Increased arterial stiffness is common in patients with diabetes, and inflammation is one of the main causes of increased arterial stiffness. Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR) are novel inflammatory markers that are reproducible, widely available, and easy to measure, and are associated with low costs. This study sought to investigate the predictive value of these novel inflammatory markers in patients with diabetes having arterial stiffness.We retrospectively included inpatients with diabetes mellitus from the Endocrinology Department of the Chengdu Fifth People’s Hospital from June 2021 to May 2022 and collected data on their general information, biochemical indicators, and brachial-ankle pulse wave velocity (baPWV). After propensity matching, the risk relationship between PLR, NLR, and MLR and arterial stiffness was assessed in the recruited patients.A total of 882 hospitalized patients with diabetes were included in this study and categorized into the low baPWV (507 cases) or high baPWV group (375 cases) based on the baPWV. After propensity matching, there were 180 patients in all in the high and low baPWV groups. Univariate and multivariate logistic regression analyses revealed that high PLR, NLR, and MLR were independently associated with an increased risk of arterial stiffness in patients with diabetes. In the receiver operating characteristic curve analysis, the NLR area under the curve (AUC) was 0.7194  when distinguishing low baPWV and high baPWV in patients with diabetes, which was higher than that for PLR AUC (0.6477) and MLR AUC (0.6479), and the combined diagnosis for AUC.NLR was superior to PLR, and MLR and combined diagnosis have certain predictive values that indicate the increase in arterial stiffness in patients with diabetes. These predictive values can help with the early identification of increased arterial stiffness in patients with diabetes. Arterial stiffness is an important indicator of arterial elasticity and function. With an increase in age , the fibVascular inflammation is a well-established risk factor and key pathogenic mediator in the development of endothelial dysfunction and consequent increase in arterial stiffness . Stimula2 or patients undergoing renal dialysis; 7) patients with malignant tumors; 8) pregnant women  and fasting venous plasma glucose levels ≥ 7.0 mmol/L, random venous plasma glucose levels ≥ 11.1 mmol/L, or venous plasma glucose level ≥ 11.1 mmol/L 2 hours after glucose loading without the typical symptoms of diabetes were indicated blood glucose retesting on another day to confirm the diagnosis. The exclusion criteria were as follows: 1) patients taking hypolipidemic agents and/or antihypertensive agents in the past 6 months; 2) patients experiencing acute complications of diabetes, such as hyperosmolar hyperglycemic state, diabetic ketoacidosis, and/or lactic acidosis; 3) patients with severe blood system diseases; 4) patients with acute or chronic infections; 5) patients with hepatic insufficiency, and ALT and/or AST > 3 times the upper limit of normal; 6) patients with severe renal dysfunction, manifesting with an estimated glomerular filtration rate (eGFR) ≤ 15 mL/min × 1.73 mnt women Figure 1The gender, age, duration of diabetes, smoking status, and drinking status of patients were collected by consulting their medical records. Blood pressure, height, and weight of patients were routinely measured, and general parameters, such as the body mass index (BMI), were calculated. baPWV was measured using the OMRON BP-203RPE III Arterial Stiffness Detection Device  by professionally trained staff. Clinical data from our hospital laboratory were collected and analyzed using a Mindray BC-6800 Plus automatic blood cell analyzer  with reagents provided by Mindray to determine platelet, neutrophil, monocyte, and lymphocyte levels. A HITACHI LABOSPECT 008AS automatic biochemical analyzer  and reagents provided by HITACHI were used to measure fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and uric acid (UA) levels. Glycated hemoglobin (HbA1c) levels were determined using liquid chromatography. Lifotronic H9 hemoglobin detector  reagent was provided by Lifotronic.Pulse wave velocity measurements are meaningful only if blood circulation is not disturbed during pulse propagation; therefore, it is important to determine whether arterial circulation in the lower extremities between the ilium and tibia is normal before measuring baPWV. When obtaining baPWV, we first measured the ankle-brachial index (ABI) of the ipsilateral limb. If the unilateral ABI is ≤ 0.9, it is necessary to first determine whether the limb is affected by peripheral vascular disease. In this case, the predictive value of baPWV will be doubted, so it was excluded. ABI > 0.9 on both sides is indicative of no severe obliterative arterial stiffness, whereas baPWV ≥ 1800 ms on either side is considered a better predictor of target organ damage –15. Thert-test used to compare the two groups when the data were normally distributed. When the data showed skewed distribution, the Mann-Whitney U test of independent samples was used to compare both groups. Chi-square analysis was used to compare the categorical variable data between groups. The PLR, NLR, and MLR values were transformed into binary variables. Univariate and multivariate logistic regression analyses were conducted in succession. Goodness-of-fit tests were performed using the Hosmer-Lemeshow test and calibration plots were drawn. The ROC curve was used to analyze and evaluate the efficacy of PLR, NLR, MLR, and combined diagnosis for arterial stiffness. The corresponding area under the curve (AUC) was calculated, and the sensitivity and specificity corresponding to the maximum Youden’s index was calculated. Normally distributed data are presented as the mean ± standard deviation (SD), whereas data with a skewed distribution are presented as median (upper and lower quartiles) [M (QR)]. A P-value of < 0.05 was considered statistically significant.IBM SPSS 27.0 was used for data entry, processing, and statistical analysis, and GraphPad Prism 9.4.1 was used to construct calibration graphs, forest graphs, and receiver operating characteristic (ROC) curves. The baseline data of both groups were matched using a 1:1 ratio using propensity score matching, and the caliper value was set at 0.02. Independent samples A total of 882 patients with diabetes were enrolled in this study. General information, including the gender, age, duration of diabetes, height, weight, BMI, blood pressure, smoking status, drinking status of patients; and the biochemical indicators, including HBA1c, FBG, TG, TC, HDL-C, LDL-C, and UA, were determined Table 1.PLR, NLR, and MLR were converted into binary variables as independent variables, and Model 1 was constructed. Results from the univariate logistic regression analysis showed that high PLR, NLR, and MLR values were associated with the increased risk of arterial stiffness in patients with diabetes. Model 2 was constructed after adjusting for gender, age, disease course, BMI, smoking status, drinking status, SBP, and DBP. Model 3 was constructed after adjustment for HBA1c, FBG, TG, TC, HDL-C, LDL-C, and UA based on Model 2. Multivariate logistic regression analysis showed that PLR, NLR, and MLR were associated with an increased risk of arterial stiffness in patients with diabetes Table 4.Actual and predicted probabilities were calculated using the multivariate logistic regression Models 2 and 3 of PLR, NLR, and MLR using the Hosmer-Lemeshow goodness-of-fit test. A calibration chart was drawn with the actual probability on the Y-axis as the dependent variable, and the predicted probability on the X-axis as the independent variable. The predicted probabilities of Models 2 and 3 of NLR and MLR are closer to the diagonal of the calibration plot Figure 3The ability of PLR, NLR, and MLR in predicting arterial stiffness in patients with diabetes was further evaluated using high baPWV as a positive diagnostic result. PLR, NLR, MLR, PLR+NLR, PLR+MLR, NLR+MLR, and PLR+NLR+MLR values were used to construct the ROC curve and calculate the AUC. The AUC for NLR was 0.7194 , which was higher than that for PLR (AUC: 0.6477), MLR (AUC: 0.6479), PLR+NLR (AUC: 0.7185), PLR+MLR (AUC: 0.6646), NLR+MLR (AUC: 0.7177), PLR+NLR+MLR (AUC: 0.7192) Figure 4In this retrospective study, we first balanced the distribution of baseline variables in the low and high baPWV groups using propensity matching. After adjustment, the consistency of the baseline data between the two groups improved, thereby enhancing the comparability of the two groups of variables. Second, the levels of PLR, NLR, and MLR in the high baPWV group were higher than those in the low baPWV group. Next, we transformed the PLR, NLR, and MLR into binary variables and constructed Model 1 for univariate logistic regression analysis. After adjusting the general information and biochemical indicators of patients, Models 2 and 3 were constructed. Multivariate logistic regression analysis of factors revealed that high PLR, NLR, and MLR were independently associated with increased arterial stiffness in patients with diabetes, but the odds ratio for NLR was the highest, indicating the strongest correlation. We further calculated the actual and predicted probabilities of Models 2 and 3 of PLR, NLR, and MLR and found that the predicted probabilities of NLR and MLR were closer to the diagonal of the calibration diagram, indicating that Models 2 and 3 of NLR and MLR predicted the effect more accurately. Lastly, ROC curve analysis showed that the NLR value for the diagnosis of increased arterial stiffness in patients with diabetes was superior to the PLR and MLR values. The combined AUCs of NLR with PLR and MLR did not significantly increase compared with the AUC of NLR alone, indicating that the combined diagnosis does not lead to a significant increase in the diagnostic power