In this study, we examined the relative usefulness of serum copeptin levels as a surrogate marker of vasopressin (AVP) in adult polycystic kidney disease (ADPKD) by correlating it with baseline and longitudinal changes in markers of both renal function and common CVD manifestations  that accompany the progression of this disease.n = 235) and measured cardiovascular function using flow-mediation dilatation (FMD), carotid intima media thickness (cIMT) and pulse wave velocity (PWV), as well as serum copeptin . The same analyses were carried out at baseline and after 3 years of follow-up.We studied a cohort of young and otherwise healthy ADPKD patients  mL/min./1.73 m2, 5.8 ± 0.9%, 0.8 ± 0.1 mm. and 8.2 ± 1.3 m/s. with all changes statistically significant. Plasma copeptin also rose from 0.62 ± 0.12 to 0.94 ± 0.19 ng/mL and this change correlated with ΔeGFR , ΔFMD , ΔcIMT  and ΔPWV  also after linear regression modeling to correct for confounders. Finally, ROC analysis was done for a high baseline copeptin with ΔeGFR [cut-off:≤59], ΔFMD [cut-off: ≤7.08], ΔcIMT [cut-off:>0.76], and ΔPWV [cut-off:≤7.80].At baseline, median eGFR was 69 mL/min./1.73 mVascular dysfunction as reflected by FMD and cIMT, but not PWV or an altered cardiac geometry, precede most other signs of disease in ADPKD but is predicted by elevated levels of the circulating AVP-marker copeptin. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequently hereditary cause of renal failure but also an important cause of hypertension and cardiovascular diseases (CVD). Renal and extra-renal cystic manifestations are the main characteristics of a disease that often leads to the need for renal replacement therapy by the sixth decade of life. The risk of CVD morbidity and mortality are both highly elevated in ADPKD as compared to the general population, but it is not known if this is mainly a consequence of the disease itself or if it is linked primarily to the drop in renal function , 2.Recent advances have linked cyst formation in ADPKD to arginine-vasopressin hormone (AVP)-signalling through the vasopressin V2-receptor and subsequent phosphodiesterase-driven cAMP modulation of that signal , 4. ClinMeasuring AVP directly is difficult, as over 90% is tightly bound to platelets . CopeptiIn this study, we examined the relative usefulness of serum copeptin levels as a surrogate marker of AVP by correlating it with baseline and longitudinal changes in markers of both renal function and common CVD manifestations  that accompany the progression of ADPKD.Between March 2012 and March 2015, all 235 ADPKD patients with normal renal function and followed at either Kayseri Erciyes University School of Medicine or the Ankara Gulhane School of Medicine (identified through the Turkish Society of Nephrology’s Polycystic Kidney Disease Working Group Registry) were screened for inclusion in the study. Prior approval for the study had been obtained from the local ethics committees at both hospitals. Eligible patients were invited to enroll in the study and, following verbal and written information about the study, asked to give written consent. Only patients that gave written, informed consent to participate in the study were recruited, and the study conformed to the Declaration of Helsinki as amended. The study was prepared according to the STROBE guidelines/methodology.n = 7), SSRIs (n = 4), NSAIDs (n = 6), demeclocycline (n = 1), statins (n = 10), clofibrate (n = 2), chlorpromazine (n = 1), and vasopressin analogues(n = 3). In the end, the study cohort comprised a total of 202 ADPKD patients with normal renal function. At 36 months after the initial evaluation, patients were recalled and asked to undergo the same procedures a second time. Four patients did not complete follow-up, but their data were kept for baseline analyses.In enrolled patients, the diagnosis of ADPKD was re-established based on clinical data, family history and a new ultrasound of the kidneys using the criteria described by Pei et al . DemograBlood pressure monitoring over 24 h was performed using a Del Mar Medical Ressurometer Model P6  together with the manufacturer’s software. Ambulatory measurements were conducted once every 15min from 7 am until 11 pm, and once every 30min from 11 pm until 7 am. Data were summarized using the mean values for day and night. Hypertension was considered to be present if the average systolic pressure was ≥130 mmHg and/or the average diastolic pressure was ≥80 mmHg for whole day, or if the individual was taking any of the allowed antihypertensive medications.Venous blood was drawn following a 12 h self-reported fast in the morning due to circadian rhytmicity of AVP. Glucose, creatinine, and lipids were assessed using standard methods. Estimated GFR (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation . High se3 − (LVEDD) 3)) + 0.6 g [All participants were examined using a Vivid 7 instrument  with a 2.5-MHz transducer and harmonic imaging. The echocardiographies were all performed by a specialist in echocardiography and according to the recommendations of the American Society of Echocardiography. Briefly, at least three consecutive beats in sinus rhythm were recorded, and the average values used. The LV end-diastolic and end-systolic dimensions (LVEDD and LVESD) and interventricular septal and posterior wall thicknesses (IVSd and LPWd) were measured from M-mode images of the left ventricle generated in the long-axis view with the cursor at the tip of the mitral valve leaflets. The LV ejection fraction was calculated using the formula: LVEF % = (LVEDV − LVESV)/LVEDV × 100. The left ventricular mass (LVM) was calculated using the formula: LVM = 0.8 × (1.04 [(IVSd + LVEDD + LPWd)  + 0.6 g .Endothelial dysfunction was assessed according to the transient ischemia method described by Celemajer et al. . MeasureUltrasonographic studies on common carotid artery was done on both sides and using high-resolution Doppler ultrasound (ATL 5000) with a 5–12 MHz linear transducer. A single blinded operator performed all measurents on two stored longitudinal images of each artery. The four values were averaged to calculate mean c-IMT.Pulse wave analysis was performed twice on each side, in the carotid and femoral arteries. We used a machine  in accordance with the manufacturer’s recommendations. PWV was calculated automatically by measuring the time for the pulse wave to travel between the carotid and femoral arteries. All measurements were performed over 15 heart beats by a single operator.p-value <0.10 were included in a backward elimination multivariate linear regression analysis, with the remaining variables compared as concerns risks by using the likelihood ratio tests. p < 0.05 was considered significant, and the confidence interval (CI) was set to 95%. All statistical analyses were performed using SPSS version 15 .Shapiro-Wilk’s test, histogram and q-q plots were examined to assess normal distribution. Levene test was performed to assess the variance in homogenity. The statistical significance of differences between groups were assessed by two-way paired t- test  or Wilcoxon t- test . In multivariate analyses, all variables for which a unadjusted, univariate linear regression analysis showed a 2; p < 0.001) and hemoglobin during follow-up, while serum phosphorus, HDL- and LDL- cholesterol, plasma glucose, average 24-h systolic and diastolic blood pressure (SBP and DBP), and proteinuria all rose. Of the studied markers of cardiovascular function, LVM , PWV , cIMT , copeptin  and hs-CRP  all increased during follow-up, while FMD  decreased , mean 24 h systolic  and diastolic  blood pressures, cIMT , eGFR  and urine osmolality . We next performed univariate regression analysis to assess correlations between changes in copeptin over time with Δ PWV , Δ cIMT  and Δ FMD   (Table p < 0.01), SBP  and copeptin  emerged as independent. Similar values were obtained for predictors of PWV and FMD, which was also predicted by changes in blood cholesterol and triglycerides. Regarding cIMT, DBP, proteinuria, copeptin and CRP emerged were found as independent predictors . Also, DBP, proteinuria, CRP and cIMT variables were found to be the most essential variables in predicting Δ copeptin  Table . We alsoD) Table . Of the We optimized the positive predictive value of copeptin by performing separate ROC-analyses for each of the CVD surrogates Table . Using tIn this study we measured common surrogate markers of hypertensive (PWV and LVM), atherosclerotic (cIMT) and endothelial (warm ischemia induced FMD) CVD in early-stage ADPKD. All analyses were repeated after a mean 36 months, and we related the results both to each other and to serum levels of the marker of AVP-activity, copeptin. Our data demonstrates that signs of cardiovascular dysfunction, especially of the endothelium, develop already in ADPKD patients with preserved renal function and progresses at a more rapid rate than that of the decline in renal function (assessed as eGFR). We also found that serum levels of copeptin are elevated already before a decline in eGFR in these patients, and that the degree of elevation correlates with functional markers of CVD and also predict a future decline in GFR as well as in FMD.The most important finding of the present study is the characterization of the vascular dysfunction that appears at an early stage of ADPKD and that may be related to the hypertension commonly seen in these patients. Based on our findings, vascular dysfunction in ADPKD is related to endothelial function (FMD) and potentially atherosclerosis (cIMT) more than to fluid overload (PWV) or cardiac failure (echocardiography). We , 17 and L-arginine  was able to restore vascular function in their model, suggesting a key role for NO signaling. Consistent with this finding, Lothioir et al. [2, 36% smokers) they found a maintained ability to dilate vessels following infusion of an NO-donor, while warm ischemia led to a markedly blunted response in patients as compared to controls. Furthermore, infusion of dopamine was able to ameliorate also the warm-ischemia induced FMD in these patients, further strengthening the reported link between ADPKD and impaired dopaminergic signaling reported previously [Regarding potential mechanisms mediating the observed endothelial dysfunction, Peterson et al.  found thr et al.  recentlyeviously , 23. Bareviously  studied In the present study, hypertension and alterations in vascular functions were predicted by an elevated baseline circulating copeptin, while changes in copeptin closely followed those in SBP, FMD, cIMT, and, to a lesser extent, PWV. This is consistent with the hypothesis that copeptin functions as a more stable marker of AVP release in response to changes in plasma osmolality and other factors. Recently, the role of AVP in ADPKD has received much attention. Studies have linked AVP-signalling through V2 receptors in the distal renal tubules and collecting ducts to a rise in intracellular cAMP-levels  that in The present study confirms and expands the previous literature by establishing a strong and independent longitudinal 3-year association both between copeptin and eGFR changes, as well as link an elevated copeptin to impaired ischemia-mediated FMD. This may offer observational support for the hypothesis that dopaminergic inhibition of AVP-driven AQP2 expression and recruitment to the cell membrane  reflectsA number of limitations of the study design should be acknowledged and kept inmind when interpreting the results. First, we did not perform genetic profiling of the included ADPKD patients and thus have no way of telling whether PKD1, PKD2 or even undescribed mutations caused the phenotype. Secondly, we did not measure kidney volumes in the study subjects either at baseline or follow-up. We are thus unable to relate copeptin levels to radiological signs of disease progression. Finally, this is a cohort study without active interventions, precluding the attribution of causality to the predictive statistical relationships.Vascular dysfunction as reflected by FMD and cIMT, but not PWV or an altered cardiac geometry, precede most other signs of disease in ADPKD but is predicted by elevated levels of the circulating AVP-marker copeptin.


