Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease that primarily affects synovial joints and is associated with increased cardiovascular (CV) mortality and morbidity. This association is only partially attributed to the presence of classic CV disease risk factors, and is strongly associated with characteristics of disease itself namely systemic chronic inflammation and autoimmune activation. Growing evidence suggests that microvascular endothelial dysfunction contributes to the initiation and progression of vascular disease. Nailfold capillaroscopy is a non-invasive method that evaluates the morphology and the structure of nailfold capillaries. Extension of this method is the Nailfold Videocapillaroscopy (NVC), which provides the possibility of combining functional and anatomical study of peripheral microcirculation. The present cross-sectional study aims to evaluate using NVC the peripheral microcirculation in adult patients with RA and investigate the associations between structural and functional indices of digital capillaries with markers of atherosclerosis. In addition, the presence of subclinical atherosclerosis in RA is common and until recently underestimated in clinical practice. The main cardiovascular risk assessment indices used primarily in patients with RA are Pulse Wave Velocity (PWV) and Carotid Intima-Media Thickness (cIMT).26An extension of the method of simple capillaroscopy is the video-capillaroscopy (NVC), which provides the possibility of structural and functional assessment of the microcirculation in the digital capillaries. The method enables the representation of the differences, in relation to rest, in the number of non-perfused capillaries after venous congestion or reactive hyperaemia after arterial occlusion (post-occlusive reactive hyperaemia). Thus, functional changes of the capillaries, in addition to the structural ones, are documented. For example, patients with arterial hypertension, who were the first group of non-rheumatic patients to have their microcirculation studied, showed reduced capillary density, both at rest and during venous congestion or after arterial occlusion.27 studied 430 patients with RA and recorded their capillary findings. The researchers observed an increased frequency of morphological capillary changes, in particular increased angiogenesis and severe capillary distortion (tortuosity). An earlier study28 also found that severe distortion and elongated capillaries are the main features of patients with RA, which concurs with previous observation,30 demonstrating low rates of scleroderma morphological lesions in patients with RA. Lin et al.31 also showed that the most prominent capillary finding in RA is increased capillary distortion and elongated capillaries. However, the association between NVC morphologic and functional abnormalities with indices of macrovascular disease in this population has not been extensively investigated. The current study aims to evaluate peripheral microcirculation assessed by NVC, in patients with RA and to explore the potential associations between structural and functional alterations of digital capillaries with markers of atherosclerosis such as cIMT and arterial stiffness.A few studies have investigated peripheral microcirculation in RA individuals. Rajaei et al.This is a prospective cross-sectional observational study, which will be conducted in the Fourth Internal Medicine Department at Hippokration General Hospital of Thessaloniki in collaboration with the Hypertension Laboratory of the Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital of Thessaloniki. The study received approval from the Aristotle University Ethics Committee. All participants will give informed consent before study entry.This study enrols patients ≥ 18 years old with RA based on the criteria of the American College of Rheumatology and the European Society of Rheumatology (ACR / EULAR 2010) who are either already attending or attending for the first time the Rheumatology Division of the 4th Department of Internal Medicine, Hippokration General Hospital of Thessaloniki. Patients will have the full ability to understand and provide written signed consent to participate in the study after being informed.The doctoral dissertation protocol will exclude patients with known, confirmed by biopsy, active malignancy, patients with myocardial infarction or unstable angina episode in the last 3 months and/or congestive heart failure category IV, according to the criteria of New York Heart Association as well as patients who refuse to participate in the study and sign the consent form. Also, patients with diabetes mellitus, chronic kidney disease stage 4 or 5 with eGFR <30ml/min/1.73m2 for at least three months will be excluded as well as patients with a change in anti-hypertensive treatment in the last month before the start of the study. Finally, patients with previous vascular carotid surgery due to anatomical difficulty in assessing the cIMT index will be excluded.Complete medical history, including medication record and smoking habits will be obtained from all participants. Patients will undergo clinical examination, office blood pressure measurement and blood sample collection for routine haematology, biochemistry including lipid profile and blood glucose and inflammatory markers. Centrifuged samples will be stored in a deep freezer (−70°C) to determine Asymmetric Dimethylarginine (ADMA) levels after collection of all samples.Following the blood sampling, the patients will undergo tonometric measurement of arterial stiffness and ultrasound determination of cIMT using SphygmoCor and Vivid 7 of General Electric devices, respectively. Finally, the patient will be transferred to the Rheumatology Division of the Fourth Department of Internal Medicine, in order to have NVC with the use of the Optilia Digital Capillaroscope device. After the end of the evaluation, the patient will receive from the rheumatologist the medical instructions that correspond to the specific scheduled visit and the monitoring within the protocol will be ceased. All vascular assessments will be performed at the same time period for each patient within 24 hours before or after blood sample collection.32 As the AIx is dependent on the transit time of the reflected wave and the time of arrival of the reflected wave during the pressure pulse, it is also sensitive to heart rate. The SphygmoCor software reports the AIx at the patient’s current heart rate, as well as giving an AIx corrected to a heart rate of 75 bpm using a regression to the population heart rate dependency of the Aix.33 PWV will then be determined in each patient as a marker of arterial stiffness. The carotid and femoral pulse is acquired by applanation tonometry sequentially, allowing a single operator to acquire the measurement. The transit time from the R-wave of the simultaneously acquired electrocardiogram to the foot of the carotid and femoral pulse is measured.34 The difference between these 2 transit times is divided by distances measured from the body surface to estimate the arterial path length in order to calculate the carotid-femoral PWV. The length of the vascular pathway is calculated by measuring linear distances between the palpation point of the carotid artery with the supernatant incision and the supernatural incision with the palpation point of the femoral artery.35The radial artery applanation tonometry method is used to record the pulse waveform in the carotid artery, using the SphygmoCor device, AtCor Medical Pty Ltd, Sydney, NSW, Australia. This method will calculate the augmentation index (AIx) based on the augmentation pressure (systolic pressure minus the inflection pressure) divided by the pulse pressure (systolic minus diastolic pressure), expressed as a percentage.36 The cIMT measurement will be performed in a region free of plaque where there is a standard double-line pattern, and the measurements are more accurate and reproducible. The sections of the arterial walls will be evaluated in a longitudinal view, strictly perpendicular to the ultrasound beam, with both walls being visible to achieve diameter measurements.37 The optimal diameter will be obtained during dilation by looking for the minimum diameter during the cardiac cycle. The cIMT will be measured on the proximal vessel wall, as the cIMT values of the distal wall are less reliable. At least 10mm in length, an arterial section will take a high-resolution image to perform a series of reproducible measurements.38Ultrasound determination of cIMT of the two common carotid arteries will be performed using Vivid 7 of General Electrics based on the consensus of Mannheim.39 In addition to the quantitative and qualitative parameters, a functional evaluation of the changes in capillary density will be performed using digital video in three phases, as follows: the capillaries will be imaged on the skin of the distal phalanges of the dorsal region of the third and fourth fingers of the two upper limbs. The imaging will be about 4.5mm near the terminal row of capillaries in the middle of nailfold. The researcher will select a skin area of 1 mm2. Capillary density will be measured in three conditions: a) baseline capillary density, which is defined as the number of continuously filled red blood cells per 1 mm2 of skin and measured for 15 seconds; b) capillary density during hyperaemia after arterial occlusion, which is evaluated after 4 minutes of arterial occlusion [use a microscopic finger cuff applied to the base of the finger under study and ‘filled’ at hypersystolic pressure (260mmHg) for 4 minutes]. Immediately after the release of the cuff, all (continuously and intermittently) paid capillaries are counted for 15 seconds and c) venous congestion density using a cuff at 60mmHg for two minutes and then all (continuously and intermittently) capillaries will be measured for 15 seconds.43NVC is an established non-invasive method to assess the capillary vasculature of the digital arteries, which provides information on the structural and functional abnormalities of the capillaries. It is performed at room temperature (22–23°C) with the patient seated and resting for 15 minutes NVC will be performed at the Fourth Internal Medicine Department at Hippokrateion Hospital using an Optilia Digital Capillaroscope. Pictures and videos of 15 seconds duration will be captured using the 200x magnification video camera from the second to the fifth finger of each hand. The images will be analysed with Optipix capillaroscopy software 1.7.x on a computer. The NVC parameters to be measured are: capillary density, capillary width and length (μm), the presence of micro-bleeding, oedema, thrombi, and the presence of any abnormalities in the morphology or disorder of capillary architecture. These parameters will be determined on each nail (except thumbs) and the average of all measurements for each patient will be calculated at the end.Investigation of the correlation between capillary density at baseline, after 4-min arterial occlusion and after 2-min venous occlusion, with atherosclerosis indices Investigation of the correlation between microangiopathy findings, as assessed by video-capillaroscopy, and biochemical markers of endothelial function, such as ADMA, CRP, and uric acidInvestigation of the correlation between microangiopathy findings, as assessed by video-capillaroscopy, and overall cardiovascular risk44 have indicated a statistically significant correlation between basal capillary density and markers microvascular disease in patients with systemic sclerosis . In the international literature46 it has a significant correlation of capillary density with factors such as gender, age, smoking, hypertension, and diabetes, while the possible effect of taking organic factors as the main medication. According to the above, one sample of 105 people has 80% statistical power to detect an expected effect size equal to 0.15 in a multiple regression model with 7 independent variables assuming type I error, α = 0.05.50 In addition, to ensure the completeness of all statistical checks our sample will includes at least ten people in each one (one in ten rule)51 from the above risk factors .Published studiesThe research hypothesis that in patients with RA a correlation is observed between the parameters of NVC with markers of endothelial dysfunction and inflammation, may contribute to the introduction of a new non-invasive reliable method for assessing the severity and progression of the peripheral microvascular disease in patients with RA. It will also help to understand the pathophysiology of vascular damage at the microvascular level and may be able to contribute to better assessment of CV risk in patients with RA. This may extend the use of NVC, as a reliable, reproducible and at the same time simple and non-invasive, complementary method for the assessment stratification of CV risk in this population.