for arterial stiffness in patients with diabetes. Moreover, our comparisons revealed that NLR had the highest sensitivity in diagnosing increased arterial stiffness. Therefore, NLR is recommended as a better predictor of arterial stiffness in individuals with diabetes.Previous studies have found that inflammatory markers may be related to arterial stiffness. The relationship between NLR and arterial stiffness, especially, is the most studied. Park et al. found that elevated NLR was independently associated with arterial stiffness in a healthy population . Yi et aWe found that high values of PLR, NLR, and MLR were independent predictors of increased arterial stiffness in patients with diabetes. Neutrophils, monocytes, and lymphocytes are representative leukocyte subtypes, and the mechanism of their involvement in increased arterial stiffness may be related to vascular adhesion protein (VAP)-1, which not only functions as an adhesion molecule but also as an amine oxidase that is involved in the production of aldehydes and hydrogen peroxide. Owing to its semicarbazide-sensitive amine oxidase activity, it is implicated in vascular injury, as the breakdown of primary amines releases formaldehyde and methylglyoxal, which cause direct cytotoxic damage to endothelial cells . The priIn this study, we adopted baPWV as a method to measure arterial stiffness in inpatients with diabetes. BaPWV is based on oscillometry and widely used in clinical practice, especially in Asian countries, owing to its advantages of simplicity, noninvasiveness, and reproducibility . At the Our study has some limitations. This single-center study only included patients of Asian/Chinese descent. Whether the results of the study can be extrapolated to other races should be further determined. We used baPWV instead of the gold standard cfPWV as a measure of arterial stiffness. Although the American Heart Association recommends baPWV as a common measure of arterial stiffness , relativAs a novel, convenient, and inexpensive inflammatory marker, NLR is superior to PLR, MLR, and combined diagnosis, and has a certain predictive value to identify the increase in arterial stiffness in patients with diabetes. Thus, this biomarker can be considered in a clinical setting to help identify the increase in arterial stiffness in individuals with diabetes as an approach to disease prevention or early intervention.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Medical Ethics Committee of the Chengdu Fifth People’s Hospital(No. 2022-020S-01). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.PN and HC conceived and designed the study. JY, YT, and YO collected and cleared the data. PN and FY analyzed and interpreted the data. PN, JK, JZ, HW, and HC drafted and revised the manuscript. All authors contributed to the article and approved the submitted version.


To assess the clinical effects of primary nursing on diabetic nephropathy patients undergoing hemodialysis and its impact on inflammatory responses.  Between July 2019 and April 2021, 80 patients with diabetic nephropathy who underwent hemodialysis in our institution were recruited and assigned at a ratio of 1 : 1 to receive either routine nursing (routine group) or primary nursing (primary group). The outcome measures included nursing outcomes, inflammatory factor levels, and psychological status. P < 0.05). Patients receiving primary nursing showed significantly lower levels of interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor-alpha (TNF-α) versus those given routine nursing (P < 0.05). The patients in the primary group had significantly lower scores on the self-rating anxiety scale (SAS) and self-rating depression scale (SDS) versus those in the routine group (P < 0.05).  Primary nursing resulted in lower levels of blood creatinine, fasting glucose, urea nitrogen, and proteinuria versus routine nursing ( Primary nursing improves the renal function of diabetic nephropathy patients undergoing hemodialysis, reduces the inflammatory response, and eliminates their negative emotions, which shows great potential for clinical application. In recent years, with improvements in people's living standards, the incidence of diabetes mellitus has been on the rise . DiabetiP > 0.05)  were comparable with those of the primary group  ( > 0.05) . This stInclusion criteria: patients without other vital organ disorders and without a history of psychiatric disorders and language and cognitive impairment were included in this study.Exclusion criteria: patients with a history of psychiatric disorders or recent use of antidepressants, with malignant tumors or hematological or immune system disorders, with congenital genetic disorders, who refused to participate in this study, with poor compliance, or who were unable to follow up were excluded from this study.Patients in the routine group received routine care. The nursing staff recorded the patient's nutrition, blood pressure, blood glucose, and relevant indicators, and informed the physicians promptly of the presence of adverse reactions in patients. The patients and their families were given health education about the disease and instructed to have a reasonable diet and appropriate exercise.Patients in the primary group received primary nursing. (1) Nursing staff educated patients about the knowledge and information of hypoglycemic drugs and taught them the correct method of insulin injection and preservation to ensure the correct and reasonable use of drugs. The patients were provided with health education about diabetic nephropathy to help them fully understand their disease . (2) HemIn addition, two groups were given traditional Chinese nursing. Patients with diabetic nephropathy suffer from dryness, heat, loss of energy, and deficiency of both Qi and Yin. The Guanyuan, Sanyinjiao, and Zusanli acupoints were massaged according to the doctor's instructions to replenish the Qi and Yin and alleviate the symptoms of palpitations and irritability. For those with spleen and kidney yang deficiency, the ward was ventilated regularly to ensure sufficient sunlight, and hot compression was applied to the waist, knees, and abdomen. For abdominal distension, moxibustion was performed at the Pishu and bilateral Shenshu acupoints.Nursing outcomes: the nursing outcomes included blood creatinine, fasting glucose, urea nitrogen, and proteinuria. Blood creatinine, urea nitrogen, and proteinuria levels were determined before and after the nursing using an immunoenzymatic assay with a fully automated biochemical analyzer. The fasting blood glucose level of the patients was determined using the Myriad BS-350 automatic biochemical analyzer with matching reagents of the analyzer. The lower the level of the above indexes, the better the nursing outcome.α). 5 ml of fasting elbow venous blood was collected before and after the intervention, and the levels of IL-6, hs-CRP, and TNF-α were determined by ELISA. The specific operation was performed according to the instructions of the kit. The lower the level of the above-mentioned inflammatory response indexes, the better the nursing outcomes.Inflammatory response indexes: the main indexes included interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor-alpha  and self-rating depression scale (SDS) were used to assess the psychological status of the patients. SAS: <50 points indicate no anxiety, 50–59 points indicate mild anxiety, 60–69 points indicate moderate anxiety, and >70 points indicate severe anxiety. <53 points indicate no depression, 53–62 points indicate mild depression, 63–72 points indicate moderate depression and >73 points indicate severe depression. The lower the score, the better the psychological status of the patient.s) and processed using the independent sample t-test. The count data were expressed as the number of cases (rate) and analyzed using the chi-square test. Differences were considered statistically significant at P < 0.05.SPSS 22.0 was used for data analyses. The measurement data were expressed as (P < 0.05)  .α than those in the routine group (P < 0.05)  .P < 0.05) (The patients receiving primary nursing showed significantly lower scores of SAS and SDS than those given routine nursing ( < 0.05) .Diabetic nephropathy is one of the major complications of diabetic patients, and diabetic nephropathy complicated by end-stage renal disease is the main cause of death in diabetic patients. Hemodialysis is an effective means for diabetic nephropathy, but prolonged hemodialysis may lead to inflammation, hypoproteinemia, muscle protein depletion, and other nutritional deficiencies in the organism, which reduces the immunity of patients, aggravates the inflammatory response, and compromises the prognosis . A relatα (TNF-α) in patients with diabetic nephropathy accelerated the renal vascular sclerosis lesions in the body, which reduces the vascular elasticity and stimulates the proliferation of glomerular thylakoid cells in the body, thereby aggravating the disease. Thipsawat et al. [α versus routine nursing, suggesting an effective alleviation of inflammatory response after the intervention of primary nursing. The reason may be that primary nursing closely monitors the patient's conditions and the medication, which allows first response strategies in the case of any adverse conditions [The results of the present study showed that primary nursing resulted in lower levels of blood creatinine, fasting glucose, urea nitrogen, and proteinuria versus routine nursing, indicating that primary nursing is effective in improving renal function and controlling glycemic index in patients , which mt et al.  stated tt et al.  demonstrnditions . In addinditions . Here, tnditions . It is wPrimary nursing improves the renal function of diabetic nephropathy patients undergoing hemodialysis, reduces the inflammatory response, and eliminates the negative emotions of patients, which shows great potential for clinical application.