Assessment and treatment of the VLBW infant with cardiovascular impairment requires understanding of the underlying physiology of the infant in transition. The situation is dynamic with changes occurring in systemic blood pressure, pulmonary pressures, myocardial function, and ductal shunt in the first postnatal days. New insights into the role of umbilical cord clamping in the transitional circulation have been provided by large clinical trials of early versus later cord clamping and a series of basic science reports describing the physiology in an animal model. Ultrasound assessment is invaluable in assessment of the physiology of the transition and can provide information about the size and shunt direction of the ductus arteriosus, the function of the myocardium and its filling as well as measurements of the cardiac output and an estimate of the state of peripheral vascular resistance. This information not only allows more specific treatment but it will often reduce the need for treatment. The determinants of cardiac output are maintained in equilibrium without interference from external factors. Postnatal factors that can affect the cardiovascular function of the VLBW infant include perinatal asphyxia, sepsis, positive pressure respiratory support, variable carbon dioxide levels, and the time of clamping of the umbilical cord. During the immediate transitional period, these factors may alter preload, and change afterload at a time of rapid transition from the fetal circulation, characterized by low systemic vascular resistance, to the postnatal neonatal circulation with higher peripheral vascular resistance. The predominantly systemic to pulmonary shunts, occurring at atrial and ductal level through persisting fetal channels, can further reduce potential systemic blood flow (SBF)  Figure .Hypotension can be defined in two ways—physiologically or population based. The physiological definition is the blood pressure value where autoregulation of vital organ (brain) blood flow is reduced or lost with an impairment of adequate delivery of oxygen to the organs and tissues. If the blood pressure further decreases (and no treatment is initiated) it will eventually reach a “functional threshold” when neuronal function is impaired, and then finally an “ischemic threshold” which may result in tissue injury with likely permanent organ damage . From a Low blood pressure may also be defined as population based. One definition is a mean blood pressure (MBP) less than 30 mm Hg in any gestation infant in the first postnatal days. This definition relates to previously observed pathophysiologic associations between cerebral injury  and MBP less than 30 mm Hg at any time point in the first few postnatal days , 5 AlthoThe preterm infant frequently has a failure of complete closure of both fetal communications, probably due to immaturity of the structural mechanisms involved , 12. TheVentricular systolic function is defined by preload (filling of the ventricle with blood prior to contraction), contractility , and afterload . The preterm myocardium is less mature than the term infant with histological differences including less numbers of mitochondria and subsequently less energy stores . This rein utero right ventricular dominance. Newer techniques such as tissue Doppler imaging may overcome these limitations  . A delayMany preterm infants are exposed to positive pressure respiratory support in the first postnatal days, although there has been a progressive reduction in the use of mechanical ventilation, particularly as an early first line treatment. Positive end-expiratory pressure is often utilized to reduce the atelectasis resulting from collapse of unstable alveoli when surfactant is lacking, particularly in more immature infants. Function can be impaired by a reduction in the preload from reduced systemic or pulmonary venous return, and/or direct compression of cardiac chambers also resulting in a reduced stroke volume or an increase in afterload. In longitudinal clinical studies of blood pressure and blood flow, mean airway pressure has a consistently negative influence on both MBP and SBF , 30–32. The classic signs of a PDA with increased pulse pressure and evidence of diastolic runoff have resulted in the perception that a PDA is mainly associated with a low diastolic blood pressure. However, several studies have suggested that the PDA can also be associated with both low diastolic and low systolic blood pressure. Thus, a PDA is one of the possible causes of systemic hypotension and PDA assessment should be part of the investigation of hypotension in the first days of life , 37. Clivia capillary refill time (CRT) and urine output and the intermittent documentation of the pulse rate and blood pressure. The acid–base balance and evidence of lactic acidosis are further important adjuncts to this assessment but, unless serum lactate levels are serially monitored, monitoring changes in pH and base deficit may be misleading due to the increased bicarbonate losses through the immature kidneys. Additionally, these measures tend to reflect cardiovascular changes some hours previously rather than the current circumstances.The assessment of cardiovascular adequacy and thus tissue oxygen delivery in the VLBW infant is more of a challenge than in infants and adults. Assessment often consists of a mainly clinical appraisal of the perfusion Capillary refill time (CRT) is a widely utilized proxy of both cardiac output and peripheral resistance in adults and older children, as well as in neonates where normal values have been documented . A studyvia a urinary catheter or via a collection bag, both techniques being invasive.Urine output is useful in the assessment of cardiovascular well-being in the adult; however, the immature renal tubule in VLBW infants is inefficient at concentrating the urine and therefore has an impaired capacity to appropriately adjust urine osmolality and flow in the face of high serum osmolality . Even ifvia baroreceptors and a subsequent increase in the heart rate in an attempt to sustain appropriate cardiac output. Heart rate is affected by many things in the immediate postnatal period so it cannot be relied upon as an accurate assessment of cardiovascular status.Preterm infants generally have a faster baseline heart rate and immature myocardium and autonomic nervous system such that the cardiovascular response to hypovolemia is different to that in older children and adults. A rising pulse rate is usually indicative of hypovolemia in the adult. The mechanism relies on a mature autonomic nervous system, with detection of reduced blood volume and then blood pressure via a peripheral artery catheter versus that obtained via the umbilical artery (Arterial blood pressure can be measured invasively using either an umbilical artery catheter placed in the descending aorta or an arterial catheter placed in a peripheral artery such as the radial or posterior tibial artery. There is good correlation between blood pressure obtained l artery . The agrl artery –48. Howel artery , 50. WitWhen oxygen delivery to organs is less than organ oxygen requirements and the compensatory mechanisms are fully utilized, there is a change to anaerobic metabolism at the cellular level. As adequate cardiovascular function is a key part of oxygen delivery, reduced SBF may result in increasing serum lactate levels. A combined lactate value of more than 4 mmol with prolonged CRT more than 4 s predicts low SBF with 97% specificity . There aThe size of neonates, particularly those less than 30 weeks gestation, with the associated difficulty of placing intracardiac catheters, has meant that the use of more invasive hemodynamic measures such as pulmonary artery thermodilution and mixed venous oxygen saturation monitoring has not been possible. Another issue specific to premature infants is the potential inaccuracy of the dye dilution and thermodilution method in the presence of intracardiac shunts through the ductus arteriosus and the foramen ovale. Noninvasive methods of measuring cardiac output, particularly using Doppler ultrasound, have become more popular, aided by improvements in picture resolution and reductions in ultrasound transducer size. Newer approaches such as impedance electrical cardiometry, which allows continuous beat-to-beat assessment of cardiac output are now becoming available and may facilitate the continuous collection of cardiac output for real-time decision making .Normal MBP does not mean normal LV output or cerebral blood flow in preterm infants, including in those who have a closed ductus arteriosus , 24, 61.via SVC flow or return of blood from the upper body to heart (Low SBF, as measured to heart , is seento heart . More reto heart , 64, 65.to heart . A substto heart . These iAppropriate assessment and treatment of the preterm infant with cardiovascular impairment or shock requires the clinician to obtain adequate information about the etiology and underlying physiologic determinants of the condition. Ultrasound evaluation can provide information about the size and shunt direction of the ductus arteriosus, the function of the myocardium and its filling as well as a cross sectional measurement of the cardiac output. This information is valuable in understanding underlying physiology and deciding on management strategies for newborn infants with cardiovascular instability and/or impairment.This article was conceived and written by MK.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.


