of the these materials will be considered.Detailed methods can be found in the supplemental information Data .−/− (apolipoprotein E–null) mice were bred in‐house at the University of Sheffield. Food and water were given ad libitum in a controlled environment . Starting at 8 weeks of age, the mice were housed individually and randomly separated into 1 of 2 groups (n=12 per group). The control group was fed a Western‐type high‐fat diet (HFD) containing 21% (wt/wt) fat, 0.15% (wt/wt) cholesterol, and 0.296% (wt/wt) sodium, whereas the DHA‐treated group received the HFD and DHA (99% purified). In this model, mice have raised blood pressure as a result of HFD feeding.Male ApoE3, containing a single dose of drug. The mice were monitored daily for their DHA intake. Body weights were measured weekly over 12 weeks. All animal care and procedures were closely conducted under ASPA 1986, UK and in accordance with Home Office guidelines under license 70/7992.DHA feeding was achieved by mixing the DHA with jelly using a previously described “jelly‐delivery” protocolTo confirm absorption of DHA, red blood cell ω‐3 composition and indexes were measured by gas chromatography in pooled blood samples of the mice (4 mice per group).Systolic and diastolic blood pressure was measured in the mice using a Visitech tail‐cuff system, as described previously.Echocardiograms were performed in the mice fed either a HFD alone or a HFD and DHA over 12 weeks, as described previously.The extent of atherosclerosis was assessed in cross‐sectional aortic sinus and brachiocephalic sections, as described.Paraffin‐embedded aortic sections were immunostained, as described previously.Computational fluid dynamics of the unsteady flow in the aortic branch, including the ostia, was performed using the unsteady Navier‐Stokes code ANSYS Fluent 17.1, following a similar model to that used by Luong et al.3. Calculated with a typical maximum flow speed of V=1 m/s and a hydraulic diameter at the aortic root of D=1.58 mm, the maximum Reynolds number is Re=ρVDη−1=488. The flow was thus modeled as laminar.The lumen was meshed using ANSYS ICEM computational fluid dynamics, generating a hybrid tetrahedral mesh with a prismatic boundary layer representation. Based on a mesh independence analysis,The inlet boundary condition was a time‐dependent prescribed velocity profile (Dirichlet condition), calculated as a third‐order Bezier spline approximationOutlet conditions at all exits were von Neumann outlet conditions with a split of 69.8%, 16%, 8%, and 6% for descending aorta, innominate, common carotid, and subclavian, respectively, and 0.14% for each of the 12 ostia. All outlet conditions were in phase with the inlet velocity profile.Numerical solutions were obtained using cell‐based gradients with second‐order pressure, quadratic upwind momentum, and second‐order implicit time discretization. Time step size was chosen as 1/1000th of the cycle time. Three cycles were simulated to allow for fully developed periodicity, and the last cycle was evaluated.Three‐dimensional time‐dependent WSS data were exported to calculate the time‐averaged WSS magnitude (TAWSS), the oscillatory shear index (OSI), and transverse WSS (transWSS):Although OSI quantifies the oscillatory character of near wall flow, transWSS is a metric for instantaneous WSS vector components that are perpendicular to the mean WSS vector in the local endothelium plane, as proposed previously.t test for normally distributed data. Statistical significance was achieved when P<0.05.Data are expressed as mean±SEM and were analyzed using Prism software . Paired blood pressure data were analyzed by paired 2‐way ANOVA followed by Sidak posttest. For 2‐group comparisons, data were analyzed by Student DHA supplementation of the HFD was well tolerated by the mice, with no side effects, and absorption was confirmed by specific changes in free fatty acid composition (increased by 38 μmol/L in DHA‐fed mice) in red blood cell membranes Figure B. The rePlasma levels of LDL‐C (low‐density lipoprotein cholesterol) in DHA‐treated mice were not significantly different from those in the controls Figure C, but thP<0.05, n=4). This fall in systolic blood pressure in the DHA‐supplemented group continued for a further 7 weeks  and week 12. In the DHA‐supplemented group, the percentage of LV ejection fraction increased after 12 weeks, although this was not statistically significant compared with control mice  compared with controls  and, more important, both OSI  and transWSS  in mice supplemented with DHA , and MCP‐1 (monocyte chemoattractant protein 1), but there was no change in TNF‐α (tumor necrosis factor α) or IL‐1 versus controls Figure A, we didContemporary primary and secondary therapies for cardiovascular disease prevent the progression of atherosclerosis and stabilize the plaque, providing significant clinical benefitIt is published that n3FAs have a blood pressure–lowering effect in both normotensiveOur data show that DHA significantly decreases blood pressure in our experimental model, reinforcing previous interventional studies in humansIn contrast, ALA supplementation did not show any significant impact on blood pressure in atherosclerotic mice . ALA as an antihypertensive agent has been studied in a limited number of studies,An independent association exists between LV mass and atherosclerotic coronary disease in patients with IHD,The local anti‐inflammatory effect of DHA has been previously associated with a thickening in the fibrous cap and more stable plaque formation.We suggest that DHA, through modulation of complex blood flow potentially via changes in viscosity,P<0.01; 75.2±1.5 versus 71.1±1.2 mm Hg, diastolic, P=ns; 93.9±1.7 versus 88.6±1.2 mm Hg, mean arterial pressure, P<0.05; n=76 patients [IL‐1ra] and n=71 [placebo], t test). Given other recent data,Our previous studies have shown that atherosclerotic mice treated with anakinra or the murine version of canakinumab, as well as IL‐1R1 knockout mice, have reduced blood pressure and atherosclerosis formation compared with controlsOur DHA study does have limitations. It is not clear, for example, whether the effect on atherosclerosis is related to a direct effect of DHA on blood pressure or whether the opposite applies. The same limitation applies to our previous studies that lowered blood pressure by inhibiting IL‐1 signaling directly, without using DHA. To fully address this question, analysis of atherosclerosis in a study group whereby blood pressure is lowered by a non‐DHA and non–IL‐1 mechanism would need to be performed.In conclusion, our study provides the first evidence that regular supplementation of DHA in the proatherogenic diet of mice influences arterial walls in such a way as to alter blood flow patterns distally in the vascular tree. We suggest that this may lead to reduced local inflammation (IL‐1 production) in vessel walls; reduced lesion burden in distal vessels; and, consequently, lowered blood pressure. Further studies targeting IL‐1 for lowering hypertension directly in mice or humans are warranted.This work was supported by a PhD studentship grant to Dr Alfaidi, from Medical School, Omar Almokhtar University, Al‐Bayda, Libya, and by British Heart Foundation grant PG/13/8/29989, UK Medical Research Council Experimental Medicine Grant (G0502131), the National Institute for Health Research, and a UK Medical Research Council Clinical Research Training Fellowship (AR‐MR/K002406/1). Rothman is supported by a Wellcome Trust Clinical Research Career Development Fellowship (206632/Z/17/Z).None.Data S1. Supplemental methods.Click here for additional data file.


Patients with chronic diseases are in need of regular health controls. Diabetes mellitus type 2 is currently the most prevalent chronic metabolic disease. A majority of diabetic patients have at least one comorbid chronic disease, where hypertension is the most common. The standard for blood pressure (BP) measurement is manual BP monitoring at health care clinics. Nevertheless, several advantages of self-measured BP have been documented. With BP data transfer from an automatic BP monitor via Bluetooth to software, for example, a smartphone app, home measurement could effectively be integrated into regular care.The aim of this study was to validate two commercially available automatic BP monitors with the ability to transfer BP data via Bluetooth (Beurer BM 85 and Andersson Lifesense BDR 2.0), against manual BP monitoring in patients with type 2 diabetes.A total of 181 participants with type 2 diabetes were recruited from 6 primary care centers in Stockholm, Sweden. BP was first measured using a manual BP monitor and then measured using the two automatic BP monitors. The mean differences between the automatic and manual measurements were calculated by subtracting the manual BP monitor measurement from the automatic monitor measurement. Validity of the two automatic BP monitors was further assessed using Spearman rank correlation coefficients and the Bland-Altman method.2. The mean difference between the Beurer BM 85 and the manual BP monitor was 11.1 (SD 11.2) mmHg for systolic blood pressure (SBP) and 8.0 (SD 8.1) mmHg for diastolic blood pressure (DBP). The mean difference between the Andersson Lifesense BDR 2.0 and the manual BP monitor was 3.2 (SD 10.8) mmHg for SBP and 4.2 (SD 7.2) mmHg for DBP. The automatic BP measurements were significantly correlated (P<.001) with the manual BP measurement values .In total, 180 participants, 119 men and 61 women, were included. The mean age was 60.1 (SD 11.4) years and the mean body mass index was 30.4 (SD 5.4) kg/mThe two automatic BP monitors validated measure sufficiently accurate on a group level, with the Andersson Lifesense BDR 2.0 more often falling within the ranges for what is acceptable in clinical practice compared with the Beurer BM 85. In recent years, there has been a rapid development in information and communication technology including the availability of digital devices for self-measurements and health promoting apps. Today, more and more patients are asking for digital solutions. Despite this, apps and devices for home measurement are seldom integrated into regular health care. Given the importance of self-care in the therapy of most chronic diseases, tools for self-measurement have the potential to play a greater role than they do today. Furthermore, the use of new technology such as mobile health, defined by the World Health Organization as medical or public health practice that is supported by mobile devices , could bDiabetes mellitus type 2 is currently the most prevalent chronic metabolic disease, and the number of cases is increasing worldwide. In 2015, the global prevalence of diabetes mellitus in the adult population (20-79 years) was 8.8%, and it is expected to rise to 10.4% by 2040 ,4.. For example, measurement at home can provide a more realistic appraisal of habitual BP than that can be obtained at a health care clinic, that is, eliminate the risk of the so-called white coat hypertension when the BP is high only in the clinical setting [. In addition, studies have also shown that the opposite, masked hypertension, that is, normal BP when measured at a clinic, but high BP when measured at home, is associated with an increased cardiovascular risk similar to the risk of patients with persistent hypertension [Today, the standard method for diagnosis of hypertension as well as for blood pressure (BP) control in antihypertensive-treated patients is manual BP monitoring at health care clinics. Nevertheless, several advantages of self-measured BP have been documented . For exa setting . In addirtension ,8. As partension , the neeSelf-measurement at home could possibly improve patient adherence to both BP controls and treatment ,11. HoweThis study was performed using BP data collected at baseline from all participants in the DiaCert-study, a randomized controlled trial of patients with type 2 diabetes. The study design has been described in detail previously . A totalBP, weight, height, and waist circumference were measured by study personnel at the baseline meeting. This has been described in detail previously . SmokingThe monitors Beurer BM 85 Bluetooth  and Andersson Lifesense BDR 2.0  are automatic devices for measuring BP at the upper arm. Both monitors can transfer data via Bluetooth to digital tools.Beurer BM 85 has a pressure range of 0 to 300 mmHg and a memory capacity of 60 measurements for 2 users. It can calculate the average value of all saved measures as well as the average of morning and evening measurements during the last 7 days. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) as well as the heart rate are displayed on a liquid crystal digital (LCD) display. The monitor can identify an irregular heartbeat, which is then displayed with a symbol on the LCD screen. The included standard cuff for Beurer BM 85 is applicable to arm circumferences ranging from 22 to 36 cm. The dimensions of the device are 180×100×40 mm, and the weight of the monitor without the cuff is 317 grams. The Beurer BM 85 is equipped with a rechargeable lithium-ion battery (3.7 V/400 mAh) that has a battery life of approximately 50 measurements.Andersson Lifesense BDR 2.0 has a pressure range of 0 to 300 mmHg and a memory capacity of 60 measurements for 2 users. It can calculate an average value of the last 3 measurements. SBP and DBP as well as the heart rate are displayed on an LCD display. The monitor can identify an irregular heartbeat, which is then displayed with a symbol on the LCD screen. The included standard cuff for Andersson Lifesense BDR 2.0 is applicable to arm circumferences ranging from 22 to 32 cm. The dimensions of the device are 180×99×40 mm, and the weight of the device without the cuff is 300 grams. For the Andersson Lifesense BDR 2.0, 4 AAA-size alkaline batteries are needed. The device has an approximate capacity of 300 measurements.t tests were performed for continuous variables. Differences between the automatic monitors and manual BP measurements were calculated by subtracting the manual measurement from the automatic ones. Participants were divided into four categories classified by the differences according to whether they were within 5, 10, 15, or more than 15 mmHg. Separate variables were created for systolic and diastolic pressure. We conducted a sensitivity analysis to see if the result of Beurer BM 85 differed when including only the 155 participants in whom BP also was measured using Andersson Lifesense BDR 2.0. The Bland-Altman method was used to assess systematic differences in BP measurements between the manual and automatic monitors and as a graphical evaluation of the associations [We categorized the participants into low or high BP. Low BP was defined as SBP less than 140 mmHg and DBP less than 90 mmHg. High BP was defined as SBP 140 mmHg or above or DBP 90 mmHg or above. We used this classification as a BP of 140/90 mmHg is the diagnostic cut-off for the definition of hypertension in Europe [P=.02) between the high and low BP groups with higher BMI in the high BP group. In addition, there was a statistically significant difference in waist circumference (P=.04) for men with greater waist circumference in the high BP group. The mean BP values for all participants with the manual monitor were 138 (SD 15.5) mmHg for SBP and 83 (SD 9.7) mmHg for DBP. The Beurer BM 85 and Andersson Lifesense BDR 2.0 mean BP values are shown in This study included 180 participants (119 men and 61 women) with a mean age of 60.1 (SD 11.4) years. Characteristics of all participants and according to low (n=83) and high BP (n=97) are shown in The mean difference between the Beurer BM 85 and the manual BP monitor was 11.1 (SD 11.2) for SBP and 8.0 (SD 8.1) for DBP. The mean difference between the Andersson Lifesense BDR 2.0 and the manual BP monitor was 3.2 (SD 10.8) for SBP and 4.2 (SD 7.2) for DBP. The number of measurements that differed from the manual measurements by 5, 10, 15 or less, and more than 15 mmHg are shown in r=0.78 for SBP and r=0.71 for DBP for Andersson Lifesense BDR 2.0, and r=0.78 for SBP and r=0.69 for DBP for Beurer BM 85 .The differences in SBP and DBP in relation to the mean between the automatic and the manual monitors are shown in Bland-Altman plots in The results of our study demonstrate that the mean difference between the manual and the automatic BP monitors Andersson Lifesense BDR 2.0 and Beurer BM 85 was small on a group level. The differences between the manual and automatic measurements were larger on an individual level.There is a lack of studies validating automatic BP monitors in patients with type 2 diabetes. However, Masding et al  comparedMasding et al  have alsSeveral automatic BP monitors without a Bluetooth connection have been validated in the general population -21. TakaThe large sample size is a notable strength of our study. Furthermore, the participants were recruited from 6 primary care centers located in different areas with diverse populations and levels of socioeconomic status. With a mean age of 60 years, the participants are younger than the general patients with type 2 diabetes in Sweden (68 years old) , which mThere is a lack of automatic BP monitors validated in the large population of patients with type 2 diabetes who are likely to use automatic BP monitors in practice. Not only are patients with diabetes often familiar with digital devices that help them with better management, for example, devices for self-monitoring of blood glucose, they are also in need of controls for comorbidities, such as hypertension, on a regular basis. Today, the routine practice for screening of hypertension consists of multiple visits to the health care clinic for repeated BP measurement. Including home measurements in the decision making would not only be more cost-efficient but also provide more reliable measurements with white coat hypertension and masked hypertension in mind. The fact that BP measurements in our study were performed in a clinical setting and not in a home setting, and only once using each monitor, may be a limitation of our study. Though, as the aim was to validate the automatic monitors against the standard method for BP measurement, the manual and the automatic measurements were performed on the same occasion at a health care clinic.Digital solutions could meet the needs and expectations of patients by making health care more accessible. Validated devices also ensure the quality of the care. However, if the BP monitors’ ability to transfer BP data via Bluetooth is to be used in future health care, it is important to emphasize that transfer of data to, for example, an electronic health record has to be compliant with security regulations and without the risk of privacy invasion of stored health data on the cloud. In addition, offering tech support, for example, an in-app chat-support, for various issues such as data transfer and uploading data could potentially increase consumer confidence in digital self-measurement devices. Gamification techniques such as visual feedback messages or a platform allowing communication could have potential to further increase the motivation of the patients to engage in their own health care . For futIn conclusion, no previous studies have validated automatic BP monitors with a Bluetooth connection in patients with type 2 diabetes. Our study shows that although the difference between the manual and the automatic BP monitors was greater on an individual level, the monitors are sufficiently accurate on a group level. Moreover, the Andersson Lifesense BDR 2.0 is more often falling within the BP ranges for what is acceptable in clinical practice compared with the Beurer BM 85.


The initial management of pneumothorax remains controversial, and we speculated that this might be because there is no method available for evaluation of air leak during initial management. We have developed a system for measurement of intrapleural pressure in pneumothorax to address air leak without the need for chest drainage. The aim of this clinical study was to confirm the ability of this measurement system and to determine the clinical impact of management of air leak.Patients in whom need aspiration was indicated for spontaneous pneumothorax were enrolled in the study. The intrapleural pressure was measured during stable breathing and data recorded when patients were coughing were excluded.p = 0.020). The number of negative mean pressure recordings in end-inspiration and end-expiration was significantly lower in patients with persistent air leak than in those without persistent air leak (p = 0.0060).Eleven patients were enrolled in the study between December 2016 to July 2017. The patterns in change of intrapleural pressure varied widely depending on the state of the pneumothorax. The mean intrapleural pressure values on end-inspiration and end-expiration in patients with persistent air leak was significantly lower than those in patients without persistent air leak (In this study, we demonstrated that intrapleural pressure could be successfully measured and visualized in patients with pneumothorax. Whether or not the pressure value is a predictor of persistent air leak needs to be confirmed in the future. The treatment of spontaneous pneumothorax has been debated for at least 80 years , 2. Pneu2O to − 20 cmH2O and showed a continuous periodic curve  as follows: mild, apex of the lung over the clavicle and equivalent state; moderate, middle range between mild and severe; and severe, total collapse and equivalent state. A persistent air leak was defined clinically as an air leak requiring chest drainage for more than 7 days. Duration of chest drainage was defined as the interval between insertion of the chest tube and its removal. After measurement of intrapleural pressure, the pneumothorax was treated conventionally by observation with rest, oxygenation, aspiration, chest tube drainage, chemical pleurodesis, or surgery.The study was approved by the Institutional Review Board of Kansai Medical University  and was performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients included in the study. Patients in whom aspiration was indicated for spontaneous pneumothorax, either primary or secondary, were enrolled. Patients with bilateral pneumothorax were excluded. Oxygen saturation was measured by pulse oximetry when the patients were in room air. The degree of lung collapse was judged by chest radiography in accordance with the guideline for spontaneous pneumothorax published by The Japan Society for Pneumothorax and Cystic Lung Diseases  with high-speed sampling (10 milliseconds) and precision  was modified for use with this system .The intrapleural pressure was measured during stable breathing for about 30 s, representing 10–15 breathing cycles. Data recorded when patients were coughing were excluded. The pressure values at end-expiration and end-inspiration were recorded prospectively. Each patient’s clinical details and the outcome of spontaneous pneumothorax were retrospectively collected for the statistical analysis. Intrapleural pressure was defined as negative if the pressure was lower than atmospheric pressure. The mean values on end-inspiration and end-expiration were calculated. The continuous data were analyzed using the Student’s Eleven patients  were enrolled in the study between December 2016 and July 2017. Four of the patients had a primary spontaneous pneumothorax and 7 had a secondary spontaneous pneumothorax; 4 patients were experiencing pneumothorax for the first time and 7 were experiencing a recurrence. Nine cases showed moderate collapse of the lung on chest radiography and two showed severe collapse . The number of negative mean pressure recordings in end-inspiration and end-expiration was significantly lower in patients with persistent air leak than in those without persistent air leak (p = 0.0060).A comparison of the patients with and without persistent air leak is shown in Table In this study, we demonstrated that intrapleural pressure could be successfully measured and visualized in patients with pneumothorax. Furthermore, we confirmed that the pressure value was a significant predictor of persistent air leak.The initial management of patients with pneumothorax remains controversial . We prevMeasurement of intrapleural pressure for better understanding of pleural physiology has been described since the 1800s and has been investigated clinically in thoracocentesis for pleural effusion –15. The Measurement of intrapleural pressure has not been adopted in routine clinical practice for patients with pneumothorax or pleural effusion , possiblThe main limitations of this study are its retrospective design, the small number of patients included, and the lack of patient homogeneity. However, we believe that our findings warrant prompt introduction of the tool we have developed for assessing air leak in patients with pneumothorax into clinical practice. A prospective study in a larger number of patients is now needed to confirm our present findings and whether or not this measurement system can predict the outcomes of treatment to establish a standard management strategy for patients with pneumothorax.The findings of this pilot study show that intrapleural pressure could be successfully measured and visualized in patients with pneumothorax. Whether or not the pressure value is a predictor of persistent air leak needs to be confirmed in the future.Additional file 1: Figure S1. (A) A handmade model of the thoracic cavity. (B) A periodic curve showing the change in air pressure using this model. (C) The change in air pressure in a model simulating tension pneumothorax produced by making a small hole in a lung balloon.Additional file 2: Figure S2. Verification using an animal model. (A) The thoracic cavity of a pig was observed by thoracoscopy. (B) A change in air pressure during puncture of the thoracic cavity. The arrow shows the entry of the tip of the needle into the thoracic cavity. (C) A periodic curve showing intrapleural pressure accompanied by pulmonary ventilation.Additional file 3: Figure S3. A needle to puncture thoracic cavity connected to the manometer to measure intrapleural pressure.