Accumulating data from both human and animal studies suggest that cannabidiol (CBD) may be associated with improved cardiovascular function, markedly with regard to reduction in blood pressure and improved endothelial function. However, there is a lack of randomized studies to support these notions, especially in at-risk populations. The principal aim of this randomized, placebo-controlled, and crossover study is to examine the influence of chronic CBD administration on 24-h blood pressure in individuals with mild or moderate hypertension who are either untreated or receiving standard care therapy. The secondary aims of the study are to determine the safety and tolerability of 5 weeks of CBD administration, and to quantify the effect on arterial stiffness, CBD and vascular health biomarkers, inflammation, heart rate variability, and psychological well-being in both groups of patients. The present single-center study is designed as a triple blind , placebo-controlled, crossover pilot study in which 70 hypertensive volunteers (aged 40–70 years) will receive DehydraTECH2.0 CBD formulation and placebo in a crossover manner. We believe that comprehensive analyses that will be performed in the present trial will decipher whether CBD is in fact a safe and valuable supplement for patients with treated and untreated hypertension. Cannabidiol (CBD) is now known to serve as an anti-anxiety agent in both animal and human models of stress ,2. StresTM (patented capsule formulation increasing CBD bioavailability) decreased diastolic BP (DBP) and mean BP (MBP) and increased cerebral perfusion [TM formulation included 45 mg or 90 mg CBD, in 120 mg or 240 mg of hemp oil, together with 600 mg or 1200 mg American ginseng and 240 mg or 480 mg ginkgo biloba, respectively. Most recently, in volunteers with pre-hypertension, we observed significant reductions in SBP and MBP, as well as arterial stiffness, over an ambulatory 24-h monitoring period following 150 mg of oral CBD DehydraTECH2.0 administered on a single day every 6–8 h  when compared to placebo (manuscript in preparation). This study used a DehydraTECH2.0 CBD formulation designed to increase CBD bioavailability, especially with regard to delivery into brain tissues, which could in turn enable greater effectiveness upon neurogenic hypertension mechanisms operating in the early stages of hypertension. However, the impact of more chronic CBD administration over a period of weeks on 24-h blood pressure, vascular health, autonomic nervous system regulation, and biomarkers of oxidation and inflammation has not been examined in patients with early, untreated hypertension. Moreover, it is unknown if CBD may further improve these measures in patients already on standard care blood pressure medication who commonly remain mildly hypertensive. This lack of information is surprising given the involvement of the cannabinoid system in several aspects of cardiovascular regulation including control of blood vessel tone, cardiac contractility, blood pressure, and vascular inflammation [The influence of CBD on the cardiovascular system in humans might depend not only on a dose and duration of administration, but also on the delivery method of CBD . For exaerfusion . TurboCBammation ,8,9.The principal aim of this randomized, placebo-controlled, and crossover study is to examine the influence of chronic CBD administration on 24-h blood pressure in individuals with mild or moderate hypertension who are either untreated or receiving standard care therapy. The hypothesis is that the hypotensive effects of CBD will be apparent in both untreated and treated hypertension. The secondary aims of the study are to determine the safety and tolerability of five weeks of CBD administration, and to quantify the effect on arterial stiffness, CBD and vascular health biomarkers, inflammation, heart rate variability, and psychological well-being in both groups of patients.ClinicalTrials.gov (accessed on 7 April 2022) (NCT05346562). The sequence of conditions the participant will receive will be generated by a research randomizer web-service  and participants will complete: (1) placebo-control and (2) DehydraTECHTM CBD . Following a two-week washout, participants will then repeat testing for another five weeks under different conditions. Participants will visit the laboratory on 6 occasions in total (3 in each study arm), each time following an overnight fast. The complete course of the study will be performed at the Department for Integrative Physiology, University of Split School of Medicine, Split, Croatia. The study design, implementation, and reporting will follow the CONSORT guidelines, including the 25-item checklist and a flow diagram , placebo-controlled, crossover pilot study in which 70 hypertensive volunteers (aged 40–70 years) will receive DehydraTECH2.0 CBD formulation and placebo in a cross-over manner. The study protocol was registered at the  diagram . The stuoAt least 30 antihypertensive drug-naïve subjectsoAt least 30 subjects treated with (1) angiotensin converting enzyme (ACE) inhibitors with or without diuretics or (2) ACE inhibitors with calcium channel blocker with or without diureticsDocumented or measured elevated blood pressure (130/80 to 139/80 mmHg), mild (stage 1) hypertension (140/90 to 159/99 mmHg), or moderate (stage 2) hypertension (160/100 to 179/109 mmHg)2)Normal or overweight Undergoing <150 min of moderate-to-vigorous activity per weekoBarrier method of contraception [condoms , diaphragm, or cervical cap with spermicideoIntrauterine device (IUD)oHormone-based oral, injectable, or implantable contraceptiveoBilateral tubal ligation/cauterizationoSurgically sterile  or vasectomized male partnerHeterosexually active female subjects of reproductive potential must be on contraception management using at least one of the following methods while taking study drug and for 30 days following the last dose of study drug:Current smoker or using vapor-based products; or a medical or recreational cannabis userSecondary hypertensionActive malignant diseaseGoutHistory of psychosis and/or depression and/or clinically diagnosed anxietyChronic kidney diseaseChronic gastrointestinal disease  or has had a cholecystectomy in the pastCurrent diagnosis or history of any seizure disorderHeart failureDiabetes mellitusPregnant, breast feeding, or plan to become pregnantHistory of opioid useDual blood pressure therapy other than ACE inhibitors with diuretic or ACE inhibitors with Calcium Channel blocker with or without diuretics Unwilling or unable to execute the informed consent documentationoULN for ALT 48 IU/LoULN for AST 38 IU/LoULN for TBL 20 μmol/LLiver disease, including taking valproate, confirmed on baseline blood biochemistry—exclusion of subjects that have >1.5 upper limit of normal (ULN) for alanine transaminase (ALT) or aspartate transaminase (AST), total bilirubin (TBL) > ULN at baseline determined by local reference population values in Croatia:ALT or AST > 3x ULN accompanied by fever, rash, fatigue, nausea, vomiting, right upper quadrant pain or tenderness, and/or eosinophilia (>5%)ALT or AST > 5x ULNALT or AST > 3x ULN and TBL > 2x baselineThe above noted inclusion/exclusion criteria are assessed with a medical screening questionnaire during a clinical examination and related baseline blood chemistry. If at any point during the trial participants meet any of the following criteria, they will be excluded:Participants allocated in the first arm  will first receive cannabidiol: 225 to 300 mg (depending on the sex and weight of the participants) split over three times daily for the initial 2.5 weeks and 375 to 450 mg split over three times for the following 2.5 weeks. After two-week washout, participants will receive Cannabidiol-matched placebo tablets for five weeks. Participants allocated in the second arm  will receive Cannabidiol-matched placebo tablets for five weeks. After two-week washout, participants will receive cannabidiol: 225 to 300 mg split over three times daily for the initial 2.5 weeks and 375 to 450 mg split over three times for the following 2.5 weeks. A detailed dosing regime is presented in Each subject will be provided with a diary to confirm the timing of each daily dose of the CBD or placebo capsules. Additionally, during each visit, physical activity and food intake diaries (24 h) will be provided for each participant. For experimental visits 2–6, participants will be instructed to follow the same pattern of both physical activity and food intake as during visit No. 1. In the event of a missed dose, a maximum of one capsule (75 mg) will be added to the next dose. Apart from insight in the dosing diary, adherence will be assessed by analyzing the blood and urine CBD and its metabolites.The primary outcome is 24-h ambulatory blood pressure measured by ambulatory blood pressure monitoring system Schiller BR-102 plus PWA . The device will be set to take measurements every 30 min through the day (8 a.m.–11 p.m.) and every hour through the night (11 p.m.