Kidney transplant is the preferred renal replacement therapy for patients with end stage kidney disease. However management of patients with kidney transplant in resource poor countries is evolving and groaning under several mental, financial and infrastructural challenges. The objective of the study is to evaluate the management of patients with kidney transplant in a kidney care Centre in Nigeria.st August 2010 and 31st December 2014.The biodata, pre and post-transplant details of these patients were documented. The data was analysed using SPSS Vs 17.This was a non-randomized prospective study. The study population were post-transplant patients presenting between 1A total of 47 patients were studied with M: F ratio of 4:1, the mean age was 45.4 ± 13.6 years. Chronic glomerulonephritis, hypertension, diabetes mellitus and HIV related kidney disease were the commonest cause of CKD. Financial constraint delayed transplant in 66% and non-availability of donor in 17.2%. About 90% of the transplants were in India and 81% either financed the transplant either directly or through a relation. There was no cadaveric transplant and about 70% of the donors were not related. Tacrolimus, mycophenolate and prednisolone were most frequently used immunosuppressive combination. The one and three years graft survival were 95.3% and 67.6% respectively while corresponding patients survival were 97.7% and 82.4% respectively. Septicaemia, acute rejection and urinary tract infection were most common complications.Management of patients with kidney transplant has good prospect despite the challenges. Marked Dec 1954 , there hDec 1954 . Developst August 2010 and 31st December 2014. The details of the study were explained to the patients and informed consent was obtained from each of them before proceeding to the study. The study was approved by the ethical committee of the institution. The demographic characteristics, clinical details of the patients and the transplant details including the indication for the kidney transplant, cause of the kidney disease, type of donor, country of the kidney transplant, sponsor of the transplant, type of immunosuppression, complication and outcome of the kidney transplant were documented. These information were obtained from the patient, patient’s relatives, the transplant and post-transplant follow up notes.This is a non-randomized prospective study. The study location is Hilton clinics, a 25 bedded private hospital located in the Southern region of Nigeria. The centre attends to patients with various types and severities of kidney and kidney related diseases. It offers various diagnostic and therapeutic renal procedures including renal imaging, renal biopsy, hemodialysis, vascular access creation, pre transplant work up and post-transplant care. The study populations were post kidney transplant patients that attended the centre between 1The data obtained were entered in a spread sheet and analysed using statistical package for the social sciences (SPSS) version 17(IBM Inc.2010). Categorical data are reported as frequencies and percentages, and continuous variables are reported as mean and standard deviation. The patient and graft survival were calculated using Kaplan Meier estimator.Forty seven patients that presented during the study period were enrolled for this study. Males constitute 76.6% (36) with M: F ratio of 4:1. The age range of the patients was 24 to 65 years with mean of 45.4±13.6 years. Nineteen (40%) were civil servants, 27.7% were unemployed and were either students, housewives or retiree.The distribution of the causes of kidney disease in these patients is as documented in The major constraint leading to delay of the transplant was finance, and this was found in 66% of the patients. Other factors that delayed transplant were availability of donor (17.2%) and medical condition (4.3%). However only 12.8% (6) patients had the transplant unhindered including one that was transplanted after few salvage haemodialysis. The location of the transplant centre is shown in Thirty eight (80.1%) patients received pretransplant and intraoperative induction imunosuppresive therapy. All the patients were initially on triple regimen of calnineurin inhibitor (cyclosporine or tacrolimus), steroid (prednisolone) and azathioprione or mycophenolate for maintenance immunosuppression. However following complication, everolimus was added in 2 patients, replaced tacrolimus in 1 patient and mycophenolate in 1 patient. Forty two (89.4%) procured their medication from India. The blood calcineurin inhibitor level was assessed regularly in only 19.1% of patients. Details of the immunosppressive drug is shown in The immediate outcome was good in 68.1%, fair in 29.8% and poor in 2.2%. 29.8% of the patients died during the study. The 1 to 4 years graft and patient survival is documented in The common complications include urinary tract infection, septicaemia and acute rejection. The details of the complication are documented in The prevalence of chronic kidney disease (CKD) and end stage kidney disease (ESRD) in Nigeria is enormous affecting over 10% of the population and constituting about 8% of medical admissions –8. The dIn conclusion, management of patients with kidney transplant in Nigeria is froth with many financial, intellectual and infrastructural challenges however the outcome is relatively good and comparatively better than other existing RRT. The prospect of kidney transplant in Nigeria is good. Thus there is need for consented effort by the government, nongovernmental organizations and industries to invest in the development of kidney transplant in Nigeria.Chronic kidney disease is prevalent;Kidney transplant centres are few in Nigeria;Kidney transplant is expensive.Majority of kidney transplant patients in Nigeria had their transplant in India;Unrelated live donation is common;Outcome is relatively good.


The fractional exhaled nitric oxide (FeNO) and blood eosinophils are biomarkers of eosinophilic airway inflammation used in the diagnosis and management of asthma, although induced sputum is the gold standard test for phenotypic asthma. Nevertheless, the clinical application of the correlation between sputum eosinophils, FeNO and blood eosinophils is controversial.To investigate the clinical application of the correlation between sputum eosinophils, FeNO and blood eosinophils with uncontrolled asthmatic patients. It also examined the relationships between these biomarkers in bronchial reversibility and bronchial hyper-responsiveness (BHR).This study evaluated 75 uncontrolled asthmatic patients (symptom control and future risk of adverse outcomes). All patients underwent the following on the same day: FeNO, spirometry, BHR or bronchodilator reversibility, sputum induction and blood collection. Eosinophilic airway inflammation was defined as sputum eosinophils ≥ 2.5% or FeNO levels ≥ 32 parts per billion (ppb).A significant positive relationship was between percentage of sputum eosinophils and FeNO  and percentage of blood eosinophils , and a significant negative correlation was between percentage of sputum neutrophils and FeNO . No relationship between FeNO and percentage of blood eosinophils (p = 0.5801). ROC curve analysis identified FeNO was predictive of sputum eosinophilia  at a cutoff point of 35.5 ppb . Percentage of blood eosinophils was also highly predictive with an AUC of 0.73 (p = 0.002) at a cut-off point of 1.5%, sensitivity and specificity were 61.5 and 78.3%, respectively. Although the sputum neutrophil percentage was correlated with FeNO, ROC curve of these parameters did not show useful values .Blood eosinophils and FeNO can accurately predict eosinophilic airway inflammation in uncontrolled asthmatic patients. FeNO is poor surrogates for sputum neutrophils and blood eosinophils. The FeNO level and blood eosinophils, which determine an optimal cutoff for sputum eosinophilia, need more studies. Asthma is a heterogeneous disease, characterized by the history of variable respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough, usually together with variable expiratory airflow limitation. This was reached by consensus, recommended by the 2017 Global Initiative for Asthma (GINA) . When exAirway inflammatory phenotype can be measured through the airway noninvasively by induced sputum analysis , 4 and fWe conducted a retrospective study to (1) evaluate the correlation between sputum eosinophils, FeNO level and peripheral blood eosinophils in patients with asthma (2) to determine the accuracy of these biomarkers as indicators of airway inflammatory phenotypes in these patients (3) assess the relationship between these biomarkers, bronchial hyper-responsiveness (BHR) and bronchodilator reversibility in asthma.1% less than normal predicated value and/or any severe exacerbation due to asthma). Uncontrolled asthmatic patient had equal to or greater than 3 features as the above.We conducted a retrospective study on a series of 65 patients with asthma visiting in The Third People’s Hospital of Guangzhou Medical College in Huizhou from April 2016 to June 2017. Asthma patients were diagnosed according to a clinical history of wheezing, cough, chest tightness or shortness of breath, as well as the presence of bronchial hyper-responsiveness or bronchodilator reversibility, based on the 2016 of the Chinese national Guidelines on Diagnosis and Management of Asthma . IncludeInclusion criteria were any patients with asthma aged ≥ 18 years who agreed to undergo detailed investigation. All the patients who had successful FeNO, lung function and sputum induction were included in the study. Data were collected during regular clinical practice and medical procedures. Their demographic and functional characteristics are summarized in Tables 1/FVC < 0.7 or FEV1/FVC < 0.7 after treatment]. Patients have used any oral or/and inhaled corticosteroid in the previous 12 weeks. Patients had a confounding pulmonary comorbidity such as a pulmonary tuberculosis, an interstitial lung disease, a lung cancer or a pulmonary infection. Patients had a cognitive impairment that may affect the collaboration or comprehension of the study.Exclusion criteria were any patients had a history with chronic obstructive pulmonary disease (COPD), or previous doctor-diagnosed asthma-COPD overlap [(ACO), COPD/ACO was distinguished according to the 2017 recommendation of GINA, on the basis of chronic respiratory symptoms and post-bronchodilator FEVThe Institutional Review Board of the Third People’s Hospital of Guangzhou Medical College in Huizhou approved the study protocol and absolved the need for written informed consent from patients as the study was a retrospective study, personal identification data were anonymized.On the same day the following tests or determinations were performed: FeNO test, pulmonary function test (PFT), BHR test or bronchodilator reversibility test, induced sputum and routine blood test. Clinical variables were recorded for the participants.FeNO: FeNO level was measured before PFT according to the guidelines in the user manual training on the NO electrochemical equipment . Patients were required to refrain from eating, drinking, and smoking for at least 1 h prior to the FeNO measurement. Patients were instructed to inhale NO-free air to total lung capacity and immediately exhale fully into the device at a sustained flow rate of 50 mL/s for 6 or 10 s, which resulted in display of FeNO value 6. A significant increase in FeNO was considered if the FeNO value was equal to or higher than 32 parts per billion (ppb) [PFT: Airway limitation was identified using lung function machine  by an experienced technician according to the 2014 recommendations of the Chinese National Guidelines of Pulmonary Function Test. Percentage predicted values (%pred) were calculated based on reference values for healthy Chinese adults. All patients were required to undergo PFT in a reproducible way, and the best values were retained .1 at about 60 s from the start of one to the start on the next inhalation from the nebulizer. Obtain an acceptable-quality FEV1 at each time point. Airway responsiveness was required to induce a 20% decrease in FEV1 (PD20), and the positive response was defined as PD20 ≤ 2.504 mg (between NS and 2.504 mg) [BHR test: PFT values were assessed prior to the methacholine challenge. Patients with a FEV1%pred < 60% were excluded from the BHR test (at baseline). The breath dosimeter method was used according to published guidelines from Chinese National Guidelines of Pulmonary Function Test. The test sequence included five steps: 0.9% NaCl only, 0.078, 0.312, 1.125 and 2.504 mg. Measure the FEV.504 mg) .1 > 12% and 200 mL after salbutamol inhalation, were obtained [Bronchodilator reversibility test: Patients were asked to inhale 400 μg salbutamol via a metered-dose inhaler after baseline evaluation, and PFT was repeated not less than 20 min. Three forced expiratory maneuvers were recorded. The positive response, which was defined as FEVobtained .Sputum induction: Sputum was induced with hypertonic saline inhalation through ultrasonic atomizer. A single hypertonic saline (3%NaCl) was used. Patients were asked to inhale 400 μg salbutamol via a metered-dose inhaler 20 min before induction. Collected lower respiratory sputum portions of induced sputum were dispersed using 0.1% dithiothreitol in a water bath (37 °C) and oscillator 15 min before the 300 mesh nylon mesh filter. Subsequently, total cell count was centrifuged, smeared and stained (hematoxylin–eosin). A differential cell count was obtained from 400 cells under 400× microscope to identify the type of airway inflammation in patients with asthma. We defined percentage of sputum eosinophils ≥ 2.5% as abnormal .Blood collection and analysis: Peripheral venous blood was measured using Automated Hematology Blood Analyzer . The results of peripheral blood eosinophil percentage and absolute eosinophil count were obtained.Analysis of the data was performed using SPSS 19 . Continuous variables are expressed as mean ± SD or median (interquartile range) for non-normal variables when appropriate, and categorical variables with the Chi square test. Non-normally distributed variables used the Mann–Whitney test. The relationship between FeNO, sputum eosinophils, blood eosinophils, BHR and bronchodilator reversibility was assessed using the Spearman’s rank correlation coefficient. Correlation between tests was performed by constructing receiver operating characteristic (ROC) curve. The optimal cutoff value was determined from the highest sum of sensitivity and specificity. Statistical significance was defined as p < 0.05.Patient demographic information is presented in Table Eosinophilic airway inflammation (sputum eosinophilia ≥ 2.5%) was present in 52 participants. The characteristics of patients are shown in Table FeNO level equal to or higher than 32 ppb was present in 45 participants. The characteristics of patients are shown in Table Eosinophilic percentage in peripheral blood ≥ 2% was present in 28 participants. The characteristics of patients are shown in Table A significant positive relationship was observed between percentage of sputum eosinophils and FeNO level  , PD20 and FeNO level (p = 0.0955), PD20 and blood eosinophil percentage/count . There were also no significant relationship between ∆FEV1  and percentage of sputum eosinophils (p = 0.3645). Neither FeNO level (p = 0.281) nor blood eosinophil percentage/count  did not correlate with bronchodilator reversibility.The ROC curve analysis identified FeNO level as the best predictor for sputum eosinophilia with an area under the curve (AUC) of 0.707 (p = 0.004). The optimum cut-point for FeNO level was 35.5 ppb, and this yielded a sensitivity of 67.3%, a specificity of 73.9%. The percentage of blood eosinophils was also highly predictive with an area under the curve of 0.73 p = 0.002) at a blood eosinophils cut-off of 1.5%, sensitivity and specificity were 61.5 and 78.3%, respectively  and absolute blood eosinophil count (p = 0.14) in the prediction of sputum neutrophilia.20/∆FEV1 association with FeNO level and percentage of sputum/blood eosinophils, which may reflect nothing.This study assessed the correlation of FeNO level, sputum eosinophils and blood eosinophils in initial diagnosis and uncontrolled asthma. All the people in the study were Chinese. FeNO level and percentage of blood eosinophils can accurately predict sputum eosinophilia. Percentage of sputum neutrophils was correlated with FeNO level and percentage of blood eosinophils, but not enough to be clinically useful. We also identified some additional findings, namely PDThere is a need to include simple and accessible biomarkers in the management of asthmatic airway inflammatory subtype, FeNO and blood eosinophils are markers of local and systemic eosinophilic inflammation, respectively. According to the literature, biomarkers of airway eosinophilic inflammation  are well correlated with each other –16. HoweFollowing the 2016 recommendations of the Chinese National Guidelines on Diagnosis and Management of Cough, eosinophilic airway inflammation was defined as percentage of eosinophils ≥ 2.5% in induced sputum . As showIn clinical practice, there is a tendency to generalize the correlation between FeNO and percentage of sputum eosinophils, although the two methods are useful to assess the eosinophilic airway inflammation –21. Our 9/L) can serve as a diagnostic biomarker of sputum eosinophilia (≥ 3%)  [The 2017 GINA recently published an evidence-based clinical research guideline that blood eosinophils may be a biomarker of exacerbation risk in patients with a history of exacerbation and can predict the effects of ICS on exacerbation prevention [ctively) . These fOne limitation of the study was that the p-value (p = 0.0477) changed slightly under 0.05, and the correlation coefficients (r = − 0.2294) were very low, as shown in Fig. The other was smoking cigarette factor. It is well known that smoking decreases FENO level . FurtherThis study provides that inflammatory biomarkers, including sputum eosinophils, FeNO level and blood eosinophils, can accurately predict sputum eosinophilia in patients with uncontrolled asthma. It suggests that peripheral blood eosinophil is a useful tool better than FeNO level for monitoring sputum eosinophilia in uncontrolled asthma. FeNO level is poor surrogates for sputum neutrophils and blood eosinophils. These data may be useful for identifying patients with eosinophilic airway inflammation who will have a beneficial response to treatment with an ICS, and it is important to help guide treatment and management of asthmatic patients.


The changes of the upper airway after large retraction of the incisors in adult class I bimaxillary protrusion patients were assessed mainly focused on the anatomic variation and ignored the functional changes. This study aimed to investigate the changes of the upper airway in adult class I bimaxillary protrusion patients after extraction treatment using the functional images based on computational fluid dynamics (CFD). CFD was implemented after 3D reconstruction based on the CBCT of 30 patients who have completed extraction treatment. After treatment, pressure drop in the minimum area, oropharynx, and hypopharynx increased significantly. The minimum pressure and the maximum velocity mainly located in the hypopharynx in pre-treatment while they mostly occured in the oropharynx after treatment. Statistically significant correlation between pressure drop and anatomic parameters, pressure drop and treatment outcomes was found. No statistical significance changes in pressure drop and volume of nasopharynx was found. This study suggested that the risk of pharyngeal collapsing become higher after extraction treatment with maximum anchorage in bimaxillary protrusion adult patients. Those adverse changes should be taken into consideration especially for high-risk patients to avoid undesired weakening of the respiratory function in clinical treatment. A constrictive airway may influence respiratory function, and induce symptoms of obstructive sleep apnea syndrome (OSAS), which affects quality of life and may be life-threatening13Bimaxillary protrusion is a common malocclusion in China. Due to the inharmonic facial profile, Patients with bimaxillary protrusion are seeking for orthodontic treatment to improve their overly prominent upper and lower incisors and lips. A popular orthodontic treatment for bimaxillary protrusion includes extraction of four first premolars combining with the retraction of anterior teeth using maximum anchorage, which help the patients achieve resultant decrease in soft tissue procumbency and convexity. The relationship between incisors retraction and lip procumbency has been well recognizedet al.et al.’s work suggested that CFD model endpoints based on pressure drops in the pharynx were more closely associated with the presence and severity of OSAS than anatomical endpoints, which may be a better tool to predict the risk of the upper airway collapsingPrevious studies have investigated the effects of extraction treatment on upper airway in bimaxillary protrusion patients using two-dimensional (2D) cephalometric measurements or three-dimensional (3D) CBCT measurements67867Computational Fluid Dynamics (CFD) is a validated method to accurately compute aerodynamic flow characteristics of the upper airway11121314The aim of this study is to evaluate the pharyngeal airflow response to large incisor retraction in class I adult bimaxillary protrusion patients using CFD simulation based on the patient-specific CBCT dataset.2) class I bimaxillary dentoalveolar protrusion patients, who were treated by extraction of four first premolars using maximum anchorage. The exclusion criteria included: (1) patients have any other severe craniofacial anomalies except class I bimaxillary dentoalveolar protrusion, (2) age under 18 years old, (3) a history of serious diseases, or acquiring serious diseases during treament, such as serious cardiovascular disease, respiratory system disease, serious craniofacial deformity, severe nasal diseases and relative surgical history, (4) weight increased apparently into obese (BMI > 30 kg/m2) after treatment. The patients were informed consent, including the potential risk associated with CT radiation and miniscrew methodologies. Oriental pre-adjusted appliance KOSAKA slot brackets  were used, and miniscrews were implanted as anchorage for the retraction and intrusion of the teeth. A force of 150 g per side of elastic chains was applied from the miniscrew to the upper crimpable hook to retract and intrude the upper anterior tooth. The patients were examined at 1-month intervals until the retraction of the upper and lower anterior teeth completed.The study was reviewed and approved by School of Stomatology Shandong University Research Ethic Board (protocol number 20160103). All the written informed consents were received from the patients, and the study was conducted according to the tenets of the Declaration of Helsinki for research involving human subjects. The methods were carried out in accordance with the approved guidelines of SCIENTIFIC REPORTS. The sample of this study consisted 30  by the same operator. Patients were guided to close their mouths with the maximum intercuspation and the tongues touching their hard palates during the scanning. The pre- and post-treatment CBCT scans of patients were collected as T1 and T2 data. Subsequently, the dataset was exported in DICOM  file format, and then was read into MIMICS16.0  software. After that, the models were reorientated in three planes: in the coronal view, the most inferior points on the infraorbital margin  lie on the same horizontal plane; in the sagittal view, the models were reorientated to make the Frankfort plane horizontal; in the axial view, the models were reorientated to make the line through the crista galli and the midpoint on the anterior margin of foramen magnum (basion) verticalUnstructured tetrahedral volume mesh was generated in ANSYS ICEM CFD (ANSYS 16.0) using hybrid mesh scheme . A grid et al.tidal volum = 600 ml. For inspiration process, an ambient static pressure condition was set at the nostril (the flow outlet), the negative value of velocity at the peak flow rate was set at the bottom of the hypopharynx (the flow inlet), the wall surface of the geometry was assumed to be non-slip.Flow simulations were performed using the Reynolds Average Navier Stokes CFD solver . Inspiratory upper airway flow was modeled, as inspiration is associated with negative pressures causing airway collapse in OSAS, greater airflow pressure and velocity gradients. Steady laminar flow field was applied in this study. Previous studies showed that fully developed turbulence would not be reached until a flow rate of 30 L/min−4 and the iteration numbers were 1000 steps when all residuals fell below 0.2%. Second-order discretization schemes were used with pressure-velocity coupling solved through the SIMPLE scheme.The effects of some factors such as the temperature, humidity and vibrissae on the fluid were neglected in the simulation, while the gravity was included. The calculation residual was set as 10na), oropharynx (Vor), and hypopharynx (Vhy) was calculated. The minimum cross-sectional area (Amin) and its location was defined. Parameters above were used to assess the size changes of the pharynx. In addition, the mean cross-sectional area (Amean) was computed by ratio of the pharyngeal volume and the length of the pharynx (V/L). Amin/Amean was also obtained to explore the uniform of the cross-sectional changes. Upper central incisor retraction amount at edge in the horizontal direction (ICE) were achieved through registration of the pre- and post-treatment models, and the process for registration was presented in details in the work of Chen Y et al.Two planes: a line passing from anterior nasal spine to posterior nasal spine and a line passing from the anterosuperior edge of the fourth cervical vertebra (C4) to menton, which have been proved to be reliable and reproducible landmarks for defining upper airway marginsmax) was defined to quantify the effect of the pharyngeal airway narrowing on the flow field. Airflow pressure drops of nasopharynx (ΔPna), oropharynx (ΔPor), and laryngopharynx (ΔPhy) were counted by ΔP = Pmax − Pmin. The resistance of the airway (R) was achieved by the formula: R = Q/ΔP . Because the flow rate was constant in our study, the ΔP reflected the changes of the resistance for each pharyngeal part.Once the simulation was completed, all of the cross sections from choana to the bottom of hypopharynx were selected per millimeter along Z-axis for parameters calculation. Area-weighted average pressure and velocity in each cross-section was extracted to evaluate the location of the minimum area-weighted average pressure and the maximum velocity in the pharynx. The area-averaged pressure drop from choana to the minimum area  were calculated. The differences between the flow dynamics and anatomical parameters of the upper airway between T1 and T2 were analyzed by paired-t test, and the relationships between the ΔP and ICE were assessed using Pearson correlation coefficient. To assess the measurement errors, all the variables were measured twice with the manual method by the same operator with a 2-week interval. The error of method was calculated as follows: 3 and 0.31 mm2, respectively, while the maximum ME of pressure measurements was 0.47 Pa in the numerical simulation of pharyngeal airflow, and 0.24 mm of the upper central incisor retraction amount at edge in the horizontal direction.No significant difference between the first and repeated measurements were observed, which proved the reliability between the first and second measurements (ICC from0.92 to 0.97). The maximum ME of pharyngeal volume and area measurements were 0.15 mmmin and Amin/Amean .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


