The clinical heterogeneity of chronic rhinosinusitis (CRS) and bronchial asthma is attributable to different underlying inflammatory profiles. However, the similarity between CRS with nasal polyps (CRSwNP) and type-2 asthma pathophysiology speculates that one biological therapy could affect both comorbidities. Despite dupilumab, a monoclonal antibody that targets IL-4α and IL-13 receptors, being used in patients with nasal polyps and severe asthma, real-life data about its efficacy in improving the quality of life and patient symptoms is still lacking. This study’s primary objective was to evaluate dupilumab treatment’s effect on the frequency of olfactory symptoms and health-related quality of life tests as measured by the Sino-nasal outcome test (SNOT-22) in patients with NP. The secondary objective was the effect of dupilumab on asthma symptom control as measured by the asthma control test (ACT).A prospective study was conducted of 166 patients with CRSwNP, with or without asthma. The following variables were collected at baseline and after at least six months of continuous dupilumab therapy; SNOT-22, olfactory symptoms frequency, and ACT score.Asthma prevalence in patients with CRSwNP was high (59.63%), and being female with a history of frequent use of oral corticosteroid (OCS) courses and repeated unsuccessful nasal and para-nasal surgeries for polyposis increased the likelihood of having underlying asthma by 2, 1 and 4 times more, respectively. Additionally, being asthmatic required a longer duration of dupilumab treatment. However, both the health-related quality of life and olfactory symptoms improved equally in both groups.Even with associated comorbid asthma in patients with CRSwNP, treatment with dupilumab could improve the quality of life, olfactory symptoms, and asthma symptom control. Affecting 5–28% of the general population, chronic rhinosinusitis (CRS) is a prevalent condition worldwide that places a heavy financial burden due to increased healthcare costs and loss of productivity –5. CRS iP < 0.01),[Two significant phenotypes are defined for CRS based on nasal endoscopic findings: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). CRSwNP, which comprises about 18–20% of all CRS cases, is linked to significant morbidity and may impact adults’ lower airway disease status . Moreove < 0.01), which is < 0.01),, 13–15.  < 0.01),–21.Patients with CRSwNP and comorbid asthma demonstrate IgE-mediated release of immune mediators and upregulation of type 2 cytokines  in the upper and lower airways , 21. FurDupilumab, an IL-4 receptor alpha antagonist, is a human monoclonal antibody of the immunoglobulin G4 subclass that specifically binds to the IL-4 receptor alpha subunit, which is shared by the IL-4 and IL-13 receptor complexes, thus inhibits IL-4 and IL-13 signaling. Dupilumab inhibits IL-4 signaling via the type 1 receptor and both IL-4 and IL-13 signaling via the type 2 receptor. It inhibits IL-4 and IL-13 cytokine-induced responses by blocking the IL-4R alpha subunit, including releasing proinflammatory cytokines, chemokines, and immunoglobulin E . By blocThis prospective follow-up study was conducted in a tertiary allergy center in Kuwait, Al-Rashed Allergy Center, from January 2021 till the end of May 2022. The primary outcome was to evaluate the frequency of olfactory symptoms (anosmia and hyposmia) and measure SNOT-22 after at least six months of continuous therapy with Dupilumab. The secondary outcome measured the changes in ACT scores in patients with asthma.Diagnosis of patients with CRSwNP was based on clinical diagnostic criteria; all patients had an endoscopic assessment for nasal polyps; additionally, 141 of 166 (84.9%) patients had a history of nasal polypectomy where the radiological finding of all cases showed polypoidal nasal mucosal thickness. Individuals displaying symptoms indicative of asthma were diagnosed based on the variability of their symptoms and the reversibility of their FEV1%. If the initial spirometry results were inconclusive, further tests such as PEF variability and FeNO were conducted to confirm the diagnosis . IndividToma et al., the SNOT-22 score was classified into mild, moderate, and severe [Demographic data, SNOT-22, and ACT scores were collected from patients’ medical charts, and all patients were followed up for at least three months. SNOT-22, olfactory symptoms frequency and ACT were re-measured. As per d severe , which lhas been obtained from Kuwait University and the Ministry of Health, in accordance with the Helsinki Declaration protocol (Research study number 2121/2022), to ensure that the research is conducted ethically and in compliance with internationally recognized standards. Informed consent has been obtained from all participants involved in the study, as well as their legal guardians, to ensure that they are