Hemodynamic monitoring and management are essential pillars of perioperative care. Innovative continuous and non-invasive monitoring solutions require profound validation before they may improve perioperative care. New monitoring tools are changing how we monitor and manage hemodynamics in surgical and critically ill patients and many of these are published in the Journal of Clinical Monitoring and Computing (JCMC). In this What-is-new review, we will highlight some of the papers focusing on what is new in the area of hemodynamic monitoring and management based on papers published in the JCMC in 2020 and 2021.Meidert et al.  conducteIn a retrospective cohort study, Yoon et al.  investigIn clinical routine, blood pressure is routinely measured non-invasively using upper-arm cuff oscillometry. However, it remains unknown whether brachial blood pressure adequately reflects aortic blood pressure – or if there are substantial differences. Chemla et al.  performeJoachim and colleagues  investigPulse wave analysis is a well-established method for continuous cardiac output monitoring based on an invasive or non-invasive blood pressure waveform . NonetheIn two recent method comparison studies, the measurement performance of a pulse wave analysis monitor using the multi-beat analysis approach  to estimate cardiac output was investigated , 4. FirsTransthoracic echocardiography is often used for bedside hemodynamic assessment. Transthoracic echocardiography also allows measuring cardiac output. In a prospective method comparison study in 50 patients one day after cardiac surgery, Juhl-Ohlsen et al.  comparedNon-invasive cardiac output monitoring remains challenging. The cardiac output measurement performance of electrical cardiometry (which was developed from bioimpedance) had not been systematically evaluated in a review and meta-analysis. Sanders et al.  thus per2O and at an adjusted positive end-expiratory pressure of 11–17 cmH2O. At baseline, the mean of the differences (95%-limits of agreement) between capnodynamic cardiac output and flow probe cardiac output was 0.5 (-0.5 to 1.5) L/min with a percentage error of 30%. After induction of lung injury with a positive end-expiratory pressure of 5 cmH2O, the mean of the differences was -0.6 (-2.3 to 1.1) L/min with a percentage error of 39%. With an adjusted positive end-expiratory pressure, the mean of the differences was 1.1 (-0.3 to 2.5) L/min with a percentage error of 38%. The concordance rate to track changes in cardiac output ≥10% caused by temporary balloon inflation in the vena cava to reduce preload and dobutamine infusion was 87% at a positive end-expiratory pressure of 5 cmH2O and 100% with adjusted positive end-expiratory pressure levels. Even though this was a small experimental study, it shows that estimating cardiac output using the capnodynamic method – even during respiratory failure – is possible, but did not show clinically acceptable agreement compared to flow probe cardiac output. Flow probe cardiac output is considered the gold standard for cardiac output measurements, but rarely feasible outside of experimental studies. It will be interesting to see how the capnodynamic method performs in clinical studies.In an experimental study with 8 pigs having ventilator-induced lung injury, Sigmundsson et al.  comparedMost studies on hemodynamic monitoring focus on monitoring in operating rooms and intensive care units. Monitoring vital signs, especially blood pressure, non-invasively and continuously on normal wards remains challenging but may be an important step to reduce postoperative mortality . In a pr2 before and 4.4 ± 2.1 L/min/m2 (p = 0.43) after initiation of ECMO therapy. After initiation of ECMO therapy, extravascular lung water index increased from 21 ± 9 mL/kg to 28 ± 11 mL/kg (p < 0.01), and global end-diastolic volume index increased from 791 ± 179 mL/m2 to 974 ± 384 mL/m2 (p = 0.04) compared to before initiation of ECMO therapy. The authors provide a list of ten recommendations for hemodynamic monitoring before and during ECMO therapy.In a retrospective analysis of a prospectively obtained database, Herner et al.  investigIt is assumed that systemic hemodynamics – reflected by cardiac output or blood pressure – are coupled with microcirculatory tissue perfusion. The peripheral perfusion index is a photoplethysmography-derived microcirculatory tissue perfusion variable that has been associated with impaired outcome in surgical patients , 24.In a prospective observational study, Højlund and colleagues  investig2O for 30 s. If stroke volume index decreased by >30% during the lung recruitment maneuver patients were considered fluid responsive and a 250 mL fluid challenge was performed over 10 min [2 to 24 ± 4 mL/m2 with a simultaneous decrease in perfusion index from 5.9 ± 3.1% to 3.8 ± 2.4%. In fluid unresponsive patients, the change in mean stroke volume index was 39 ± 11 mL/m2 to 33 ± 9 mL/m2 with a simultaneous decrease in perfusion index from 7.6 ± 4.4% to 6.2 ± 3.5%. Pearson’s correlation coefficient between changes in stroke volume index and perfusion index was r2 = 0.34. In the 24 patients considered fluid responsive, fluid boluses increased mean stroke volume index by 16% and perfusion index by 17% - with a weak correlation (r2 = 0.19). The authors conclude that monitoring the perfusion index – especially during lung recruitment maneuvers – is a simple and non-invasive method to detect fluid responsiveness. It may therefore provide important information when stroke volume monitoring is not indicated – or as an additional tool.De Courson et al. investigated whether changes in perfusion index reflect changes in stroke volume during lung recruitment maneuvers in 47 patients having neurosurgery . Peripher 10 min . Twenty-These studies show the vast potential of measuring the peripheral perfusion index. A recent retrospective study further showed a strong correlation between impaired intraoperative peripheral perfusion index and postoperative outcomes . With grAn interesting study on artifact detection in vital signs time series was conducted by Pasma et al. . In the risk spikes could predict 7.3% of intensive care unit transfers with a positive predictive value of 7.4%, which may be a fair but not an outstanding result. Risk spikes were introduced as they may serve as a correction for a patient’s own baseline physiology, which scores such as the National Early Warning Score (NEWS) do not. Unfortunately, the paper did not report and discuss detailed results of a reference model/predictor, such as the NEWS score’s performance. The authors made a propensity score matching which may be better than a more random selection of non-events. Still, a subsequent clinical implementation of the risk spike algorithm is likely to perform dramatically different from the results obtained with a case-control design, because the case-control design applied to time-series is inherently contributing a temporal bias in the analysis [A study published in 2020 by Keim-Malpass et al.  investiganalysis . Applyinanalysis .In 2021, JCMC also published a highly interesting study investigating closed-loop (CL) resuscitation in an experimental animal (pig) model of hemorrhagic shock . AnestheReducing myocardial injury during acute myocardial infarction remains a major medical challenge. It has been suggested that glucose-insulin-and-potassium infusion may reduce myocardial injury during acute myocardial infarction. The results from studies investigating possible protective effects of glucose-insulin-and-potassium infusion vary substantially .Licker et al.  performePerioperative goal-directed therapy, especially cardiac output-guided goal-directed therapy may improve patient outcomes in high-risk non-cardiac surgery . In a beIntraoperative hypotension, although still not clearly defined, is associated with postoperative cardiac and renal morbidity and mortality . SponholThe renal resistive index is defined as the difference of the peak systolic and end-diastolic blood velocity divided by the peak systolic velocity measured by Doppler ultrasound in kidney arteries. The renal resistive index is used to evaluate vascular and parenchymal renal abnormalities, but growing evidence indicates that it may also reflect systemic vascular properties . GiustinThis review summarizes new scientific findings in the area of hemodynamic monitoring and management published in the last two years in the JCMC. The JCMC is glad to provide a platform for new research and evidence in this field. More trials investigating how these new methods and technologies for hemodynamic monitoring can improve outcome of surgical and critically ill patients are needed.


In this study is to examine the effect of kefir consumption on blood pressure, some blood parameters and anthropometric measurements in hypertensive individuals.The study is a randomized controlled clinical trial. The mean systolic blood pressure in hypertensive individuals was taken as 145.2±19.2. The minimum sample size was determined as 30 for each group with a 95% CI and 80% power. The study was conducted by face-to-face interviews with a total of 100 volunteers, 35 male, 65 female, aged 18 and over, who were hypertensive and volunteered to participate in the study and applied to the internal medicine outpatient clinics of Akçadag Public Hospital between September 2020 and May 2021. The experimental (n = 42) and control (n = 58) groups that the patients are randomly assigned into, the experimental group was ensured to consume 250 ml/day kefir for 28 days. During the study, The study was completed with 56 volunteers. At the beginning of the study and the end of 4 weeks, blood samples, blood pressure, pulse and anthropometric measurements of the individuals were taken.When the anthropometric measurements were compared, the body weight, body mass index, waist circumference, and hip circumference of the individuals in the experimental group decreased significantly at the end of the study. There was no significant difference between the experimental and control groups in terms of glycemic parameters. While no significant change was observed in the lipid profile in the experimental group, total and LDL cholesterol levels decreased in the control group. There was no statistically significant difference in kidney function parameters in both groups. In addition, at the end of the study, there was no significant change in diastolic blood pressure and pulse in the experimental group, but systolic blood pressure decreased significantly.Regularly kefir consumption has positive effects on systolic hypertension and weight control.• Regular daily consumption of kefir reduces systolic blood pressure and provides weight control.• Regular daily consumption of kefir did not lead to an effective result on blood and kidney parameters.


