We aimed to confirm this hypothesis using the gold-standard for defining LV contractility, afterload, and evaluating ventricular-arterial (VA) coupling and LV efficiency during different loading and contractile experimental conditions. Twelve Yorkshire healthy female pigs submitted to three consecutive stages with two opposite interventions each: changes in afterload (phenylephrine/nitroprusside), preload (bleeding/fluid bolus), and contractility (esmolol/dobutamine). LV pressure-volume data was obtained with a conductance catheter, and arterial pressures were measured via a fluid-filled catheter in the proximal aorta and the radial artery. End-systolic elastance (Ees), a load-independent index of myocardial contractility, was calculated during an inferior vena cava occlusion. Effective arterial elastance  was calculated as LV end-systolic pressure/stroke volume. VA coupling was defined as the ratio Ea/Ees. LV efficiency (LVeff) was defined as the ratio between stroke work and the LV pressure-volume area. Eadyn was calculated as the ratio between the aortic pulse pressure variation (PPV) and conductance-derived stroke volume variation (SVV). A linear mixed model was used for evaluating the relationship between Ees, Ea, VA coupling, LVeff with Eadyn. Eadyn was inversely related to VA coupling and directly to LVeff. The higher the Eadyn, the higher the LVeff and the lower the VA coupling. Thus, Eadyn, an easily measured parameter at the bedside, may be of clinical relevance for hemodynamic assessment of the unstable patient.Dynamic arterial elastance (Ea Dynamic arterial elastance, the ratio between PPV and SVV, defines the relationship between the changes in the arterial pulse pressure and SV during a respiratory cycle . This indyn is related to arterial stiffness. Indeed, Eadyn was initially proposed as an index of arterial tone  at the Edwards Research Center, and all procedures were performed in accordance with the USDA Animal Welfare Act regulations (AWArs), and the Guide for the Care and Use of Laboratory Animals . The ARRIVE guidelines were used for the elaboration of this manuscript .ad libitum. Before anesthesia induction, a general physical examination was performed. If found to be stable, the animal was premedicated with an intramuscular injection of telazol (4.4 mg/kg), ketamine (2.2 mg/kg), and xylazine (1.1 mg/kg). They were orally intubated, and their lungs mechanically ventilated in a volume-controlled mode . Ventilatory settings were maintained unchanged throughout the experiment. Following endotracheal intubation, general anesthesia was maintained with isoflurane 1.5–2.5% and a mixture of oxygen , oxygen/air  and oxygen/air/nitrous oxide . The level of anesthesia was adjusted and kept at the lowest possible dose. No neuromuscular blocking drugs were used. Animals received a loading dose of heparin (300 I.U./kg) with additional boluses during follow-up  for preventing coagulation. Fluid maintenance was provided intravenously by a continuous infusion of Ringer’s lactate solution at 4 ml.kg–1.h–1. Rectal temperature was monitored and kept at 37°C  using a heating pad. Arterial blood gases were monitored periodically and acid-base balance was corrected by infusing bolus sodium bicarbonate or by changing ventilator frequency if required. The depth of anesthesia was assessed throughout the study for muscular reflex by checking the jaw tone and the toe pinch assessment. Animal anesthesia was monitored and recorded approximately every 15 min for the duration of the experimentation. All the experimental procedures were performed by the same skilled operator.Experiments were performed in 12 female Yorkshire crossbreed pigs of 5.5 ± 0.8 (mean ± SD) months old weighting 81 ± 6 kg. Animals were maintained in a temperature and humidity-controlled rooms with a typical light-dark cycle and given standard chow and tap water ®, CD Leycom, Zoetermeer, Netherlands). The catheter tip was positioned in the long axis of the LV, and the correct placement was confirmed by fluoroscopy and the examination of the individual segmental LV PV loops.Instantaneous LV PV measurements were obtained from a 7Fr-lumen dual-field conductance catheter introduced through the left external carotid artery with 12 equidistant electrodes and a high-fidelity pressure sensor  connected to a PV signal processor  inserted percutaneously through the right internal jugular vein to the pulmonary artery using the standard thermodilution method for the determination of CO. The average value of 3 to 5 thermodilution boluses randomly injected during the respiratory cycle was used for volume calibration. Correction for parallel conductance  was performed with the 10 ml boluses of 5% hypertonic saline through the distal port of the pulmonary artery catheter during a short period of apnea . The con0, where V0 is volume-axis intercept or the LV unstressed volume. An example of a PV loop analysis is shown in Left ventricle pressure-volume data acquisition and analysis were performed by a dedicated software system . The signals were recorded at 250 Hz and filtered using a 25 Hz low-pass filter. Before and after each experimental stage, three transient occlusions of the inferior vena cava (IVC) were performed using a 25 mm Fogarty balloon  percutaneously introduced into the right femoral vein. All recordings were done during prolonged apnea in end-expiration. This procedure was repeated if ectopic beats were detected. End-systolic pressure, SV, CO, LV EDV, LV ESV, LV EDP, LVEF, and effective arterial elastance  were caA 5-French pigtail catheter was inserted using fluoroscopy through the right carotid or femoral artery into the aortic arch for continuous measurement of central aortic pressure. The radial artery was surgically exposed and cannulated with a 5-French catheter. Arterial pressure waveforms from the ascending aortic and radial arterial artery were continuously recorded with a fluid-filled pressure transducer  at a sampling rate of 100 Hz, using the EV1000 monitor (Edwards Lifesciences) and then transferred onto a computer. The pressure signals were filtered to remove noise and artifacts using a 10 Hz low pass filter.0). The ratio of SW/PVA represents the LVeff of converting the total mechanical energy available into SW /(PPmax + PPmin)/2] × 100, and SVV = [(SVmax−SVmin)/(SVmax + SVmin)/2] × 100. Where PPmax and SVmax, and PPmin and SVmin represent the maximal and minimal arterial pulse pressure and stroke volume determined during the same respiratory cycle, respectively. PPV and SVV values were obtained simultaneously and averaged during 1-minute just before the IVC occlusion. A peripheral Eadyn was also calculated as the ratio between PPV obtained from the radial arterial line and conductance derived SVV. Although arterial load was globally assessed by Ea, we evaluated the contribution of its main components with a two-element Windkessel model of the arterial system, consisting in the net arterial compliance (Cart = aortic pulse pressure/stroke volume) and total peripheral resistance [TPR = mean aortic pressure (MAP)/CO] as a measure of total LV pressure load  until no further increase in CO. Then they were allowed to stabilize for at least 10 min. Stability was defined as heart rate and MAP variation <5% (–1.min–1) to increase MAP by 40% mmHg from baseline and were allowed to recover at least for 10 min. Then they were treated with sodium nitroprusside (100–200 mg.kg–1.min–1) to decrease MAP by 40% from baseline but not below 50 mmHg for allowing an adequate hemodynamic tolerance during the IVC occlusions, followed by recovery to baseline status at least for 10 min. Subsequently, for preload interventions, the animals were submitted to stepwise bleeding of 12 ml.kg–1 (50 ml.min–1) and the blood stored into a heparinized sterile bag. Then the blood was reinfused at the same rate and a fluid bolus of 10 ml.kg–1 of a colloid was infused in 5 min. After the fluid administration, the contractility interventions followed: an esmolol infusion was started at 50 μg.kg–1.min–1 and increased until reducing LV dP/dtmax by 50% from its previous value, with a limit dose of 200 μg.kg–1.min–1. Then the esmolol infusion was stopped and, after a minimum period of 10 min for recovery, the animals were treated with a dobutamine infusion (5 μg.kg–1.min–1) to increase LV dP/dtmax by 50%. LV PV loops and arterial pressure waveforms were obtained at each baseline and after each intervention. At the end of the experiment the animals were euthanized with an intravenous dose (1 ml/4.5 kg) of a euthanasia solution .Animals were initially resuscitated with colloids 1 and SPPS .Data are expressed as mean ± SD. The normality of data was checked by the Shapiro-Wilk test. The intra-observer variability for thermodilution-derived CO measurements and Ees calculation was analyzed with the intraclass correlation coefficient (ICC) with its 95% confidence interval (95% CI), where a ICC > 0.9 represents an excellent agreement between repeated measurements . Since wia value . Model p2O. Blood gas analysis at the beginning of the experiment was: pH 7.53, pCO2 42 mmHg, pO2 149 mmHg, and HCO3– 32.2 mmol/L.The ICC for thermodilution CO measurements was 0.979 (95%CI: 0.948 to 0.994) at the first calibration and 0.987 (95%CI: 0.965 to 0.996) after fluid administration, respectively. The mean ICC for Ees calculation during all experimental stages was 0.903 (95% CI: 0.822 to 0.985). The mean peak inspiratory was pressure 25 ± 3 cm Hmax by 49 ± 16%, while dobutamine increased it by 89 ± 23%.The evolution of the hemodynamic variables throughout different experimental conditions is detailed in eff during each experimental stage are shown in eff. These changes were related to the relative variations on Ea and Ees. Afterload interventions mainly modified VA coupling by altering Ea . Radial and aortic PPV were highly correlated . There was a significant relationship between PPV (but not SVV) and arterial system properties: a low TPR value and high compliance were associated with a higher PPV .rminants . Changesng Eadyn , includidyn, VA coupling and LV mechanical efficiency while altering loading and contractile conditions in anesthetized healthy pigs. Our conclusions are twofold. First, Eadyn changes were related to both afterload and LV contractility. The relative contributions of these two factors to both PPV and SVV eventually lead to the observed Eadyn value. These findings agree with previous reports and confirm the compound nature of Eadyn  and arterial system properties (Ea), a significant relationship between Eadyn and VA coupling exists with higher Eadyn associated with better VA coupling. Moreover, since the LV oxygen consumption required for a given SW depends on both loading conditions and myocardial contractile state  would be related to a lower Eadyn value. Moreover, as LV mechanical efficiency depends on the interaction of the arterial load and LV function .In our study, PPV was significantly associated with changes in Ea and related to both TPR and Ces Eadyn . Consequfunction , we alsodyn on the clinical setting was as an index for predicting the arterial pressure response to fluid administration , confirmed these findings in 53 mechanically ventilated, preload-dependent patients with acute circulatory failure  to a higher SW status   . Thus, astration . Kim and studies . As Eadyefficacy .dyn appears to be related to the mechanical performance of the coupling between the left ventricle and the arterial circulation, the ability to increase pressure with fluids will depend eventually on the biventricular preload-dependency. If changes in preload are not followed by an increase in CO, then an increase in arterial pressure should not be expected  for predicting preload-responsiveness after positioning the patient in Trendelenburg position. They found that the degree of fluid responsiveness was not associated with baseline Eadyn values , which indicates that arterial pressure was already optimized, and the vascular system was likely operating to keep constant pressure, as reflected in the modest MAP increase (from 75 to 77 mmHg) in those 23 patients with a significant increase in SV.There have also been negative studies about the usefulness of Ean values . Since Tdyn was able to predict the MAP decrease associated with a reduction in norepinephrine dosage and, therefore, it could be used as an aid for titrating this vasoactive therapy in patients with septic shock or during vasoplegic syndrome following cardiac surgery. Patients with an Eadyn value > 0.94 were able to sustain MAP despite a decrease in vasopressor support, while patients with a lower Eadyn significantly reduced MAP after decreasing