Patients with end-stage kidney disease (ESKD) receiving maintenance dialysis experience an overall burden of physical and emotional symptoms. However, there were limited alternative treatments to dialysis.A 79-year-old woman with chronic kidney disease stage 5 (CKD5) and gout had refused to be on dialysis. She also had hypoglycemia, hypertension, and heart disease.The patient had received the ultrasonography, the renal biopsy and biochemical examinations, confirming the diagnosis of renal impairment, primary hypertension, and chronic nephritic syndrome with unspecified morphologic changes.Astragalus membranaceus 3 g, Codonopsis pilosula 3 g, Ligustrum lucidum 3 g, Panax quinquefolius 1.3 g, and Rhodiola sacra 1.3 g) orally twice a day for 6 months in addition to her regular medications.She was administered with 20 mL Eefooton  and serum creatinine concentrations were decreased. In addition, further reduction in BUN concentration was observed 2 months posttreatment.This case demonstrated that Eefooton has potential therapeutic significance in patients with CKD5 who chose conservative treatment over dialysis. These patients exhibit irreversible loss of kidney function, resulting in the accumulation of wastes and fluid, electrolyte imbalance, and acid alkaline imbalance. The progression of CKD is monitored by assessing several parameters. Decreased kidney size results from the loss of nephrons due to tubular atrophy, a hallmark of CKD. Glomerular dysfunction in CKD decreases the estimated glomerular filtration rate, resulting in increased concentrations of serum creatinine from muscle metabolism and blood urea nitrogen (BUN), a normal waste product from the breakdown of proteins in food.Chronic kidney disease (CKD) is a major health problem worldwide. Characterized by the gradual loss of kidney function over time, CKD can progress to end-stage kidney failure, Patients on maintenance dialysis experience an overall burden of physical and emotional symptoms, depression, and low quality of life. In addition, many patients with end-stage renal disease are elderly. In patients over 75 years of age, approximately 40% are affected by CKD, with a 1-year mortality rate following the initiation of dialysis of 41%. Therefore, the identification of potential palliative treatments for patients with CKD and end-stage renal disease is needed.Once the kidneys have failed, the patient faces the choice of 3 management options: hemodialysis (HD), peritoneal dialysis, or transplantation. The decision to transplant is made carefully. This surgical procedure itself is taxing on a patient already ill, one likely suffering from comorbidities such as hypertension or diabetes.Ligustrum lucidum and its constituents are reported to exhibit hepatoprotective effects, anticancer activity, antioxidant activity, immunomodulating effects, antiviral activity, and antiosteoporosis activity. Compounds in Rhodiola sacra were observed to reduce pulmonary hypertension.Astragalus, a dried root known as Huang Qi in Chinese, has demonstrated a wide range of immunopotentiating effects and has proven efficacious as an adjunct cancer therapy.Panax quinquefolius, commonly known as ginseng, possesses anticancer, antidiabetic, and immunomodulatory activities and has been shown to improve the central nervous system function.Codonopsis pilosula, a flowering plant also known as dang shen, has demonstrated effects against tumors, diabetes, and aging and has positive effects on the gastric mucosa, blood system, and immunity.Active compounds have been identified in many plants used in Chinese medicine, with a broad range of important biological activities reported. For example, Astragalus membranaceus, C pilosula, L lucidum, P quinquefolius, and R sacra.We herein described the case of a 79-year-old woman with stage 5 CKD who chose not to undergo HD despite a rapid elevation in serum creatinine concentration from 3.85 to 7.25 mg/dL within 9 months. This deterioration of kidney function was palliated by the administration of Eefooton, a liquid formula of herbal extracts containing 2A 79-year-old woman with gout had diagnosed with stage 5 CKD which was characterized by renal impairment, primary hypertension, and chronic nephritic syndrome with unspecified morphologic changes and presented to the clinic on March 2016.During a 2-years observation period, the trend of serum creatinine concentrations of the patient was increased dramatically within 9 months (from March to December 2016) from 3.85 to 7.25 mg/dL , the ultrasonography of the patient had shown that the size of the right kidney was measured at 8.42 × 4.41 cm2 in the patient's blood, while the concentrations of sugar, creatinine, inorganic phosphate, and K were decreased. In addition, the BUN and creatinine concentrations were further reduced at 2 months follow-up after the completion of the Eefooton treatment and remained steady  with no sign of factors causing the pathological kidney enlargement, such as tumors, kidney stones, and hydronephrosis. The trend of rising serum creatinine concentration was abated at the end of the 6-months Eefooton adjunctive treatment and remained at the elevated level but not continuously increased. These observations had suggested that her renal atrophy had been slightly recovered. Therefore, the administration of Eefooton had slowed the progression of CKD in the patient.Here, we had reported the improvements in kidney function with the Eefooton treatment in a patient with stage 5 CKD who had decided against dialysis. Concerned about her rapid progression of the kidney atrophy, we had enquired that the size of each kidney in the patient should be monitored by her physician during the 2-years observation period. After the 6-months Eefooton treatment, the sizes of both kidneys in the patient were increased by about 8% . Elevated BUN and serum creatinine levels in kidney-damaged mice were reduced by the treatment with P quinquefolius. In our case, the patient had experienced a decrease in BUN level after the Eefooton treatment. C pilosula modulates immunomodulation and inflammation which increase granulocyte macrophage colony-stimulating factor secretion by macrophages and thus may enhance hematopoiesis in the setting of CKD.,19 Despite its antioxidant effects that reduced tissue injury, R sacra may alleviate the renal damage. Thus, the improvements in kidney function observed in our study may be in accordance with previous reports of Eefooton individual components. There may be a possible synergistic effect of herbal extracts in Eefooton for our case.Although the Eefooton with the unique herbal formulation has not been explored previously, the effects of herbal extracts in the Eefooton liquid formula on the kidney function have been reported. Eefooton is a combination of herbal extracts included After the administration of Eefooton, the improved kidney function was observed in our patient. No previous case report focused on the use of Eefooton for CKD. Eefooton may have an inhibitory effect on BUN and serum creatinine levels which could improve the glomerular filtration rate and prevent the kidney atrophy by reversing the loss of glomerular cells in CKD. The use of Eefooton for CKD may be beneficial for patients with abnormal serum creatinine level approximately up to 7 mg/dL, or patients require the imminent dialysis initiation. However, the present study was a preliminary clinical observation of 1 patient. Eefooton was used as an adjuvant treatment in addition to Western medicines, the observed improvement of kidney function in the patient attributed as the sole effect of Eefooton could not be determined. The long-term effect, prognosis, the possible mechanism of Eefooton would require further investigations.It is worth noting that we are planning a well-organized clinical trial as a cohort study in the efficiency of Eefooton on the end-stage CKD patients.The treatment with invasive HD or peritoneal dialysis is compulsory for the survival of the end-stage CKD patients. In our case, we shared our experience with Eefooton, highlighting its positive effect on a stage 5 CKD patient with no dialysis. Our result had revealed a potential treatment option for the end-stage patients who refuse these invasive procedures.Conceptualization: Chien-An Yao.Data curation: Chih-Hui Lin.Formal analysis: Chien-An Yao, Chih-Hui Lin.Investigation: Chien-An Yao.Writing – original draft: Chien-An Yao, Chih-Hui Lin.Writing – review & editing: Chien-An Yao, Chih-Hui Lin.