Non-invasive coronary assessment using single-photon emission computerized tomography (SPECT) testing for potential cardiac ischemia is an essential part of the evaluation of kidney transplant candidates. We aimed to examine the prognostic value of preoperative SPECT test results in kidney transplanted patients.P = 0.019). Differences were mostly derived from significantly increased rates of myocardial infarction events . Yet, MACE rate was not statistically different at 1 year . Importantly, the prognostic impact of an abnormal SPECT was significantly attenuated for all outcomes following multivariable adjusting for conventional cardiovascular risk factors and coronary revascularization.We retrospectively analyzed the pre-surgical nuclear SPECT test results in a registry of kidney transplanted patients. Follow-up at 1 month and 1 year recorded major adverse cardiac events (MACE) including non-fatal myocardial infarction, all-cause mortality and hospitalization due to cardiovascular disease following the renal transplantation. Of 577 patients available for analysis, 408 (70.9%) patients underwent nuclear SPECT test pre-transplant and 83 (20.3%) had abnormal results with either evidence of ischemia or infarct. A significantly higher incidence of post-operative MACE at 1 month was evident among patients with abnormal SPECT test compared to patients with no evidence of ischemia (10.8 vs. 4.3% respectively; Pre-surgical cardiac risk assessment of kidney transplant candidates with nuclear SPECT test was found to be predictive of post-operative MACE, yet apparently, its prognostic value was significantly attenuated when adjusted for cardiac risk factors. An important part of the pre-surgical evaluation of kidney transplant candidates (KTCs) includes assessment for a coronary disease, as chronic kidney failure patients are at excessive risk for coronary artery disease (CAD) –3. IndeeThus, although kidney transplantation is considered intermediate risk surgery  , in mostFollowing recommended guidelines of the preferred diagnostic method for perioperative cardiovascular evaluation –16; overNonetheless, despite efforts at examination and validation throughout the past 2 decades, current evidence on the association between SPECT test results in KTCs and their clinical cardiac outcomes following transplantation is still conflicting , 17–21. 1. to examine the prognostic value of preoperative cardiac evaluation for myocardial ischemia among kidney transplanted patients and2. to assess the correlation between the SPECT results and prognostic measures following kidney transplantation.The present study was a retrospective analysis of prospective data from a cohort of patients treated at one of the two institutions  at Rabin Medical Center, who underwent kidney transplantation between the years 2016 and 2019. Patients included in the analysis were all 18 years old or above. Exclusion criteria included: concomitant heart or liver transplantation.The data collected from the registry for each patient included demographics (age and gender) and medical history: comorbidities , smoking, chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), cerebrovascular accidents (CVA)], the presence of arteriovenous fistula (AVF), duration of dialysis and allograft source (living vs. cadaver).Pre-transplant cardiac investigation data collected included: nuclear SPECT scan protocol , and cardiac results ; coronary angiographic findings, basic echocardiographic data  and clinical events. Mortality outcome was retrieved through the hospital administration system (ATD) which is updated by the Israel's Ministry of Health's registration.For the analyses patients were categorized according to the preoperative evaluation with nuclear SPECT test results. A SPECT scan with reversible ischemia, perfusion defects or transient ischemic dilatation was considered positive. The study protocol was approved by the local Institutional Review Board of our medical center.Major advance cardiac events (MACE) at 1 month and 1-year post-transplantation was considered the primary endpoint. Clinical outcomes: MACE, comprising non-fatal myocardial infarction (MI), all-cause mortality and hospitalization due to cardiovascular disease following renal transplantation were retrospectively collected from the institutional database, or when indicated, records from other hospitals were acquired to verify the events in the follow-up period. All events were further confirmed by two researchers . Survival status at follow-up was assessed by review of ATD registries up to 3 years. MI was defined according to the forth universal definition of MI type 1 or type 2 .P-value of <0.05 was considered statistically significant.Continuous data are summarized as mean and standard deviation (SD) or median and interquartile range (IQR) and were compared using Student t tests or analyses of variance. Categorical variables are presented as frequency and were compared by chi-square or Fisher's exact tests. The normality of variable distributions was assessed using the Kolmogorov–Smirnov test. Time-to-event curves were constructed using the Kaplan–Meier method and compared using log-rank test. Cox regression analyses were performed to identify independent predictors of the primary end point. Covariates for the Cox model were chosen according to their known association with myocardial ischemia and clinical outcomes, and included age, sex, diabetes mellitus, the presence of an AV-fistula, duration of dialysis, known ischemic heart disease, percutaneous coronary intervention (PCI) and the presence of ischemia as evident in the SPECT testing. Effect sizes are presented as hazard ratios and 95% confidence intervals. All statistical analyses were performed with IBM SPSS statistics V.27 software. A p < 0.001). Importantly, the rate of MACE was significantly higher 13.0 vs. 1.8% in the SPECT test group (p < 0.001).A total of 577 patients were available for analysis. Of them, 408 had nuclear SPECT test results, as part of the pre-transplant cardiac assessment. As presented in P = 0.28). Seventy one out of 83 (85.5%) patients in the abnormal SPECT test group underwent an invasive coronary angiography procedure prior to transplant, compared to 109 out of 316 (34.5%) in the normal SPECT group (p< 0.001). Rates of PCI performed were 33.7 and 7.1%, respectively (p< 0.001).Of the 408 patients who underwent nuclear SPECT test, 83 (20.3%) had a positive SPECT result, with evidence for ischemia of any degree, fixed perfusion defects or transient ischemic dilatation. Technetium was used as the radioactive substance more frequently among patients with negative SPECT results, compared to patients in the positive SPECT tests, and Bruce protocol was more frequently used in the latter group . CompariP = 0.019). Differences were mostly derived by increased rates of post-transplant myocardial infarction . Yet the MACE rate was no longer statistically different at 1 year following kidney transplantation . Moreover, as depicted in The incidence of MACE at 1 month was significantly higher among patients with abnormal SPECT test compared to patients with no evidence of ischemia , male gender , prior history of ischemic heart disease , duration of dialysis , and the presence of AV fistula . PCI and diabetes were not among the predictors of 1 year MACE (Notwithstanding, risk factors were found predictive for MACE at 1 year including: patient age (OR 1.06 for each additional year 95% CI 1.03–1.09; ear MACE .Our study demonstrate the prediction value of pre-surgical cardiac evaluation of kidney transplant candidates with nuclear SPECT test. We have found the test to be predictive of post-operative MACE, although its prognostic value was attenuated significantly when adjusted for risk factors. The study expands upon previous observations with an updated analysis of a real-world large cohort of kidney transplant patients and their post-surgical cardiovascular outcomes. The results may further challenge clinicians evaluating KTCs for transplant, as positive SPECT test was not found to have a significant prognostic impact after adjustment for risk factors and for pre-transplant coronary revascularization. We suggest to rely on cardiovascular risk assessment and subjective clinical impression, with a high index of suspicion aimed toward male candidates with advanced age, long duration of dialysis and known IHD, as these were found to be independent predictors of MACE. A positive SPECT scan may represent all of these predictors and thus can support a clinical decision to proceed to coronary angiography.In the first analysis we found that patients who had undergone nuclear SPECT test, as part of their pre-surgical evaluation, tended to be older with significantly higher rates of cardio-metabolic comorbidities compared to those with no prior cardiac functional test. The rates of 1 year MACE were higher in this group, as expected, according to their augmented risk factors. In the second analysis, we first compared rates of MACE among patients with abnormal SPECT tests vs. those with normal SPECT imaging results. Analysis of the raw data implied that an abnormal SPECT scan has a prognostic value with increased risk of MACE at 1-month post-surgery. However, following adjustment for confounding risk factors, the positive SPECT test was no longer predictive of MACE at 1 month or even at 1 year.Previous publications suggested that positive results on non-invasive stress testing in patients assessed for kidney transplantation is predictive of cardiovascular mortality , 17. HowResults are not unexpected as the sensitivity and specificity of non-invasive stress tests, including SPECT test in renal failure patients are relatively low. Positive SPECT results not reflected on coronary angiography may be a consequence of microvascular disease and/or endothelial dysfunction syndrome. On the other hand, false negative results might have a few explanations: the presence of multi-vessel disease resulting in balanced\global ischemia; the presence of collateral vessels that produce the compensatory appearance of more homogeneous perfusion; and higher resting levels of adenosine, resulting in higher resting coronary flow and reduced responsiveness to dipyridamole, causing inadequate functional stress myocardial response .post-hoc analysis of the ISCHEMIA-CKD trial published in 2020. In the first study, 26 kidney transplant candidates with diabetes and obstructive CAD were randomly assigned to medical therapy vs. revascularization. A combined cardiovascular endpoint occurred in 10 of 13 medically managed patients, compared to 2 of 13 re-vascularized patients, within 8.4 months (post-hoc analysis of the randomized control ISCHEMIA-CKD trial, examined intervention vs. conservative management in 194 participants listed for transplant compared to 583 patients not listed. Pre-emptive coronary revascularization in patients on the waiting list was not associated with improved survival, although only a minority of patients had kidney transplant and there was no reported data of outcomes post-surgery (Whether coronary angiography and/or revascularization during the pre-transplant evaluation could prevent future cardiovascular events is debatable. Two randomized control trials previously addressed this issue: a small trial published in 1992 and a much more recent, 4 months . NeverthThe study has a few limitations. Due to the observational design, there is a clear selection bias of patients to undergo nuclear stress test and coronary angiography. The characteristics of patients in the different groups may vary and possibly could not be completely corrected using multivariate analysis. Moreover, revascularizations were performed more frequently among patients with positive SPECT scans, which might have an impact on the study results. Nevertheless, this is an updated real-world study that assessed the occurrence of MACE and the predictive value of abnormal nuclear stress test in the population of patients undergoing kidney transplant.Overall, decisions regarding the pre-transplant cardiac evaluation of KTCs should be tailored made with careful consideration of the patient‘s complains, medical history, laboratory tests, images, renal function and prognosis. Treatment considerations in patients on the waiting list should include the potential future damage to the transplanted kidney with the need of performing coronary revascularization post-surgery. The “heart team” forum should consult with the nephrologists how to optimize the medical care for the heart and kidneys together.Pre-surgical cardiac evaluation of kidney transplant candidates, with nuclear SPECT test was found to be predictive of post-operative MACE, although its prognostic value was attenuated significantly, when adjusted for risk factors. A personalized clinical assessment, in which the SPECT scan results would be a decision supporting tool rather than a single and exclusive criteria, should be considered to guide treatment.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by 0151-19-RMC. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.TS: writing—original draft. LP: methodology and software. BZ: writing—review and editing, methodology, and software. MA: data curation. RK and AH: investigation and supervision. AS: writing—review and editing. EN, RR, and TG: visualization. KS: conceptualization and writing—original draft. All authors have read 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction: Increase in blood pressure is the leading cause of comorbidity, especially cardiovascular and cerebrovascular disease, but its variability represents an independent risk factor for the same in menopausal women. Dramatic decrease of estrogen production in menopause interferes with many metabolic pathways leading to insulin resistance, increased body mass index (BMI) and dyslipidemia hence cardiovascular morbidity and mortality. In this study an assessment of the variability of blood pressure in postmenopausal women and its association with BMI have been highlighted.Method: In this cross‐sectional study, a total of 175 postmenopausal females more than 50 years of age who were admitted to or visited medicine wards with no known major medical condition were enrolled between June and July 2019. Recording of both diastolic and systolic blood pressure of postmenopausal women was done at 6 am, 12 pm and 7 pm manually by mercury sphygmomanometer. In addition, BMI, neck circumference, and lipid profile values were also recorded.2 ) were 128.57 ± 12.68/78.93 ± 9.56; 124.64 ± 12.32/77.14 ± 5.35 and 124.29 ± 12.60/75.36 ± 6.37 mmHg respectively. Neck circumference (>32 cm) was similar at 128.89 ± 13.49/79.86 ± 8.47; 124.58 ± 12.99/77.08 ± 7.59 and 125.56 ± 12.21/76.94 ± 7.62 mmHg respectively.Results: Variation of both systolic and diastolic blood pressure at 6 am, 12 pm and 7 pm in association with various parameters like BMI (more than 25 kg/mConclusion: BMI and neck circumference as well as triglyceride and cholesterol increase may all independently contribute to the blood pressure variability in menopausal women. Palpitations, hot flashes, family history of heart disease, shortness of breath, chest heaviness, headache, lightheadedness or dizziness, diabetes or dyslipidemia, and obstructive sleep apnea are important symptoms and conditions which should not be taken lightly as they may be an indication of high blood pressure (BP) in menopausal women. Blood pressure variability (BPV) represents an independent risk factor for cardiovascular diseases especially in postmenopausal women where the hormonal protective effect is decreased . Though Postmenopausal women have an increased risk of cardiovascular and cerebrovascular morbidity and mortality, probably due to the appearance of major risk factors such as dyslipidemia, diabetes, obesity and hypertension ,5. Many There are not enough data on the assessment of BP variability in postmenopausal women in India. The research question for the current study was to assess the variability of blood pressure in postmenopausal women and to compare this variability of blood pressure with special reference to BMI, dyslipidemia and neck circumference.Study settingThis cross-sectional study was carried out in the Department of Medicine, Acharya Vinoba Bhave Rural Hospital and Jawaharlal Nehru Medical College attached with Datta Meghe Institute of Medical Sciences, Wardha.Study populationAll consecutive postmenopausal females of more than 50 years of age admitted/visited in medicine wards with no known major medical condition.The sample size was calculated by the formula n = Z (⌊1−α /2⌋) ². p (1-p)d² where, Z /IEC/2019/8010).Data collection methodFor a period of two months beginning June 2019, all prospectively enrolled postmenopausal female patients were studied.2 was calculated and overweight and obesity was considered when BMI was between 25-29.9 kg/m2 and more than 30 kg/m2 respectively.Apart from noting demographic features like age, education, social status, BMI and the recording of both diastolic and systolic blood pressure of postmenopausal women were done at 6 am, 12 pm and 7 pm. All anthropometric measurements  were performed according to WHO guidelines ,16. WeigStatistical analysisWe performed the Wilcoxon Test and Spearman Correlation in order to assess possible correlations between mean BP and BP variability data with BMI, neck circumference and lipid profile. Data were expressed as mean value ± SD. P value less than or equal to 0.05 was statistically significant.Out of 175 patients, 122 (69.7%) were illiterate and 127 (72.6%) were from a rural background. The mean BMI was 21.37±4.27 kg/m2 and the mean neck circumference was 31.23±2.28cm. All other parameters are shown in Table Table Table The decline in hormones following menopause, especially low estrogen levels, affects blood flow, putting more strain on the heart to ensure proper blood circulation, leading to increased blood pressure ,4. SometIncrease and variability in blood pressure have more risk of cardiovascular as well as cerebrovascular diseases in menopausal women. However, risk increases with age or the body mass index is not clear. In a study by Zanchetti et al., it was concluded that blood pressure of menopausal women is significantly, though slightly, higher than that in age- and BMI-matched premenopausal women. The author also reported that age and BMI do not affect the incidence of hypertension .Our study showed that BMI and neck circumference were associated positively with SBP and DBP variability at 6 am, 12 pm and 7 pm in postmenopausal women. At 6 am and 12 pm, patients with high BMI and neck circumference had higher blood pressure, but there was dipping of blood pressure at 7 pm. Total cholesterol and triglyceride had also shown some variability in the morning, noon and evening, but they were statistically insignificant. Proposed hypothesis, for haemodynamic changes like blood pressure variation though not clear, it maybe the expression of baroreflex impairment due to menopausal atherosclerosis. Another possibility may be the cardiovascular response to centrally induced sympathetic hyperactivity .There are no other studies that have compared the BPV in morning, noon and evening hours. Few studies have shown a significant increase in blood pressure variability in menopausal women when compared to fertile women, even after exclusion of confounding factors, such as aging and BMI -17. MenoOne study, in which 24-hour blood pressure of menopausal women was monitored, revealed that diastolic blood pressure was increased during the night hours in the symptomatic group compared to the asymptomatic group. Baroreflex dysfunction was the possible explanation as this causes a peripheral vasoconstriction leading to increases in heartbeat and heart output thence high systolic blood pressure during the day hours. They also showed no variation in systolic blood pressure during the night while sleeping .LimitationBlood pressure variability was assessed manually, ideally it should be by continuous Holter monitor, being the main limitation of the study. As it was a short-term studentship research training programme, the sample size was small.BPV in postmenopausal women is more in the morning and noon but not in the evening. BPV, especially a rise during sleep, may lead to cardiovascular complications like carotid intima thickening and carotid plaque formation. BPV in menopause may be an expression of baroreflex impairment and centrally induced sympathetic hyperactivity. Cholesterol and triglycerides are also correlated with this variability, but not statistically. More studies are required to confirm this hypothesis of the influence of menopausal status on BPV.


Background: Patients with severe acute kidney injury (AKI) require continuous renal replacement therapy (CRRT) when hemodynamically unstable. We aimed to identify prognostic factors and develop a nomogram that could predict mortality in patients with AKI undergoing CRRT.Methods: Data were extracted from the Dryad Digital Repository. We enrolled 1,002 participants and grouped them randomly into training (n = 670) and verification (n = 332) datasets based on a 2:1 proportion. Based on Cox proportional modeling of the training set, we created a web-based dynamic nomogram to estimate all-cause mortality.Results: The model incorporated phosphate, Charlson comorbidity index, body mass index, mean arterial pressure, levels of creatinine and albumin, and sequential organ failure assessment scores as independent predictive indicators. Model calibration and discrimination were satisfactory. In the training dataset, the area under the curves (AUCs) for estimating the 28-, 56-, and 84-day all-cause mortality were 0.779, 0.780, and 0.787, respectively. The model exhibited excellent calibration and discrimination in the validation dataset, with AUC values of 0.791, 0.778, and 0.806 for estimating 28-, 56-, and 84-day all-cause mortality, respectively. The calibration curves exhibited the consistency of the model between the two cohorts. To visualize the results, we created a web-based calculator.Conclusion: We created a web-based calculator for assessing fatality risk in patients with AKI receiving CRRT, which may help rationalize clinical decision-making and personalized therapy. Acute kidney injury (AKI) is a sudden decline in kidney function that includes structural damage and renal function impairment. AKI occurs in more than half of critically ill patients  and has Typical prognostic indicators for AKI include AKI stage, urine output, and comorbidities. Among these variables, the AKI stage is crucial for estimating outcomes. There is a definite linear association between the AKI stage and mortality . PreviouIn this study, we created a model utilizing Cox regression to estimate the short-term prognosis of AKI patients based on regularly utilized and easily accessible clinical variables. Univariate and multivariate analyses were conducted to identify risk variables independent of each other. The visualization model was created using a nomogram and web-based calculator, and the estimation performance was assessed based on discrimination, calibration, and clinical value.www.datadryad.org). It is a user-friendly resource. All authors have waived their copyright to the original research data. Thus, we utilized these data for secondary analysis without violating author rights. This study data was shared by Jung et al. and saved in the Dryad Data Resource (https://datadryad.org/stash/dataset/doi:10.5061%2Fdryad.6v0j9) . As all data were abstracted via an online data resource, clearance from the institution’s ethical committee was not required.The data were abstracted from the “DATADRYAD” data resource . Patients were excluded who met the following criteria: age <18 years, pregnancy or lactation, history of CKD or dialysis or CRRT before the study, postrenal obstruction and prior kidney Transplantation. All eligible patients were randomly assigned to one of two groups in a ratio of 2:1 (training and verification sets).We conducted a secondary assessment using data from the resources mentioned above. We selected 30 promising prediction indicators, including age, myocardial infarction, sex, congestive heart failure, dementia, hypertension, chronic obstructive pulmonary disease, cerebrovascular disease, potassium, phosphate, Charlson comorbidity index (CCI), body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), mechanical ventilation (MV), peripheral vascular disease, white blood cells, diabetes mellitus, levels of hemoglobin, blood urea nitrogen, creatinine, and albumin, glomerular filtration rate (GFR), acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA) score, CRRT cause, and CRRT dose. The vital status and duration of follow-up for each patient with AKI were retrieved.p < 0.05) were then incorporated into a multivariate Cox regression analysis to generate an integrated nomogram via a stepwise feature selection approach based on AIC. To enhance clinical utilization, a web-based calculator visualization tool was developed.Cox proportional hazard regression models were used to screen for possible predictive variables and determine their weights based on the training set. Univariate Cox regression analysis was conducted to identify possible variables. The selected predictive variables from the univariate analysis  curve (AUC) values from the ROC analysis and C-index. The calibration in the training and verification sets was used to evaluate the performance of the novel model. Decision curve analysis (DCA) was used to check the clinical usefulness of the model. These assessments were conducted using training and validation sets.p < 0.05. Statistical analyses were performed using SPSS software (v24.0) and R software v3.6.2.Continuous data with a normal distribution were reported as mean ± standard deviation, while categorical variables were expressed as percentages. Analyses of the differences between the training and verification sets were performed using chi-square tests for categorical variables and t-tests for continuous variables. Statistical significance was set at n = 670) and validation cohorts (n = 332). The demographic and clinical characteristics (before the initiation CRRT) of all participants, and participants in the training and validation sets are presented in This study included 1,002 participants . PatientUnivariate and multivariate analyses were performed to screen independent prognostic factors to build the model. Univariate Cox regression analysis indicated that diabetes mellitus, hypertension, phosphate, CCI, BMI, SBP, DBP, MAP, MV, levels of creatinine and albumin, GFR, and APACHE II and SOFA scores correlated with survival time. Multivariate Cox regression analysis showed that phosphate, CCI, BMI, MAP, levels of creatinine and albumin, and SOFA score were independent prognostic factors for patients with AKI .n = 335) groups. The risk score distribution in the training set is shown in Through multivariate Cox regression analysis screening, the final prediction model established included phosphate, CCI, BMI, MAP, levels of creatinine and albumin, and SOFA scores as predictors. The prediction model was presented in a nomogram, which was used to quantitatively predict the 28-, 56-, and 84- day overall survival probability . A totalhttps://crrtaki.shinyapps.io/predict/) for clinical use and visualization of the prediction model to estimate the course of AKI based on the nomogram  to predict mortality in patients with AKI undergoing CRRT. This model may be a reliable tool for determining AKI treatment strategies and potential outcomes. The new, user-friendly nomogram developed in this study may accurately estimate the prognosis of AKI patients.