–8 a.m.) [Cannabidiol levels in peripheral blood sample.Safety .Calories burned, total sleep time, number of awakenings—Physical activity and sleep quality (actigraphy) will be monitored via a wrist-based health and fitness tracker FitBit  with a large organic light-emitting diode screen featuring heartrate monitoring and tracking of steps, distance, calories burned, floors climbed, active minutes, and sleep duration. These devices have been well-validated against gold-standard measures with good accuracy .Pulse wave velocity, augmentation index, and total peripheral resistance measured by Schiller BR-102 plus PWA .Volume of hippocampus and internal carotid artery blood flow—Volume of hippocampus will be assessed by magnetic resonance imaging (MRI), T1-MPRAGE sequence, whereas blood flow through internal carotid artery will be measured by 1.5T MRI, 4D flow.®AR Holter recorder .Heart rate variability measured by Schiller medilogCardiovascular risk assessed by tissue levels of advanced glycation end-products (AGEs)—The AGE Reader  is a non-invasive monitoring device that uses ultra-violet light to excite autofluorescence in human skin tissue. The autofluorescence reflects tissue levels of AGEs . The meaCirculating levels of blood biomarkers—Circulating (steady-state) plasma concentrations of CBD, inflammation  and gold-standard biomarkers of plasma nitric oxide  will be measured from peripheral blood sample. Lipids , glucose, insulin, HbA1C, renal (creatinine), hepatic , drug toxicity (acyl glucuronide), and cardiovascular disease markers (hs-CRP) will also be measured.Salt intake measured by Big life sodium calculator Sleepiness measured by Epworth sleepiness scale Geriatric depression measured by Geriatric depression scale-short form Physical activity measured by Global Physical Activity Questionnaire -min is calculated in a following manner: (Minutes engaged in moderate-intensity activity each week X 4 MET) + (Minutes engaged in vigorous-intensity activity each week X 8 MET) Memory measured by Memory Complaint Questionnaire Sleep quality measured by Pittsburgh sleep quality index Perceived stress measured by Perceived stress scale General health measured by Short form-36 (SF-36) Anxiety measured by State-Trait Anxiety Inventory Obstructive sleep apnea risk measured by STOP-BANG Depression measured by Beck’s Depression Inventory Mediterranean diet serving score Outcomes assessed using questionnaires:The secondary outcomes are: ad lib. During each experimental visit, a sample of venous blood will be taken from the forearm  using a sterile disposable needle and a previously cleansed skin surface. All blood samples will be procured in the early morning visit, prior to consuming the CBD or placebo capsules. This procedure will be performed by a trained laboratory technician. A maximum of 3 to 22 mL of blood will be drawn. Part of the sampled blood will be sent for immediate analysis, whereas part of the sample will be aliquoted and stored on −80 °C for subsequent analysis of biomarkers. All blood samples will be analyzed in the same certified institutional biochemical laboratory, by using the standard operating procedures. In addition, a sample of urine will be collected and stored for analysis of CBD and its metabolites with LCMS in plasma and urine.The initial screening visit was comprised of initial assessment of anthropometrics , blood pressure and relevant vital signs, assessment of eligibility for study participation, and obtaining the past medical history. A total of 117 volunteers were screened, 15 patients did not meet the inclusion criteria and 30 patients met the exclusion criteria. After the completion of the screening procedures, eligible participants were randomly assigned to one of the two experimental groups. Following randomization, participants will undergo their first set of physiological, neuroimaging, sleep, and cognitive assessments. Additionally, participants will complete several lifestyle and psychological questionnaires . This baFollowing the extraction of the initial blood sample, subjects will be evaluated using bioelectrical impedance scale Tanita DC-360 S  and AGE Reader and then instrumented with the 24-h ambulatory blood pressure monitor that will be used to assess continuous blood pressure measurements away from the laboratory. The device will be set to take measurements every 30 min through the day (08:30–23:00) and every hour through the night (23:00–8:00). Subjects will be also instrumented with 24-h ECG monitor. Subjects will also be asked to wear a Fitbit activity and sleep monitor. Finally, prior to discharge, subjects will be given an appropriate set of questionnaires. Apart from the bioelectrical impedance analysis which will be performed only during experimental visit 1 and 4, and AGE Reader measurement, which will be performed during visits 1, 3, 4, and 6, the protocol will be the same for all experimental visits. The whole procedure will take about 40 min per visit.Sample size analysis has been conducted using data from our previously published pilot study in which similar active intervention and outcomes were investigated . The calThe present study confers a minimal risk of adverse events (AE). The safety (lack of AEs) of acute dosing of 300 mg DehydraTECH2.0 CBD has been established; and previous studies have used much higher acute dosing without reports of related AEs . SpecifiObtained data of interest will be recorded during each visit and entered on a special research form (respondents’ card) by study researchers, and it will subsequently be archived and protected by a unique code of the participant. For keeping data, we will use a paired digital archive consisting of computer’s internal memory and external hard drive. The lab book will be kept at the Department of Integrative Physiology, and after the research is completed, the raw data will be available on request from the corresponding author. The data will not be publicly available because some of the dataset will be used for further research.® . Quantitative data will be expressed as mean ± standard deviation or median and interquartile range, as appropriate, while qualitative data will be expressed as a whole number and percentage. Kolmogorov–Smirnov test will be used to estimate the normality of data distribution. A comparison of quantitative variables will be conducted using Student’s t-test for independent samples, or Mann–Whitney U tests where appropriate. Data will be analyzed for repeated measures analysis using either general or mixed linear models . Yet, the final analysis plan, which includes analyses of the secondary outcomes and strategies for handling missing/incomplete data, will be formalized by the biostatistician prior to breaking the blind. The data analysis will only begin once data collection is complete. Significance will be set at p < 0.05 for all comparisons.Collected data will be analyzed with the statistical software SPSS statistics  and Prism 6 for WindowsAccumulating data from both human and animal studies suggests that CBD may be associated with improved cardiovascular function, markedly with regards to reduction in blood pressure and improved endothelial function ,28,29. N


Present guidelines recommend a life-long therapy with mepolizumab in patients suffering from severe eosinophilic asthma as several studies proved the disadvantages of treatment cessation. This study evaluated the possibility of extending the dosage intervals of mepolizumab in those patients with severe eosinophilic asthma after being well controlled.Eighteen patients diagnosed with severe eosinophilic asthma were started on treatment with mepolizumab in regular 4-week intervals. Symptom control was measured using the asthma control test (ACT) and pulmonary function test every 3 months. The amount of oral corticosteroids needed to maintain symptom control was monitored at every visit. After achieving good symptom control, defined as well controlled ACT ≥20, injection intervals were prolonged from 4 up to 6 to 8 weeks. The evaluation of this data was approved by the ethics committee.ACT and pulmonary function values significantly improved after initiating therapy with mepolizumab on a regular 4-weekly injection interval. After extending the dosage intervals, both ACT and pulmonary function remained on a stable level without significant changes during the follow-up visits for 1 year. Median dosage of prednisolone declined significantly in the studied group under mepolizumab therapy and stayed on a low level during the follow-up visits with only a single patient using prednisolone after 1 year.In patients with fully or well controlled eosinophilic asthma treated with mepolizumab extending the dosage intervals between the injections up to 8 weeks bears the potential to save costs for the health care system. With improved well-being and reduced symptom severity the first step would be a reduced dosage or a cessation of oral corticosteroid (OCS) therapy. After stopping oral treatment, decreasing from high dose to moderate dose ICS would be the next preferred option. A further reduction or a complete cessation of inhaler therapy is not supported by current guidelines. Thus, the biologic itself remains as an adjustment option. Discontinuation of mepolizumab worsens asthma control and increases the risk of acute asthma exacerbations.The remaining option would be an extension of the injection intervals. For therapy with omalizumab, an anti-immunoglobulin E monoclonal antibody, interval extensions were shown to be a reasonable approach to maintain asthma control.This study investigates the effects of interval extension of mepolizumab on asthma symptoms in patients achieving good disease control after initiation of anti-IL-5 therapy.This retrospective study