norepinephrine dose. These authors argued that Eadyn can be considered as a functional assessment of arterial tone. Considering the current results, a patient with a higher Eadyn should have better VA coupling and be able to generate an increase in SW that keeps MAP despite the decrease in the external vasopressor support and potentially vasomotor tone. Moreover, these patients showed a decrease in Eadyn after reducing norepinephrine dose, supporting the hypothesis that the cardiovascular system shifted from a better LVeff and to a higher mechanical efficacy for sustaining MAP. In concordance with this hypothesis  to 0.68 (0.3). Furthermore, in a recent multicenter study (dyn from 0.67 (0.48–0.80) to 0.54 (0.37–0.68). Therefore, our results underscore the message that Eadyn does not represent an index of arterial vasomotor tone nor arterial load, although changes in arterial load may affect Eadyn. The unspoken other conclusion of these findings is that phenylephrine is a poor cardiovascular treatment for sustained hypotension because of its detrimental effects on Eadyn and LVeff.er study  have shodyn from 1.16  to 0.96 . These findings agree with those observed in the sequential changes in PPV and SVV observed by dyn. Interestingly, the effect of increasing tidal volume from 5 ml/kg to 20 ml/kg also augmented this ratio.Only a few studies have directly addressed the impact of contractility changes in the PPV and SVV relationship. Although the concept of the coupling between the heart and the arterial system has been described for more than 30 years, it has resurged recently in the critical care settings , 2014. TThe cardiovascular system aims to deliver adequate blood flow and pressure to sustain normal physiological functions. Flow is important to deliver oxygen whereas pressure is important to allow for autoregulation of blood flow distribution. Because the interaction of arterial system with the heart, a given arterial pressure and CO that maintains necessary organ perfusion can be achieved by different cardiovascular configurations . Howeverdyn, being affected by both Ea and Ees, and then significantly related to VA coupling and LVeff. In light of these results, the definition of Eadyn as a dynamic assessment of arterial load  at the Edwards Research Center, and all procedures were performed in accordance with the USDA Animal Welfare Act regulations (AWArs), and the Guide for the Care and Use of Laboratory Animals .MMG, MP, and MC contributed to the conception of the study. MMG, ZJ, and MP contributed to the design of the study. MMG, ZJ, and FH performed experimental research. MMG, ZJ, FH, JS, and MP analyzed and interpreted the data. All authors drafted the manuscript, reviewed it, contributed significantly to its critical review, approved the final version of the manuscript and ensure the accuracy or integrity of the results of this study and will be accountable for any question related to this work.MMG was a consultant to Edwards Lifesciences and received honoraria and or travel expenses from Deltex Medical. MP was a consultant to Edwards Lifesciences, LiDCO Ltd., and Cheetah. MC has received honoraria and/or travel expenses from Edwards Lifesciences, LiDCO, Cheetah, Bmeye, Masimo, and Deltex Medical. ZJ, JS, and FH are Edwards Lifesciences employees.


Chronic kidney disease (CKD) occurrence is rising all over the world. Its presence is associated with an increased risk of premature death from cardiovascular disease (CVD). Several explanations of this link have been put forward. It is known that in renal failure, an array of metabolites cannot be excreted, and they accumulate in the organism. Among them, some are metabolites of tryptophan (TRP), such as indoxyl sulfate and kynurenine. Scientists have become interested in them in the context of inducing vascular damage in the course of chronic kidney impairment. Experimental evidence suggests the involvement of TRP metabolites in the progression of chronic kidney disease and atherosclerosis separately and point to oxidative stress generation as one of the main mechanisms that is responsible for worsening those states. Since it is known that blood levels of those metabolites increase significantly in renal failure and that they generate reactive oxygen species (ROS), which lead to endothelial injury, it is reasonable to suspect that products of TRP metabolism are the missing link in frequently occurring atherosclerosis in CKD patients. This review focuses on reports that shed a light on TRP metabolites as contributing factors to vascular damage in the progression of impaired kidney function. Chronic kidney disease (CKD) is one of the most commonly occurring diseases in the world, with more than 850 million people afflicted . As a coAtherosclerosis, a chronic inflammatory disease, is characterized by the accumulation of inflammatory cells and lipids in the artery wall, intima thickening, and vessel calcification. Over decades, it has afflicted more and more people, with increasing number of patients suffering from the cardiovascular disease. One medical condition that increases the risk of atherosclerosis is CKD. There is growing evidence that vascular endothelium damage begins in an early stage of CKD. The consequence is higher mortality from CVD in CKD patients than in patients without kidney impairment . Several2−), alkoxyl radical (RO·), peroxyl radical (ROO·), hydroxyl radicals (OH·), peroxynitrate (ONOO−), hydrogen peroxide (H2O2), ozone (O3), and hypochlorous acid (HOCl) . To. To98]. The effectiveness of hemodialysis for kynurenines elimination is limited. It has been reported that they are present in the dialysate, and their plasma level in hemodialyzed patients was higher compared with healthy volunteers . MoreoveThe metabolites of the kynurenine pathway play a significant role in the modulation of physiological, as well as pathological processes, including redox homeostasis. KYN, the first product of TRP degradation, exerts prooxidant effects, and the aerobic irradiation of KYN produces superoxide radicals and leads to cytochrome C reduction . MoreoveAs mentioned above, the accumulation of KYN metabolites in the course of CKD may induce oxidative cell damage, which leads to inflammatory processes. Okuda et al. reported that the excess of 3-HKYN enhances ROS generation, leading to mitochondria function impairment . It alsoThe available data demonstrated that the accumulation of toxic TRP metabolites in the body seems to be an important factor affecting vascular endothelial dysfunction leading to atherosclerosis  110, 11. It has γ levels, the main inductor of this protein. Also, increased cytokine levels can affect the hypothalamo-pituitary-adrenal axis, which in turn enhances TDO activity [As mentioned above, under normal conditions, TRP is metabolized mostly in the liver. Nevertheless, during pathological processes, like chronic kidney disease, its conversion changes significantly. Depletion of TRP in CKD patient serum has been reported multiple times , 149. Moactivity . Altogetactivity .2O2, has been pointed out, which proves the predicted mechanism of action [The abovementioned experimental outcomes indicate IS and kynurenines as mediators of ROS generation, taking part in enhancing both CKD and atherosclerosis. Since it is known that atherosclerosis develops often in patients suffering from CKD, it is logical to suspect TRP metabolites as agents that by accumulating in kidney failure lead to vascular impairment. In nephrectomized rats, augmentation of aortic media thickness and decrease of the aortic lumen diameter was observed. The authors reported higher endothelial dysfunction, reduction of the eNOS expression, and diminution of NO production in nephrectomized rats on additional IS treatment when compared to controls. In this study, the authors confirmed ROS involvement in the IS mechanism of action, by showing a significant elevation of superoxide levels in the aortic walls of rats with kidney impairment . Analysif action . Anotherf action .Hypertension, a constant symptom of CKD, appears to have a complex association with endothelial dysfunction. In turn, hyperkynureninemia increases the risk of hypertension occurrence in patients with chronic kidney disease (CKD) . In addiThe available data provide evidence that the accumulation of TRP toxic metabolites in the body seems to be one of the key factors underlying the development of uremic symptoms, including impaired lipid metabolism and vascular endothelial dysfunction, leading to atherosclerosis in the course of CKD. The main reason is their ability to induce oxidative stress, leading to the exacerbation of simmering inflammation. Complete understanding of the impact of TRP active metabolites on overall body homeostasis, as well as on the condition of many organs, may provide the basis for the development of innovative therapeutic options that improve the diagnosis and treatment of CKD and systemic disorders related with its progression, such as atherosclerosis.


Animal studies suggest that inhaled NO2 has the potential to increase plasma [nitrite]1; a chemical originally considered to be physiologically inert before we found that its reduction to nitric oxide protects the myocardium against ischemia-reperfusion injury and lowers blood pressure in humans.2Air pollution is a major cause of cardiovascular and all-cause mortality. Disentangling the relative contributions of pollutants is challenging, as epidemiological data measuring exposure to one  versus control (room air) on plasma [nitrite] (primary end point) and blood pressure (secondary end points) in 12 healthy participants. All underwent both interventions/visits  in a computer-generated randomized order. Baseline characteristics (mean±SD): 26±4years, 10/12 female, body mass index 21.9±3.0 kg/m2, systolic blood pressure 113.8±7.9 mm Hg, diastolic blood pressure 72.8±5.7 mm Hg. The exposure phase was followed by a 90 minutes washout phase at background [NO2]. Participants fasted for 12 hours before each visit and received 250 mL low-nitrate water at time 0 h/1.5 h. The study was powered for a difference in plasma [nitrite] of 27±40 nmol/L on repeated-measures, 2-way ANOVA  following D’Agostino-Pearson normality-confirmation, with Sidak post-test (GraphPad Prism v8.2.1).3We conducted an acute, randomized, controlled, crossover study to assess the impact of 90 minutes exposure to NOThe data that support the findings of this study are available from the corresponding author upon reasonable request.2]: 276.3±38.5 versus 27.6±2.8 ppb (P<0.001). Plasma [nitrite] was increased through both the 90 minutes NO2 exposure and 90 minutes washout . NO2 exposure decreased both systolic blood pressure and diastolic blood pressure . The largest decrease in systolic blood pressure relative to control occurred at 45 minutes  and 90 minutes . The effect of NO2 on diastolic blood pressure was maximal at 45 minutes .Relative to control, exposure increased ambient  and systolic blood pressure/diastolic blood pressure reduction (≈5 mm Hg) is consistent with studies investigating dietary nitrate.3Previously, an increase in plasma [nitrite] at 2 hours following diesel exhaust inhalation was thought to be due to particulate matter-mediated induction of inflammatory pathways.2  and presents a plausible mechanism through which inhaled NO2 increases plasma [nitrite].1 This novel ecophysiological NOx cycle may directly feed into the established nitrate-nitrite-nitric oxide pathway and contribute nitric oxide-mediated cardiovascular effects.2 Adverse respiratory effects of inhaled NO2 were not investigated here.1However, our data suggest a more rapid increase in plasma [nitrite] which favors chemical conversion from NO2 exposure and cardiovascular mortality.1 However, particulate matter-free NO2 does not appear to impair either vascular function, fibrinolysis, or affect heart rate variability in patients with coronary heart disease: parameters adversely affected by increased ambient NO2 exposure in epidemiological studies.5 This study expands our understanding of how inhaled NO2 might impact the cardiovascular system, and the role of diet in disease: it is not just what you eat, but how you cook it that matters.These data must be considered in the context of the strong epidemiological association between NOKing’s Together Multi and Interdisciplinary Research Scheme . H. Walton and D. Evangelopoulos’s posts part-funded by NIHR-HPRU on Health Impacts of Environmental Hazards at KCL in Partnership with PHE and ICL, London, UK. Internal infrastructure financial support: KCL-BHF Centre, NIHR-CRF/NIHR-BRC at GSTFT/KCL. Views expressed are authors’ (not necessarily NHS/NIHR/DHSC/PHE).None.