ONHBF) has been postulated to play an important role in primary open‐angle glaucoma (POAG). We used laser Doppler flowmetry (LDF) to estimate quantitatively the ONHBF and compared ONHBF autoregulation between glaucoma patients and healthy controls during isometric exercise.Abnormal autoregulation of optic nerve head blood flow  was measured continuously using LDF. Systemic blood pressure, intraocular pressure and ocular perfusion pressure were assessed in all participants.Forty patients with ONHBF in either group. Three of the glaucoma patients and two of the healthy subjects showed a consistent 10% decrease in blood flow during isometric exercise, in spite of an increase in their blood pressure. This difference between groups was not significant (p = 0.61). Four other glaucoma subjects showed a consistent increase in blood flow of more than 10% during isometric exercise, whereas this was not seen in healthy subjects (p = 0.035).Isometric exercise was associated with an increase in ocular perfusion pressure during all handgripping periods in both groups (p < 0.001). However, there was no change in ONHBF autoregulation is more often seen in patients with POAG than healthy control subjects. The relationship to the glaucoma disease process is currently unknown and requires further investigation.This study suggests that abnormal  Abnormal autoregulation of the optic nerve head blood flow (ONHBF) has been implicated in the pathophysiology of primary open‐angle glaucoma (POAG) (Flammer & Mozaffarieh Measuring ONH blood flow (ONHBF) autoregulation is challenging. Firstly, it is technically difficult because of the complex angio‐architecture of the optic nerve head region  guidelines. Forty patients with POAG and 40 healthy age‐ and sex‐matched control subjects were included in this study. All participants signed written informed consent after the nature of the study had been explained in detail. Each subject passed a screening examination that included medical history and physical examination. Subjects were excluded if they were pregnant, were smokers, had uncontrolled hypertension or if any abnormality was found as part of the pretreatment screening unless the investigators considered the abnormality to be clinically irrelevant.Patients with POAG were recruited from the outpatient clinic of the glaucoma service at the Department of the Ophthalmology, Medical University of Vienna Austria, and the private praxis of Dr. Anton Hommer. The healthy control subjects were recruited from the database of the Department of Clinical Pharmacology, Medical University of Vienna, Austria. All participants underwent a standardized ophthalmic examination, including slit lamp biomicroscopy, indirect funduscopy, gonioscopy and applanation tonometry. In subjects with childbearing potential a pregnancy test was performed. Diagnosis of manifest POAG was defined as pathological optic disc appearance, glaucoma hemifield test outside normal limits and pathological thinning of retinal nerve fibre layer as shown in optical coherence tomography (OCT‐RNFL). Glaucoma patients were excluded if they met these criteria: exfoliation glaucoma, pigmentary glaucoma, history of acute angle closure, mean deviation (MD) of visual field testing  worse than −10, intraocular surgery or laser trabeculoplasty within the last 6 months, ocular inflammation or infection within the last 3 months and pregnancy. Further exclusion criteria were ocular disease other than glaucoma potentially interfering with the purposes of the study as judged by the investigators. Healthy control subjects were age‐ and sex‐matched and had to have normal ophthalmic findings, that is no evidence of increased IOP in previous ocular history as well as no structural and/or functional signs of glaucomatous damage and IOP <20 mmHg on at least three measurements.Sample size calculation was performed according to previous reproducibility data in healthy subjects , diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) were measured on the upper arm by an automated oscillometer. Pulse rate (PR) was recorded from a finger pulse‐oxymetric device .Measurements were performed using a laser Doppler flowmeter for ONHBF . Briefly, the Doppler shift power spectrum is used to measure blood flow, blood velocity and blood volume based on a theory of light scattering in tissue. Velocity is calculated as the mean velocity of the red blood cells moving in the sampled tissue proportional to the mean Doppler frequency shift. Volume is the number of moving red blood cells in the sampled tissue proportional to the amount of Doppler shifted light. Blood flow is calculated as the product of velocity and volume. Only data with a direct current (DC) value of ±15% to the baseline value were included for analysis. Subjects were excluded from analysis if they did not meet this reproducibility criterion during each of the 2‐min period. The laser beam was directed towards the temporal neurovascular rim, and any visible vessels within the scattering volume were avoided. Data were corrected for differences in DC as published previously  was measured using Goldmann applanation tonometer. Ocular perfusion pressure in the sitting position was calculated as 2/3* MAP – IOP .An independent n = 18, controls: n = 7; p = 0.09), there was no difference in the frequency of hypercholesterolemia . There was no difference in age or gender distribution between the two groups. Systolic blood pressure was slightly higher in POAG patients than in healthy control subjects. Table Baseline characteristics of the participants are presented in Table anova). There was no significant difference between POAG patients and healthy control subjects . The effect on OPP and ONHBF is depicted in Fig. The effect of isometric exercise on MAP and PR is shown in Table Individuals exhibiting changes in ONHBF of more than 10% were observed Table . Four glIn the present study, we observed that a proportion of POAG patients showed an abnormal ONHBF autoregulation when compared to healthy control subjects. Changes in OPP during handgripping periods and ONHBF autoregulatory range were similar in the whole‐population sample Fig. . HoweverA number of previous studies indicated abnormal ocular blood flow autoregulation in glaucoma using different technologies for the assessment of ocular perfusion. Many of these studies used measurement of retrobulbar flow velocities with colour Doppler imaging (CDI) to gain insight into ocular hemodynamics (Evans et al. The number of studies that focused specifically on ONHBF is small. Variations of ONHBF during diurnal variations in OPP were studied using scanning LDF (Sehi et al. A technique related to LDF is laser speckle flowgraphy (Sugiyama et al. The present study has some strength and weaknesses: we used repeated continuous stimuli which hopefully better identify individuals with abnormal blood flow response rather than solely relying on group averages. We had a relatively small number of patients in the present study. This, in part, is related to the difficulty of operating the LDF. In addition, we chose a margin of 10% change in blood flow as having an autoregulatory response. This is based on our previous data (Boltz et al. Also, we could only reliably obtain blood flow information from approximately 80% of subjects which indicates that the current technique is not ideal for clinical setting (Luksch et al. In conclusion, the present study provides direct evidence for altered ONHBF regulation in some POAG patients. Using repeated stimuli with isometric exercise, we were able to identify subjects with abnormal ONHBF regulation patterns and these subjects were more frequently identified in the glaucomatous group than in the healthy control group. There is a need to further refine this technique to improve its feasibility for the clinic, thereby allowing future studies to investigate the autoregulatory abnormalities in the disease process.


Neonatal asphyxia caused kidney injury and severe hypertension in a newborn. An unusually dilatated ascending aorta developed. Dialysis and pharmacological treatment led to partial recovery of the ascending aortic diameters. It was hypothesized that the aortic dilatation may be associated with aortic stiffening, peripheral resistance, and cardiovascular changes. Mathematical modeling was used to better understand the potential causes of the hypertension, and to confirm our clinical treatment within the confines of the model’s capabilities.The patient’s systolic arterial blood pressure showed hypertension. Echocardiographic exams showed ascending aorta dilatation during hypertension, which partially normalized upon antihypertensive treatment. To explore the underlying mechanisms of the aortic dilatation and hypertension, an existing lumped parameter hemodynamics model was deployed. Hypertension was simulated using realistic literature informed parameter values. It was also simulated using large parameter perturbations to demonstrate effects. Simulations were designed to permit examination of causal mechanisms. The hypertension inducing effects of aortic stiffnesses, vascular resistances, and cardiac hypertrophy on blood flow and pressure were simulated. Sensitivity analysis was used to stratify causes.In agreement with our clinical diagnosis, the model showed that an increase of aortic stiffness followed by augmentation of peripheral resistance are the prime causes of realistic hypertension. Increased left ventricular elastance may also cause hypertension. Ascending aortic pressure and flow increased in the simultaneous presence of left ventricle hypertrophy and augmented small vessel resistance, which indicate a plausible condition for ascending aorta dilatation. In case of realistic hypertension, sensitivity analysis showed that the treatment of both the large vessel stiffness and small vessel resistance are more important in comparison to cardiac hypertrophy.Large vessel stiffness was found to be the prime factor in arterial hypertension, which confirmed the clinical treatment. Treatment of cardiac hypertrophy appears to provide significant benefit but may be secondary to treatment of large vessel stiffness. The quantitative grading of pathophysiological mechanisms provided by the modeling may contribute to treatment recommendations. The model was limited due to a lack of data suitable to permit model identification. Ascending aortic dilatation and arterial hypertension may be related to an increased aortic blood vessel stiffening . Aortic In silico biophysical modeling is now an established diagnostic-prognostic methodology which is increasingly assisting clinicians in their practice  by day 2 of life. She developed arterial hypertension, which was likely because of volume overload  and minimum  values, this pumping action leads to an oscillating left ventricular pressure as shown in The model  compliance, CSAT; vena cava compliance, CSVN; and pulmonary vein compliance, CPVN. These compliances of the large blood vessels permitted simulation of aortic blood vessel stiffening, as well as stiffening of vena cava and pulmonary veins. The elastance of the left ventricle, Elv, oscillates between prescribed minimum  and maximum  values in the model. To simulate hypertrophy, the left ventricular pumping function, Elv,max, was increased.Relevant model