used data from the outpatient clinic of the [blinded in this version] collected between 2016 and 2020. Selected patients needed to have uncontrolled severe eosinophilic asthma despite high dose ICS/LABA to initiate treatment with mepolizumab. Patients received mepolizumab according to official product information with a fixed dose of 100 mg subcutaneously every 4 weeks.,Initial injections (visit −1) were given at the outpatient clinic, later injections were either continued at the clinic or self-administered via autoinjector or pre-filled syringes by the patient itself as approved by the European Medicines Agency (EMA).Disease control was evaluated every 3 months  for 1 year using the asthma control test. Pulmonary function was monitored by spirometry measuring the forced expiratory volume in 1 s (FEV1) and the forced vital capacity (FVC). Daily intake of oral corticosteroids for asthma therapy was registered at each visit.Patients missing the last follow-up visit 1 year after the start of interval extension conducted a postponed visit (visit 5). Every other patient was able to participate at visit 5, though it was not obligatory.The evaluation and publication of data reported in this manuscript was approved by the institution's ethics committee.Statistical analyses were computed with IBM SPSS Statistics 27 for Windows and Microsoft Excel for Microsoft 365. A p-value < 0.05 was accepted as statistically significant. Data are described as median with range if not stated otherwise. Because of the small sample size, only non-parametrical tests were used. Differences between characteristics at date of first injection and start of interval extension were analyzed with the Wilcoxon signed-rank test. During the follow-up visits, differences were calculated with the Friedman test.From a total of 64 patients treated with mepolizumab in the outpatient clinic, 18 patients undergoing interval extension were identified in this retrospective analysis. Demographics are shown in Length of time between beginning of mepolizumab treatment and start of interval extensions was 20.3 (13–81) weeks. Planned 3 monthly follow-up visits were conducted after 13.3 (12–17) weeks at first visit, 26.9 (24.7–31.1) weeks at second visit, 40 (34.6–41.9) weeks at third visit, 52.6 (43.3–68.9) weeks at fourth visit and 84 (80.3–109.6) weeks at fifth visit.Visits 1–4 were attended by 16, 16, 15, and 16 patients, respectively, for each visit and 5 patients at visit 5.At beginning, intervals were prolonged to a 6-weekly course for everybody but 1 patient, who started with an 8-weekly interval upon specific patient request. At the fourth visit, 4 patients (22.2%) had been changed to an 8-weekly interval while the others remained on the 6-weekly course. Intervals were never shortened when prolonged once.Asthma control test results significantly improved from 16 (range 9–22) to 21.5 (20–25) points after initiating mepolizumab therapy (p < 0.001). Equally, FEV1 increased from 1.8 L (0.6–2.9) to 2.6 (0.8–3.6) (p < 0.001), FEV1% from 59 (33–78) to 74.5 (44–91) (p < 0.001) and FVC from 3.5 (1.2–5.0) to 3.8 (1.4–5.6) (p = 0.01) at visit 0. Both ACT and pulmonary function values stayed on a stable level without significant changes during the follow up visits , Fig. 2.Eight patients (44%) needed OCS (prednisolone) at start of therapy with mepolizumab. At the beginning of the interval extensions, 3 of 8 patients were still on OCS. Median dosage in this patient group declined from 6.5 mg (range 2.5–20 mg) to 0 mg (range 0–12 mg) (p = 0.012). Two of these patients had ceased OCS at the first and second visit, respectively . During While several studies proved the disadvantages of discontinuation of mepolizumab therapy in patients suffering from severe eosinophilic asthma to the authors knowledge no data exists evaluating the effects of a reduced cumulative dosage by either reducing the single dosage or extending the intervals between the injections of mepolizumab. In this retrospective study, the injection interval of mepolizumab was extended from 4 to 6–8 weeks in 18 patients. Both asthma control and lung function remained stable over the 12-month observation period. None of the patients suffered from an asthma exacerbation in the observed period.A pharmacokinetic study reported the terminal half-life of mepolizumab after subcutaneous injections as 22 days.Though no study exists observing the effects of an interval extension of mepolizumab in asthma patients, some data sustaining our findings can be derived from studies evaluating the cessation of the biologic therapy. The COMET trial evaluated the effects of ceasing therapy with mepolizumab in individuals treated with 100 mg subcutaneously for at least 3 years.,Though our study may not be directly comparable as median time until start of prolonged intervals was only 20 weeks and the ACQ-5 as the tool of symptom control specifically asks for symptoms in 1 week recall as the ACT recalls the past 4 weeks, we also did not observe loss of asthma control up to 8 weeks after the last injection. Further interval extensions might be not beneficial. Two studies evaluating the effects of stopping mepolizumab treatment reported increased exacerbation rates, rising blood and sputum eosinophils and less controlled asthma symptoms according to ACQ-5 scores 12 weeks after the last injection.At least 2 trials exist treating patients with mepolizumab injections in prolonged intervals. Roufosse et al evaluated the efficacy of mepolizumab in hypereosinophilic syndrome.Another small case study reported an interval extension from 4 to 8 weeks for 2 asthmatic patients with chronic eosinophilic pneumonia.As this study was analyzed using retrospective data, it has important limitations. First, the number of included patients is small (n = 18). Secondly, due to its real-life character no matched control group maintaining the regular 4-weekly injection interval could be included in this study. Moreover, during the follow-up visits none of the patients experienced an asthma exacerbation. Thus, no statement can be made about the rate of exacerbations under extended dosing intervals. Possibly a longer observation period with more patients included yields further information in this relevant knowledge gap in biologic treatment.Biologics for Severe Asthma are in use as “add-on therapy”. In many cases, they are extremely successful in avoidance of exacerbations, reduction of oral steroids, and increase of FEV1 and asthma control. In real life a part of patients who achieved all these points are reducing also their inhaled steroid and the use of long-acting betamimetics. Some of them use only their biologic as self-application despite the current guideline recommendations. Our data suggest that interval extension of mepolizumab injections from 4 to 6 up to 8 weeks might be an option in patients with well-controlled asthma seeking to reduce their therapy burden. This mode may be seen as patient-individual therapy.ACQ5, Asthma Control Questionnaire-5; ACT, asthma control test; FEV1, forced expiratory volume in one second; FEV1%, forced expiratory volume in one second predicted in percent; FVC, forced vital capacity; ICS, inhaled corticosteroid; IL-5, interleukin-5; LABA, long-acting beta-2-agonist; OCS, oral corticosteroids.None.No funding to declare.The data used and analyzed for this study is available from the corresponding author on reasonable request.KCB designed the study. XT and KCB acquired the data. GB performed the statistical analysis. GB, XT, TZ, JB and KCB evaluated and interpreted the data. All authors participated in drafting and revising the article and approved the final manuscript for submission.The study was approved by the Ethics committee of the Charité – Universitätsmedizin Berlin (No. EA1/098/18). All research was conducted in accordance with the Declaration of Helsinki.All authors reviewed the final manuscript and provided consent to its publication.TZ reports consultancy from Bayer Health Care, FAES, Novartis and Henkel, grants/grants pending from Novartis and Henkel, payments for lectures from AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Leti, Meda, Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Stallergenes, Takeda, Teva, UCB, Henkel, Kryolan and L’Oréal, organizational affiliations as committee member in WHO-Initiative “Allergic Rhinitis and Its Impact on Asthma” (ARIA), member of the Board in German Society for Allergy and Clinical Immunology (DGAKI), head of European Centre for Allergy Research Foundation (ECARF), president of Global Allergy and Asthma European Network (GA2LEN), member of Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO), outside of the submitted work. JB reports personal fees from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Purina, Sanofi-Aventis, Takeda, Teva, Uriach, other from Kyomed-Innov, outside the submitted work. KCB reports personal fees for lectures from ALK, AstraZeneca, Allergopharma, Almirall, Bencard, Chiesi, GSK, HAL, LETI, Lofarma, Mundipharma, Novartis, Sanofi, non-financial support as Chair of German Pollen Information Service Foundation, personal fees and non-financial support from consultant physician for ECARF, personal fees and non-financial support from Advisory Board member of AstraZeneca, ECARF, GSK, Robert-Koch- Institute Berlin , Sanofi, outside the submitted work. GB und XT report no competing interests.