TRPA1 gene contributes to the vasodilator effect of propofol. Hypotension is crucial for anesthesiologists because it is deleterious in the perioperative period. We tested whether the TRPA1 gene polymorphisms or haplotypes interfere with the hypotensive responses to propofol. PCR-determined genotypes and haplotype frequencies were estimated. Nitrite, nitrates, and NOx levels were measured. Propofol induced a more expressive lowering of the blood pressure (BP) without changing nitrite or nitrate levels in patients carrying CG+GG genotypes for the rs16937976 TRPA1 polymorphism and AG+AA genotypes for the rs13218757 TRPA1 polymorphism. The CGA haplotype presented the most remarkable drop in BP. Heart rate values were not impacted. The present exploratory analysis suggests that TRPA1 genotypes and haplotypes influence the hypotensive responses to propofol. The mechanisms involved are probably other than those related to NO bioavailability. With better genetic knowledge, planning anesthesia with fewer side effects may be possible.Anesthesia with propofol is frequently associated with hypotension. The  Propofol  is a general anesthetic widely used for the induction and maintenance of anesthesia in different clinical scenarios ,2. GivenConcerning Transient receptor potential ankyrin subtype 1 (TRPA1), its gene is in chromosome 8 in humans, and it is a ligand-gated cation channel that plays a pivotal role in regulating pain and inflammatory pathways . StudiesTRPA1 gene polymorphisms and haplotypes contributed to the heterogeneity of acute pain [In addition to being expressed in sensory nerves, activation of vascular TRPA1 and the subsequent production of nitric oxide contributes to the vasorelaxation effects of propofol . Moreoveute pain . However, the effects of TRPA1 polymorphisms on blood pressure responses to propofol have not yet been evaluated. Therefore, we hypothesized that TRPA1 polymorphisms might somehow correlate to the effects of propofol on blood pressure. The TRPA1 polymorphisms studied  were selected based on their prevalence and functional or clinical implications. They were associated with increased TRPA1 receptor activation in response to agonists and asthma in children . TRPA1 rn = 164) were selected for the study according to the eligibility criteria, which included American Society of Anesthesiologists (ASA) physical status I or II, age between 20 and 80 years, and body mass index ≤30 kg/m². Patients with evidence of severe hypertension; uncontrolled respiratory, renal, hepatic, or hematological disorders; and a history of stroke or myocardial infarction were excluded from the study. We also excluded subjects with hypotensive episodes that required management with vasopressor drugs. All patients underwent bowel preparation within 24 h of the procedure according to the center’s standard protocol, and the clinicians involved in data collection were blinded to the polymorphisms of interest.Patients undergoing colonoscopy , heart rate, non-invasive blood pressure, and blood oxygen saturation until complete recovery. After the initial evaluation, a venous blood sample was collected (at baseline). Then, propofol at a 2 mg/kg dosage was administered intravenously by bolus injection. A second blood sample was collected 10 min later. We registered systolic (SBP), diastolic (DBP), and mean (MBP) blood pressure values at baseline, and at 4 and 10 min after propofol infusion. Blood samples were promptly centrifuged at 1000× Exploratory endpoints were blood pressure changes calculated by subtracting the values observed 4 min after propofol anesthesia from the baseline values and NO marker delta levels calculated by subtracting the values observed 10 min after propofol anesthesia from the baseline values.We measured plasma nitrite levels using an ozone-based reductive chemiluminescence assay , and theGenotypes for the TRPA1 SNPs were determined using TaqMan Allele TaqMan PCR. Thermal cycling was performed in standard conditions, and fluorescence was recorded by StepOne Plus Real-Time PCR equipment . Quality control of genotyping quality was carried out using previously assessed positive and negative controls. Moreover, we randomly repeated the genotyping for 10% of the whole sample and achieved 100% consistency. The manufacturer’s software was used to analyze the results.http://www.stat.washington.edu/stephens/software.html (accessed on 25 January 2021) to estimate haplotype frequencies. The possible haplotypes formed by the rs920829, rs16937976, and rs13218757 TRPA1 SNPs were CCG, CGA, CGG, CCA, TCG, and TGA. The CGG, CCA, and TGA haplotypes were observed in frequencies <2% and therefore were not included in subsequent analyses. The genotypes and haplotype frequencies are demonstrated in We used the Bayesian statistical-based program PHASE  and are presented as means ± SDs. Statistical significance was assessed with one-way ANOVA, with treatment interactions assessed by Tukey’s post hoc multiple comparisons test. The sample sizes were adjusted after initial data collection. The study was exploratory research and did not test a prespecified statistical null hypothesis; therefore, the t-test or Mann–Whitney test was used according to the number of groups and parametric or nonparametric distributions of quantitative data. A p < 0.05 was considered statistically significant in all analyses. The power analysis calculations determined the minimum effects we could detect with our sample size.Continuous data were tested for normality. Clinical and laboratory characteristics of the patients are expressed as means ± SDs. In contrast, the changes in hemodynamic and biochemical parameters after the induction of anesthesia with propofol are expressed as means ± SEMs. A chi-squared test evaluated deviation from the Hardy–Weinberg equilibrium. The effects of TRPA1 genetic markers on hemodynamic and biochemical parameters were tested by analysis of variance followed by Tukey’s posttest or Kruskal–Wallis followed by Dunn’s posttest. When appropriate, Student’s p values were two-sided, and the alpha value was set at 0.05. Data were analyzed using Jamovi (Version 1.8), retrieved from https://www.jamovi.org (accessed on 10 October 2021).We performed multiple linear regression (MLR) analyses to assess the contribution of Angiotensin-converting enzyme inhibitors (ACEi) used for pressure estimate (PE) separately. Crude regression coefficients (β) and 95% confidence intervals (CI) of possible predictors were respectively estimated with linear regression (model 1). In addition, we minimally adjusted for baseline characteristics (age and BMI) in model 2 and fully adjusted for baseline characteristics (age and BMI) and clinical factors  in model 3. Those covariates were adjusted as mediators for the association. In mutually adjusted models, we simultaneously included explanatory variables and polymorphisms (model 4). For this, we used a combination of the TC genotypes of TRPA1 rs920829 C>T SNP, CG+GG genotypes of TRPA1 rs16937976 C>G SNP, and of the AG+AA genotypes of TRPA1 rs13218757 G>A SNP, which correspond to the genotypes with the variant allele according to dbSNP. All p < 0.001) after propofol administration. There was no difference in heart rate.p > 0.05). Interestingly, patients carrying the CG+GG genotypes for the rs16937976 polymorphism showed lower decreases in MBP and SBP in response to propofol than those carrying the CC genotype (p < 0.05). In addition, we found more intense decreases in MBP and SBP in patients carrying the GG genotype for the rs13218757 polymorphism compared with patients carrying the AG+AA genotype (p < 0.05). We evaluated the effects of TRPA1 genotypes on changes in SBP, MBP, and DBP after propofol administration. The different genotypes for rs920829 did not impact blood pressure changes , without any significant difference in the blood pressure. On the other hand, we discovered that the rs16937976 and rs13218757 polymorphisms and CGA haplotype impacted blood pressure decrease without affecting NOx, nitrite, or nitrate levels after propofol anesthesia (p > 0.05). None of the studied haplotypes showed a significant change for NOx or nitrate variations. .Our second question was whether TRPA1 genotypes and haplotypes influence the changes in plasma NOx, nitrate, and nitrite levels in response to propofol anesthesia. Patients carrying the TC genotype for the rs920829 polymorphism showed higher increases in NOx and nitrate levels in response to propofol than carriers of the CC genotype (p < 0.05) for the CGA haplotype compared with CGG. Regarding the haplotypes, after linear regression analysis, we also found a significant difference in the systolic pressure (p > 0.05). None of the studied polymorphisms or haplotypes showed a significant change in heart rate values . TRPA1 gTRPA1 gene were associated with lower blood pressure drops after propofol anesthesia compared to the ancestral genotype CC; (ii) ancestral genotype (CC genotype) for the rs13218757 polymorphism in the TRPA1 gene was associated with more intense decreases in blood pressure after propofol anesthesia compared with variant (AG+AA) genotypes; (iii) the TRPA1 CGA haplotype was associated with lower decreases in blood pressure after propofol anesthesia compared with the CGG haplotype; (iv) patients carrying the CT genotype for the rs920829 polymorphism showed a higher increase in NOx and nitrate levels in response to propofol than carriers of the CC genotype and rs16937976 and rs13218757 polymorphisms, and the haplotypes did not affect the changes in NOx, nitrite, or nitrate levels after propofol anesthesia. None of the studied genotypes or haplotypes showed a significant change in HR variation. This study was a pioneer in evaluating whether TRPA1 genotypes and haplotypes affect hemodynamic parameters and NO bioavailability after propofol anesthesia. The main findings were that: (i) variant genotypes (CG+GG) for the rs16937976 polymorphism in the Pereira et al.  discover2+ influx that subsequently causes the release of calcitonin gene-related peptide (CGRP) from the sensory nerves that innervate the vascular wall. CGRP binds its G protein-coupled receptor (GPCR) on smooth muscle cells (SMCs) and causes membrane hyperpolarization, myocyte relaxation, and