CBF) is essential for cerebral metabolism and function, whereas hypoperfusion in relation to hypovolemia and hypocapnia can lead to severe cerebral damage. This study was designed to assess internal carotid artery blood flow (ICA‐BF) during simulated hypovolemia and noninvasive positive pressure ventilation (PPV) in young healthy humans. Beat‐by‐beat blood velocity (ICA and aorta) were measured by Doppler ultrasound during normovolemia and simulated hypovolemia (lower body negative pressure), with or without PPV in 15 awake subjects. Heart rate, plethysmographic finger arterial pressure, respiratory frequency, and end‐tidal CO2 (ETCO2) were also recorded. Cardiac index (CI) and ICA‐BF were calculated beat‐by‐beat. Medians and 95% confidence intervals and Wilcoxon signed rank test for paired samples were used to test the difference between conditions. Effects on ICA‐BF were modeled by linear mixed‐effects regression analysis. During spontaneous breathing, ICA‐BF was reduced from normovolemia  to hypovolemia . During combined PPV and hypovolemia, ICA‐BF decreased by 15% . Regression analysis attributed this fall to concurrent reductions in CI  and ETCO2 . Mean arterial pressure was maintained and did not contribute to ICA‐BF variance. In healthy awake subjects, ICA‐BF was significantly reduced during simulated hypovolemia combined with noninvasive PPV. Reductions in CI and ETCO2 had additive effects on ICA‐BF reduction. In hypovolemic patients, even low‐pressure noninvasive ventilation may cause clinically relevant reductions in CBF, despite maintained arterial blood pressure.Intact cerebral blood flow ( Preserving cerebral blood flow (CBF) in patients during surgery and anesthesia may be challenging as it requires good control over both circulation and ventilation, and CBF is not easily monitored. Factors such as dehydration, acute blood loss or acute peripheral vasodilation that change intravascular volume may compromise cerebral perfusion. Baroreflex engagement and activation of the sympathetic nervous system (SNS) compensate for mild to moderate hypovolemia, maintaining mean arterial blood pressure (MAP). Lassen's CBF autoregulation curve is traditionally used to guide clinical decisions concerning safe blood pressure limits Lassen .2), and even mild hypocapnia can significantly reduce global CBF  has been found to determine CBF independently of MAP. A linear relationship between middle cerebral artery blood velocity and CO has been demonstrated despite MAP preservation , CO, and MAP.The aim of this study was to investigate central circulatory and CBF changes in young healthy subjects during standardized challenges: simulated moderate hypovolemia and noninvasive PPV. We used a lower body negative pressure (LBNP) chamber to induce abrupt central blood volume shifts during spontaneous breathing and PPV. The application of −30 mmHg LBNP induces moderate hypovolemia corresponding to 10–20% of total blood volume  years, body mass index 23.4  were recruited and gave written, informed consent to participate. All procedures conformed to the Declaration of Helsinki. The regional ethics committee  approved the protocol and procedures.None of the subjects were tobacco smokers or taking any medication. They were instructed to abstain from caffeine and strenuous physical activity for at least 12 h and avoid food and drink for 2 h and alcohol for 24 h before each experiment. All subjects reported good health and hydration status on the day of the experiment.2O and 4.5 cmH2O, respectively, for all subjects. No inspiratory trigger was used. Positive end‐expiratory pressure (PEEP) was set to 1 or 2 cmH2O. Table Experiments took place in a quiet room with an ambient temperature of 22–24°C, continuously recorded to ensure stable conditions. All experiments took place between 11.00 am and 3.00 pm. Pressure‐regulated volume control ventilation  was administered noninvasively via a face mask . A customized LBNP chamber was used to induce simulated hypovolemia  and rigid aortic ring were obtained at the measurement site using B‐mode Ultrasound    > 15 bpm, systolic blood pressure <70 mmHg, or if the subject suffered presyncopal symptoms or simply wanted the procedure to end  and calculated into ETCO2 breath‐by‐breath. Blood velocity waves, RF, ECG, arterial blood pressure waves, HR (finometer), SV (finometer), LBNP, and room temperature were sampled at 100 Hz and transferred on‐line to a recording computer running a dedicated data collection and analysis program .Mean ICA velocity  and maximum aortic velocity  were recorded concurrently by two trained operators, using Doppler ultrasound. ICA velocity was measured approximately 2 cm above the bifurcation of the common carotid artery in order to avoid turbulent flow  were calculated from blood velocities and the diameters of the aortic valvular orifice . The recorded signals were inspected and medians were calculated along 2‐min periods of continuous, technically successful recordings from each 5‐min period. All technically successful recordings from each subject were included in the analysis. We compared the cardiovascular values in four different states: Spontaneous breathing during normovolemia (Normovolemia), positive pressure ventilation during normovolemia (PPV), Spontaneous breathing and hypovolemia (Hypovolemia) and PPV and hypovolemia combined (PPV + hypovolemia).P = 0.01.Medians and 95% CI were calculated by Hodges–Lehmann's estimate . Because the study used a repeated‐measures design, each subject contributed minimum 3 and maximum 12 observations. In order to account for the correlation among the repeated observations in each subject, Subject identity was entered as random effect in the model.The ICA‐BF response to PPV and/or simulated hypovolemia was modeled using linear mixed‐effects multiple regression . ICA‐BF was the response variable. LBNP and PPV (dichotomous variables: Yes/No) and the randomized initial stimulus of the sequence (dichotomous variable: PPV/Spontaneous Breathing) were categorical predictors (fixed effects). CI, MAP, ETCOP < 0.1 were kept in the model as a variable marginally associated with the outcome may potentially have a considerable effect on the coefficients of the other explanatory variables  was calculated using quantities from the corresponding Analysis of Variance table.P‐values were obtained by likelihood ratio tests of the full model with the relevant effects against the model without these effects (null model). The statistical significance level was set at P < 0.05.The ICA velocity recordings were analyzed from 15 subjects in total. More specifically, in ten subjects we obtained good ICA velocity recordings from both rounds; in two subjects only recordings from one round were of adequate quality to be included in the analysis. The last three subjects were unable to breathe in synchrony with the ventilator and thus provided only partial data (without PPV). In six of 15 subjects, recordings of aorta velocities were of inadequate quality, an anticipated failure rate. CO from the noninvasive arterial blood pressure curve was obtained in all subjects.Induction of LBNP  caused a drop in ICA‐BF and a simultaneous drop in CI and SV. A concurrent, transient drop in MAP was rapidly restored, while HR increased during hypovolemia Fig. . The chaP = 0.15) from normovolemia to hypovolemia, whereas ICA‐BV significantly decreased by 0.8 mL . CI was reduced by 0.7 L/min/m2  from normovolemia to hypovolemia. MAP showed an increase of 3.2 mmHg (1.1–4.1) and HR increased by 6 bpm (3.7–7.9) from normovolemia to hypovolemia.ICA‐BF tended to decrease with a median change of 16 mL/min  from normovolemia to PPV. ICA‐BV decreased by 0.4 mL . No change was observed between normovolemia and PPV in CI and MAP. HR tended to decrease by 1.4 bpm .ICA‐BF showed a median decrease of 29 mL/min  from normovolemia to PPV + hypovolemia. ICA‐BV decreased by 1.1 mL . CI was reduced by 0.8 L/min/m2  from normovolemia to PPV + hypovolemia. MAP showed no change to PPV + hypovolemia (1.1 mmHg (−2.0–3.0)) and HR increased by 7 bpm (3.6–10.2).ICA‐BF decreased significantly by 37 mL/min , Table ETCOR2 = 0.78, P = 0.0001). CI and ETCO2 contributed significantly to ICA‐BF variance; MAP, Pmean and PPV did not, and were removed from the model. A drop of 1 L/min/m2 in CI predicted a 43 mL/min drop in ICA‐BF (P = 0.013), whereas a drop of 1 kPa in ETCO2 predicted a drop of 33 mL/min in ICA‐BF  and PPV (P = 0.003).This analysis was also performed using ICA velocity as the response variable, since blood velocity is often used as a substitute for blood flow. The second analysis showed that ICA velocity was predicted by CI  when ICA‐BV was decreased by 24%. Thus, despite the counteracting circulatory adaptations to simulated hypovolemia, ICA‐BF decreased significantly under both LBNP and PPV due to a drop in CI combined with mild hypocapnia.2 transport to the lungs. The hypocapnic reactivity of CBF has been calculated to 2–3%/mmHg  may influence ICA‐BF regulation.Pmean and PPV did not contribute to ICA‐BF variance in our model. This was probably due to the low‐grade positive intrathoracic pressure inflicted, the lack of Pmean measurements during spontaneous breathing, and the close correlation between PPV and slight hypocapnia, making it difficult to statistically distinguish between their effects. When ICA blood velocity was used as the response variable, the dichotomous variable PPV (Yes/No) contributed to ICA blood velocity variance while ETCOInterestingly, the respiratory state starting the randomized sequence (PPV or spontaneous breathing) was found to contribute slightly but significantly to ICA‐BF variance. Within‐experiment “learning” has been demonstrated for other cardiorespiratory control systems, but our data cannot point to any underlying mechanisms.Gender differences in response to LBNP have been reported regarding several determinants of CBF such as SV, CO, and sympathetic nerve activity. Women are considered to be less tolerant to hypovolemia at presyncopal level (Convertino In clinical situations, the combination of volume depletion and mild hypocapnia can be a threat to cerebral perfusion (Dippmann et al. Our experiments most closely resembled an intensive care unit situation where a hypovolemic unsedated patients is treated with noninvasive ventilation. Older age, comorbidities, anesthetic agents, invasive ventilatory support or the need for higher intrathoracic pressures could aggravate the situation further, as would acute blood loss, dehydration, and pneumoperitoneum during laparoscopy.2 (Meng and Gelb Our findings confirm and supplement previous findings indicating that preservation of MAP in the “plateau area” of the well‐known cerebral autoregulation curve may not be sufficient to preserve cerebral perfusion. Lassen's curve of cerebral autoregulation was constructed by data points obtained from different patient groups with hypotensive or hypertensive disorders. This method generated a group curve with a wide “plateau area” with a lower limit, a curve that cannot precisely predict the CBF–MAP relationship in individual subjects (Tzeng and Ainslie 2 and ETCO2 values is 0.27–0.67 kPa (Anderson and Breen 2 on ICA‐BF may be slightly overestimated. ETCO2 provides an accurate estimate of PaCO2 in mechanically ventilated and nonintubated patients (Barton and Wang In healthy humans with no significant ventilation–perfusion mismatch, the usual difference between PaCO2 changes >1.3 kPa cause ICA diameter changes (Sato et al. 2 in our experiments was 1.1 kPa, MAP was preserved and the LBNP level was −30 mmHg, we assumed that ICA diameter remained constant.To calculate ICA‐BF, we assumed that vessel diameter remained stable throughout the experiment. It is debated whether PaCO2 when PPV was included in the model, probably because these variables were very closely correlated. With PPV removed, ETCO2 was found to contribute significantly to ICA velocity variance.For simplicity, we used a linear approach to model ICA‐BF changes, since an almost linear relationship has been reported in the range 3.3–7.3 kPa (Hauge et al. The combination of simulated moderate hypovolemia and noninvasive mechanical ventilation resulted in a significant decrease in ICA‐BF, larger than in PPV or hypovolemia alone. The drop in ICA‐BF was mediated by slight hypocapnia and a marked fall in CI and occurred despite an unchanged MAP. Our findings indicate that in a clinical setting of hypovolemia close attention to CO measurements and ventilator settings is needed to preserve patient CBF.None declared.