Clinically overt contrast-induced nephropathy (CIN) is one of the most feared complications in patients exposed to iodinated contrast media and has been extensively studied over the years. Meanwhile, the incidence and evolution of subclinical contrast-induced kidney injury remain elusive. With the continuous increase in the number of patients that are repeatedly exposed to contrast media, elucidating these issues is of critical importance. Accordingly, we aimed to evaluate the incidence and the evolution of clinical and subclinical kidney injury in patients exposed to contrast media. A total of 178 patients who underwent elective percutaneous angioplasty procedures were evaluated prospectively. Serum creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels were evaluated pre-procedurally, 48 h and 1 month after administration of contrast media. The evolution of creatinine and NGAL levels was analyzed at the three time points, and the potential predictors of contrast-induced clinical and subclinical renal injury were evaluated. Clinically overt CIN occurred in 10 (5.6%) patients. Baseline serum creatinine and the volume of contrast media were the only independent predictors of CIN and in all 10 patients creatinine levels returned to baseline by 1 month (p = 0.32). Subclinical contrast-induced kidney injury was much more common, affecting 32 (17.9%) patients, was only predicted by the baseline serum creatinine, and persisted in 53.1% of patients after 1 month. This study showed that whereas clinically overt CIN is rather rare and regressive, subclinical contrast-induced kidney injury is considerably more frequent, affecting almost 18% of patients that receive intraarterial contrast media. More importantly, subclinical kidney injury persisted after 1 month in more than 50% of the initially affected patients, who may thus be at increased risk for further renal impairment, particularly if exposed to nephrotoxic agents or repeated administration of contrast media. One of the most feared complications in these patients is contrast-induced nephropathy (CIN). The use of less nephrotoxic agents has significantly reduced this risk. Yet, the risk of CIN remains considerable (2–25%) in this population, with up to 0.5% of patients requiring dialysis2.In parallel with the major advancements in diagnostic and therapeutic imaging techniques, the number of patients exposed to iodinated contrast agents has tremendously increased over the past decades3. The same criteria, based on altered creatinine levels, suggest that CIN is most commonly a transient process that is usually followed by full restoration of kidney function within 7–14 days. However, the exact effects of contrast administration on the kidneys remain incompletely elucidated, particularly over the long term.Currently, the diagnosis of CIN relies on a relative and/or absolute increase in serum creatinine following contrast administration, reflecting an acute impairment in kidney function4. Pathophysiologically, persistence of at least a certain degree of tubular damage following contrast administration seems highly plausible. The occurrence of CIN has been linked mechanistically to vasoconstriction, followed by renal hypoperfusion and hypoxia, cytotoxicity caused by increased local production of reactive oxygen species, and direct tubular toxicity, characterized by vacuolization and necrosis of kidney tubular cells5. Episodes of ischemia–reperfusion similar to those seen in CIN have also been related to subsequent loss of peritubular capillaries and progressive tubular fibrosis6. Together, these observations strongly suggest that renal injury associated with contrast administration may not be entirely transient and that biomarkers more sensitive than creatinine may be needed to fully understand the impact of contrast agents on the kidneys.Serum creatinine alone provides only a rough estimation of the impact of contrast agents on the kidneys and is incapable to exclude the persistence of a degree of subclinical kidney injury over the long term7, appears to be a promising candidate in this regard. Unlike serum creatinine, which provides a rather late and strictly functional reflection of renal injury, NGAL is an early marker of tubular damage that can unmask the presence and the evolution of renal injury even in the absence of a significant functional impairement4. With the widespread use of procedures that rely on contrast administration, many patients are likely to receive repeated doses of contrast agents throughout their lives. If contrast-induced kidney injury proves to be persistent, even at a subclinical level, such an effect could become highly relevant in the following decades.Neutrophil gelatinase-associated lipocalin (NGAL), a glycoprotein that is rapidly released into the bloodstream in response to renal tubular injuryAccordingly, in the present study, we aimed (1) to evaluate the incidence of clinical and subclinical kidney injury in patients exposed to iodinated contrast agents and (2) to assess the evolution of clinical/subclinical kidney injury in these patients over the long term.2. Exclusion criteria included acute severe conditions, regardless of their nature, ongoing non-steroidal antiinflammatory or antibiotic therapy, exposure to contrast media over the past 6 months, dialysis or history of kidney transplantation, multiple myeloma, and lymphoplasmacytic lymphoma. The research protocol complied with the Declaration of Helsinki and was approved by the local Ethics Committees of the Emergency Institute for Cardiovascular Diseases and Transplantation Târgu Mureș  and of the University of Medicine, Pharmacy, Science and Technology “George Emil Palade” of Târgu Mureș . All patients gave written informed consent to participate in the study.Consecutive patients who underwent elective angioplasty procedures in our center between January 2020 and November 2021 were evaluated in a prospective observational study. All patients included in the study were ≥ 18 years of age, were admitted to hospital for an elective angioplasty procedure, and had an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 mAge, gender, body mass index, left ventricular ejection fraction assessed by transthoracic echocardiography, associated conditions , and ongoing therapy with potentially nephrotoxic  and/or nephroprotective  drugs were recorded for each patient on admission. Arterial hypertension was considered present if a diagnosis of hypertension was present in the patient’s medical records, was established during hospital stay, in accordance with current guidelines, or if the patient was under ongoing antihypertensive therapy. Pre-procedural hydration status was evaluated in all patients based on the maximum inferior vena cava diameter measured by echocardiography in subcostal 4-chamber view. Venous blood samples were collected from each patient prior to the angioplasty procedure and total blood count, hemoglobin, plasma glucose and lipids, total protein and albumin, and uric acid levels were evaluated using standardized laboratory tests. Serum creatinine was measured using a modified buffered kinetic Jaffe reaction and eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation. Serum levels of NGAL were measured using an enzyme-linked immunosorbent assay  on the Elisa Dynex DSX fully automated Elisa analyzer . The volume and type  of contrast agent administered were also recorded.8 was calculated for each patient 24 h after the angioplasty procedure. Administration of potentially nephrotoxic and/or nephroprotective drugs, as listed above, during the 48 h after the angioplasty procedure was recorded for each patient. Occurrence of death, cardiogenic shock, acute pulmonary edema, the need for dialysis and/or positive inotrope agents during the 48 h after the procedure, and the length of hospital stay were also recorded. A second venous blood sample was collected from each patient 48 h after the angioplasty procedure and the serum levels of creatinine, total protein and albumin, uric acid, sodium, and NGAL were measured as described above. The eGFR was calculated using the MDRD equation.The Mehran scoreAdministration of potentially nephrotoxic and/or nephroprotective drugs and the occurrence of death, interventions requiring repeated contrast administration, hospitalizations, and the need for dialysis during the first month following the angioplasty procedure were also recorded. A third blood sample was collected from each patient 30 days after the angioplasty procedure and serum creatinine, total protein and albumin, uric acid, and NGAL levels were measured as described above. The eGFR was calculated using the MDRD equation.9, CIN was defined as an increase in serum creatinine by at least 25% 48 h following contrast administration vs. baseline. Early subclinical kidney injury was defined as an increase in NGAL by at least 25% 48 h following contrast administration compared to baseline. Kidney dysfunction/injury was considered persistent if serum creatinine or NGAL levels, respectively, remained at least 25% higher 1 month following contrast administration compared to baseline in patients in whom early CIN or subclinical kidney injury was initially detected.In accordance with current recommendationsvs. baseline using the paired t-test or the Wilcoxon matched-pairs signed-ranks test, as appropriate.Continuous variables are presented as mean values ± standard deviation or median and interquartile range, as appropriate. Categorical data are summarized using frequencies and percentages. The occurrence of early  kidney dysfunction/injury was assessed by comparing renal parameters  measured at 48 h after contrast administration t-test or the Mann–Whitney U test (for continuous variables), or Fisher’s exact test . Logistic regression analysis was used to assess predictors of CIN and of early subclinical kidney injury. The models were adjusted for parameters that differed significantly between the groups. For the continuous variables, the cutoff values were established using receiver operating characteristic analysis. The evolution of kidney dysfunction/injury at 1 month was evaluated in patients who presented CIN or early kidney injury by comparing renal parameters  measured at 1 month vs. those measured at 48 h after contrast administration using the paired t-test or the Wilcoxon matched-pairs signed-ranks test, as appropriate. All tests were two-sided, and a p-value of less than 0.05 was considered statistically significant. All data were computed using MedCalc for Windows, version 12.4.3.0 .The patients were divided into groups depending on the presence or absence of CIN and on the presence or absence