parameters were assigned the following interpretation within the scope of this study. The systemic capillary bed resistance, RSAT, was recorded to characterize arterial hypertension. The pulmonary artery pressure, PPAT, was used to characterize effects of hypertension inducing factors on the pulmonary circulation. Reduced renal function may simultaneously reduce blood flow in the vena cava and urine amounts. An explicit excretion process is unavailable in the model. In the event of increased renal arterial microvascular resistance, the draining venous  flow may be reduced and be at a significantly lower pressure. Due to the structure of our model, an increased peripheral  microvascular resistance may be expected to reduce both quantities. Urine output was therefore characterized using vena cava flow, QSVN. In addition to PSAT, the systemic artery blood flow, QSAT, was recorded to characterize the effects of hypertension on aortic flow. Among the wide spectrum of clinically significant conditions causing pediatric aortic dilatation  were reduced to simulate increase of stiffness. The effect of an increased heart rate was simulated by altering the pacing period of the heart as described in the model  was defined as hypertension. Whereas the clinically accepted definition of hypertension encompasses multiple factors, the data informing this study was that of the patient’s arterial systolic blood pressure. Simultaneous increase of the flow through the aortic valve, QAO, and the left ventricle systolic pressure, PLV, was assumed to be directly proportional to ascending aortic diameters. The flows in the systemic vein (or vena cava), QSVN, pulmonary artery, QPAT, as well as the pressure in the pulmonary artery, PPAT, were used to assess status of venous flow and pulmonary sufficiency. The left ventricle pressure, Plv, and volume, Vlv, were recorded to construct pressure-volume loops. Areas of pressure-volume loops represent cardiac stroke work and were used to compare cardiac status under normal, hypertensive, hypertrophied, and other conditions.Following definitions of the clinical conditions within the scope of the model were used. The volume overload due to the acute kidney injury, as well as autoregulatory responses such as to the renin-angiotensin-aldosterone system were assumed to increase systemic microvascular resistances, Rhe model , b. Finahe model , b. MultSAR) on model output . Dynamic sensitivity analysis was used to assess impact of parameter alterations on time varying model output. Whereas global sensitivity measures provide information regarding overall model metrics  combination of interest. As Sij is local, it was computed under control and pathological conditions to permit assessment of the changes in sensitivity of relevant variables Vi to pj at different values , thus permitting to assess the maximum effectiveness of a given treatment in a range of parameter values. To the best of our knowledge, quantitative data regarding alterations of model parameters under pathological conditions is scarce. We reiterate that our aim was to indicatively simulate the effects of hypertension, and as such, the results are phenomenological. We first identified parameter values to provide a definition of realistic hypertension . lv was approximately 200% higher in the normotensive group when compared to the mean Elv across all there hypertensive groups. When investigating the relationship between aortic compliance and human hypertension  was also simulated using their exaggerated values. The diseased condition was simulated by increasing RSAR by 25-fold, reducing CSAT  to 0.25 of its baseline value, and increasing Elv by tenfold  systolic pressure. The echocardiographic data was taken to represent events at the ascending aorta.As shown in Analysis of the echocardiography based four ascending aorta diameters  per cardDuring dialysis, the patient’s urine output was alarmingly negligible. As shown in The model’s baseline behavior is reproduced in SAT) and flow (QSAT) on model parameters is shown in SAT by 17% due to small vessel resistance increase  by 75%. A similar but smaller effect was observed due to hypertension 1 conditions. Increased aortic stiffening (4-fold reduction in CSAT) lead to a modest reduction of PPAT , and an increased heart rate, where hypertension 2 parameter values for RSAR and CSAT were used. When heart rate was increased, the area of the pressure-volume loop was significantly smaller than that of that in the baseline case. The pressure-volume loops for increased RSAR and for decreased CSAT bound a similar area as in the baseline case, they were, however, elongated. Hypertension 1 showed similar but less marked alterations of the pressure-volume loops (not shown).The pressure-volume loops under four conditions are shown in SAR, the ascending aorta blood flow increased due to increased hypertrophy. The aortic flow at baseline RSAR was 450 ml/s, at hypertension 1 was 1250 ml/s, and at hypertension 2 was 920 ml/s  and arterial stiffness   . Figure e, CSAT) . The core, CSAT)  appear te, CSAT) , arteriae, CSAT) . SupplemSAT to parameters RSAR, CSAT, and Elv is shown in SAT, has a small sensitivity to the peripheral resistance, RSAR  in this study, increased the pressure of blood ejected from the left ventricle. At higher pacing rates, the increased pressure causes blood to flow at a higher pressure into the aorta, simultaneous to high systemic resistance  could be identified as aortic stiffness. In our model left ventricular hypertrophy and increased resistance in the systematic arteries were also associated with arterial hypertension. It may be noted that an increase of the microvasculature resistances increased systolic pressure but decreased systolic flow in the systematic arteries . In contsistance . At moresistance . As the Although biophysically detailed, the presented phenomenological results must be considered cautiously bearing model limitations in mind. For efficacy, 0D models should be further informed by 3D simulations and experimental-clinical data to produce physiological flow rates and pressures. The Windkessel parameters can be estimated using non-invasive and routine clinical measurements such as systolic and diastolic pressures, as well as heart rates. 0D models can also be calibrated for patient-specific geometries and measurements . Howeverde novo descriptions will incorporate extant data. As the peripheral resistance is clinically defined as the ratio of blood pressure and cardiac output, routine clinical assessments can provide estimates of cardiac output may permit estimation of the peripheral resistance , where H is the circumferential wall stress, P is the transmural pressure gradient, r in the radius and T is the wall thickness; therefore, for a given transmural pressure and aortic diameter there must be a proportional wall thickness to maintain normal wall stress.In the context of this clinical-modeling study, we need to discuss the physiology of the arterial tree to understand the possible mechanisms that can lead to transient proximal aortic dilatation. The arterial tree has two purposes: first it acts as a conduit relying on width of the arteries and systemic vascular resistance, the second purpose is to ensure continuous steady flow in systole and diastole by dampening pressure oscillations cause by the intermittent ejection from the left ventricle (Windkessel effect). The arterial blood pressure wave is amplified as it travels away from the heart due to the summation of forward and reflective waves, the reflective waves are higher further away from the proximal aorta . The wayIn our case the acute elevation of arterial hypertension without a compensatory thickening of the wall, would increase the wall stress and produce aortic dilatation, this was reverted when the blood pressure was controlled and was not likely related to the kidney injury. This is different in children and young adults with arterial hypertension where prevalence of ascending aortic dilatation is 10% which is usually associated with increased ventricular mass, and it appears to be a chronic phenomenon . In summThe presented model permits exploration of overall blood flow and pressure dynamics in the whole body. Although relatively simple as compared to other contemporary models, it has a large number of variables and parameters that have been validated using clinical data. It assisted us to highlight the most effective parts of the anti-hypertensive therapy with and without thrombosis. Therefore, as a first recourse, use of the Shi model is justified. However, in future studies, more detailed representations (0D or otherwise) of organ and whole-body vasculature will be implemented to further permit personalization of the computer models to clinical service. This is relevant as several clinically identified mechanisms are known to be present .From a clinical treatment design perspective, the model confirms our diagnosis and provides further indications. The modeling results firstly confirm the clinical diagnosis of arterial stiffness, cardiac hypertrophy, and augmented peripheral resistance as a cause of hypertension . IncreasA spectrum of other computational studies have explored the hemodynamics of hypertension to uncover relationships among vascular structure and hemodynamic observables. Similar to presented Despite the straightforward nature of the model used, this study has provided insights into the mechanisms of the observed hypertension. It has provided a plausible explanation for the observed aortic dilatation, as well as providing potential predictions.1.To the best of our knowledge, this is the first case report in newborn with arterial hypertension secondary to acute kidney injury who developed significant aortic dilation in month 1 of her birth, which was reversible up on stringent blood pressure therapy.2.Ascending aorta dilatation may develop very quickly in a patient with arterial hypertension. The dilatation should be explored as a potential diagnostic marker of arterial hypertension, especially since it can be examined non-invasively using echocardiograms as done in the clinical part of this study.(i) Arterial stiffness should be treated for most effective treatment of hypertension.(ii) In the treatment of hypertension, treatment of micro-vascular resistance and cardiac hypertrophy is also important.(iii) Cardiac hypertrophy is a factor that acts along with microvascular resistance and aortic stiffness to promote a dilated ascending aorta.https://github.com/mccsssk2/Arterial-Hypertension.git.For reproducibility and future development, our codes and anonymized data used in this study are available from the open source repository: All datasets generated for this study are included in the manuscript and the LA-D, GF, and CM designed and performed the clinical diagnostic exams, and delivered the therapy. SK and CM designed the modeling study. SK implemented the computer model codes, designed the simulation experiments, and performed the high throughput computing. AK assisted in model testing and annotating. SK and AK constructed the modeling figure drafts. LA-D and GF wrote the clinical draft sections. SK, AK, and BS wrote the modeling draft sections. All authors revised and approved the manuscript.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.