To date, few studies have focused on the clinical and allergic characteristics of asthma in the elderly, defined as asthma in people aged 60 or over. Thus, we propose to identify and study the clinical and allergic characteristics and comorbidities of patients with asthma among the elderly.A retrospective, observational, descriptive study was developed in five clinics and hospitals in Argentina. Allergy Physicians analyzed their patients’ medical records in 2014 and included those adults over the age of 60, who had been diagnosed with asthma according to the GINA guidelines. Clinical and allergic characteristics were analyzed.p <  0.05).It is worth mentioning that almost half of the patients with LOA had allergies at the nasal level.A total of 152 patients diagnosed with asthma, of whom 73% were women and 11% ex-smokers, were included in this study, with a mean age of 66 years. Only 10.5% of the participants had onset asthma past the age of 60. Regarding asthma severity, 74.3% were diagnosed with moderate persistent asthma, and 7.2% with severe persistent asthma. Eighty-four percent of the patients were treated with an inhaled corticosteroid (ICS) along with a long-acting β 2-adrenergic agent (LABA). More than half of the patients had two or more comorbidities simultaneously. Allergic comorbidities were the most frequent comorbidities, followed by arterial hypertension. Among allergic comorbidities, most patients presented allergies at the nasal level. There were no significant differences between the subpopulations of patients with late-onset asthma (LOA) and asthma with onset before the age of 60, i.e. early onset asthma (EOA) in most of their clinical characteristics. However, it was observed that EOA accounted for a higher percentage of patients with nasal allergies as compared to LOA (71% vs 46%, These results may provide a better understanding of the clinical characteristics of asthma in the elderly in Argentina, thus, enabling the development of future therapeutic strategies and a better quality of life for our elderly asthma patients. In the past, asthma was mainly considered a childhood illness. However, recent epidemiological studies indicate that new incident asthma can occur at any age, and it is in fact highly prevalent in the older adult population and its prevalence ranges from 4.5% to 12.7%. According to the current demographic trends, a 100% increase in the number of people over the age of 65 is expected in the next 20 years [The mainstay of asthma management at any age is to achieve and keep the disease under control. The pharmacological control depends on the clinical and allergic characteristics of the disease, and, in addition, symptoms may be influenced by age-related factors such as an increased frequency of comorbidities and patients prescribed with multiple drugs simultaneously. In addition, specific problems associated with the management of asthma in the elderly have been described, such as improper use of the inhaler, poor adherence to treatment, increased adverse effects, and declining response to medications. The study of the clinical characteristics of asthma in the elderly is of utmost importance in terms of providing evidence to identify those diagnostic and therapeutic methods that are safe and effective , 3.Comorbidities are considered to be some of the key characteristics of geriatric patients and contribute to the clinical complexity of the elderly. In addition, they contribute to poor asthma management outcomes in this group as compared to younger asthmatic patients. The presence of comorbidities has been shown to influence the quality of life of the elderly with asthma, which in turn affects adherence to treatments. In this context, specific comorbidities may also prevent the correct use of inhaler devices, for example, in patients suffering from arthritis, orthodontics, dementia, etc , 4.Knowing the epidemiology of asthma is essential for the planning of health services, but our knowledge about this disease is still incomplete. Historically, clinical studies on asthma have frequently excluded the elderly population, and there are still few observational epidemiological studies which could shed light on the nature or the pathophysiology of the disease. Consequently, it is imperative to study the clinical and allergic characteristics of asthma in the elderly, on the one hand, and their comorbidities, on the other hand, in order to propose new therapeutic and diagnostic strategies, and ultimately, to improve the patients’ quality of life , 5.Therefore, we aim to identify and study the clinical and allergic characteristics, as well as the medical and allergic comorbidities of asthma in patients over the age of 60 in Argentina.A retrospective, observational, descriptive study was developed in five clinics and hospitals in Argentina: Allergy and Respiratory Diseases Research (InAER), Autonomous City of Buenos Aires, Argentina; Hospital Area General De Agudos Dr. Ricardo Gutierrez, La Plata, Argentina; Allergy and Immunology Service, Hospital San Roque, Cordoba, Argentina; Private Medical Centers, Ramos Mejia, Buenos Aires, Argentina. Allergists analyzed their patients’ medical records for three months in 2014, and included those aged 60 or older diagnosed with asthma, according to the GINA guidelines. It should be noted that some patients did not present reversibility in the cross-section of this study, although prior to the diagnosis of asthma they did present it, according to the GINA guidelines.For each asthmatic patient over 60 years, researchers gathered the following information: 1) age, sex and race; 2) smoking status; 3) age at the onset of asthma, defined as the age at which the patient is diagnosed with asthma; 4) asthma severity (according to the GINA guidelines); 6) Pulmonary function values; 7) positive reaction to the Skin Prick Test (SPT) ; 8) exacerbation triggers ; 9) total serum IgE (IgE ˃ 100 UI/ml were considered subjects with high IgE); 10) eosinophil count ,; 11) current treatment they receive; 12) dose of inhaled corticosteroids; 13) Medical comorbidities , dyslipidemia, coronary heart disease, diabetes, pulmonary hypertension, other cardiovascular diseases) and allergic conditions , eosinophilic esophagitis).t and Fisher’s Exact Test, as appropriate. P values below 0.05 were considered to be statistically significant.Data are expressed as a percentage, except for the age of onset and the time span with asthma, which are presented as mean and standard deviation (SD). The clinical characteristics of the EOA and LOA subpopulations were compared using unpaired Student A total of 152 patients with a defined diagnosis of asthma were included in this study, with a mean age of 66 (SD 6.5) years, of whom the majority were women (73%). Regarding the racial characteristics of the participants, all of them were were Caucasian. None of the patients were currently smokers, and only 11% had previously smoked. The mean age of onset of asthma symptoms was 33.4 (SD 22.9) years, with an average of 34.2 years (SD 21.9) (Table p <  0.0001) (Table Late-onset asthma (LOA), defined as the onset of asthma after the age of 60, was observed in 10.5% of the patients, with a mean age of onset of 69.2 (SD 6.8) years, having had asthma for an average of 7.3 (SD 4) years. On the other hand, the mean age of onset of symptoms in patients with asthma with an onset before the age of 60 (EOA) was 29 (SD 12.4) years, having had the disease for 37.4 (21 years); both the age of onset of asthma and the time span with asthma were significantly different between both subpopulations  was 73%, and FEV1/forced vital capacity (FVC) was 69%. In addition, 39% presented normal values of FEV1 (higher than 80%), with 59% reversibility. Among the LOA patients, we found that 50% had normal FEV1 (mean FEV1 of 71%), and 62% were reversible. While among the EOA patients, 37% had normal FEV1 (mean FEV1 of 73%), and 58% were reversible, with no statistical difference between the EOA and LOA populations , only 4% did not present any positive response. Among the allergens investigated, mites (70%), fungi (58%) and pollen (32%) were included , exercise 39%) and aeroallergens (21%). Also, 31% of the patients presented other triggers not included among the mentioned ones, such as dyes, perfumes and temperature changes. On the other hand, 4% of the patients did not present any triggers  along with a long-acting β-adrenergic agent. Sixty percent of all patients used fluticasone and salmeterol, while 24% used budesonide and formoterol. The ICS dose was greater than 1000 mg/day in 24% of the patients. On the other hand, 16% had not been prescribed any specific treatment for asthma. The main rescue treatment option chosen by the patients was fast-acting β-adrenergic agonists, with salbutamol being the most widely used one (91%), and only a few of the patients used ipratropium bromide. On the other hand, 9% of the patients did not use any rescue treatment. Among the EOA and LOA patients, no significant differences were observed in terms of the treatments used , followed by hypertension (45%), GERD (16%), diabetes (12%), obesity (9%), coronary diseases (8%), osteoarthritis, arthritis (7%), hypothyroidism (7%), Chagas disease (4%), and dyslipidemia (3%). Other comorbidities were also found, such as gastritis, celiac disease, breast cancer and pulmonary hypertension, but only in a few patients. There were no significant differences in the percentages of these comorbidities between the EOA and LOA patients . However, it is worth noting that almost half of the patients with LOA had chronic rhinosinusitis or allergic rhinitis. Among the patients with EOA, we observed that a similar proportion of patients had seasonal rhinitis, perennial rhinitis and chronic rhinosinusitis , while 13% had chronic rhinosinusitis and perennial rhinitis. Only a small percentage of patients had chronic rhinosinusitis and seasonal rhinitis [Among allergic comorbidities, patients mainly had nasal allergies 68%). Among them, mainly perennial rhinitis (23%), seasonal 18%) or chronic rhinosinusitis (15%), and, in addition, some patients presented chronic rhinosinusitis and perennial rhinitis simultaneously (12%). Only a few patients had chronic rhinosinusitis and seasonal rhinitis (1%). Other allergic comorbidities were uncommon, such as allergic conjunctivitis, sinusitis, nasal polyposis, eczema, chronic or acute urticaria, and intolerance to NSAIDs. Twenty-nine percent of the patients did not present any of the comorbidities sought. On the other hand, EOA patients represented a higher percentage of patients with nasal allergies as compared to LOA  and eosinophils (6.1%) were higher than those reported in the study by Inoue et al.  . One pos1 (73%), and FEV1/FVC (69%) were similar to those obtained by Park et al. and Inoue et al., who reported values of 75% and 66%, and 81% and 72%, for FEV1 and FEV1/FVC, respectively. In both studies it was observed that values are significantly lower than when compared to non-elderly asthmatics. It is important to emphasize that the population described in this study presents an average age lower than the average age of the patients described in the studies of Inoue et al. and Park et al. , and the duration of the illness is much longer . In this sense, Inoue et al. demonstrated that asthma in the older adult is characterized by an airway obstruction that is independent of age per se and the duration of the disease [On the other hand, the values obtained from FEVAs with other populations of elderly asthma patients, most patients are treated with ICS along with a long-acting β-adrenergic agent , 6, 7. AMost patients presented comorbidities, as described for older asthmatic adults . Howevern = 16) in the LOA group.However, the comorbidities found match what has been previously reported for this population with a high frequency of arterial hypertension and allergic comorbidities, and, to a lesser extent, diabetes mellitus, cardiovascular diseases, and osteoarthritis or arthritis , 6, 7. ORecruitment was in Allergy Units, although many asthmatics are also treated by primary care Physicians, Pulmonologists and internists. Also, not all the population had skin tests performed and/or diagnosis and treatment of upper airway punctuated. On the other hand, some of these patients may also display an ASTHMA-COPD overlap syndrome . FinallyThese results may provide a better understanding of the clinical characteristics of asthma in the elderly, and thus enable the development of future therapeutic strategies and a better quality of life for our elderly asthmatic patients.