of subclinical kidney injury, respectively, and all parameters were compared between groups using the unpaired A total of 178 patients  were included in the present study. Pre-procedural intravenous hydration  was used in 35 (19.6%) of the study patients. All patients were evaluated at baseline and at 48-h follow-up and 63 of the 178 study patients completed the 1-month follow-up. Patients’ characteristics at the three time points are summarized in Table There was no significant difference in serum creatinine levels measured 48 h (1.01 ± 0.39 mg/dL) or 1 month (0.96 ± 0.24 mg/dL) following contrast administration vs. baseline . Consequently, no significant difference was recorded in eGFR in neither of the two moments  vs. baseline (both p > 0.05). The same results were obtained when NGAL levels were assessed comparatively at the three time points (both p > 0.05).2; Overall, 10 (5.6%) of the 178 study patients fulfilled the criteria for CIN 48 h after contrast administration and in all of them creatinine levels returned to baseline values by the 1-month follow-up p = 0.32). Compared to patients who did not develop CIN, those who presented CIN  and significantly positively correlated  with those measured 48 h after contrast administration. Subclinical kidney injury was still present 1 month after contrast administration in 17 (26.9%) of the 63 patients that underwent the 1-month follow-up. All those 17 patients were among the 32 patients who presented early subclinical kidney injury (53.1%); in 9 (28.1%) of those 32 patients the renal injury regressed after 1 month, and 6 (18.7%) of those patients were lost of follow-up.Early subclinical kidney injury, defined as ≥ 25% increase in NGAL levels at 48 h after contrast administration compared to baseline, was identified in 32 (17.9%) of the 178 study patients. Only 3 of these 32 patients presented CIN, defined as ≥ 25% increase in serum creatinine levels 48 h after contrast administration compared to baseline, whereas in the other patients there was no significant change in serum creatinine (p = 0.32). One month following contrast administration, NGAL levels remained stationary  was independently predicted only by the baseline kidney function, and (6) was persistent at the 1-month follow-up in more than 50% of the initially affected patients.The main findings of the present study Fig.  were tha1. One of the most feared complications of such procedures is CIN. However, our data indicate that in the era of modern iodinated contrast agents, the incidence of CIN is rather low, affecting 5.6% of the study patients.With the progressive increase in the prevalence of atherosclerotic disease, the rate of angioplasty procedures is on a continuous rise worldwide10. Indeed, studies have shown similar rates of acute kidney injury in patients undergoing computed tomography scanning with and without intravenous administration of contrast media, and suggested that the risk of CIN may essentially be nonexistent in patients with normal baseline renal function11. The relationship between contrast media administration and CIN appears to be, however, rather solid, when the contrast agent is administered intraarterially12. Several hypotheses have been proposed to explain this discordance. Patients that undergo angiography procedures have more severe arterial disease than those who require intravenous administration of contrast media and are therefore at higher risk of acute kidney injury. Manipulation of the aorta could lead to dislodgement of cholesterol crystals, atherosclerotic plaque fragments, or thrombi, and to renal microembolization and could therefore promote kidney injury during intraarterial procedures13. Moreover, intraarterial administration of contrast media, particularly in the abdominal aorta, above the level of the renal arteries, is associated with higher contrast concentrations in the renal vasculature12. Together, these data suggest that the risk of CIN is therefore not directly linked to the route of contrast administration, but rather to the patients’ comorbid conditions, the characteristics of the procedure, and the volumes of contrast media administered.Several large-scale studies have even questioned the concept of CIN and the relationship between contrast media administration and acute kidney injury14. Due to the major impact that diabetes mellitus exhibits on the renal and cardiovascular systems15, this condition was also seen as a major non-modifiable risk factor for CIN16. Several other parameters, such as advanced age16, female gender17, history of congestive heart failure18, anemia19, hyperuricemia20, hypercholesterolemia14, and the use of nephrotoxic drugs21, have also been linked to an increased risk of CIN in various clinical studies, although their impact remains highly controversial12. Multiple sources have also reported a dose-dependent relationship between the volume of contrast administered and the risk of CIN22. In the present study, only basal renal function, as reflected by the baseline serum creatinine, and an increased volume of contrast administered were independently associated with an increased risk of CIN. For other parameters that were associated with CIN in univariate analysis , the association was lost in the multiple logistic regression analysis.Indeed, several risk factors have been associated with an increased risk of CIN. Among them, preexisting renal disease has been proposed as the most relevant risk factor for CIN. A linear relationship has been shown to exist between baseline serum creatinine and the risk of CIN, with an incidence of contrast-induced acute kidney injury of up to 62% in patients with preexisting chronic kidney disease and serum creatinine ≥ 2 mg/dL23, clinically overt CIN was a transient, reversible event in the present study, and was associated with more prolonged hospital stay.In accordance with previous studies24, increased production of oxygen-free species, and subsequently to renal injury25. Other factors, including a rise in blood viscosity, changes induced by the contrast media on the renal blood supply26, ischemia–reperfusion injury, release of angiotensin II, dopamine, and vasopressin, and a direct cytotoxic effect of contrast agents on the renal tubular cells have also been shown to contribute to the deleterious effects exhibited by contrast media on the kidneys16. These mechanisms strongly suggest that contrast agents may not be entirely innocuous over the long term and that, similar to other clinical settings28, measurement of biomarkers more sensitive than serum creatinine may be required to detect subtle renal changes in this setting. The diagnosis of CIN relies at present on measurement of serum creatinine. This approach has, however, several limitations, including the delayed and non-linear response to renal impairment of serum creatinine and its sensitivity to numerous non-renal factors, such as age, gender, diet, medication, muscle mass, hydration status, and volume of intravascular fluid29. Moreover, creatinine is a marker of glomerular filtration, and not a marker of tubular damage, which is the injury typical for CIN. Meanwhile, NGAL has been proposed as one of the most promising biomarkers of renal structural injury30. Unlike serum creatinine, NGAL is produced by the distal nephron and rapidly released into the bloodstream, which makes NGAL a much more sensitive marker of kidney injury31. Studies have also pointed NGAL as an earlier marker of kidney injury than serum creatinine in various clinical settings, including in patients with normal renal function, with septic shock, or post-cardiac surgery33, causing NGAL to be seen as a ‘kidney troponin’34. Based on these data, the Acute Dialysis Quality Initiative proposed a combination of kidney functional  and structural  damage markers to stratify the risk of acute kidney damage30.Clinically overt renal dysfunction related to contrast administration therefore appears to be entirely regressive in one month. However, mechanistically, it seems unlikely that contrast-induced renal injury could be fully devoid of any long-term impact. The pathophysiology of CIN remains incompletely elucidated at this point. The most accepted theory involves contrast-induced vasoconstriction, leading to renal hypoxiaIn line with these data, in the present study, repeated NGAL evaluation demonstrated that acute renal injury was much more common than reflected by serum creatinine, affecting almost 18% of the study patients. Moreover, our data indicate that unlike CIN, which was regressive at the 1-month follow-up, subclinical kidney injury was still present after 1 month in more than half of patients in whom the kidneys were initially affected by the contrast media. In addition, similarly to what was seen for clinically overt CIN, the occurrence of subclinical kidney injury was also independently associated in the present study with the basal renal function, as reflected by the baseline serum creatinine. Moreover, the risk of developing subclinical kidney injury following contrast administration was related to a lower degree of baseline kidney dysfunction than the risk of clinically overt CIN.35. However, such approaches may not be efficient for reducing the risk of contrast-induced subclinical kidney injury. Unlike CIN, contrast-induced subclinical kidney injury was not affected by contrast volume in the present study, but only by a non-modifiable factor—the baseline kidney function. Oral and intravenous hydration, and pharmacologic strategies such as methylxanthines, statins, ascorbic acid, N-acetyl cysteine, or dihydropyridine calcium channel blockers have all been proposed as potentially efficient interventions for the prevention of CIN16. None of the patients included in the present study was receiving methylxanthines, ascorbic acid, or N-acetyl cysteine, and almost all patients  were undergoing statin therapy. Thus, the potential impact of such strategies on the risk of CIN could not be evaluated in the present study. Dihydropyridine calcium channel blockers did not appear to affect, however, the risk of CIN or of subclinical kidney injury in the present study. Previous studies have also suggested a higher risk of CIN with low-osmolar than with high-osmolar contrast media in patients with pre-existing chronic kidney disease36, whereas the benefit of iso-osmolar over low-osmolar contrast agents remains debatable38. In the present study, there was no significant difference in the type of contrast media used between patients with and without CIN or subclinical kidney injury. However, all patients in this study received low-osmolar contrast agents and more than 85% of them received the same contrast