fully aware of the nature and purpose of the research. They have given their voluntary and informed consent to participate.Basic demographic data were collected from the patient’s files, including age, sex, SNOT-22 score, nasal polyps surgery, oral corticosteroid use, presence of anosmia/hyposmia, ACT, and duration of dupilumab therapy. After at least three months of patient recruitment, ACT score, SNOT-22 score, and olfactory symptoms were reassessed.a p-value below 0.05 was considered significant.Categorical variables were presented as numbers and percentages, while continuous variables were provided as mean and standard deviation (SD). The normality of data was examined using the Shapiro-Wilk test, and the descriptive statistics were performed using Minitab 17.1.0.0 for Windows . The comparison between two means or medians was made using an independent t-test or Mann-Whitney test, while the frequency comparison was made using the chi-square test. We conducted a multiple logistic regression analysis using a stepwise elimination technique to identify potential predictors of underlying asthma in patients with CRS and nasal polyps, in which the collinearity among the potential confounders was estimated using correlation coefficient, and a sensitivity analysis was done within the test by removing one potential confounder at a time and examining the changes in the coefficients of the independent variable(s). The performance of oral corticosteroid course number in predicting associated asthma was evaluated using the ROC curve, and the area under the curve (AUC) above 0.6 was considered acceptable. All tests were two-sided, and A total of 166 patients were diagnosed with CRSwNP, of which 99 cases (59.63%) were also diagnosed with asthma. However, 25 patients were excluded from the study due to not meeting the criteria for starting biologics, and an additional 33 individuals opted out of biologic treatment, as shown in Fig. In patients with CRSwNP, female sex and polyposis surgery were found to be significant independent risk factors for asthma, with a p-value of less than 0.05 and odds ratios of 2.13 and 4.04, respectively. Additionally, every additional course of OCS increased the likelihood of asthma coexistence up to two times more, with an odds ratio of 1.56 and a p-value of 0.05  were diagnosed with CRSwNP with asthma. These figures were comparable to others reported by n et al. ; to inven et al. . This neFemale sex, SNOT-22 score, SNOT-22 (severe), polyposis surgery, polyposis surgery number, OCS use, and OCS course number; all were statistically significantly higher in the subgroup of patients diagnosed with CRSwNP and asthma compared to the other one. These results imply that asthma independently influences CRSwNP patients’ quality of life.Li and colleagues; based on medical histories and clinical examinations, risk factors for concomitant asthma in CRSwNP patients were investigated. The study showed that among patients with CRSwNP, having a female gender, a history of allergic rhinitis, elevated serum T-IgE levels (> 69.0 kU/L), and a blood eosinophils count (> 0.35 109/L) were independent risk factors for comorbid asthma [The results of the current study revealed that female sex and polyposis surgery are independent risk factors for asthma in patients with CRSwNP (P < 0.05). These are compatible with a previous cross-sectional study by d asthma . Female d asthma –39.Exploring risk factors linked to a specific phenotype may be more beneficial for managing individuals with asthma. Compared to asthmatics without CRSwNP, those with concomitant CRSwNP are likely to have more severe and persistent asthma, a lower quality of life, and fixed airflow limitation . Also, aDupin et al. [Mümmler and colleagues [Pelaia et al. [p < 0.0001); moreover, in a more comprehensive observational study, the ACT score increased from 14 (10–18) to 22 (20–24) (p < 0.0001), [Our results revealed that the ACT score was significantly higher after dupilumab treatment than before dupilumab treatment, which follows data reported by n et al. . They relleagues . They rea et al. ; followi0.0001), .Mustafa and colleagues [For the SNOT-22 score, the significant decrease recorded after the dupilumab treatment compared to the baseline score in the current study indicated a significant impact on the patient’s QoL. This result aligns with data from a randomized controlled trial by lleagues . AERD paBuchheit and colleagues [For the olfactory symptoms, we reported a significant decrease in the overall frequency of anosmia after dupilumab treatment which is consistent with the results demonstrated by lleagues . They inlleagues .More than half of our cohort with CRSwNP had associated asthma. However, treatment with Dupilumab effectively controlled asthma symptoms and improved both the quality of life and olfactory symptoms.