arterial dilation. TRPA1 agonists in the bloodstream may activate the channel in endothelial cells, resulting in Ca2+ influx. High intracellular Ca2+ leads to hyperpolarization of the endothelial cells via the stimulation of the Ca2+-activated K+ channels (KCa).Numerous studies have identified that propofol has vasodilatory properties in vivo  and in vThe mechanism through which propofol acts on the vasculature is controversial. It may involve direct modulation of vascular tone in an endothelium-dependent or endothelium-independent manner depending on the species  and vascular bed (thoracic and coronary) from which the arterioles were obtained . SpecifiTRPA1 channels have been identified as essential modulators of vasomotor tone in vivo and in vitro ,33. SinhThe classical mechanism proposed for the propofol vasorelaxant effect is through NO upregulation ,34. IndeRegarding the interference of the studied polymorphisms, we found that NOx and nitrate levels were affected by the rs920829 polymorphism. Patients with genotype CC showed higher increases in NOx and nitrate levels in response to propofol than carriers of the CT genotype. However, this was insufficient to produce more intense hypotension and affect the nitrite levels after propofol infusion for unknown reasons. Indeed, NO has a very brief half-life, limiting the evaluation of endogenous NO production in vivo . TherefoThe rs16937976 and rs13218757 polymorphisms and the haplotypes did not present any additional impact on the NOx, nitrite, or nitrate levels, leading us to conclude that these TRPA1 polymorphisms may modify blood pressure decrease induced by propofol throughout another mechanism than modulating NO bioavailability. Propofol is a TRPA1 agonist on sensory neurons, as identified by Lee et al. . TRPA1 aThe application of TRPA1 agonists causes the dilation of several arteries, and these responses are minor if vessels are treated with TRPA1 blockers or in preparations isolated from TRPA1-deficient mice ,48,49. NMoreover, the depressor response provoked by propofol is not entirely eliminated when TRPA1 is deleted . Even coAlternatively, other mediators and channels may be involved. Some previous reports have demonstrated a role for ATP-gated K+ channels and cyclooxygenase products in mediating propofol-induced depressor responses ,51. ThusFurthermore, TRPA1 agonists cause the release of adrenaline from the adrenal cortex , leadingPatients undergoing colonoscopy have risk factors for hypotension, such as bowel preparation, age, and comorbidities, and are thus an appropriate group to monitor for sedation-induced hypotension . AccordiThere are some limitations in our study. We did not examine other polymorphisms in genes encoding proteins related to TRPA1 modulation that could affect the hypotensive responses to propofol, such as PRKCA ,62 and VTRPA1 gene polymorphisms rs16937976 and rs13218757. Considering the haplotypes, the most negligible variations in systolic, mean, and diastolic blood pressure drops were for the CGA haplotype. Interestingly, there was no relationship between higher baseline blood pressure values for any genotypes in the studied polymorphisms. Moreover, they did not correlate in prevalence regarding age, BMI, or sex among the studied patients.In summary, our results present that propofol anesthesia induces more intense hypotensive responses in patients with dominant homozygous genotypes (CC and GG) to With improved genetic knowledge, it is expected that medications will be better indicated for each patient based on their genotype and haplotype in the future. Furthermore, our findings could help predict the hemodynamic side effects of propofol, a common anesthetic. Finally, because anesthetics activate TRPA1, it could help with drug development, particularly when it comes to modifying propofol management in uncompensated hypertensive and hypotensive patients.


Are kidney health outcomes different in children and adolescents compared with adults with focal segmental glomerulosclerosis (FSGS)?This cohort study with 482 patients from 3 independent cohorts found no significant differences by age in the median time to kidney failure, 11.9 years, or to the composite outcome of time to kidney failure or 40% reduction in kidney function, 5.7 years, despite differences in clinical context and medical management.These findings suggest that the adverse outcomes of FSGS on kidney survival are severe and comparable across the lifespan. This cohort study examines whether there are differences in the kidney health outcomes among children, adolescents, and adults with focal segmental glomerulosclerosis (FSGS). Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials.To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS.This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record–based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022.APOL1 genotype, urine protein–to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy.Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria.The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years . There was no difference in ESKD risk among children vs adults  or adolescents vs adults . The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12  and adolescents vs adults of 1.06 .In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages. There are no US Food and Drug Administration (FDA)–approved treatments for FSGS. While novel FSGS therapies are currently in various stages of clinical development, clinical trials usually focus on the adult patient population. Consequently, therapeutic development for affected children and adolescents with FSGS remains unaddressed.5 However, because of potential differences in disease presentation, evaluation, and utilization of therapy, the issue remains unresolved.The inclusion of children and adolescents in clinical trials requires an understanding of the natural history and long-term outcomes of disease and safety considerations regarding the test therapy. This information can be used by regulatory agencies, such as the FDA and European Medicines Agency, to assess whether special study design and end point selection are needed for drug development plans that aim to include children and adolescents. Delineation of the short- and long-term impact of FSGS in pediatric vs adult patients is a key element in these deliberations. Estimates from the Toronto Glomerular Disease Registry suggest that the clinical course of FSGS is similar in children and adults.Therefore, we conducted this study to test the hypothesis that kidney survival and proteinuria outcomes in pediatric patients with FSGS are similar to their adult counterparts. We used 3 complementary data sets, including 1 prospective cohort study, 1 clinical trial, and 1 clinical data set.In this cohort study, analyzing a pooled data set from 3 existing data sources, the main outcomes of interest were ESKD, a composite of ESKD or 40% decline in estimated glomerular filtration rate (eGFR), and complete and/or partial remission of proteinuria. The primary exposure was age, categorized as child (<13 years), adolescent (13-17 years), and adult (≥18 years).6 Data capture included demographic characteristics with patient-reported race and ethnicity, symptoms, coexisting conditions, hospitalizations, procedures, physical examination, medications, laboratory values, and patient-reported outcomes. In addition, urine, blood, and kidney biopsy tissue samples were stored in a biobank. The visit schedule included a baseline assessment within 30 days of the qualifying kidney biopsy and visits every 4 months during the first year and every 6 months thereafter for a maximum of 5 years. Race and ethnicity were collected as demographic variables to assess the representativeness of the studies with the affected population. Additionally, for National Institutes of Health (NIH)–sponsored studies, such as NEPTUNE, we are required to report demographic variables including race and ethnicity in our annual progress reports, thereby mandating these data collection items.Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE) is a prospective cohort study of primary proteinuric kidney diseases, including FSGS, that was launched in 2010. Patients were enrolled at the time of their first clinically indicated kidney biopsy.7 The trial tested the efficacy on proteinuria of 52-week therapy with cyclosporine among 72 patients vs combination therapy with oral pulse dexamethasone and mycophenolate mofetil among 66 patients. Participants were enrolled in the US and Canada between November 2004 and May 2008. Race and ethnicity were self-reported. All patients received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Patients with no response by week 26 were declared nonresponders.The FSGS clinical trial (FSGS-CT) was a multicenter randomized clinical trial of children and adults with steroid-resistant FSGS.9 Inclusion in this analysis was limited to patients with FSGS with a known date. KRN registry collects EHR data monthly, including demographic characteristics (with race and ethnicity extracted from the EHR), diagnoses, vital signs, laboratory results, medications, procedures, ESKD status, kidney biopsy reports, and vital status. Retrospective data were extracted from the earliest existing health record data point. The primary kidney diagnosis was confirmed by the patient’s nephrologist at the time of consent.The Kidney Research Network (KRN) is an electronic health record (EHR)–based patient registry of children and adults with proteinuric kidney diseases in the United States, which was opened to enrollment in November 2015.STROBE) reporting guideline.For NEPTUNE and FSGS-CT, the institutional review board (IRB) at each participating site approved the study protocol. For KRN, the protocol was reviewed and approved by the University of Michigan IRB, which serves as IRB of record for all enrolling sites. Informed consent and, as applicable, assent were obtained in accordance with IRB approval from each NEPTUNE (in-person), FSGS-CT (in-person), and KRN (in-person or via telephone) participant. This study followed Strengthening the Reporting of Observational Studies in Epidemiology  and weight status categorized by latest guidelines13; urine protein–to-creatinine (UP:C) ratio; eGFR, calculated using the age- and creatinine-based U25 formula in those aged younger than 25 years and race-free 2021 Chronic Kidney Disease–Epidemiology Collaboration (CKD-EPI) creatinine equation for those aged 25 years or older17; serum albumin and lipid levels; prior immunosuppressive therapy (IST); and comorbidities. In addition, the following genetic and pathologic data from the NEPTUNE and FSGS-CT studies were included in this analysis: (1) APOL1 genotype assessed directly via Sanger sequencing of the last 250 bases of exon 7; (2) evidence of monogenic disease based on a bioinformatics pipeline using stringent pathogenicity filtering19; and (3) the extent of interstitial fibrosis and global and segmental sclerosis on kidney biopsy. Participants with evidence of monogenic disease were excluded from primary analyses.Baseline characteristics were compared by age category at time of first biopsy (KRN and NEPTUNE) or disease presentation (FSGS-CT) using medians and IQRs for continuous variables and frequencies and percentages for categorical variables. We subcategorized the pediatric population into 2 subgroups to reflect the common approach to regulatory considerations separating adolescents from younger children. This separation captures the potential impact of puberty on disease progression and clinical management compared with younger children. Characteristics studied include age; sex; race; ethnicity; Columbia FSGS pathology classification2 tests for categorical variables based on complete case analyses. No adjustments for multiplicity were made, as a penalty would bias the estimates toward the null and in favor of our hypotheses.In the KRN cohort, laboratory data obtained within a month prior to the kidney biopsy were considered baseline. Comparisons of characteristics by age group were tested using Kruskal-Wallis tests for continuous variables and χPractice patterns in the observational NEPTUNE and KRN studies were compared by age by reporting frequencies and percentages of treatments after biopsy. These analyses also tested for differences in likelihood of IST exposure after biopsy among those IST naive at biopsy using logistic regression. Unadjusted comparisons were made by age and after adjusting for UP:C ratio and eGFR.20 Analyses were done for each of these end points except time to partial remission. In the KRN data set, proteinuria was commonly monitored based on screening dipstick testing and reflexive UP:C ratio per clinician preference. Given the substantial differences in proteinuria assessment in KRN compared with NEPTUNE and FSGS-CT, KRN was not included in the proteinuria analyses.Kaplan-Meier plots with log-ranked tests were used to compare the following end points by age: (1) time to ESKD, (2) time to ESKD or 40% reduction in eGFR, (3) time to complete remission (UP:C ratio <0.3 g/g), and (4) time to complete remission or partial remission defined as either a 40% reduction in UP:C ratio to a value less than 1.5 g/g or a 50% reduction to a value less than 3.5 g/g.APOL1 status, initial UP:C ratio, and treatment . Significant interactions would indicate whether the association between these characteristics and outcomes may differ by age.Tests for effect modification in time to ESKD or 40% reduction in eGFR and time to complete remission were performed using Cox proportional hazards models with interaction terms for subgroups of interest, as follows: sex, disease duration, 2), a common finding among individuals with nephrotic syndrome, the analyses winsorized the eGFR distribution greater than 120 mL/min/1.73 m2 by imputing values greater than 120 mL/min/1.73 m2 to 120 mL/min/1.73 m2.Linear mixed-effects models with random slope (time) and intercept (participant) terms were used to compare trajectories of eGFR by age. Models used eGFR as the outcome, with an interaction term between time (years) and age category used to determine whether trajectories of eGFR differed by age. To handle hyperfiltration  had 2 Sensitivity analyses including monogenic patients in the models are shown in eTable 7 in the APOL1 risk genotype, initial UP:C ratio, and treatment are shown in eTable 8 and eFigure 5 in the Tests of effect modification by sex, disease duration, Average eGFR trajectories derived from mixed models are shown in In pooled analysis of NEPTUNE and FSGS-CT only, adults were less likely to achieve complete remission than adolescents or children . By 12 mThis report describes the natural history of patients with FSGS in a pooled analysis of 482 participants with FSGS from 3 contemporary cohorts. Although there were differences in clinical presentation and treatment patterns in child, adolescent, and adult patients, the disease course based on the composite kidney health outcome of a 40% reduction in eGFR or ESKD was remarkably similar in the 3 groups. To our knowledge, this report is unique in that it captures patients from across North America and represents populations from 3 distinct settings: a cohort study, a randomized clinical trial, and clinical data from medical practices across the United States. As such, it reduces the magnitude of any unique design-related bias that may have influenced previous publications that focused on a single population. The ability to compare kidney function outcomes in pediatric vs adult patients with FSGS in such diverse contexts represents a unique feature of our study that enhances its external validity.21Children tended to present with overt nephrotic syndrome, less interstitial fibrosis in the kidney, and higher eGFR than adolescents or adults. In addition, they were more likely to receive IST. Nevertheless, all age groups lost kidney function at a comparable rate over time, and the majority of patients in each age group did not achieve a complete proteinuria remission. The 5-year kidney survival in pediatric patients with FSGS in the pooled analysis was comparable with published outcomes from the pediatric steroid-resistant nephrotic syndrome PodoNET registry.21 After excluding patients with known monogenic disease, the natural history of FSGS was comparable in pediatric vs adult patients. Adult patients may have a higher burden of comorbid conditions that theoretically may accelerate the progression of kidney disease. However, our findings suggest that despite these potential differences, in the aggregate, the clinical course of FSGS is similar across the lifespan.The biological context in which FSGS develops is undoubtedly different within the full spectrum of affected patients. Individuals with a monogenic etiology of FSGS are usually younger and less likely to respond to treatment.22 These pathogenetic subtypes are likely to occur in all ages, contribute to the poor outcomes of FSGS, and provide justification for drug development of targeted therapies in mechanistically defined patients regardless of age.23It is increasingly acknowledged that the diagnosis of FSGS, which is based on histopathological findings, provides limited information about prognosis and appropriate therapy. FSGS is recognized to be a heterogeneous group of disorders with distinct molecular injury pathway(s).There is a well-documented shortfall in the performance of adequately designed and powered clinical trials in nephrology. This is especially the case for pediatric patients. A review of ClinicalTrials.gov  identified 12 ongoing trials for FSGS. Of these, 5 of 12 (42%) are open to the enrollment of children and adolescents, 3 of which are testing a single agent. A key first step in expanding drug development for all ages is an accurate delineation of natural history and relevant health outcomes for the disease being studied. Our finding that key kidney function outcomes in patients with FSGS are poor and comparable in children, adolescents, and adults highlights the unmet clinical need across the lifespan. This information clearly needs to be supplemented by information about the safety of the therapeutic agent under investigation that is germane to pediatric patients. Nevertheless, this study provides essential information to inform clinical trial design for specific and combined age groups.FSGS is a rare glomerular disease and our overall cohort is one of the largest and diverse with comprehensive assessment of long-term kidney function. However, there are limitations to this study. First, the sample size in pooled analysis was modest and may have limited the power to detect differences in outcomes. For example, we were only powered for an HR difference of 0.56 in the pooled analyses of time to ESKD comparing children vs adults. In fact, we observed an HR of 0.67, a difference in magnitude that would be clinically significant, if confirmed with larger sample size, and suggest that children have slower progression to ESKD despite having no difference in eGFR slope or time to the composite end point of 40% eGFR loss or ESKD. However, we posit that this discrepancy is instead because children had higher initial levels of eGFR. Most of the remaining HR results were close to unity. Second, we cannot be certain that the underlying pathogenetic mechanisms of FSGS are similarly distributed across the age groups. However, the cohorts reflect contemporary approaches to the diagnosis, classification, and management of FSGS in children and adults. Third, there was incomplete harmonization of the data collection across the data sources. Genetic testing was not performed in all patients. Consequently, the exclusion of patients with monogenic FSGS was likely incomplete. Sensitivity analysis obtained similar results with inclusion or exclusion of patients with known monogenic causes of FSGS.This report found a reasonably consistent clinical trajectory under current standard of care therapies for FSGS. We have quantified the uncertainty in the estimates to inform trial design and support decision-making. Our findings provide evidence of kidney disease progression trajectories for children, adolescents, and adults with FSGS that can be used to strengthen clinical trial design and extrapolation studies. This should facilitate selection of population, end points, and analysis plan when designing clinical trials of potential novel therapies for children, adolescents, and adults with FSGS.