The aging kidney manifests structural, functional as well as pharmacological changes, rendering elderly patients more susceptible to adverse environmental influences on their health, dehydration in particular.Higher temperature is associated with renal function impairment in patients 65 years and older who routinely take thiazide and/or ACE-inhibitors/ARBs.We obtained health data of patients older than 65 who were admitted to a large tertiary center during the years 2006–2011, with a previous diagnosis of hypertension, and treated with thiazide, ACE-inhibitors/ARBs or both. We collected environmental data of daily temperature, available from collaborative public and governmental institutions. In order to estimate the effect of daily temperature on renal function we performed linear mixed models, separately for each treatment group and creatinine change during hospital admission.We identified 26,286 admissions for 14, 268 patients with a mean age of 75.6 (±6.9) years, of whom 53.6% were men. Increment in daily temperature on admission of 5°C had significant effect on creatinine increase in the no treatment  and dual treatment groups . Sub-analysis stratified by advanced age, chronic kidney disease and primary diagnosis on hospital admission, revealed a significant association within patients admitted due to acute infection and treated with dual therapy.Whereas previous studies analyzed sporadic climate effects during heat waves and/or excluded older population taking anti-hypertensive medications, the present study is novel by showing a durable association of temperature and decreased renal function specifically in elderly patients taking anti-hypertensive medications. Elderly people (over 65 years old) are more susceptible to environmental influences on their health including dehydration . Since aThe use of antihypertensive medications, commonly prescribed for elderly patients, may augment the risk for insensible loss, dehydration and eventually impaired kidney functions in several mechanisms. ,5. PreviIn this study we sought to explore the effect of ambient temperature on renal function in hypertensive elderly patients taking medications with potential effect on kidney function, hypothesizing that higher temperature will be associated with renal function impairment especially in patients treated with common antihypertensive drugs.We obtained health data of all patients above 65 years old admitted to Soroka University Medical Center (SUMC) during the years 2006–2011. SUMC is the only medical center in this area serving a population of approximately 700,000 as the only primary hospital in Northern Negev desert and nearly 1.2 million as a tertiary hospital. This study was approved by the institutional ethics committee of Soroka University Medical Center. The institutional ethics committee waived the need for written informed consent from the participants due to the anonymously data analysis. We extracted demographic and clinical data from the records computerized database. We used the first measure of laboratory and other clinical parameters (e.g. blood pressure) of each patient, taken during the first hour from the admission to SUMC emergency department (ED). The primary diagnosis for admission was extracted from the ED medical records. Past medical history was extracted from previous hospitalizations or outpatient clinics encounters according to ICD-9 codes and definitions. All variables had less than 5% of missing values, except for the chronic kidney disease stage (See below). Patients were identified by the national ID number which was encoded before data analysis.Change in serum creatinine, rather than estimated glomerular filtration rate (eGFR) was selected to reflect change in renal function. In acute kidney injury (AKI) the correlation between the GFR and serum creatinine is poor. Therefore, KDIGO guidelines for AKI focus on serum creatinine changes and urine output rather than eGFR. We usedWe divided the anti-hypertensive drugs  into three main groups: angiotensin-converting-enzyme inhibitors (ACE) or angiotensin receptor blockers (ARBs) without thiazide (1) thiazide only and (2) ACE-inhibitors or ARBs with thiazide (3). Patients with none of the aforementioned medications comprised the reference group.The environmental data were available from collaborative public and governmental institutions . Spatial2 (chronic kidney disease stage V) due to the poor renal compensatory capability and high prevalence of renal replacement therapy . Fr. Fr17]. The mechanism of creatinine increase during exposure to the high ambient temperature described in this study may be related to reduced kidney perfusion. AKI has been reported among 5–7% of hospitalized patients, and despite improved awareness it still carries a high mortality risk among the older and sicker patients . These rIn contrast to other anti-hypertensive medications, continuous utilization of thiazide and ACE-inhibitors/ARBs may lead to increase in serum creatinine, and predispose to AKI, especially in persons with pre-existing renal impairment –30. EldePrediction models for AKI are of growing interest. Relevant predicting factors may include age, volemic state, underlying kidney function, diabetes mellitus and CHF, all proven to be associated with future AKI. The additive effects of those factors have been partially tested in previous studies ,32,33. Istatistically significant data may provide a proof of principle rather than individually clinically significant scenarios for a given patient.We acknowledge several data related limitations. First, this study is of an observational nature and cannot establish causality between temperature changes and renal function. Second, due to the observational settings with data obtained from the health information exchange systems, we could not establish the primary indications to initiate each treatment. The lack of treatment indications bares some major implications on our findings since different indications may lead to different outcomes (for instance the use of ACE-inhibitors/ARBs for hypertension in diabetic versus heart failure patients). Third, we have not assessed the effect of loop diuretics or mineralocorticoid receptor antagonist, since these medications are frequently used to treat heart failure rather than hypertension. Additionally, we have not included other medications that induce excessive fluid loss . Fourth, inherently to the ecological type of study we could not assess the personal exposure of the patients to heat or the individual time spent outdoors. Fifth, the results obtained from this study may not be equally applied to patients with different types of renal disorders. Moreover, creatinie measurements prior to hospitalization were available for only 61.5% of the patients. This subgroup showed statistically but not clinically significant differences in baseline characteristics (sicker and older) compared to those without prior creatinine measurement. Sixth, in addition to ambient effect on the dual treatment groups, similar effect was observed on the no-treatment group. This finding may be due to poor medical condition of this group which may also alter medications use, as demonstrated by higher rate of patients with dementia and cancer. Finally, wide use of air-conditioning could minimize the heat exposure in our cohort, and locations of the patients in the preceding days could alter body acclimatization. Of special note, our We demonstrated a statistically significant association between ambient temperature and increase in creatinine in elderly patients taking both thiazide and ACE-inhibitors/ARBs. After validating our results in future research, it may be possible to acknowledge that “real life” kidney function has better plasticity than assumed before, enabling more aggressive anti-hypertensive treatment and decreasing co-morbidity complications in the elderly population.S1 FigInt J Climatol. 2004;24(12):1013–1021. ACE/ARB—ang iotensin-converting-enzyme inhibitor or angiotensin receptor blockers.Based on Alpert P et al, (TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


The effects of sitagliptin in patients with type 2 diabetes mellitus and hypertension are unclear. Therefore, we evaluated the long-term effects of sitagliptin in those patients.In the PROLOGUE study, 365 patients were diagnosed as type 2 diabetes mellitus and hypertension, and 189 patients in the sitagliptin group, 176 patients in the conventional group. Fasting blood glucose (FBG), HbA1c, systolic pressure (SP), diastolic pressure (DP), serum urea nitrogen (BUN) and serum creatinine (SCR) were measured at the beginning of the study and after 12 and 24 months of treatment.FBS and HbA1c levels were not significantly decreased after treatment . BP and DP levels were not significantly decreased after treatment ; OR: 0.6, 95% CI ; 24 months: OR: -0.5, 95% CI ; OR: -1.6, 95% CI , respectively]. Furthermore, BUN and SCR levels were not significantly decreased after treatment ; OR: 0.0, 95% CI ; 24 months: OR: 0.4, 95% CI ; OR: -80.8, 95% CI , respectively]. After adjusting for confounding factors, our results did not change.In our study, there was no evidence that treatment with sitagliptin can improve FBS, BP, DP, BUN or SCR in patients with type 2 diabetes mellitus and hypertension.University Hospital Medical Information Network Clinical Trials Registry UMIN000004490. With the development of the social economy, all kinds of pressure, the change in lifestyle and the aging population, the incidence of diabetes is increasing year by year. According to incomplete statistics, diabetes patients in China have exceeded the total number of diabetic patients in Europe and the United States, with China ranked second in the world , 2. DiabType 2 diabetes is a chronic, complex metabolic disease . Its patSitagliptin , a