Background and aims: Chronic kidney disease (CKD) has been regarded as a severe threaten to public health, a large percentage of CKD are secondary to other diseases. Serum creatinine is the most common marker of renal function, but it did not always reflect glomerular filtration rate (GFR) accurately. In order to investigate the prevalence of kidney disease in non-renal departments and to provide a basis for the prevention of kidney injury, the present study was conducted in several medical centers.Methods: A total of 17,462 outpatients were selected randomly from the departments of cardiology, endocrinology, and neurology in 16 hospitals and the incidence of kidney disease was screened. Estimated GFR (eGFR) was calculated by using MDRD-formula.Results: There are 5293 (30.1%) patients’ eGFR above 90 mL/min/1.73m2 among all the subjects in non-renal departments, and 4055(23%) patients’ eGFR lower than 60 mL/min/1.73 m2 including 80 patients whose eGFR were below 15 mL/min/1.73 m2. Furthermore, among 16616 subjects who have a normal SCr level, there are 3209 respondents’ eGFR lower than 60 mL/min/1.73 m2. Moreover, individuals with hypertension or diabetes had a high prevalence of decreased renal function.Conclusions: This survey indicated kidney injury wildly existed in non-renal outpatients, and the incidence of CKD is underestimated. Accompanied by the demographic of the outpatient population changing, individuals suffer from preexisting kidney injury grow increasingly.Kidney disease is known to be associated with other diseases. Risk factors for CKD include age (more than 60 years), hypertension, diabetes, cardiovascular disease, and a family history of the renal disease. Meanwhile, several studies have reported that kidney dysfunction, even at early stages, is an important independent risk factor for many other diseases and death.Since kidney injury is closely associated with many other diseases, the morbidity of kidney injury in non-nephrology departments is underestimated. Although most patients with early stages of chronic kidney disease are asymptomatic, kidney injury is being recognized by nephrologists as an important health problem for a long time.The study was approved by Ethical Committee of Shanghai Jiao Tong University Affiliated Sixth People's Hospital and written informed consent was obtained from all subjects. From 1 December 2015 to 29 February 2016, 17462 subjects selected from the departments of cardiology, endocrinology, and neurology in sixteen hospitals were screened for kidney injury. Actually, our study was conducted widely in given departments of different medical center. Patients are selected randomly from different medical center. After the obtained patients’ consent, the survey includes medical records and other basic data were collected. When they are qualified our inclusion criteria, their fasting venous blood was collected in the morning for measurement. Inclusion criteria was listed as below: (1) outpatients with diagnosed related disease; (2) no kidney disease history. These individuals visited hospitals for hypertension, diabetes mellitus, and other non-renal diseases.−1.154 × age−0.203× .Creatinine Assay Kit  was used for serum creatinine measurement. Clinical data, serum creatinine, and the estimated glomerular filtration rate (eGFR) were calculated. Kidney function was assessed by using eGFR, which was determined according to the simplified Modification of Diet in Renal Disease (MDRD) formula: eGFR is equal to 186 × Scrt-tests or analysis of variance (ANOVA). Nonparametric data are expressed as medians (25–75% interquartile range). A two-sided p values <0.05 was considered significant.Normally distributed data are expressed as the mean standard deviation; groups were compared using two independent sample There are 18,007 patients enrolled in the research from 2015 to 2016. A total of 17,462 individuals were included in the final analysis. Patients were excluded for missing data or known kidney disease. Overall, the study included 17,462 patients, mean age of 67.6 ± 13 years, of whom 8285 (47.4%) were females, mean age 68.1 ± 12.9, and 9177 (52.6%) male, mean average age 67.1 ± 13.1. 11,035 (59.5%) respondents were older than 65 years. Besides, more than half of respondents (54.6%) developed hypertension. Hypertension with type-2 DM was confirmed in 18.3% of patients, while those who suffered from type-2 DM isolated were present in 22.6% cases. Additionally, there are 257 (1.5%) patients suffer from coronary heart disease according to the datum.2 including 80 patients whose eGFR below 15 mL/min/1.73 m2. Besides, patients who have eGFR between 6 0 ∼ 90 mL/min/1.73 m2 have the largest population. There are 8185 (46.7%) patients in that range, almost account for half of the respondents. Furthermore, there are only 5256 (30.1%) patients’ eGFR above 90 mL/min/1.73 m2  patients’ eGFR lower than 60 mL/min/1.73 m/1.73 m2 .2. Different kinds of diseases have different proportions (Among 16,616 subjects who have a normal SCr level, there are 3209 respondents’ eGFR lower than 60 mL/min/1.73 mportions  (Figure Individuals with hypertension or diabetes had a high prevalence of decreased kidney function . As for Kidney injury, includingAKI and CKD, is a severe and common clinical syndrome with adverse outcome and it becomes a worldwide public health problem.In this study, we investigated the renal function in 17,462 non-nephrology outpatients. Firstly, compared with the reported incidence of kidney injury in public, the proportion of the renal injury is relatively higher in the fields of cardiology, endocrinology, and neurology. This phenomenon is particularly remarkable among respondents with both hypertension and diabetes. Previous studies had indicated that hypertension, diabetes, and CKD interacted to each other. They also confirm that early chronic kidney disease is high prevalence in high-risk outpatients in Sarajevo.Our study has some limitations as well. One is that some data were missing since it is difficult to trace outpatient clinic information. However, the sample size is large enough, thus the result is reliable. Another limitation is that our research only covered several departments, and hence, outpatients that we random chosen cannot represent all kinds of basic diseases patients, and as a result, it may lead to outcome bias. In addition, only once measure was not enough for steady-state assessment for patient. There may be sampling error existed. However, as large sample size enough, we still believe that the sample error was minimized and our results are reliable.,Among patients with cardiovascular or endocrine diseases, the high prevalence of kidney injury and general underestimated by clinicians has important implications. For the sake of safety treatment, physicians should avoid overlooking kidney injury in those non-nephrology outpatients. Since the serum creatinine cannot reflect kidney function accurately, physicians who rely on serum creatinine to identify underlying kidney disease will under-diagnose the presence of impaired kidney function. Physicians suggested be educated that estimated GFR should be measured, no matter whether SCr level is normal.As for outpatients, leading to lifestyle modifications and risk factors treatments are necessary for preventing progressive kidney diseases.Chronic kidney disease has a high prevalence in the non-nephrology departments. However, this incidence is underestimated by not only the general public but also clinicians. Since renal injury can directly affect therapeutic schedules, non-nephrology physicians should pay close attention to kidney function.


Sputum induction is an important noninvasive method for analyzing bronchial inflammation in patients with asthma and other respiratory diseases. Most frequently, ultrasonic nebulizers are used for sputum induction, but breath-controlled nebulizers may target the small airways more efficiently. This treatment may produce a cell distribution similar to bronchoalveolar lavage (less neutrophils and more macrophages) and provide deeper insights into the underlying lung pathology. The goal of the study was to compare both types of nebulizer devices and their efficacy in inducing sputum to measure bronchial inflammation, i.e., cell composition and cytokines, in patients with mild allergic asthma and healthy controls.The population of this study consisted of 20 healthy control subjects with a median age of 17 years, range: 8–25 years, and 20 patients with a median age of 12 years, range: 8–24 years, presenting with mild, controlled allergic asthma who were not administered an inhaled steroid treatment. We induced sputum in every individual using both devices on two separate days. The sputum weight, the cell composition and cytokine levels were analyzed using a cytometric bead assay (CBA) and by real-time quantitative PCR (qRT-PCR).We did not observe significant differences in the weight, cell distribution or cytokine levels in the sputum samples induced by both devices. In addition, the Bland-Altman correlation revealed good concordance of the cell distribution. As expected, eosinophils and IL-5 levels were significantly elevated in patients with asthma.The hypothesis that sputum induction with a breath-controlled “smart” nebulizer is more efficient and different from an ultrasonic nebulizer was not confirmed. The Bland-Altman correlations showed good concordance when comparing the two devices.NCT01543516 Retrospective registration date: March 5, 2012. Sputum induction is a well-known, noninvasive method for analyzing bronchial inflammation in patients with asthma and other respiratory diseases , 2. StanAlthough sputum protocols have been developed to optimize the duration of inhalation and saline concentrations used, few protocols have compared different nebulizers , 8. DaviSeveral nebulizers are available, and the size of produced respirable particles is important for lung deposition. Conventional nebulizers deliver aerosol particles of approximately 5–10 μg in size, and most droplets are shed in the upper and larger airways. Ultrasonic nebulizers provide smaller droplets of 2–5 μg, and these droplets may be inhaled more easily in the lower airway. For ultrasonic nebulizers, such as the Omron nebulizer, a number of published studies have shown superior efficiency . In addiTherefore, the technical standardization of sputum induction seems to become more important for more efficiently targeting the small airways and providing deeper insights into lung pathology, comparable to BAL. Based on this information, we investigated whether sputum induction with a smart nebulizer and its technical settings produce a sputum cell distribution similar to BAL. In the present study, we compared sputum weight, cell composition and cytokine levels following treatment with an optimized smart nebulizer and an ultrasonic nebulizer.The study included 20 healthy control subjects with a median age of 17 years, range: 8–25 years, and 20 patients with a median age of 12 years, range: 8–24 years, who presented with mild, controlled allergic asthma but were not receiving an inhaled steroid treatment ).Total RNA was extracted from induced sputum samples using the Qiagen RNeasy Mini Kits , according to the manufacturer’s instructions. All sputum plugs were processed with RNAprotect cell reagent and PBS, according to the manufacturer’s instructions. Before reverse transcription, a DNase treatment was performed using DNase I , as described recently . The prTranscripts were quantified using two-step real-time RT-PCR with an Eppendorf Mastercycler RealPlex S detection system  in Greiner 25 μL 96-well reaction plates . The expression of the IL-5, IL-8, TNF-α and IFN-γ mRNAs was normalized to the endogenous control glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), and the relative quantification and calculation of range of confidence was performed using the comparative threshold cycle (2 − ΔΔCt) method (relative gene expression). All amplifications were performed in at least duplicate reactions. The expression data and statistical analysis of the genes involved in immune cells and inflammatory markers were analyzed as previously described , 15.The data were analyzed with Microsoft Excel , GraphPad Prism 5.0  and BIAS for Windows 11.0 software . The results are presented as medians ± ranges. The differences between the nebulizers were calculated using the Wilcoxon matched-pairs test and the Bland-Altman method. The differences between the patients with asthma and the controls were calculated using the Mann-Whitney test.The demographic and clinical characteristics are shown in Table The analysis of the sputum weight [g] did not reveal statistically significant differences between the two devices. The median preprocessing sputum weight of the controls was 5.64 [g] (2.77–22.09) at V1 and 6.60 [g] (2.72–14.10) at V2. For patients with asthma, the median preprocessing sputum weight was 5.14 [g] (2.55–8.09) at V1 and 4.97 [g] (2.64–10.52) at V2. The median weight of the induced sputum in the group of controls was 3.19 [g] (1.22–6.6) at V1 and 3.85 [g] (1.89–7.82) at V2. In patients with asthma, the median weight was 2.90 [g] (1.71–5.03) at V1 and 3.18 [g] (1.82–7.19) at V2 Fig.  and b.Fip = 0.41; patients with asthma: p = 0.33) [Fig. Total cell counts [106 cells/ml] were compared between the controls and patients with asthma and between the nebulizers. A difference in the total cell counts in induced sputum was not observed between the devices in either group (controls: 33) Fig. .Fig. 2Top = 0.605; patients with asthma: p = 0.737). Additionally, a significant difference in the percentage of neutrophils after the use of the different devices was not observed in either group . The percentages of eosinophils did not differ between sputum collected with the different devices , but the percentage of eosinophils differed significantly between patients with asthma and controls based on the inclusion criteria . The results are shown in Fig. Each cell subtype was compared between the sputum collected with the ultrasonic and smart nebulizers. A comparison of the percentage of macrophages after induction with the ultrasonic or the smart nebulizer did not show significant differences in either group (controls: p = 0.0360 at V1 and p = 0.0115 at V2) [Fig. p = 0.420 vs. IL-8 in patients with asthma p = 0.7439 and IFN-γ in controls p = 0.695 vs. IFN-γ in patients with asthma p = 0.327) were not different between the patient groups. In addition, no differences in cytokine levels measured using CBA were identified between the two nebulizers.The cytokine levels measured by qRT-PCR and CBA were compared between the devices. No significant differences were observed for levels of the cytokine proteins and mRNAs between the sputum collected with the two devices. As expected, qRT-PCR revealed that patients with asthma had significantly higher levels of IL-5 than controls (V2) Fig. . IL-8 anThe correlation between both devices was analyzed using the Bland-Altman method, which compares differences in two methods using their means. We compared the cell counts obtained after the use of both devices. A small bias of − 0.2441 and a SD of 9.614 were found for the macrophage population, and a bias of − 0.5075 and a SD of 8.016 were identified for the neutrophils. The results are shown in Table Because sputum induction is a noninvasive method for evaluating bronchial inflammation, particularly for diagnostic research purposes, the induction methods, including devices and their technical settings, must be standardized . For thiThe total deposition of aerosols in the lungs depends on the particle size, breathing pattern, and lung volume . In addiHowever, the hypothesis that sputum induction with a smart nebulizer, here, the Akita Jet, and its technical settings produce a sputum cell distribution similar to BAL was not confirmed in our study. In addition, significant differences in any of the investigated parameters, including gene expression levels and cytokine patterns, were not observed between the two devices. One criticism is that the nonrandomized design of our study may induce a small learning effect in favor for the Akita Jet results. However, when we considered the difference in handling of both nebulizers, the learning effect was neglected. The Bland-Altman correlations showed good concordance when comparing the two devices. This finding is contradictory to previous studies showing that smart nebulizers are more efficient drug delivery devices that deposit larger amounts of the inhaled dose in the small airways , 23, 24.One possible explanation for this discrepancy is related to the saline particles. Hygroscopic particles such as NaCl tend to increase in size when passing through the lung due to humidity, thus limiting the diameter for the minimum deposition in the peripheral lung . AdditioConversely, the inhalation of an aerosol, regardless of whether it is deposited in central or peripheral airways, must not lead to a higher expectoration of sputum and inflammatory cells. Because the underlying pathological mechanism of asthma involves hyperplasia of the smooth muscle, the expectoration of peripheral sputum is likely limited due to decreases in the diameter of the lumen, which might retain secretions. Indeed, Pavia et al. have identified a positive correlation between patients’ FEV1 and the depth of deposition –28. In aFinally, breathing patterns have been shown to influence lung deposition in several studies , 27, 30.In conclusion, we did not detect differences in sputum induction between the ultrasonic nebulizer and smart nebulizer. The sputum weight, the cell composition and cytokine levels showed good concordance when comparing the two devices. In particular, for academic purposes, additional investigations aiming to standardize the technical settings of sputum induction should be performed in the future.


Monoamine oxidase (MAO) activity has been traditionally implicated in blood pressure through its effects on biogenic amine levels such as catecholamines, serotonin, and dopamine. Nowadays, this role is considered relegated to side‐effects such as orthostatic hypotension and/or hypertensive crisis derived from MAO‐inhibitory treatments in patients with psychiatric disease.MAOB gene and arterial hypertension in obese hypogonadic patients. The study cases comprised a series of 219 nondiabetic males with a body mass index ≥30 kg/m2 and aged <45 years. Hypogonadism was defined as subnormal testosterone concentrations, when free testosterone values ranged <65 pg/ml.In the present work we have found an association between a polymorphic variant of MAOB rs3027452‐A allele carriers were significantly over‐represented among hypertensive (HT) patients (25.49%) in comparison to either the non‐HT patients  and the control population series of nonobese nor hypogonadic males . Upon adjusted, an independent association was shown with the hypogonadic group with hypertension when compared with nonhypertensive hypogonadics . When quantitative analysis was performed, hypertensive patients harboring rs3027452‐A allele showed higher systolic blood pressure values  as well as an increased Systolic‐Diastolic range despite following HT treatment . Previous studies on MAOB revealed that rs3027452‐A allele has been correlated to a lower activity of the enzyme, what gives a functional evidence over our observation.If this result could be extrapolated to other hypertensive patient groups, it would implicate a review of the markers and therapeutic targets on human hypertension. MAOB gene and arterial hypertension in obese hypogonadic patients.Male hypogonadism is a disorder in which the testes are not functional or there is a genetic inability of the hypothalamus to secrete normal amounts of GnRH. The masculine sexual characteristics are not developed and can bring a wide range of clinical manifestations. We have found an association between a polymorphic variant of  It has been shown that MAO activity in the cerebral spinal fluid is associated to the serotonin activity  has first been described as a serum vasoconstrictor molecule and subsequently has been identified as a neurotransmitter  recruited between 2013 to June 2015. Hypogonadism was defined as subnormal testosterone concentrations, defined when free testosterone values <65 pg/ml or total testosterone <3.5 ng/ml. Exclusion criteria for this study were previous diagnoses of hypogonadism, diabetes mellitus, use of antidiabetic medication, or being under any treatment known to affect the gonadal axis. Subjects with hepatic or renal impairment, established cardiovascular disease or cancer were also excluded. All subjects had a normal pubertal development and referred intact sense of smell. The control population consisted on 228 males recruited among healthy volunteers from the School of Medicine, University of Malaga. The study was reviewed and approved by the Ethics and Research Committee of Virgen de la Victoria Clinical University Hospital, Malaga (Spain), and was conducted according to the principles of the Declaration of Helsinki. The participants, all volunteers, provided signed consent after being fully informed of the study goal and its characteristics.The study cases comprised a series of 219 nondiabetic obese males with a body mass index (BMI) ≥ 30 kg/m2.2Cases provided a blood sample while healthy controls provided buccal swap that was used to extract genomic DNA using salting out method followed by ethanol precipitation. DNA quantity was determined using nanodrop prior to genotyping. Genotyping was outsourced to Genologica SL. SNP analysis was performed using the TaqMan Open Array Genotyping System from Applied Biosystems. The results obtained were processed using TaqMan Genotyper Software. The selected SNPs were chosen from the literature among those affecting the MAO activity . Bivariate regressions were used to adjust genetic Odds Ratios (OR). Multivariate results were expressed as standardized coefficient (beta). Significance was established for 3MAOA and MAOB polymorphisms among a hypogonadic population. No differences were observed between the genotype distribution of rs3788862, rs979605 nor rs3027452 between control population and the hypogonadic series. However, when the hypogonadic population was stratified according to the hypertensive status we found that rs3027452‐A carriers were significantly over‐represented among hypertensive (HT) patients (25.49%) in comparison to either the non‐HT patients  and the control population series of nonobese nor hypogonadic males  nor to therapeutic alternatives (MAOIs). Nevertheless, a genome linkage study found that two HT 2. We have not found a correlation between the studied polymorphisms and free or total testosterone levels. On the other hand, the association between sympathetic effects of obesity in the generation of HT is well known  and all of them with a BMI >30 kg/mnown Re, . It has MAOA genotype. A previous work quantified MAO activity in platelets for the different MAOB polymorphisms   was the least active in males. This haplotype is the only one that contains the MAOB rs3027452‐A allele, which is the polymorphism we have found to be overrepresented among our hypogonadic HT patients. Therefore, it might happen that the higher blood pressure found in these hypogonadic HT subjects could be due to the lower activity of MAOB associated to the A‐allele.Associations between blood pressure and the studied MAO alleles were only present in the hypogonadic HT group even though these subjects were treated with several antihypertensive drugs. Thus, systolic blood pressure was associated with the allele rs3027452‐A independently of the MAOB (which in turn can be associated to a lower MAOB activity) with blood pressure in obese hypogonadic patients with HT regarding the possible HT treatment. This would be of clinical interest since the assessment of genetic background in hypertension subjects could serve as starting point for personalized treatment. However, we are aware that our sample size might compromise the robustness of our findings. For this reason, further studies are necessary to replicate our results and eventually dig on the molecular mechanism by which these genetic variations can influence HT. Therefore we propose a genetic variant as a new etiological agent for HT that in turn may serve as a key target for new therapeutic approaches.In conclusion we report an association between the A‐allele of the rs3027452 polymorphism for The authors declare that there is no conflict of interest regarding the publication of this article. Click here for additional data file. Click here for additional data file.