What are the main findings?We found new aspects of fixed airways obstruction in severe asthma probably linked to late asthma diagnosis.Asthma with and without fixed airways obstruction had similar outcomes.What is the implication of the main finding?A prompt differential diagnosis between severe asthma and COPD is essential.The above is important to avoid further airway remodeling.p < 0.05). ACT at T0 and ΔT0–T1, FEV1 at ΔT0–T1 and number of exacerbations at T0 and ΔT0–T1 did not differ between groups. Despite a widespread perception of FAO, per se, as a severity factor for asthma, we found similar severity profiles and amelioration after one year of treatment in the FAO+ and FAO− groups. The only factor linked to FAO development in our population was a delay in asthma diagnosis from respiratory symptoms onset, which may have led to airway remodeling. Physicians should characterize patients with FAO for avoiding misdiagnosis between asthma and other respiratory diseases and for establishing the appropriate therapy.We aimed to evaluate asthmatic patients with fixed airways obstruction (FAO) and to verify the impact of follow-up in an asthma-dedicated outpatient clinic on symptoms control and spirometry compared to asthmatics without FAO. We enrolled 20 asthmatic FAO+ patients and 20 FAO− asthmatics at baseline (T0) and at a one-year follow-up visit (T1). FAO+ and FAO− groups were compared for anamnesis, FEV1, asthma control test (ACT) and their ΔT0–T1. FAO+ and FAO− groups did not differ for age, BMI, pack-years, allergy, T0 blood eosinophils, comorbidities or GINA therapy step at T0 and T1, whereas, in the FAO+ group, we found more patients with a delay >5 years between symptoms onset and correct asthma diagnosis ( Asthma is an inflammatory chronic disease of the bronchi, which is characterized by symptoms such as cough, chest tightness, dyspnea and wheezing and pathophysiological alterations including obstructive ventilatory defect and hyperinflation, which may vary in intensity and over time . Indeed,However, a small group of asthmatic patients may develop fixed airway obstruction (FAO) due to airway remodeling, which is a mechanism characterized by bronchial epithelial cells apoptosis, smooth muscle cells proliferation and fibroblast-driven extracellular matrix changes leading to persistent narrowing of small and large airways ; the mecGiven the similar clinical and functional manifestations in asthma with FAO and COPD, it is essential to obtain a better characterization of patients with non-reversible obstructive lung disease. Indeed, asthma with FAO can be considered a type of severe asthma ,4 and maBased on the above, the aim of our study was to deepen our knowledge about FAO in asthma by investigating a population of patients with asthma and FAO in terms of clinical, functional and biological characteristics, compared with a population of asthmatic patients without FAO.A total of 40 patients were enrolled into this study, with an unsupervised approach.The first group was composed of 20 consecutive patients with asthma and with fixed airflow obstruction (FAO+). FAO+ was defined as patients showing values of post-bronchodilator Forced Expiratory Volume in the 1st second/Vital Capacity (FEV1/VC) < limit of the 5th percentile (LLN) and FEV1% < 90% despite adequate control therapy, stable throughout the one-year follow-up.The second group consisted of 20 consecutive patients with asthma and without fixed airflow obstruction (FAO−).All patients were recruited from those attending the respiratory diseases outpatient clinic of the University hospital of Policlinico, Bari, Italy, from January 2017 to February 2020.Inclusion criteria for both groups were diagnosis of asthma strictly following GINA guidelines and pack/year value under 10, whereas exclusion criteria for both groups were refusal of written informed consent, a more probable diagnosis of COPD (or asthma/COPD overlap) and/or any other lung diseases and/or any systemic diseases with potential lung involvement, such as Eosinophilic Granulomatosis with Polyangiitis (EGPA) or autoimmune diseases and neoplasms.All patients gave voluntary consent to participate in the study and to process personal data.The present study was conducted according to the World Medical Association’s 2008 Declaration of Helsinki, the guidelines for Good Clinical Practice and the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) guidelines .In addition, this study was approved by the local Institutional Review Board .We conducted an observational prospective study. Patients were evaluated during two visits, at the first visit (T0) and at a control visit (T1) after 1 year. During this time span, patients were followed-up by our outpatient clinic, and the frequency of the visits and the prescribed therapies followed GINA guidelines according to the severity of each patient.At both T0 and T1, all patients were investigated for respiratory symptoms onset, year of asthma diagnosis, any possible diagnosis delay (late diagnosis was considered if asthma diagnosis occurred more than 5 years from symptoms onset), common asthma comorbidities , obesity, gastro-esophageal reflux disease (GERD), obstructive sleep apnea (OSAS)), asthma controller therapy  and blood eosinophils, and screened for alpha-1 antitrypsin deficiency with serum dosage. At both T0 and T1, all patients underwent a lung function test and symptoms assessment with an asthma control test (ACT). Comparisons were made between FAO+ and FAO− group for disease onset prevalence, comorbidities prevalence, naïve patients’ prevalence, FEV1 variations between T0 and T1 (intended as percentage of T0 change in volume between T1 and T0) and ACT value variations between T0 and T1. We also compared frequency distribution of positive minimally clinical important difference (MCID) in FEV1 and ACT between FAO+ and FAO− groups. An FEV1 positive MCID was considered when having an increase in FEV1 between T0 and T1 of at least 15%, whereas an ACT positive MCID was considered when having an ACT increase of at least three points between T0 and T1.All lung function tests were performed with Jaeger™ Masterscreen Body  following the current recommendations . The folAll continuous variables were tested for normality with a Shapiro–Wilk test.Normal variables are shown as mean ± standard deviation (SD) and non-normal variables are shown as median (interquartile range).t-test for parametric variables and with a Mann–Whitney test for nonparametric variables.Comparisons between continuous variables were tested with Student’s Comparisons between frequencies distributions of prevalence were tested with Fisher’s exact test.P values were considered significant under 0.05.The software used for statistics was SPSS .p < 0.05), and, considering the abovementioned definition of late diagnosis, nine patients (45%) in the FAO+ group received a late diagnosis of asthma, whereas this happened in only two patients (10%) of the FAO− group .Comparison of spirometric values, symptoms evaluation and steps of therapies between FAO+ and FAO− groups at T0 and T1 are presented in p < 0.01, p < 0.01). Conversely, FEV1 variation between T0 and T1 did not differ between FAO+ and FAO− groups (1.92 (−3.75–15.75) vs. 8.37 (−3.55–14.57); p = 0.66, p = 0.72).Baseline post-bronchodilator FEV1 was, as expected, significantly lower in the FAO+ group (79.50 (65.50–81) vs. 90 (83.75–97); p = 0.25) and the variation of last-year exacerbations number did not change significantly between groups (0 (−1–0) vs. −1 (−1–0); p = 0.33).Number of last-year exacerbations at baseline did not differ between FAO+ and FAO− groups (0 (0–1) vs. 1 (0–1.75); In our study we found that, unexpectedly, the FAO+ group and the FAO− group significantly differed only for lung function, years from asthma diagnosis and ACT improvement MCID, whereas other biological, anamnestic and clinical factors were similar in the two groups.Our groups did not significantly differ for baseline general characteristics, and, in a similar way, comparison between FAO+ and FAO− groups for blood eosinophil counts, aeroallergen sensitivity and common asthmatic comorbidities prevalence  did not show significant differences. Contrarily, in 2015 Konstantellou et al. recruited 170 asthmatic patients and identified 60 with persistent airflow limitation, and, again, through a cluster analysis, showed that the persistent airflow limitation cluster was the one with highest systemic and inhaled corticosteroid usage with highest type-2 inflammation biomarkers [In addition, prevalence of GERD and OSAS, which are considered determinant comorbidities for difficult-to-control asthma, did not differ between groups. The history of tobacco exposure, expressed as P/Y, was similar in FAO+ and FAO− groups, but we chose to consider a P/Y < 10 in our inclusion criteria for general study population in order to better define asthma diagnosis, so this result is expected. Konno et al., in 2017, showed, through a cluster analysis on 127 severe asthmatic patients, that smoking is related to low FEV1 in two different clusters of patients, both T2 high and T2 low, as well as obesity , while oWe also compared the steps of asthma therapy according to GINA guidelines between FAO+ and FAO− groups, both at baseline and after T1 visit, and we did not find any significant difference, having as well a similar median ACT between groups at baseline and a similar variation in ACT values after the one-year follow-up at our dedicated outpatient clinic. Despite this, significantly more FAO− patients presented a positive MCID for ACT from T0 to T1, showing a better feeling of symptoms amelioration in this group after the one-year follow-up. Conversely, Smith et al., in a 2019 study, demonstrated that FAO patients are characterized by higher systemic corticosteroids dependence, higher inhaled corticosteroids dosages and an overall higher severity of asthma [Obviously, in the FAO+ group, baseline as well as T1 FEV1 are significantly lower than in the FAO− group, but this finding is due to the FAO+ inclusion criteria that allowed only low FEV1 patients to enter this group. On the contrary, interesting evidence is that median FEV1 variations between T0 and T1 are similar in the two groups, and, also, comparison between positive MCID in FEV1 variations show the same result, demonstrating that also patients with a more compromised lung function may benefit from a better asthma therapy setting.Both groups were characterized by a low median number of previous-year exacerbations at baseline and a similar amelioration of this value after one year.These findings depict a similar patient severity profile in the two groups according to symptoms control and previous-year exacerbations, and this contrasts with the diffuse belief, also found in ATS/ERS 2014 severe asthma guidelines [Interestingly, we found a trend towards a longer year from asthma diagnosis in the FAO− group and a significantly higher number of late diagnoses in the FAO+ group that could explain worse FEV1 values in the FAO+ group, considering the delay of a proper asthma control therapy setting with anti-inflammatory inhaled steroids that may have led to airway remodeling, the pathologic mechanism behind FAO.In our opinion, the change in therapeutic strategies for COPD led by GOLD 2017 guidelines, which suggested ICS therapy only in a minor subset of COPD exacerbator patients, contributed to help proper diagnosis, especially in elderly patients with fixed airway obstruction asthma, allowing us to enrich our population of FAO+ patients with patients that, since 2017, were misdiagnosed with COPD, not characterized by evident type-2 inflammation markers or by high exacerbation number or OCS dependence, classic asthmatic stigmata.Misdiagnosis of obstructive lung diseases has always been a hot topic, already evidenced during the past decades , and stiRegarding this topic, 2014 GINA Asthma/COPD Overlap Syndrome (ACOS) guidelines  already Our work presents some limitations, such as the scarce numerosity of our population and the short follow-up period to the lack of endotype characterization of our patients with more proper biomarkers  apart from blood eosinophils and anamnestic determination of aeroallergen sensitization and type-2 comorbidities presence, but they are linked to the real-life setting of this study.In conclusion, despite a widespread perception of FAO as an important, per se, characterizing severity factor for asthma, in our study, we found a similar severity profile in FAO+ and FAO− groups and a similar amelioration in symptoms control and lung function improvement  after one year follow-up at our asthma dedicated outpatient clinic. The only factor that is linked to FAO development in our population is a delay in asthma diagnosis from respiratory symptoms onset, that may have led to airway remodeling. The difference between our results and those found in the literature may be explained by the inclusion in our FAO+ group of patients that, up to 2017 GOLD COPD guidelines publications, were easily misdiagnosed as COPD. Clinicians in real-life settings, often characterized by few resources and time to dedicate to single patients, must pay particular attention to anamnesis and type-2 inflammation markers in patients presenting respiratory symptoms and not only to lung function to avoid misdiagnosis and to give asthmatic patients the right anti-inflammatory inhaled therapy that leads to important results also in this subtype of patients and may avoid further airway remodeling.A practical approach to the problem of the misdiagnosis of asthma may be represented by the further implementation of more tests apart from spirometry in respiratory patients with FAO, for example, the evaluation of easily obtainable type-2 biomarkers such as fraction exhaled nitric oxide (FeNO) or peripheral blood eosinophil count, as proposed by Paraskevi et al., in children patients .