Despite the expansion of the understanding in asthma pathophysiology and the continual advances in disease management, a small subgroup of patients remains partially controlled or refractory to standard treatments. Upon the identification of immunoglobulin E (IgE) and other inflammatory mediators, investigations and developments of targeted agents have thrived. Omalizumab is a humanized monoclonal antibody that specifically targets the circulating IgE, which in turn impedes and reduces subsequent releases of the proinflammatory mediators. In the past decade, omalizumab has been proven to be efficacious and well-tolerated in the treatment of moderate-to-severe asthma in both trials and real-life studies, most notably in reducing exacerbation rates and corticosteroid use. While growing evidence has demonstrated that omalizumab may be potentially beneficial in treating other allergic diseases, its indication remains confined to treating severe allergic asthma and chronic idiopathic urticaria. Future efforts may be bestowed on determining the optimal length of omalizumab treatment, seeking biomarkers that could better predict treatment response and as well as extending its indications. Asthma is responsible for considerable global morbidity and healthcare costs . It is aPersistent inflammation of the airways not only causes asthma symptoms but also leads to the remodeling process. AR is a process of reconstruction of the bronchial wall, and it is characterized by (1) smooth muscle hypertrophy/ hyperplasia, (2) mucus gland hyperplasia, (3) shedding and metaplasia of the epithelium, (4) angiogenesis, (5) subepithelial collagen and glycoprotein deposition and (6) extracellular matrix (ECM) deposition in the submucosa, muscle and adventitia ,9.According to studies, allergic asthma is the predominant phenotype, which is over 60% of the total asthma group ,11,12. IRecent data have suggested that allergen exposure markedly increased the expression of immunoreactivity for three alarmin cytokine, TSLP, IL-22 and IL-25, in both human airway epithelium and bronchial mucosa . CombiniAs a result of AR, asthma patients, who have persistent chronic airway inflammation, may experience airway obstruction, which leads to worsening lung function, symptoms and response to bronchodilators. Moreover, IgE receptors are expressed on several effective cells and structure cells; IgE, therefore, could directly interact with these inflammatory cells and leads to related cytokines, which all promote AR .1 and AQLQ scores. Changes in FEV1 and sputum eosinophils correlated with changes in WA percentage [50 levels and sputum eosinophils. Riccio et al. [Omalizumab, an anti-IgE treatment, was the first humanized biologic for SAA in the world. In addition, the mechanism of action of omalizumab are: (1) neutralization of free-form IgE and (2) downregulation of FcεRI on inflammatory cells  as well as structure cells . Therefore, omalizumab could cover up- and downstream inflammatory processes through previous mechanisms . Recent rcentage . Mauri ercentage  showed trcentage  reportedo et al.  showed to et al.  reportedFor regulation of AR mediators perspective: It has been reported that omalizumab was able to significantly decrease eosinophil counts in blood, sputum and bronchial submucosa ,35,36. IFrom a lung function improvement perspective, a significant benefit regarding the change from baseline in FEV1% predicted for subcutaneous omalizumab versus placebo was observed by Normansell et al. . In two Evaluation of airway remodeling could be divided into two parts: one is functional assessment, pulmonary function test, the other one is structural assessment. In this section, we summarize current methods of airway remodeling assessment. Methods for evaluating airway remodeling include: (1) direct assessment of airway tissues, (2) indirect assessment of using body fluids, (3) radiological assessment, and (4) physiological assessment .Direct airway tissue assessment is the most confident and strongest evidence regarding airway remodeling assessment. Surgical lung specimen: It can provide a unique and global view of pathological features by taking specimens from the central airway, alveoli, and pulmonary circulation. In addition, it can allow physicians to observe the changes in goblet cells, mucus gland, smooth muscle mass, subepithelial fibrosis, epithelial alteration, and angiogenesis. On the other hand, it also has limitations, including samples, which are difficult to obtain, less accurate knowledge of past medical history, inability to perform physiological tests, as well as few patients would be willing to undergo such invasive biopsy before and after treatment .Endobronchial biopsy—performed under flexible bronchoscopy and is the standard approach to evaluating airway remodeling ,47. ThisTransbronchial biopsy—like endobronchial biopsy, it is also performed under flexible bronchoscopy. It can obtain specimens from the distal lung to allow the study of changes in the distal airway wall and alveolar tissues. Moreover, it is able to evaluate airway inflammation, and remodeling is comparable to surgical biopsy. However, to date, there are only a few studies which have been performed using transbronchial tissue due to high-risk of major bleeding, pneumothorax complications as well as low success rate to obtain adequate distal airway wall sample ,48.Trans/endobronchial cryobiopsy—can collect larger specimens than conventional biopsy to evaluate remodeling in the large and distal airway. Major complications of this procedure are linked to the larger samples taken, which increases the risk of major bleeding and pneumothorax. A recent study suggested that transbronchial lung cryobiopsy combined less invasiveness and higher capacity to provide enough samples for morphological analysis in asthma disease. Therefore, the authors indicated that it could be useful research in the pathobiology of asthma and severe asthma .Bronchoalveolar lavage (BAL)—performed under flexible bronchoscopy, and it can be obtained at the same time as the endobronchial biopsy. It is used to study cellular composition and measure cytokine/chemokine levels in the distal airway and alveoli. Through the process of BAL, procollagen degradation and synthesis products, MMP, tissue inhibitor of metalloproteases (TIMP), and profibrotic cytokines can be quantified ,50. LimiInduced sputum—a relatively noninvasive process and is commonly to evaluate central airway inflammation and levels of soluble remodeling-associated proteins: procollagen synthesis peptides, MMPs , TIMPs , cytokines, elastase, and α1-antitrypsin ,52,53,54Exhaled breath condensate—a noninvasive but complicated method. It reflects the composition of the fluid lining the airway and successfully measures hydrogen peroxide, leukotrienes, prostaglandins, isoprostanes, nitric oxide-derived products, and hydrogen ions . HoweverBlood—markers of collagen synthesis and degradation can be quantified in blood. Other markers, including MMP-9, TIMP-1, cytokines, eotaxin, and eosinophil cationic protein, have been measured in the plasma of asthma patients ,58. LimiUrine testing—an unconventional way to evaluate airway remodeling. The study result, which was published by Priftis et al., demonstrated that urine tests could detect glycosaminoglycans, a component of ECM in urine samples of asthma patients . HoweverComputed tomography (CT)—allows the study of the airway lumen and wall dimensions without invasive process, which may be considered to evaluate airway remodeling in children and clinical studies ,61. It cOptical coherence tomography (OCT)—produces 2-dimensional images of the airway wall, which uses near-infrared light. For chronic obstructive pulmonary disease (COPD) patients, there is a strong correlation between OCT and CT measurements of average wall area and lumen area . For astEndobronchial ultrasound (EBUS)—performed with an ultrasonographic probe through the working channel of a fiberoptic bronchoscope. In the equine model, it can access airways as small as 4 mm in internal diameter and visualize multiple layers of the airway wall without the use of radiation , but canPositron emission tomography (PET)—able to measure pulmonary perfusion and ventilation when adding adequate isotope. According to previous studies, fluorodeoxyglucose (FDG)-PET was demonstrated as a good imaging biomarker of lung inflammation in asthmatic patients because neutrophils are the primary source of increased FDG uptake in the lungs. FDG-PET has the potential to be used to better understand asthma pathogenesis, phenotype differentiation, and response to anti-inflammatory treatment, but the cost is high .Hyperpolarized  MRI—hyperpolarized noble gases are used as MRI contrast media for measuring pulmonary function biomarkers: lung ventilation, airway microstructure quantification, and gas exchange . However1/FVC ratio is one of the characteristics of airway remodeling. Furthermore, Ward et al. [Pulmonary function test (PFT)—In clinical practice, a low post-bronchodilator FEVd et al.  found thIn conclusion, IgE is one of the major causes of the allergic inflammation process. IgE can interact directly and indirectly with effective inflammatory cells, such as dendritic cells, mast cells, eosinophils and, etc., as well as airway epithelial cells and ASMCs. Therefore, several Th2 mediated cytokines, IL-4, IL-5, IL-13, and remodeling mediators, IL-33, IL-25, TSLP, ET-1, MMP-9 and TGF-β, could be produced, promoting persistent airway inflammation. Through blocking IgE, it may break this vicious cycle to allow physicians to control patients’ asthma symptoms and to gain a better quality of life.Omalizumab was the first and, for a long time, the only biologic drug registered for asthma therapy. It is able/capable of remarkably improving—when added to the standard antiasthma treatment—respiratory symptoms, quality of life, lung function and exacerbation rate ,42,43,67The gold standard assessment of airway remodeling evaluation is obtained by direct tissue assessment, surgical lung species, endobronchial biopsies, transbronchial biopsies and cryobiopsies, through flexible bronchoscopy. Although these assessment tools are standard, the main limitation is that few patients would be willing to undergo such an invasive evaluation process. Within the indirect analysis of BAL, blood, urine, induced sputum and exhaled breath condensate, the process is much easier than direct assessment tools, but not specific. Other alternative tools, including CT, EBUS/OCT, PET and MRI, can be easily studied, but the cost is high as well as related specialized gas and equipment are needed. Lastly, PFT is a regular study in clinical practice, and it can be used as screening tools. However, the correlation between PFT results and airway remodeling should be considered.


Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States and changes in lifestyle can minimize the likelihood of succumbing to heart disease. Anti-inflammatory agents are commonly used to reduce the chronic inflammatory state behind the pathogenesis of CVD. Multiple studies have been published correlating nut consumption with a reduction in both heart attacks and strokes. The goal of this study is to determine to what extent the consumption of almonds, hazelnuts, and walnuts have on the blood markers associated with cardiac disease and inflammation.Methods: This was a six-week study in which subject’s baseline values act as controls. Fasting blood draws occurred at week 0, week 2, and after four weeks of intervention (week 6). All participants had undesirable lipid profiles and no medications related to heart disease.Results: Total cholesterol (TC): high-density lipoprotein (HDL-C) ratio was lowered a statistically significant amount at the six-week time point (3.89 ± 0.74) compared to both the zero-week  and two-week  timepoints. Low-density lipoprotein (LDL) measurements were lowered a statistically significant amount at the six-week time point (135.6 ± 15.0 mg/dL) compared to the zero-week . Erythrocyte sedimentation rate (ESR) was lowered a statistically significant amount at six-week time point (10.44 ± 5.05 mm/h) compared to the zero-week .Conclusions: Blood markers associated with CVD specifically and the general marker for inflammation associated with many chronic diseases can be favorably modified with the consumption of specific nuts as demonstrated by this study. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States and worldwide . The curAtherosclerosis, the most common cause of heart disease, has been widely linked to high cholesterol levels. However, it is now widely accepted that the innate immune system triggers cytokines and chronic inflammation. The key hallmark of an atheromata is lipid-laden “foam cells” that originate from mononuclear phagocytes . ErythroAfter extensive literature review, it was found that there are no published studies using this combination of nuts to assess cardiovascular risk determining markers (CRDM) or inflammatory markers such as ESR. It was hypothesized that consuming the daily combination of nuts we prescribed would improve lipids, lipoproteins, and apolipoproteins and decrease ESR. Additionally, our study is unique in that we investigated the anti-inflammatory effects of the above-mentioned nuts by monitoring ESR levels.Patients from the City of Montclair’s Medical Clinic  who were identified as having elevated cholesterol levels were invited in 2009 to participate in the study. This clinic is the city’s service to the local community that is supported by family medicine residents of the Montclair Doctors Hospital. Some 11 patients were enrolled in the study, which consisted of eight women and three men with an average age of 52. All patients were of Mexican descent and were not taking any medications or supplements (i.e. red yeast rice or fish oil) related to cholesterol. Patients were instructed to not make any changes to their diet or exercise programs, but to only introduce the consumption of specific nuts on a daily basis and surveyed weekly to assure compliance. The exclusion factors included having a known allergy to any nut or if the potential subject had any type of bleeding disorders (based on the recognition that each subject would be receiving three blood draws for the study and wanting to avoid any associated problems). Any previous history or current use of any lipid lowering agents  also excluded patient subjects.The subjects acted as their own controls and all blood draws were collected after fasting. Laboratory markers included: total cholesterol (TC), triglycerides, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) levels, and ESR. The clinical endpoints were measured at three time points, specifically: the beginning of the study, at two weeks, and at six weeks after the nut consumption protocol was introduced into their diets beginning at week 2.The protocol consisted of three almonds, three hazelnuts, and three walnuts to be consumed each morning for four weeks. To ensure that this happened, each subject received 28 packets, each filled with a day’s ration of nuts, one for each day of the study. This regimen of nuts and number of nuts was devised based on previous studies with each of the following nuts -9.Following the six-week period of investigation, patients achieved notable changes in their serum lipids, lipoproteins, and apolipoproteins and ESR. Our data collection and analysis demonstrated several significant mean differences between our baseline, control, and protocol periods across all five parameters measured, namely TC, HDL-C, TC:HDL-C ratio, LDL-C, triglycerides, and ESR Table . It is cTotal cholesterol was reduced in eight of the 11 patients and there was a statistically significant difference between measurement points as determined by one-way analysis of variance (ANOVA) for correlated samples . A Tukey post-hoc test revealed that the TC was lowered a statistically significant amount at six-week time point  compared to the zero-week  time point. There were no significant differences noted between the TC measurements at the zero-week and two-week time points , or were there significant differences noted between the two-week and six-week time points (p = 0.0620).HDL-C was increased in 10 patients with a complete post-protocol record and there was a statistically significant difference between measurement points as determined by one-way ANOVA for correlated samples . A Tukey post-hoc test revealed that the HDL measurements were raised a statistically significant amount at six-week time point (61.5 ± 13.2 mg/dL) compared to both the zero-week  and two-week  time points respectively. There were no significant differences noted between the HDL measurements at the zero-week and two-week time points (p = 0.138).The TC:HDL-C ratio was decreased in 10 patients with a complete post-protocol record and there was a statistically significant difference between measurement points as determined by one-way ANOVA for correlated samples . A Tukey post-hoc test revealed that TC:HDL-C ratio was lowered a statistically significant amount at the six-week time point (3.89 ± 0.74) compared to both the zero-week  and two-week  time points respectively. There were no significant differences of the TC:HDL-C ratio noted between the zero-week and two-week time points (p = 0.3984).LDL-C levels were reduced in all 11 patients and there was a statistically significant difference between the measurement points as determined by one-way ANOVA for correlated samples . A Tukey post-hoc test revealed that the LDL measurements were lowered a statistically significant amount at six-week time point (135.6 ± 15.0 mg/dL) compared to both the zero-week  and two-week  time points respectively. There were no significant differences noted between the LDL measurements at the zero-week and two-week time points (p = 0.402).Triglyceride levels were found to be reduced at all post-protocol measurement points across 10 patients with a complete data set and there was a statistically significant difference between measurement points as determined by one-way ANOVA for correlated samples . A Tukey post-hoc test revealed that the triglyceride measurements were lowered a statistically significant amount at six-week time point (129.3 ± 37.4 mg/dL) compared to both the zero-week  and two-week  time points respectively. There was also a statistically significant difference between the measurements at the zero-week and two-week time points (p < 0.01).The ESR was decreased at all post-protocol measurement points across nine patients with complete datasets and there was a statistically significant difference between measurement points as determined by one-way ANOVA for correlated samples . A Tukey post-hoc test revealed that the ESR was lowered a statistically significant amount at six-week time point (10.44 ± 5.05 mm/h) compared to both the zero-week  and two-week  time points respectively. There were no significant differences noted between the ESR measurements at the zero-week and two-week time points (p = 0.989).The purpose of this research was twofold; determining to what extent the consumption of specific nuts would have on the blood markers associated with CVD and evaluating if nut consumption reduced the level of inflammation. This study answers both questions.The ability of almonds to lower LDL-C levels in a dose-dependent fashion has been well documented -11. HazeThis combination of nuts is unique and unequivocally demonstrates that regimented consumption of a modest amount of almonds, hazelnuts, and walnuts can, over a four-week interval, manifest significant changes in serum measurements of LDL-C, HDL-C, triglycerides, and ESR Figure .These findings point to the critical role that dietary modification and lifestyle interventions have in implementing a comprehensive management plan for patients with an increased risk for developing CVD.The most promising of our results is the reduction in TC:HDL-C ratio, which was statistically significant. The TC:HDL-C ratio is considered one of the most predictive laboratory measurements to best predict coronary atheroma progression and cardiovascular-related events .The statistically significant decrease in triglycerides between week 0 and week 2 was noted, but as there was no intervention administered between this time, the authors do not have an explanation for this. Perhaps, despite being told not to change dietary habits, Hawthorne effect took place and some of the subjects made changes to their diets.Some of the limitations of this study include the paucity of subjects, fund availability, and number of markers followed. The authors also note a lack of generalizability as the study predominantly evaluated those of Hispanic descent, the majority of whom were women, but still believe that the data and findings are valuable for a pilot study. Additionally, the principal investigator of the study had intended to use ESR and high sensitivity C-reactive protein (hs)CRP as a level, but due to issues with the laboratory collecting and reporting only ESR was included in the study. This is the same issue that caused two of the data points to not be reported and the data reflect this. Future directions for expanding this line of inquiry include recruiting a larger cohort, expanding the laboratory panel to further track changes in systemic inflammatory burden, a longer longitudinal outcome measurement, and, ultimately, correlating patient outcomes with the nut consumption protocol.This study reaffirms the important impact that a healthy diet, specifically nuts, can have on both the preventative and management aspects of CVD. The daily consumption of these nuts produced a favorable change on the cardiovascular risk markers and especially important is the TC:HDL-C ratio and inflammation in general. There are no other studies in the current literature that link the consumption of nuts with the reduction of inflammation by measuring ESR, which we found to be statistically significant despite of the small number of subjects and the relatively small number of nuts consumed daily. Our data suggest that nut consumption reduces inflammation; the vast majority of chronic diseases are associated with higher inflammatory states. Nut consumption is protective and explains why nut consumers have a “reduction in all-cause mortality and morbidity.” A meta-analysis with over 6300 patients showed that one serving of unspecified nut consumption per week decreased coronary heart disease risk. Our data suggest that a daily intake of specific nuts may have even a greater positive impact on heart disease and it is our hope that nut consumption will become a recognized standardized approach in all patients with cardiac disease.Further studies could assess the molecular mechanisms that nut consumption has on cholesterol metabolism and inflammation. The recommendation to consume nuts as part of daily diet has shown in many studies and in our study to be cardioprotective and anti-inflammatory. Discovering the mechanisms of how lipid and inflammation levels are decreased could provide more insight into our nut protocol as well as how effective other combinations of nuts are in decreasing these levels.