Low oxygen delivery during cardiopulmonary bypass is related to a range of adverse outcomes. Previous research specified certain critical oxygen delivery levels associated with acute kidney injury. However, a single universal critical oxygen delivery value is not sensible, as oxygen consumption has to be considered when determining critical delivery values. This study examined the associations between oxygen delivery and oxygen consumption and between oxygen delivery and kidney function in patients undergoing cardiopulmonary bypass.Oxygen delivery, oxygen consumption and kidney function decrease were retrospectively studied in 65 adult patients.2, mean oxygen delivery was 281 ± 39 ml/min/m2. Twenty-seven patients (42%) had an oxygen delivery lower than the previously mentioned critical value of 272 ml/min/m2. None of the patients developed acute kidney injury according to RIFLE criteria. However, in 10 patients (15%) a decrease in the estimated glomerular filtration rate of more than 10% was noted, which was not associated with oxygen delivery lower than 272 ml/min/m2. Eighteen patients had a strong correlation (r >0.500) between DO2 and VO2, but this was not related to low oxygen delivery. Central venous oxygen saturation (77 ± 3%), oxygen extraction ratio (21 ± 3%) and blood lactate levels at the end of surgery (1.2 ± 0.3 mmol/l) showed not to be indicative of insufficient oxygen delivery either.Mean oxygen consumption was 56 ± 8 ml/min/m2 delivery and O2 consumption or kidney function decrease, even at values below previously specified critical levels. The variability in O2 consumption however, is an indication that every patient has individual O2 needs, advocating for an individualized O2 delivery goal.This study could not confirm an evident correlation between O DO2 is dependent on hemoglobin concentration, oxygen saturation and blood flow. When either of these factors decreases the reduction is met by an increase in organ O2-extraction rate (OER) to meet metabolic needs, until the point of maximum O2-extraction. When DO2 falls beyond this point, referred to as the critical DO2 level (DO2crit), a pathologic supply dependency arises as organ oxygen consumption (VO2) decreases proportionally to decreasing DO2. At this point, cells enter the anaerobic metabolism phase and lactate levels rise [Oxygen delivery , and arterial pO2 was kept between 10–15 kPa as measured by CDI500. Mean arterial blood pressure was kept between 70 and 80 mmHg using phenylephrine titration when applicable. Cardiac arrest was induced using either cold crystalloid cardioplegia  or warm blood cardioplegia . After cessation of CPB, protamine in a proportion of 1.0–1.2 mg/100 IU of the initial heparin dose was used as an antidote. If after this dose the ACT was still prolonged compared to baseline, the patient received an additional dose of protamine accordingly.General anaesthesia was induced using weight-related infusion of sufentanil (1.0 μg/kg), midazolam (0.1 mg/kg) and rocuronium bromide (1.0 mg/kg). Subsequently, maintenance doses of 5.0 mg/kg/h of propofol and 1.0 μg/kg/h of sufentanil were used. A Stöckert S5 heart-lung machine with a CP5 pump unit  was used in all cases, and comprised a phosphorylcholine-coated adult oxygenator tubing pack  and a Revolution centrifugal pump (LivaNova). Before initiation of CPB the patient received a bolus (300 IU/kg body weight) of heparin . CPB was started when activated clotting time  was extended to at least 400 seconds. After central cannulation, pulsatile CPB  was started with a pump flow indexed at 2.4 l/min/mContinuous inline monitoring of arterial and venous blood gas parameters during cardiac arrest was done using the CDI500, which was calibrated according to the instructions for use. In addition, arterial and venous blood samples were sent to the laboratory when on full CPB support and before initiating weaning from CPB. Laboratory results were used to recalculate the CDI500 data for hemoglobin towards more accurate results by means of regression. These, and all other CPB data were digitally gathered in a patient data management system . All data were automatically synchronized by the PDMS and combined into one output file at a rate of 6 data points per minute.2 and VO2 were calculated using recalculated CDI data as follows:DOb is blood flow in dl/min/m2 body surface area (BSA) and CaO2 and CvO2 are arterial and venous oxygen content respectively (in ml/dl). The latter were calculated using the following equations:Where Q2 and SvO2 are arterial and venous O2 saturations  and PaO2 and PvO2 are the partial pressures of O2 in arterial and venous blood respectively (in mmHg).Where hb is hemoglobin concentration in g/dl; SaO2 and DO2:The oxygen extraction ratio (OER) was calculated by dividing VO2 and DO2 are in ml/dl/m2.Where both VO2 above 270–300 ml/min/m2 [2crit level found by Ranucci et al [2) applies to our patient population. Therefore, the population was split in a group with a mean DO2 higher than 272 ml/min/m2 during the aortic cross clamp time (group DO2 >272) and a group with a mean DO2 lower than 272 ml/min/m2 (group DO2 <272). The two groups were then compared on the prevalence of postoperative kidney function decrease, which was assessed by calculating the estimated glomerular filtration rate (eGFR) using the simplified 'modification of diet in renal disease' formula [As most perfusion goals are aimed at keeping DOl/min/m2 , 9 we chci et al   compared to the preoperative value as declined postoperative kidney function.Where Sing >24h , 12. HowPatients were divided into a group with >10% kidney function decline and a group with less decline or no decline at all. Differences between these groups were then analysed.2 and ΔeGFR groups on pre-, intra- and postoperative characteristics, Mann-Whitney U tests and Chi-squared tests were performed. Analysis of the relation between DO2 and ΔeGFR was done by crosstab analysis with the exact test module [2 and VO2 per patient, and crosstab analysis with an exact test was used to analyse the effect of low DO2 on these correlations. Blood lactate levels at the start of CPB and at the end of CPB were compared with a paired sample t-test.Statistical analysis was performed using IBM SPSS, version 23. Data are presented as mean ± standard deviation (sd) where applicable. To compare the DOt module , 14 and The majority of the patients (n = 48) included in this study underwent isolated coronary artery bypass grafting (CABG) or isolated aortic valve replacement . One case was a combined intervention (CABG + AVR) and one case was a mitral valve plasty (MVP). All these procedures were performed under normothermic CPB. Additionally, two procedures were performed using mild hypothermia .2 was 56 ± 8 ml/min/m2, varying between 38 and 76 ml/min/m2, whereas mean OER was 20 ± 3%. Mean oxygen delivery was 281 ± 39 ml/min/m2, ranging from 181 ml/min/m2 to 415 ml/min/m2. Twenty-seven patients (42%) had an average DO2 <272 ml/min/m2, the other 38 patients (58%) had an average DO2 >272 ml/min/m2. The preoperative EuroSCORE II and the percentage of patients with diabetes were significantly higher in the DO2 <272 group  in 18 patients, of whom 5 patients were in the DO2 <272 group. Crosstab analysis showed that DO2 <272 was not related to having a correlation between DO2 and VO2 (p = 0.260).The correlation between DO2 groups concerning the percentage of patients with a ΔeGFR >10%  had a ΔeGFR <10%, whereas 10 patients (15%) had a ΔeGFR >10%. Crosstab analysis showed no significant differences between the two DO2, VO2 and OER did not significantly differ between the ΔeGFR groups.Comparing the two ΔeGFR groups in terms of other patient and CPB characteristics  revealed2 and VO2 and AKI in patients undergoing CPB for cardiac surgery at our institution and to verify if the previously found DO2crit of 272 ml/min/m2 was applicable. Twenty-seven patients (42%) had an average DO2 lower than the DO2crit of 272 ml/min/m2, caused by a significantly lower perioperative hemoglobin level. Even though DO2 in this group was lower than the proposed critical DO2 value of 272 ml/min/m2, there were no patients with AKI according to the RIFLE criteria (>25% decrease in eGFR). To still be able to analyse if the low DO2 led to decreased kidney function, we chose to define decreased kidney function as a more than 10% decrease in eGFR compared to the preoperative value. Whether this decrease is clinically relevant, needs to be further determined. Previous research, however, has shown that even small decreases in eGFR and/or small increases in serum creatinine, and even detection of renal injury markers without actual renal function decrease are related to increased morbidity and mortality [2.This study was intended to explore the relationship between DOortality . Other rortality . There w2/DO2 relationship per individual patient, 18 patients had a positive correlation between DO2 and VO2. This however, showed not to be related to DO2 <272 ml/min/m2. Moreover, other parameters supported that the positive correlation between DO2 and VO2 in these patients did not arise because of pathologic supply dependency and that DO2 was adequate for aerobic metabolism. Central venous oxygen saturation (SvO2) is a routinely used marker of systemic tissue perfusion, reflecting the balance between DO2 and VO2. In our study population SvO2 was 77 ± 3%, which is higher than associated with tissue hypoxia and increased postoperative morbidity and mortality [2 as well. Furthermore, the lactate level before weaning (1.2 ± 0.3 mmol/l) was in the physiologic range, after a clinically not relevant increase from 1.0 ± 0.3 mmol/l at the start of CPB. A possible explanation for this trivial increase in lactate levels prior to CPB cessation might be washout of lactate accumulated in the heart during the aortic occlusion time. All this indicates that, despite mostly normothermic CPB and “low” DO2 in 42% of the patient population, DO2 seems to have been sufficient to prevent kidney function decrease or the commence of anaerobic metabolism.When analysing the VOortality . The OER2 groups, respectively), which was similar to the optimal blood pressure during CPB found by Hori et al. [2) [Analysing the differences between the two ΔeGFR groups, we found that all the tested parameters were similar, except for the preoperative hemoglobin level. This value however (8.6 ± 0.8 mmol/l in the ΔGFR <10% group and 8.1 ± 0.7 mmol/l in the ΔGFR >10% group), was still well above anaemia levels associated with increased risk of AKI . Moreovei et al.  and the i et al. . In addi al. [2) . Whether al. [2) –25. An e al. [2) , 26.2crit levels for patients in this study, as we did not find an association between DO2 and kidney function decrease, nor did we find an indication of the onset of the pathologic supply dependency between DO2 and VO2. The large range of VO2 values (ranging from 38 to 76 ml/min/m2) makes clear though, that it is a highly variable factor depending on many elements and that therefore, a perfusion goal targeting a generic pre-established value for DO2 just above a general DO2crit level cannot guarantee appropriate DO2 for all patients at all times. Indexing DO2 to patient body surface area (as is done for DO2crit levels) allows for differences in physique, but does not take into account e.g. differences in gender and age. Furthermore, the oxygen necessity during CPB depends not only on patient characteristics, but also on factors like anaesthesia technique and temperature management. Thus, when targeting or studying DO2, VO2 should always be taken into account.We were not able to calculate DO2, VO2 and kidney function in patients undergoing CPB at our institution, as we questioned the usefulness of universal DO2crit levels from previous research. The limited database compared to the large study populations in previous studies [2crit values.This study was solely designed to look for the relationship between DO studies –7 result studies –29, we e2 delivery and kidney function decrease in patients undergoing CPB for cardiac surgery. In addition, there was no indication for the presence of a pathologic supply dependency between DO2 and VO2. The variability in O2 consumption, however, is an indication that every patient has individual O2 needs, advocating for an individualized O2 delivery goal instead of a generic DO2crit level.In conclusion, this study could not confirm an evident correlation between low O