dipepHowever, whether sitagliptin is advantageous to the prognosis of type 2 diabetes patients with hypertension, the conclusion is still controversial. Ogawa S  conducteThe PROLOGUE study  was a prTable Table Table Table Table Table Table To our knowledge, the PROLOGUE study is the largest trial to investigate whether DPP-4 inhibitors  slow the progression of carotid IMT in participants with T2DM. The major finding of our study is that there was no evidence that treatment with sitagliptin can improve fasting glucose, HbA1c, systolic pressure or diastolic pressure in type 2 diabetes patients complicated with hypertension during a 2-year study period. In addition, for patients with type 2 diabetes complicated with hypertension, the kidney is one of the most easily damaged organs, which can lead to renal insufficiency and even renal failure. The PROLOGUE study followed up the patients for two years, but our result did not find that sitagliptin has a protective effect on renal function of patients with type 2 diabetes complicated with hypertension, as the changes in serum urea nitrogen and serum creatinine levels were similar to the conventional group. These results may suggest that sitagliptin failed to inhibit fasting glucose, HbA1c, blood pressure and kidney progression relative to the conventional therapy in patients with type 2 diabetes complicated with hypertension, despite its glucose-lowering effect in patients with type 2 diabetes.It is well known that, with the growth of age and the acceleration of population aging all over the world, the lifetime risk of cardiovascular disease in patients with type 2 diabetes is approximately 67-78%. ManagemSitagliptin, an orally administered dipeptidyl peptidase 4 (DPP-4) inhibitor, prolongs the action of incretin hormones, by inhibiting their breakdown . This imTo date, mechanisms related to the antihypertensive effects of DPP4 therapies have not been fully elucidated and some evidence remains inconclusive . PreviouOn the other hand, the mechanism of DPP-4 inhibitors, such as sitagliptin, on the protective effect of renal function in type 2 diabetes patients complicated with hypertension remains unclear , 30. IncThere are several limitations of our present study. First, our present study was a sub-analysis of the PROLOGUE study, and the number of study subjects was relatively small. Therefore, there is no sample size for a power calculation since fasting glucose, HbA1c, systolic pressure, diastolic pressure, serum urea nitrogen and serum creatinine were voluntary measured parameters in the PROLOGUE trial, and this may be underpowered. Second, the PROLOGUE study was conducted with a PROBE design, which might have introduced bias in the assessment of outcomes. Third, the patients of our study are Japanese, and perhaps race, gene polymorphism, diet and other factors also dictate the effects of sitagliptin in patients with type 2 diabetes complicated with hypertension. Fourth, baseline fasting glucose, HbA1c, systolic pressure, diastolic pressure, serum urea nitrogen and serum creatinine levels were not very high, probably because participants’ diabetes was well-controlled without insulin treatment in the participants. Therefore, the findings of our study should be interpreted with caution.The rationale and design of the PROLOGUE study  have been described previously . The PROBetween June 2011 and September 2012, a total of 463 patients with type 2 diabetes were enrolled in the PROLOGUE study and randomly assigned in a 1:1 ratio to either add-on sitagliptin treatment (sitagliptin group: n=232) or conventional antihyperglycemic treatment . The treatment randomization was based on age, gender, use of statins, pretreatment diabetic type , HbA1c level (<7 or ≥7%), office systolic blood pressure (<135 or ≥135 mm Hg), and maximum IMT (<1.0 or ≥1.0 mm) [In the PROLOGUE study, the primary endpoint was the change in mean common carotid artery IMT at 24 months after treatment. Carotid ultrasound examinations were performed at the beginning of treatment and after 12 and 24 months of treatment. The secondary outcomes included changes in FMD in the brachial artery after 12 and 24 months of treatment. In all of the participating institutions, FBS, HbA1c, BP, DP, BUN and SCR were measured in all patients during an optional examination at the beginning of the study and after 12 and 24 months of treatment. Among the 463 participants in the PROLOGUE study, 365 patients were diagnosed with type 2 diabetes mellitus complicated with hypertension. One hundred and eighty-nine patients were randomly assigned to either add-on sitagliptin treatment (sitagliptin group) and 176 patients were randomly assigned to continue conventional treatment . The data for these 365 patients were analyzed in our study. This sub-study is a pre-specified analysis. The ethical committees of the participating institutions approved the study protocol. Written informed consent for participation in the study was obtained from each subject.All studies were performed in the morning, after overnight fasting, in a quiet, dark, and air-conditioned room (constant temperature of 22–25 °C). The subjects were kept in the supine position throughout the study. The observers were blind to the type of treatment.−2) was calculated. At the time of the health examinations, after a brief period of rest, SBP and DBP were measured in either the right or left arm using a sphygmomanometer  with the participant in a sitting position. Blood pressure was measured once in most participants, but up to three measurements were taken at 1–2-min intervals in participants who had hypertensive or prehypertensive SBP and DBP values. The lowest reading was used in the analysis to assess the incidence of hypertension. Smoking habit and parental history of hypertension were assessed by a questionnaire, as was a self-reported history of hypertension. Blood samples were collected after an overnight fast, and measurements were made using an automatic clinical chemistry analyzer . FBS, HbA1c, BUN and SCR levels were measured using enzymatic methods at the beginning of the study and after 12 and 24 months of treatment.The same protocol for measuring FMD in the brachial artery was used in our study. Height and weight were measured and body mass index  or the mean±SD. Categorical variables were compared using the chi-square test. We compared the mean values of continuous variables between the 2 groups using student’s unpaired In the analysis comparing the treatment effects, the baseline-adjusted means and their 95% CIs, as estimated by analysis of covariance (ANCOVA), were compared between the two groups. This analysis was carried out while considering the variation caused by treatment effects. Furthermore, a multivariate regression analysis was conducted for adjusting confounding factors, such as age, body height, body weight, DBP, SBP, creatinine, heart rate, uric acid, total cholesterol, fasting plasma glucose, HDL, blood urea nitrogen, HBA1C, cystatin-C, triglyceride, waist circumferences, small dense LDL, high molecular weight adiponectin, insulin, history of dyslipidemia, history of kidney disease, history of liver disease, history of cerebrovascular disorder, history of cardiovascular disorder, history of cerebral infarction, history of cerebral hemorrhage, history of transient ischemic attacks, history of cerebrovascular disorder, history of myocardial infarction, history of arrhythmia, history of percutaneous coronary intervention, history of heart failure, history of cardiovascular disorder, smoking habit, drinking habit, and history of coronary artery bypass graft.www.Empowerstats.com, X &Y solutions, inc. Boston MA) and the R Project (http://www.R-project.org).All analyses were performed using Empower (R) ; Toru Aoyama ; Tetsuya Babazono ; Yasuko K. Bando ; Hiroyuki Daida ; Jun Fukui ; Kumiko Hamano ; Shigemasa Hashimoto ; Kazunori Hayashi ; Tsutomu Hirano ; Hideki Horibe ; Kazuo Ibaraki ; Takako Iino ; Kenji Iino ; Yutaka Ishibashi ; Yuko S. Ishiguro ; Masaharu Ishihara ; Ryoji Ishiki ; Tomoko Ishizu ; Hiroshi Ito ; Masaaki Ito ; Yoshito Iwama ; Hideo Izawa ; Kohei Kaku ; Haruo Kamiya ; Kenshi Kan ; Naoki Kashihara ; Akira Kimura ; Ichiro Kishimoto ; Kazuo Kitagawa ; Masafumi Kitakaze ; Tomoki Kitano ; Yoshihisa Kizaki ; Kenji Kohara ; Hiroshi Koiwaya ; Taizo Kondo ; Toshimitsu Kosaka ; Nehiro Kuriyama ; Shigetaka Kuroki ; Koji Maemura ; Hiroaki Masuzaki ; Munehide Matsuhisa ; Kaori Miwa ; Takashi Miwa ; Tetsuro Miyazaki ; Kazutaka Mori ; Tomoatsu Mune ; Ikue Nakadaira ; Mashio Nakamura ; Yoshihito Nakashima ; Masayuki Nakayama ; Mamoru Nanasato ; Kosaku Nitta ; Yasunori Oguma ; Hirotoshi Ohmura ; Shinji Okubo ; Jun-ichi Oyama ; Sosho Ri ; Kenji Sadamatsu ; Makoto Saitoh ; Masaki Sakakibara ; Yasunori Sato ; Yoshisato Shibata ; Toshimasa Shigeta ; Kenei Shimada ; Fuji Somura ; Takashi Takei ; Toshiro Tanaka ; Yoshito Tanioka ; Akihiro Terasawa ; Masahiko Tsujii ; Shuichi Tsuruoka ; Hiroyuki Tsutsui ; Hisashi Umeda ; Mitsuyoshi Urashima ; Hiroki Watanabe ; Masato Watarai ; Takaaki Yamada ; Hiroshi Yamamoto ; Akira Yamashina ; Kentaro Yamashita ; Takanori Yasu ; Chie Yasuoka ; Kiyoshi Yokoi .http://dx.doi.org/10.5061/dryad.qt743/2).All relevant data are within the paper and the Dryad Digital Repository (The ethical committees of the participating institutions approved the study protocol. All participants provide written informed consent before data collection.In our study, there was no evidence that treatment with sitagliptin can improve fasting glucose, HbA1c, systolic pressure, diastolic pressure or renal function in type 2 diabetes patients complicated with hypertension during a 2-year study period. Thus, sitagliptin may be used in type 2 diabetes patients complicated with hypertension, but with caution. Further randomized trials are warranted.