The long-held notion that, without urinary tract or circulatory infection, bladder urine and blood are sterile biofluids has been disproven. There have been no previous reports on the kidney pelvis urinary microbiome after bladder disinfection in kidney stone patients. This study aimed to determine whether a kidney pelvis urinary microbiome is present after eliminating the influence of the bladder urinary microbiome, whether the microbiome composition is different in patients with stone kidney pelvis (SKP) and non-stone kidney pelvis (NSKP), and the correlation between SKP and patient clinical characteristics.Corynebacterium was significantly higher in SKP compared to NSKP. Several bacteria were associated with patient characteristics, including Lactobacillus, which was positively correlated with fasting blood glucose, and Prevotella was negatively correlated with BMI. Lactobacillus was significantly higher in SKP compared to blood but not in NSKP compared to blood.Comparisons of bacterial diversity and community structure exhibited that urine in bladder was similar to SKP and NSKP. However, the comparisons showed that urine samples were different from blood. The most common operational taxonomic units were shared by all three types of urine samples. The composition of the kidney pelvis urinary microbiome after disinfection of the bladder and its similarity to the bladder microbiome indicate that bladder urine can be used to replace kidney pelvis urine in microbiome research. Additionally, the comparison of SKP and NSKP and clinical associations suggest that the occurrence of kidney stones is responsible for the SKP urinary microbiome. Kidney stones affect approximately one in 11 individuals in their lifetimes, and their prevalence is increasing , and somAlthough the bladder was previously considered to be “sterile”, it has been shown to possess its own urinary microbiome , 9. The Fifty patients with unilateral kidney stones who were negative on EQUC in post-iodophor bladder lavage urine were recruited for the study. Table A total of 219 samples were collected, and detectable bacterial DNA was found in 47/50 Bladder A samples (urine samples aspirated before bladder disinfection), 44/50 Bladder B samples (newly formed urine after bladder disinfection), 48/50 urine samples of stone kidney pelvis , we can visualize the similarities of the operational taxonomic units (OTUs) among the samples. Statistically significant differences in the PCoA were only observed between the urine samples of Bladder A/Bladder B/SKP/NSKP and blood samples , Bifidobacterium, Sphingomonas, and Prevotella in the Bladder B group , Sphingomonas, Acinetobacter, and Bifidobacterium in the SKP group , and Acinetobacter, Sphingomonas, and Delftia in the NSKP group . Whereas, Sphingomonas, Acinetobacter, and Propionibacterium were predominant in the blood group  , whereas Staphylococcus, Pontibacter, Sphingomonas, Propionibacterium and Prevotella were predominant in the female Bladder A samples . The pre menstrual and post menstrual female Bladder A samples were dominated by Pontibacter, Streptococcus, Sphingomonas, Propionibacterium and Bifidobacterium ; the post-menstrual samples were dominated by Staphylococcus, Prevotella, Sphingomonas, Roseburia and Propionibacterium , Bifidobacterium (5.30%), Acinetobacter (4.83%), Propionibacterium (3.28%) and Delftia (3.16%). , Staphylococcus (8.25%), Pontibacter (4.89%), Propionibacterium (4.42%) and Acinetobacter (4.40%), etc. When the female SKP samples were divided into pre menstrual and post menstrual subgroups, the samples of pre menstrual females were dominated by Staphylococcus, Pontibacter, Sphingomonas, Faecalibacterium and Bacteroides , whereas the samples of post menstrual females were dominated by Sphingomonas, Acinetobacter, Staphylococcus, Propionibacterium and Delftia , Arthrobacter was positively correlated with BMI , Prevotella was negatively correlated with BMI .Notably, several bacterial genera showed associations with patient characteristics. For example, The old dogma that urine in healthy bladder is sterile has been challenged with the application of 16S rRNA sequencing technology and the EQUC technique –24. The The numbers of sequencing-positive Bladder A, Bladder B, SKP and NSKP samples were similar; however, this number was lower in the blood group. Consistent with the sequencing results, the comparison of alpha diversity revealed that the blood samples exhibited the lowest bacterial diversity compared with the urine samples either from the kidney pelvis or bladder. These findings suggest that the bacterial biomass in the blood is lower than that in the urine of patients with kidney stones. This may be attributed to the kidney function insufficiency noted in approximately half of the patients. A recent study reported that patients with chronic kidney disease had decreased bacterial diversity in their blood .Both PCoA and Venn diagram demonstrated that the microbiome composition in the kidney pelvis urine was similar to that in the bladder urine. The resemblance between the urinary microbiome in the kidney pelvis and bladder was consistent with the findings of Dornbier et al., in which the microbiomes of the urine in the upper urinary tract and the bladder of patients with kidney stones were similar . In the Acinetobacter, Bifidobacterium, Corynebacterium, Lactobacillus, Staphylococcus, and Streptococcus, were also previously reported as the dominant bacteria in patients with urinary stones [Delftia, Propionibacterium and Sphingomonas, have not been reported in a previous study on the urinary microbiome in kidney stone patients, they have been demonstrated to be associated with human health status in the urine microbiome. For example, Delftia was overrepresented in urine from patients with type 2 diabetes mellitus [Propionibacterium was enriched in the urine of patients with bacterial vaginosis [Sphingomonas tended to be more abundant in kidney transplantation individuals with stable status [Some bacterial genera in the bladder and kidney pelvis, including y stones , 28. Altmellitus , Propionaginosis , and Sphe status . More stCorynebacterium was significantly increased in the SKP group compared with the NSKP group. Previous studies have confirmed that Corynebacterium spp. is associated with stone formation [Corynebacterium was considered a major bacterial genus in two samples in the report of Dornbier et al. on the microbiome in human kidney stones [Corynebacterium might be a protective response in the SKP in KSD patients.Most of the major bacterial genera in SKP and NSKP were similar. However, ormation , 32. Simy stones . Thus, tPseudomonas and Roseburia were significantly higher or lower in NSKP compared to Bladder A, respectively. These findings might be because vesicoureteral reflux is common in patients with kidney stones [We observed that there was no significant difference in the major bacterial genera between Bladder A and SKP samples, while the abundances of y stones , i.e., tLactobacillus was significantly higher in SKP compared to blood but not in NSKP compared to blood. This finding indicates that the occurrence of kidney stones may activate the self-protective response in the kidney pelvis urinary microbiome, since Lactobacillus is a probiotic that is able to prevent kidney stones because of its oxalate-degrading activities [When the microbiomes in the kidney pelvis and blood were compared, we found that the numbers of the major bacterial genera showing significant differences between the SKP and blood samples were greater than those between the NSKP and blood samples. These findings indirectly suggest that the occurrence of kidney stones affected the urinary microbiome in the kidney pelvis. It is worth noting that the abundance of tivities .Ochrobactrum spp. based on EQUC, but the sample was dominated by Corynebacterium and Enterobacteriaceae [We observed that the EQUC results for some samples were not consistent with the results of detected taxonomy  in bladder urine. Similar findings were reported by Dornbier RA et al.; for example, one female sample contained eriaceae . These fLactobacillus increased with patient fasting blood glucose, which is similar to a previous human urinary microbiome study conducted by Chen JW et al. In their study, Lactobacillus was overrepresented in the high haemoglobin A1c group [Prevotella was linked to a low BMI. It is difficult to determine the role of Prevotella in human health, since a recent study reported that the correlations between Prevotella and BMI in previous human studies were not consistent [Although our present study did not reveal that patient gender, age or menstrual status were correlated with bacterial composition in the bladder and SKP urine at the present sample size, which is dissimilar to the human gut microbiome, we found that several major bacterial genera were associated with patient clinical parameters. For example, the abundance of 1c group . In addinsistent .Corynebacterium in the SKP samples. Although the mechanism responsible for this observation remain unclear, the results suggest that kidney stones can be improved by targeting modification of Corynebacterium; for example, dietary therapy. In addition, we found that the bacterial profile in SKP was related to the clinical characteristics of the patients, indicating that modifying these characteristics, including fasting blood glucose and BMI, using microbiome-based therapy might play a role in controlling kidney stone occurrence. It is worth noting that the present study demonstrated that the presence of bacteria in the urine bladder and kidney pelvis, and the blood. Further study should characterize the consistency of their alterations, which might provide strategies for holistic therapy in maintaining microbiome balance.This study demonstrated the existence of the urinary microbiome in the kidney pelvis after bladder disinfection, and the urinary microbiome in the kidney pelvis was similar to that in the bladder urine, but the microbiomes in both bladder urine and kidney pelvis urine were dissimilar to the blood microbiome. To some extent, we revealed that the urinary microbiome in the SKP samples was different from that in the NSKP samples, which is related to alterations in A limitation of this analysis is that the sample size was insufficient, which reduced the statistical power of detecting true differences in this study. Moreover, although the bladder was repeatedly disinfected prior to the collection of kidney pelvis urine, this cannot completely prevent contamination of the kidney pelvis urine by the bladder urine. As the cystoscope and the tube were passed through the urethra and bladder into the kidney pelvis to collect urine samples; it was possible for intracellular bacterial colonization in the urothelium to contaminate the instruments and samples . TherefoThe study protocol was approved by the Affiliated Wuxi Second Hospital, Nanjing Medical University, Ethical Review Committee , and patients provided written informed consent for the use of their samples. The process was in compliance with the Declaration of Helsinki, which included risk and benefit assessment. Kidney calcium stones were confirmed by abdominal X-ray, ultrasonography, and computed tomography scans. Patients undergoing ureteroscopic lithotripsy were recruited between October 2018 and April 2019. The following exclusion criteria were applied: menstruation or pregnancy, cancer, autoimmune disease, urinary tract disease , urinary tract deformity, known urinary tract infection based on clinical assessment, urinary catheterization in the previous 4 weeks, and treatment with antibiotics in the previous 4 weeks. Based on previous studies that compared microbiomes in different body niches , 38, 50 Six surgeons with ≥10 years of experience in conducting ureteroscopic lithotripsy were trained to use the procedures of disinfection and collection of urine samples; this guaranteed that the surgeons used unified methods to disinfect the urethra and its surrounding tissues and bladder. In addition, they were required to use unified methods to insert the ureteroscope and tube into the kidney pelvis. Specifically, after the administration of general anaesthesia to the patient, the following procedures were used to collect samples: (a) Disinfection of the perineum area and the urinary meatus with iodophor at least three times. (b) Insertion of a ureteroscope  and withdrawal of 3 mL of urine from the bladder (labelled Bladder A). EQUC technique was used to detect the presence of living bacteria (> 10 colony-forming units per mL) in bladder urine . Patient2 at 35 °C for 48 h. For a second set of BAPs, each was inoculated with 0.1 ml of urine and incubated in room atmosphere at 35 °C and 30 °C for 48 h. Next, 0.1 ml of urine was inoculated onto each of two CDC anaerobic 5% sheep blood agar plates and incubated in a Campy gas mixture  at 35 °C for 48 h. The detection level was 10 CFU/ml, which was represented by 1 colony on any of the plates. Finally, to detect any bacterial species that may be present at quantities lower than 10 CFU/ml, 1.0 ml of urine was placed in thioglycolate medium (BD BBL prepared tubed media) and incubated aerobically at 35 °C for 5 days. If growth was visible in the thioglycolate medium, the medium was mixed, and a few drops were plated on BAP and CDC anaerobic 5% sheep blood agar plates for isolation and incubated aerobically and anaerobically at 35 °C for 48 h. All of the plates and media used in the present