agent .In line with previous studies, our data indicate that the occurrence of clinically overt CIN is favored not only by non-modifiable (baseline kidney function), but also by modifiable factors—the volume of contrast administered. Technological innovations and technical adjustments, such as lowering the X-ray voltage or using the latest generation imaging platforms could thus be of use for CIN prevention by reducing the amount of contrast media that is being administered12. Although NGAL is clearly a valuable biomarker of contrast-induced subclinical kidney injury, one should be aware that NGAL is not specific for this condition and that low levels of NGAL can also originate from other sources, such as neutrophils, cardiomyocytes, prostatic cells, or respiratory and gastrointestinal epithelia4. None of the patients evaluated at the 1-month follow-up presented anamnesis, clinical signs or symptoms of inflammatory disease. However, no specific laboratory analyses were performed at that time to this end. To date, there is no official definition for early subclinical kidney injury. In the present study, subclinical kidney injury was defined by analogy with clinically overt CIN. Future long-term studies will have to establish the most appropriate NGAL cut-off values for the diagnosis of subclinical contrast-induced kidney injury. Finally, the impact of contrast media on the kidneys was evaluated in the present study using serum creatinine and NGAL. Evaluation of additional parameters, such as urinary NGAL, molecule-1, or cystatin C would also have been of interest to fully elucidate the renal effects of contrast media.The effects of contrast media at the renal level were assessed in a prospective study, using both functional  and structural  renal damage markers, providing a comprehensive view on contrast-induced kidney injury. In addition, to the best of our knowledge, this is the first study to evaluate the long-term effects of contrast media on subclinical kidney injury, as reflected by the levels of NGAL. These analyses demonstrated that subclinical kidney injury was still present after 1 month in more than half of patients in whom the kidneys were initially affected by the contrast media, suggesting that these patients may be at increased risk for further, potentially clinically significant renal impairment, particularly if exposed to nephrotoxic agents or repeated administration of contrast media. Studies with longer-term follow-up of renal function, including after repeated administration of contrast agents, will have to clarify this issue. The long-term impact of the renal changes identified in the present study on ‘hard’ clinical endpoints  also remains to be clarified. In the present study, only 35.3% of the study patients underwent, however, the 1-month follow-up. The high rate of loss of follow-up was mainly related to the fact that the angioplasty procedures took place in a tertiary center, and the patients’ subsequent follow-ups were mainly performed in their home centers. Future studies will have to further elucidate the impact of contrast media on subclinical kidney injury over the long term. The prospective nature of the present study allowed us to evaluate the renal impact of a large series of parameters associated with contrast-induced kidney injury in previous studies. Yet, only baseline kidney function and the volume of contrast administered were identified as independent predictors of CIN, whereas subclinical contrast-induced kidney injury was only independently predicted by the baseline serum creatinine. The relatively low number of patients included in the present study may have affected our ability to detect other potential predictors of contrast-induced acute kidney injury. However, with the exception of baseline kidney function, which has been related to CIN in the vast majority of previous studies, the role of the other tested factors is highly controversial in the literatureThe present study showed that in the era of modern contrast media, clinically overt CIN is rather rare, regressive, and that its occurrence is affected by only the baseline renal function and the amount of contrast media administered. Subclinical kidney injury was, however, considerably more frequent in patients receiving intraarterial contrast media. More importantly, subclinical contrast-induced kidney injury persisted after 1 month in more than 50% of the initially affected patients. Pending confirmation in future studies, these data suggest that patients who develop subclinical contrast-induced kidney injury may be at increased risk for further, potentially clinically significant renal impairment, particularly if exposed to nephrotoxic agents or repeated administration of contrast media.Supplementary Tables.


Lung function and asthma control improved significantly  and eosinophil levels were significantly reduced (p = 0.004). Low scores in the Asthma Control Test were associated with the oral corticosteroid-saving effect; lower previous FEV1 levels and absence of chronic obstructive pulmonary disease (COPD) were related to improvement in lung function, and prior FEV1 values higher than 80% and absence of gastroesophageal reflux disease (GERD) with a reduction in exacerbations. The results of this study confirm the clinical benefit obtained after the introduction of omalizumab and the possible predictive biomarkers of response to the treatment.Most patients with asthma can control their symptoms with a basic standard of medical care and with maintenance and rescue medication. However, between 5% and 10% of asthmatics worldwide do not achieve control of their symptoms and have recurrent exacerbations and respiratory difficulties. The objective of the study was the real-life evaluation of the clinical improvement of patients with severe eosinophilic asthma treated with omalizumab, together with the search for biomarkers associated with the response. An observational retrospective cohort study was conducted that included patients with severe uncontrolled allergic asthma being treated with omalizumab. Three types of response were evaluated: lower use of oral corticosteroids, improvement in lung function, and reduction in exacerbations. A total of 110 patients under treatment with omalizumab were included, with a mean age of 48 ± 16 years. After 12 months had elapsed, significant reductions were found in the number of exacerbations, use of oral cortico-steroids and doses of inhaled corticosteroids ( Asthma is a chronic respiratory disease with a high incidence worldwide, characterized by a chronic obstruction of the airways, which causes patterns of inflammation and bronchial remodeling ,2,3. MosImmunoglobulin E (IgE) is a type of antibody related to hypersensitivity and allergic reactions, which causes an immune response by binding to the high-affinity receptor FcεRI located on the surface of mast cells and basophils, promoting the release of inflammatory mediators .®) is a humanized monoclonal antibody that binds selectively to IgE and prevents it from binding to the FcεRI receptor in basophils and mast cells, thereby reducing the amount of free IgE available to trigger the allergic cascade  mg/day, and 77.27% (85/110) needed OCS, with a median of two [1–3] cycles. Mean %FEV1 was 76.12 ± 21.68, and a median blood eosinophil count of 250 [127.5–485] cells/μL was recorded, and IgE of 310.45 [142.5–716.25] IU/mL. There were 61.82% (68/110) who suffered at least one exacerbation during the year prior to the treatment and the median ACT score was 12 [10–16] points. Of the 110 patients, 42.73% required changing to another monoclonal therapy for asthma control.The effectiveness of omalizumab was assessed in 110 (97.35%) patients of the 113 candidates for the study . The treAfter a year of treatment with omalizumab, the 50% reduction in OCS was satisfactory in 51.38% (56/110) of the patients and 14.68% (16/110) did not require OCS during the first 12 months of biological therapy. The %FEV1 increased by at least 10% in 46.15% (42/91) of cases and 75.53% (71/94) showed FEV1 values higher than 80%. The reduction in at least 50% in exacerbations requiring emergency department treatment and/or hospitalization was satisfactory in 49.09% (54/110) of the patients and 34.55% (38/110) had no exacerbations.p < 0.001). The results of the comparative analysis are shown in After 12 months of biological therapy with omalizumab, daily doses of ICS showed significant reductions of 42.50% , annual exacerbation rate , ACT questionnaire score , and in the proportion of patients that received OCS, which fell significantly  [p = 0.011) and a higher risk of exacerbations with omalizumab if they had been suffered the previous year , which is in line with our study, and they did not look for biomarkers associated with the OCS-saving effect [In this study, omalizumab was associated with a significant improvement in lung function (FEV1) and the control of asthma symptoms, evaluated using the ACT questionnaire, and significant reductions in the rate of severe exacerbations per year, blood eosinophil level, OCS cycles per year, and ICS doses. The response to treatment with omalizumab achieved in our study is in line with the previous published real-life studies, collected by Jean Bousquet et al. in their meta-analysis published in 2021, which found significant improvements in lung function  . It shoug effect . Other ag effect ,36,37,38This study, being a real-life investigation, lacked a placebo control group, and this could be considered its main limitation. The absence of a control group means that the magnitude of the results observed lacks the firmness of a comparison with a control group. Another inherent limitation of retrospective studies is the lack of data collection such as in the ACT and the sample size. Nevertheless, although randomized clinical trials remain the gold standard, this type of study makes it possible to extrapolate these results to uncontrolled and heterogeneous settings.Omalizumab was the first biological therapy approved for the treatment of asthma and has brought about a great improvement in the quality of life of patients with severe allergic asthma. Its efficacy and safety have been demonstrated in numerous controlled clinical trials and the results attained in this study show very promising data in real life. Omalizumab achieved significant improvements in the three responses evaluated, reducing the use of oral corticosteroids, improving lung function, and decreasing and/or preventing the presence of exacerbations in many of the patients studied. In addition, response markers could be a useful tool for making decisions in clinical practice.