study were prepared by Comagal Microbial Technology Co., Ltd., China. All procedures of EQUC, bacterial isolation and genomic DNA isolation were performed in a biosafety cabinet that was sterilized using chlorine disinfectant, alcohol solution and ultraviolet irradiation in advance. PCR for the amplification of the 16S rRNA gene was carried out using universal primers; 27F as the forward primer, and 1492 as the reverse primer. The PCR band from each of the isolates was Sanger sequenced, and the bacterium was identified to the strain level using BLAST. If the genome sequence of a bacterium was identified as heterozygous three times or was difficult to bind, the bacterium was defined as an unidentified bacterium. The similarity of the bacterial sequence cutoff is 97% [The procedure of EQUC was as follows: 0.1 mL of urine was inoculated onto 5% sheep blood agar plate (BAP), chocolate and colistin, and nalidixic acid (CNA) agars, streaked for quantitation, and incubated in 5% COf is 97% . When thAn experienced nurse collected all blood samples as follows: (a) The skin of the intravenous injection site was disinfected with iodophor; (b) A needle was inserted into the vessel, and blood (5 mL) was drawn; (c) The stopper of a vacutainer containing ethylenediaminetetraacetic acid (EDTA) was removed, the blood was gently injected into the vacutainer, and the stopper was then put back on the vacutainer.The Bladder A, Bladder B, SKP, and NSKP samples were immediately placed in a foam box with ice packages in the operation room and then immediately transferred to the lab in our hospital within 10 mins. A total of 1 mL of urine was centrifuged at 20,000×g for 30 min, and the resulting pellet was resuspended in 150 μL of lysis buffer . As described in our previous study, Sera-Mag™ SpeedBeads Carboxylate-Modified Magnetic Particles  were used to extract the DNA according to the instructions provided by the manufacturer . Buffy cBacterial DNA was amplified via polymerase chain reaction with 35 cycles using the universal primers 341F and 806R , which tp < 0.1 [Paired-end reads were assigned to the samples based on their unique barcode and truncated by cutting off the barcode and primer sequence. Paired-end reads were merged using FLASH. Quality filtering of the raw tags was performed under specific filtering conditions to obtain high-quality clean tags according to fqtrim v0.94. Chimeric sequences were filtered, and sequences with ≥97% similarity were assigned to the same OTUs using Vsearch v2.3.4. Representative sequences were chosen for each OTU, and taxonomic data were then assigned to each representative sequence using the Ribosomal Database Project (RDP) 11.5, released on September 30, 2016, with a confidence value of 0.8 as the cutoff. The sequences were used as queries to search against the National Center of Biotechnology Information (NCBI) nucleotide database (downloaded in April 2019). Samples with < 30,000 clean tags were removed. Contaminant sequences (based on the negative controls) were removed using Decontam v1.2.1 and the threshold p < 0.1 , 44.The OTU abundance data were normalized using a standard sequence number corresponding to the sample with the smallest number of sequences. Alpha diversity was used to analyse the complexity of species diversity in each sample using QIIME v1.8.0 to calculate the alpha-diversity index, including observed species, Chao1, Shannon index, and Simpson’s index . The obs2. Patients were stratified into five groups by baseline eGFR: Stage 1, eGFR > 90; Stage 2, eGFR 60–89; Stage 3, eGFR 30–59; Stage 4, eGFR 15–29; and Stage 5, eGFR < 15.The kidney function estimators were measured on an Olympus AU5421–04  in the clinical lab in our hospital. The normal range of blood urea nitrogen (BUN) was defined as 2.5–7.1 mmol/L, and blood urea acid (BUA) was 200–430 mmol/L in men and 140–360 mmol/L in women. eGFR was expressed in ml/min/1.73 mt-test was used [P-values were corrected using the Benjamin–Hochberg false discovery rate correction, and q-values < 0.05 were considered statistically significant [The data were not normally distributed. Thus, for pairwise comparisons of bacterial communities, White’s nonparametric was used . For gronificant .Additional file 1: Table S1. The 100 most common OTUs in the five groups of samples. Abbreviation: operational taxonomic units, OTUs.Additional file 2: Table S2. Bacteria in bladder urine detected by EQUC and 16S rRNA sequencing Abbreviation: colony forming units, CFU. a The similarity of bacterial sequence cutoff is 97%. b If the genome sequence of a bacterium was identified as heterozygous three times or was difficult to bind, the bacterium was defined as an unidentified bacterium.Additional file 3: Figure S1. Bacterial structure between groups of males and females and pre menstrual and post menstrual females. PCoA shows the bacterial composition clustering of the groups based on Bray–Curtis distances, with each point corresponding to a patient and coloured according to the sample type of male or female in the SKP samples (A), pre menstrual and post menstrual females in the SKP samples (B), male or female in Bladder A samples (C), and pre menstrual and post menstrual females in the Bladder A samples (D). PERMANOVA indicated that the bacterial communities between males and females were not significantly different in the SKP samples (p > 0.05).Additional file 4: Figure S2. Bacterial genera distribution between the groups. The relative abundances of the major genera in males and females in the SKP samples (A), in pre menstrual and post menstrual females in the SKP samples (B), in males and females in the Bladder A samples (C) and in pre menstrual and post menstrual females in the Bladder A samples (D), as determined by 16S rDNA gene sequencing, in the SKP and NSKP samples were more similar to the Bladder A samples than the blood samples. “Others” includes all detected bacteria.


Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. This current research is a double blinded, randomized, and prospective trial to determine the effect of dapagliflozin on cardiovascular outcomes in type 2 diabetes.P < .05 was regarded as statistically significant.This randomized controlled, double-blinded, single center trial is carried out according to the principles of Declaration of Helsinki. This present study was approved in institutional review committee of the Lianyungang Hospital affiliated to Xuzhou Medical University (LW-20200901001). All the patients received the informed consent. Diabetic patients were randomized equally to receive 28-week treatment with dapagliflozin or matching placebo. The major outcome of our current study was the change in the level of hemoglobin A1c (HbA1c) from the baseline to week 28. Secondary outcome measures contained the levels of fasting blood glucose, the mean change in seated systolic and diastolic blood pressure, body weight, and the mean change in calculated average daily insulin dose in patients treated with insulin at baseline, the other laboratory variables, and self-reported adverse events. The We assumed that the dapagliflozin administration in patients with type 2 diabetes would reduce HbA1c, body weight, systolic blood pressure, and achieve the goal of glycemic control, without adversely impacting cardiovascular risk.This study protocol was registered in Research Registry (researchregistry5987). Food and Drug Administration have issued guidelines requiring the novel treatments for diabetes to exclude an unacceptable increase in the risk of cardiovascular disease. We need effective and safe treatment strategies to control the hyperglycemia and increase the clinical benefits.,9The cardiovascular disease (CVD) is still a direct and major cause of incidence rate and mortality among type 2 diabetic patients. In comparison with the non-diabetic people, the risk of cardiovascular disease is about 2 times that of non-diabetic patients.,11 and thiazolidinediones, metformin, glucagon-like peptide-1 analog, dipeptidyl peptidase-4 inhibitors as well as the α-glycosidase inhibitors) are insulin-dependent in their efficacy. In the development of type 2 diabetes, when the function of the islet β-cells decreases, they become less effective. Thiazolidinediones and sulfonylureas contribute to the weight gain and then in-depth worsen the insulin resistance. Not surprisingly, about two-thirds of type 2 diabetes patients fail to achieve their goal of blood glucose control under the regular treatment. In contrast, as the inhibitor of sodium glucose co-transporter 2 (SGLT2) with highly selective. Dapaglilizin is a kind of selective inhibitor of sodium–glucose cotransporter-2 (SGLT2), it reduces the levels of blood glucose via decreasing the reabsorption of glucose in kidney, it does not depend on the effect or secretion of insulin, leading to enhanced the urine glucose excretion, accompanied by caloric loss and osmotic diuresis. In the clinical trials, dapagliflozin has been well tolerated as the monotherapy or in combination with insulin, sulfonylureas and metformin.,20 The action mechanism of dapaglilozin can affect many risk factors for cardiovascular disease, especially lowering the blood pressure, weight loss, decreasing the serum uric acid and albuminuria levels, lowering the waist circumference, and decreasing the inherent risk of hypoglycemia.,23The familiarly utilized antidiabetic drugs . All the patients received the informed consent. It was also registered at the Research Registry (researchregistry5987).2.12 and greater than 60 ml/minute/1.73 m2, the urinary albumin to the ratio of creatinine less than 300 mg/g, and the index of body mass ≤45.0 kg/m2, with an insufficient control of blood pressure, which was defined as the diastolic blood pressure less than 105 mm Hg and ≥80 mm Hg, and/or the systolic blood pressure less than 165 mm Hg and ≥130 mm Hg. Exclusion criteria included: a recent history of cardiovascular events, gestational diabetes, unstable renal disease, retinopathy, hepatic, or hematologic disease.Inclusion criteria were the female or male patients with type 2 diabetes, and the age range is between 30 and 79 years, with an inadequate glycemic control, which were defined as HbA1c ≤9.5% and ≥6.6%. Subjects were required to register C-peptide≥ 0.27 nmol/l, the rate of estimated glomerular filtration less than 150 ml/minute/1.73 m2.2Each study group had an equal number of envelopes and the envelopes were produced via a research assistant through utilizing a computer-based random number generator who did not participate in any follow-up studies or contact with other study group members during the research period. He has prepared 150 identical, sealed, sequentially numbered, and opaque envelopes, with 30 envelopes containing the instructions for each group. These above envelopes have been submitted to the principal investigator for filing . Patients were equally given once-daily doses of dapagliflozin , or were given a matched placebo dose in combination with an established stable background treatment. Safety and efficacy were assessed at all study visits, the other laboratory variables, and self-reported adverse events. A value of 2.4All the primary and critical secondary impact variables are pre-specified. The primary influencing variable was HbA1c change from baseline to week 28. At 28 weeks, the 5 primary secondary influencing variables involved:1.the change of overall weight from baseline;2.the change of 24-hour ratio of urine glucose to creatinine;3.the average change of sitting diastolic and systolic blood pressure from baseline;4.the change of fasting blood glucose from the baseline; and5.the average change of calculated daily dose of insulin in the insulin treated patients at baseline.The vital signs, laboratory parameters, and data on adverse events were collected for the evaluation of the long-term tolerability and safety of dapaglifrozin for 28 weeks.2.52 test was utilized to compare the categorical variables. A value of P < .05 is considered as the significant in statistics.With the Statistical Package for Social Sciences, the statistical analysis was implemented . The statistical analysis was carried out via independent experts and it was not participated in the research program. The values of mean (range) and median were presented. Non-paired t-test was utilized for the numerical data of normal distribution. Non-parametric simulation was utilized where appropriate. The x3With the growth of age, type 2 diabetes patients usually treated through the antidiabetic drugs combining with other concomitant drugs to control comorbidities, for instance, obesity, hypertension and the cardiovascular disease. It is a recognized problem that type 2 diabetes patients possess an enhanced possibility of cardiovascular disease. Dapagliflozin is a kind of selective inhibitor of sodium-glucose co-transporter-2 that decreases the reabsorption of renal glucose with an insulin-independent mode. We attempted to determine the influence of dapagliflozin on lowering HbA1c, reducing systolic blood pressure and BW in patients at high risk for future cardiovascular disease events.Conceptualization: Dong Yin.Data curation: Dong Yin.Formal analysis: Dong Yin.Funding acquisition: Yi Xu.Investigation: Dong Yin.Methodology: Yuan Hui.Project administration: Yuan Hui, Yi Xu.Resources: Yi Xu.Software: Chuanhui Yang.Supervision: Chuanhui Yang, Yi Xu.Validation: Yuan Hui, Chuanhui Yang.Visualization: Yuan Hui.Writing – original draft: Dong Yin.Writing – review & editing: Chuanhui Yang, Yi Xu.


Uncontrolled blood pressure (BP) is an important modifiable risk factor for recurrent stroke. Secondary prevention measures when implemented can reduce stroke re-occurrence by 80%. However, hypertension control rates remain sub-optimal, and little data is available from primary care where most management occurs.The aim of this study was to describe BP control in primary care-based patients with a previous stroke or transient ischaemic attack (TIA) in Ireland, and to concurrently examine antihypertensive medication-dosing.Study participants most recent office-based BP reading was compared with the NICE (NG136) and European Society of Hypertension/ European Society of Cardiology (ESH/ESC 2013) goal of BP < 140/90 mmHg. Optimal anti-hypertensive medication dosing was determined by benchmarking prescribed doses for each drug with the World Health Organisation-Defined Daily Dosing (WHO-DDD) recommendations.n = 207). Of those with BP ≥140/90 (n = 116), just under half  were adequately dosed in all anti-hypertensive medications when compared with the WHO-DDD recommendations.We identified 328 patients with a previous stroke or TIA in 10 practices. Blood pressure was controlled in almost two thirds of patients when measured against the ESH/ESC and NICE guidelines (63.1%, Blood pressure control in patients post stroke/TIA appears sub-optimal in over one third of patients. A comparison of drug doses with WHO-DDD recommendations suggests that 47% of patients may benefit from drug-dose improvements. Further work is required to assess how best to manage blood pressure in patients with a previous stroke or TIA in Primary Care, as most consultations for hypertension take place in this setting. Stroke has a major impact on people’s lives, with often devastating personal, social and economic consequences for the individual and their family. The cost of stroke in the European Union (EU) in 2015 was estimated at €45 billion, accounting for a total mortality rate of 17% within the EU, making it the second most common cause of death . The repManagement of risk factors such as smoking, hyperlipidaemia, obesity, diabetes, atrial fibrillation, sedentary lifestyle, raised body mass index and hypertension, have the potential to reduce recurrent events by up to 80% , 5. Of tIn a survey of secondary prevention of stroke in Europe, satisfactory levels of blood pressure (BP) control are achieved in less than 60% of countries . FiguresReasons for sub-optimal BP control are multi-faceted and include patient factors (adherence) , 10, phyBlood pressure guidelines for the prevention of stroke have been the subject of much discussion with differences emerging between specialist groups. The recent American Heart Association (AHA) guidelines have adopted a target of < 130/80 mmHg for the secondary prevention of stroke  to < 130The Irish health care system does not have universal registration with a GP or mandatory coding of diseases. Almost half of the population is registered through the Primary Care Reimbursement Service (PCRS) and registered to one single general practitioner . The remThe primary aim of this study was to describe the prevalence of sub-optimal blood pressure control in a cross-sectional cohort of patients with a previous stroke/ TIA in primary care. Secondly, we wished to examine the characteristics of this cohort- looking for associations that could predict poor blood pressure control and thirdly we wished to assess anti-hypertensive drug dosing schedules in these patients. To our knowledge, this is the first study examining these issues in primary care.General practices in the University of Limerick, Education and Research Network  were invData collection was conducted in July and August 2019 according to a prespecified data extraction protocol designed by RD . Data coEligible patients were identified as those patients who were coded for stroke or TIA or those who were not coded but had a hospital diagnosed stroke or TIA in their discharge summaries from specialists. These events were classed as either ischaemic stroke, haemorrhagic stroke, TIA or unknown. If patients had more than one of these events, they were classed based on their most severe event. Disease coding typically categorised the type of each stroke, where this was not available or ambiguity existed, hospital discharge summaries and consultant reports were examined to clarify the diagnosis.All practices used electronic health care records, but used a variety of software systems; Socrates®, Health One™ or Helix Practice Manager. Search methods differed between the systems, some using specific diagnostic searches and others disease coding, each using the analysis function inbuilt in that system.In Socrates®, the International Classification of Disease-10 (ICD-10)  codes G4Sub-optimal BP control was assessed by comparing the last office BP on file with the ESH/ESC 2013  and NICE(Type 2 Diabetes Mellitus), patient’s active diagnosis contained diabetes keyword, or were taking insulin or oral hypoglycaemic agents. Patients were described as having CKD if an estimated Glomerular Filtration Rate (eGFR) less than 60mls/ min/ 1.73m2 was recorded in the last two renal function tests [To help describe the characteristics of these patients we recorded, if available, demographics, stroke subtype, blood pressure, kidney function, lipid profile and drug data. Co-morbidities of diabetes and chronic kidney disease (CKD) were also recorded. Patients were described as having diabetes if they had ICPC codes T89 (Diabetes insulin dependent) or T90 (Diabetes non-insulin dependent), ICD codes E10 (Type 1 Diabetes Mellitus), E11 on tests . Anti-hyon tests , and incThe use of ambulatory blood pressure monitoring (ABPM) was examined, especially in those with sub-optimal BP control to identify cases of white coat hypertension . Day time average readings > 134/84 mmHg signified sub-optimal BP control .Optimal anti-hypertensive medication dosing use was determined by benchmarking prescribed anti-hypertensive drug doses, for each individual prescribed drug, against the World Health Organisation-Defined Daily Dosing (WHO-DDD) schedule. We used this as a surrogate for investigating the adequacy of dosing. The WHO-DDD is the assumed average maintenance dose per day for a drug, used for its main indication in adults . Egan etGraphical summaries were created for all patient characteristics to identify any anomalies or potential outliers. Summary statistics were generated that were appropriate for the explanatory variable in question . Independent t-tests were used to compare the mean of the various quantitative variables between the groups, controlled (< 140/90 mmHg) and uncontrolled (≥140/90 mmHg) and a two-sample comparison of proportions (chi-square test) to similarly compare factors. Chi-squared tests were also used to test whether a significant difference was found between the expected frequencies in different categories in controlled (< 140/90 mmHg) versus uncontrolled (≥140/90 mmHg) patients. Binary logistic regression was used to model the association between the (log) odds of BP control (< 140/90 mmHg) and explanatory variables of interest. All statistical analysis took place in SPSS- version 26 .Ten practices participated Table  with 328n = 328) studied are male with 37.8% female. Stroke subtype included 29.3% ischaemic stroke, 9.8% haemorrhagic stroke and 41.2% TIA, with 19.8% unknown or not recorded. 87.8% were registered with PCRS for free GP services. Multimorbidity is a common feature within this cohort of patients, 15.5% had diabetes, 22.6% had CKD and 4.9% had both diabetes and CKD.Patient characteristics are described in Table Independent t-tests were used to compare the mean of the various quantitative variables  between the two groups, controlled (< 140/90 mmHg) and uncontrolled (≥140/90 mmHg). A two-sample comparison of proportions (or chi-square test) to compare factors  was also performed. No statistically significant differences between the groups were demonstrated.Chi-squared tests were also used to test whether a significant difference was found between the expected frequencies and the observed frequencies in different categories in controlled (< 140/90 mmHg) versus uncontrolled patients (≥140/90 mmHg), and no significant differences were observed in sex, stroke subtype, GMS status and comorbidities. Binary logistic regression was used to model the association between the (log) odds of BP control and explanatory variables of interest. No predictors of sub-optimal BP were identified.Detailed data on drug-dosing was available for 252 patients prescribed antihypertensive medications Table . For thon = 64), nine patients demonstrated white coat hypertension, the remaining 55 had sub-optimal BP control, with average day time readings > 134/84 mmHg [Results of ABPM were available for 64 (55.2%) of the 116 patients with sub-optimal BP control. Of those who had ABPM  of patients according to ESH/ESC 2013 and NICE (NG136) guidelines, where BP < 140/90 mmHg is deemed satisfactory. Anti-hypertensive medication dosing appears sub-optimal in close to half of these patients when compared with WHO-DDD criteria.Of those identified with a previous stroke or TIA, 63.1% had blood pressure controlled to < 140/90 mmHg. This compares well with results from a study in Norwegian general practice finding that 47% of patients, 1 year post stroke, had BP controlled to < 140/90 mmHg . HoweverDue to an aging population, the number of people with stroke is set to rise by 58% between 2007 and 2021 . This prFor clinicians, deciding which is the most appropriate target for blood pressure control in this group of patients is difficult. Having two or three differing guidelines, each recommending different targets can cause confusion regarding the most appropriate clinical management. The United Kingdom, National Institute for Health and Care Excellence   has receAchieving blood pressure targets in this complex co-morbid group of patients – with a mean age of 73 years, and in whom a quarter have CKD - can be difficult. There are occasions in practice when meeting blood pressure guidelines is not appropriate and higher blood pressure readings are acceptable– those with concurrent unstable coronary artery disease, those with previous anti-hypertensive based acute kidney injury or cerebral hypo-perfusion. A further group worth mentioning are those with extreme variability in blood pressure readings (mixed high and low) or those with isolated systolic hypertension and a large pulse pressure. These groups cannot often tolerate focused blood pressure reduction programs and treating physicians do not pursue further after trial of treatment, as this can impact seriously on their quality of life. We accept this may be a reality for some patients.n = 116), 22 patients did not have any anti-hypertensive medications prescribed and a further 31 patients had only a single agent prescribed. Current ESC/ESH guidelines advise that two anti-hypertensive agents are required to ensure BP control in most instances, and these should be commenced initially as a fixed dose combination therapy [Interestingly, of those with uncontrolled BP ≥140/90 mmHg n = 6, 22 patn = 44) of these did not meet the recommended dose in all their anti-hypertensive drugs when measured against the WHO-DDD guidelines . As this was a retrospective study, there was no common protocol for the measuring and recording of office BP. It is also accepted that the WHO-DDD is a surrogate marker for assessing the adequacy of drug-dosing.The results of this study have provided important information on blood pressure control in patients who have had a previous stroke or TIA. Recent stroke audits have focused primarily on acute hospital care , 40, 41.A new contract for general practice services in Ireland has been negotiated recently . This aiThere is clear evidence that reducing blood pressure to below 140/90 mmHg benefits those who have had a previous stroke or TIA . This BPBlood pressure control appears sub-optimal in at least one-third of patients with a previous stroke or TIA. Half of these patients could respond to anti-hypertensive dose escalation. Further work is required to see how best to manage blood pressure in patients with a previous stroke or TIA in Primary Care, as the majority of consultations for hypertension take place in this setting.


PCA was conducted to consolidate baseline data into three factors—(1) psychosocial factors , (2) age, and (3) BMI, which explained 66.8% of the total variance. The ANN model produced similar results as the PCA. Patients who completed CR sessions had greater extremity strength and flexibility, longer six-minute walk distance, more CR knowledge, and a better quality of life. The present study demonstrated that patients who were older, obese, and who had depression, anxiety, or a low quality of life were less likely to complete the CR program.Although cardiac rehabilitation (CR) is clearly beneficial to improving patients’ physical functioning and reducing heart disease progression, significant proportions of patients do not complete CR programs. To evaluate the prevalence and predictors of completion of a center-based CR program in eligible cardiac patients, existing data collected from electronic medical records were used. To identify the predictors of CR completion, we used principal components analysis (PCA) and an artificial neural network (ANN) module. Among 685 patients, 61.4% ( Cardiovascular disease (CVD) is the leading cause of mortality and morbidity, and has a rising clinical and economic burden worldwide ,2. In maThis study used a secondary, retrospective cohort study design. De-identified clinical data collected from the electronic medical record (EMR) were used for analysis.The de-identified medical records of 685 patients who were eligible to attend an academic medical center-based CR program in the Southeastern US, between April 2012 and April 2018 were included. The study included patients who (1) had an acute coronary syndrome; (2) underwent percutaneous coronary intervention, open-heart surgery ; (3) had stable chronic heart failure; and (4) had current stable angina (chest pain). The patients who did not have 3-months of data available for review were excluded from the study. The study was approved by Augusta University Institutional Review Board (1295531 on 27 August 2018 and 1609080 on 27 July 2020)The study participants were patients who were eligible for a 12-week CR program, after discharge from hospital. The CR program included three 1-h sessions per week, with a total of 36 exercise sessions. The supervised exercise training consisted of warm-up, stretching, treadmill, bicycle ergometer, and arm ergometer, with each activity performed over 10–20 min. Psychological support and nutritional counseling were offered to all patients. Blood pressure, heart rate, as well as exercise intensity were monitored by physical therapists during the CR program. Based on the completion status, we divided the participants into 3 groups—graduates, dropouts, and referrals. Graduates were patients who completed 36 CR sessions, dropouts withdrew from the program prior to completion, and referrals were sent for but failed to initiate the CR program.In order to identify potential factors associated with CR completion, participants’ characteristics were captured at baseline, prior to the CR program and 3 months after baseline. The data included sociodemographic variables , clinical variables , percentage of body fat), laboratory variables , triglycerides, low-density lipoproteins (LDL), fasting blood glucose (FBG), hemoglobin A1C (HbA1c)), and physical performance variables , extremity flexibility, and strength assessment). CR knowledge test  was usedt-tests were used with a level of statistical significance set at p < 0.05. The student’s paired t-test was used to examine differences before and after, for each group. One-way analysis of variance (ANOVA) was employed to identify the relationships between variables.All statistical analyses were performed using IBM SPSS statistics for Windows, version 26.0 . Data were displayed as mean ± SD or percentage (N) for numerical variables or categorical variables, respectively. For all analyses, two-tailed Principal components analysis (PCA), a statistical procedure aimed to reduce the dimensionality of multiple correlated measurements to fewer numbers of linearly uncorrelated variables, was used to investigate the variation of the original data ,25. PCA Artificial neural network (ANN) modules are non-linear mapping structures that imitate the learning process of the human brain. They are powerful tools for processing problems involving non-linear and complex data, especially when the underlying data relationship is imprecise and noisy. Variables that are identified by linear modeling to be statistically associated with CR utilization status  were used for neural network modeling. The data set included three distinct sets—training, testing, and validation. The training set was used to learn data patterns, the testing set was to evaluate the generalization ability of the trained network, and the validation set was used to check the trained network performance. The ANN procedure was carried out using a PC laptop computer, equipped with a 64-bit operating system, 2.90 GHz microprocessor, and 8.00 GB of RAM.In this study, we used clinical data to identify the predictive model of CR utilization, which posed significant challenges for statistical analysis. The clinical data collected over time were voluminous, with large number of variables that were correlated or uncorrelated. There were many different types of observations with different levels of measure and measurement scales, which made it difficult to standardize. Large number of missing data reduced power and validity. The temporal relationships between variable were often nonlinear . PCA is The baseline demographic and clinical characteristics of the study population is summarized in p < 0.001 by paired t-test). Moreover, the Graduates had significantly reduced anxiety and depression compared to Dropouts and Referrals, after completing CR . While both Dropouts and Referrals had increased 6MWT distance (p = 0.038 and p = 0.001) and 6MWT Metabolic equivalent of tasks (METs) (p = 0.038 and p = 0.001), respectively, after 3 months, significant changes were not observed in the other variables  at baseline and at 3 months (the standard duration of our program). Graduates exhibited greater extremity strength and flexibility, longer six-minute walk distance (6MWT), superior CR knowledge score, and a higher SF-36 PF score .One-way ANOVA test was used to analyze the demographic factors contributing to the CR completion status. According to the results presented in 2 = 267.885, p < 0.001), both indicating that the sampling adequacy and correlation matrix was satisfactory for PCA.Principal component analysis (PCA) was conducted to consolidate baseline data into three factors, which explained 66.8% of the total variance. The Kaiser-Meyer-Olkin (KMO) statistic was 0.75, which exceeded the minimum recommendation of 0.60, and the Bartlett test of sphericity was statistically significant  addressed psychosocial variables , which accounted for 38.5% of the variance. The second principal component (PC2), which only included age as a variable, contributed to 14.5% of the variation. Finally, the third principal component (PC3), which included BMI variables, explained an additional 13.8% of the variation. PCA showed that patients who were older, obese, and who had depression, anxiety, or a low quality of life, were less likely to complete the CR program. A summary of the loadings, after varimax rotation, related to the variables in each component, is provided in Finally, ANN was used to validate the results from PCA. It used feed-forward architecture with multi-layered perception. The same seven variables identified by linear modeling were confirmed in the input layer of the ANN module . The desThis study aimed to identify the predictors of CR completion among patients with CVD. Among patients who were eligible for CR, approximately 32% of them dropped out, and 7% referred patients failed to initiate CR therapy. Identified predictors of completion fall into three categories—psychosocial, demographic, and clinical aspects, which account for 66.8% of the total variation among the studied variables.The psychosocial domain included HRQoL (assessed by SF-36 PF and SFGH), anxiety, and depression (assessed by HADS). Consistent with previous studies, HRQoL played a significant role in patients’ decision to utilize CR. Compared to patients who completed CR, those who failed to initiate or complete the CR program had lower HRQoL at baseline. Most studies reported an improvement of HRQoL after CR completion, which was congruent with our findings, but few studies examined the impact of HRQoL on CR utilization in CVD patients . Unlike As reported in previous studies conducted by Lane et al.  and PetrAmong all variables examined in the clinical domain, BMI was found to predict CR completion. Recent studies provided strong evidence that obesity is associated with physical inactivity . PhysicaThere are several limitations in our study. First, this study was an observational investigation using a convenient sample of patient data from a single CR program in an academic, hospital-based setting. Therefore, the results might not be generalized to national or international CR patients. Based on a recent study describing national CR participants’ characteristics , howeverSecond, the list of explanatory variables that could contribute to CR utilization was limited to what was available in the EMR. Factors such as economic scarcity, financial scarcity, social support, health belief, health literacy, and personality traits, were not available in EMR . These mThe study identified important factors predicting CR utilization. Our statistical modeling revealed three domains that explained 66.8% of the total variance, including age, BMI, HRQoL, anxiety, and depression. Pre-CR screening and tailored interventions are needed to promote CR utilization in high-risk populations.