Elevated pulse pressure (ePP) is an independent marker of cardiovascular risk (CVR) in people older than 60, and a functional marker of subclinical target organ damage (sTOD) which can predict cardiovascular events in patients with hypertension (HTN), regardless of sTOD.To evaluate the prevalence of ePP in adult population seen in primary care and its association with other vascular risk factors, sTOD and with cardiovascular disease (CVD).Observational multicentre study conducted in Spain  from the prospective cohort study IBERICAN recruited in Primary Care. Pulse pressure (PP) was defined as the difference between the systolic blood pressure (SBP) and the diastolic blood pressure (DBP) ≥60 mmHg. Adjusted (for age and sex) ePP prevalence were determined. Bivariate and multivariate analyses of the possible variables associated with ePP were carried out.p < 0.001) in patients with HTN (56.58 vs. 48.45 mmHg) The prevalence of ePP adjusted for age and sex was 23.54% . The ePP prevalence rates increased linearly with age (R2 = 0.979) and were significantly more frequent in population aged ≥65 than in population aged <65 . HTN, left ventricular hypertrophy, low estimated glomerular filtration rate, alcohol consumption, abdominal obesity, and CVD were independently associated with ePP. 66.27% of patients with ePP had a high or very high CVR, as compared with 36.57% of patients without ePP (OR: 3.41 [95% CI 3.08–3.77]).The mean of PP was 52.35 mmHg, and was significantly higher  and CVD; because of this, the ePP was associated a higher cardiovascular risk. In our opinion, the ePP is an importer risk marker and its early identification lets to improve better diagnostic and therapeutic management. Hypertension (HTN) is an important cardiovascular risk factor (CVRF), both at individual and population levels , 2. Its The pulse pressure (PP) is an index of the distensibility of the great arteries, and therefore it is a functional marker of subclinical target organ damage (sTOD), it predicts cardiovascular events in patients with HTN , 6, and From a pathophysiological point of view, the early phases of HTN are characterised by changes in the blood circulation of the small blood vessels caused by the systemic vascular resistance. The stiffness of the great vessels increases and they lose elasticity as they age, so a greater pressure is needed which causes left ventricular hypertrophy (LVH). In adults aged <55, the increased vascular resistance results in elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP), and both are predictors of cardiovascular disease (CVD). On the other hand, in people aged >55, the DBP tends to increase until it reaches its peak at the age of 55–60, and then it decreases, in such a way that whereas the DBP decreases, the SBP continues to increase. This would explain the fact that an elevated DBP on its own is less useful as a CVR predictor in older patients, while the prediction of the SBP for CVD is maintained .Kodama et al.'s meta-analysis  showed tLike other biological variables, PP is a continuous variable that can increase the absolute risk of cardiovascular events in older subjects (≥50) despite the observed decrease in the relative risk . It can It should be noted that the population with HTN and very high CVR [with diabetes mellitus (DM) and/or previous CVD] has higher values of PP than the rest of patients without DM or CVD , 17. MorIt is very important to consider a comprehensive approach to CVR in all patients in primary prevention, before the development of CVD, and which includes the determination of the PP together with the rest of main CVRF. In order to increase knowledge in this regard, the objective of this study is to evaluate, in the context of the IBERICAN study, the presence of ePP in population seen in Primary Care, and its association with other CVRF, sTOD and CVD.An observational, cross-sectional analysis was carried out from the inclusion visit of the IBERICAN cohort, which is a multicentre study conducted in Primary Care centres of the Spanish National Health System and whose methodology has been previously published . Using ct-Student test or analysis of variance. The association between variables was estimated with a 95% confidence interval (95% CI) and level of significance p < 0.05. The crude prevalences and prevalences adjusted for age and sex were determined through direct method, using standardized 10-year age groups according to the information on the Spanish population aged 18–85 provided by the National Institute of Statistics on July 1st 2021 . The qualitative variables were analysed with frequency distribution, percentages, chi squared test, and odds ratios (OR). The continuous variables were evaluated with the determination of the arithmetic means with standard deviation (±SD), median and interquartile range (IQR) of the variables age and PP, p < 0.10, except the variables age, sex and CVR categories which were analyzed individually. The distribution of the specific rates of ePP prevalence by 10-year age groups was analysed using linear regression. Collinearity was previously examined through Spearman's rank correlation coefficient. The model included the variables that showed correlation coefficients higher than 0.5. Then, the variable that contributed least to the adjustment of the analysis was eliminated in each step. All the tests were considered to be statistically significant if the two-tailed p value was lower than 0.05. A literature search was carried out on PubMed, Medline, Embase, Google Scholar and Web of Science to compare this study with other similar studies published since 1997.To assess the individual effect of comorbidities and CVRF on the dependent variable ePP, a binary unconditional multivariate logistic regression analysis was performed using the backward stepwise method, initially introducing into the model all the variables which showed association in the univariate analysis up to a value of p < 0.001) in men [53.65 (±12.50) mmHg] than in women [51.26 (13.21) mmHg]. In patients with HTN, the mean (±SD) and the median (IQR) of the PP were 56.58 (±13.22) mmHg and 55.0 (49.0–64.0) mmHg respectively, where the mean PPs were practically the same (p = 0.981) in men [56.58 (±13.17) mmHg] and in women [56.57 (±13.29) mmHg]. In patients without HTN, the mean (±SD) and median (IQR) of the PP were 48.45 (±11.37) mmHg and 50.0 (40.0–55.0) mmHg respectively, where the mean PP in men [50.31 (±10.77) mmHg] was significantly higher (p < 0.001) than in women [47.16 (±11.60) mmHg].The IBERICAN cohort included 8,066 subjects aged between 18 and 85 (54.5% women), with a mean (±SD) age of 58.41 (±14.83) and a median (IQR) of 59.77 (48.97–69.91) years. The mean (±SD) and the median (IQR) of the PP of the study population were 52.35 (±12.95) mmHg and 50 (43–60) mmHg respectively, where the mean PP was significantly higher (p < 0.001) in men [32.55% (95% CI 31.04–34.10)] and in women (27.92% [95% CI 26.60–29.27]). The prevalence of ePP adjusted for age and sex was 23.54% .The crude prevalence of ePP was 30.03% (95% CI 29.03–31.04), being significantly different (R2 = 0.979) according to the function y = 0.095x–0.0194, being significantly higher in men up to the age group 50–59, and without significant differences in the oldest age groups (p = 0.983) in men (45.49% [95% CI 42.88–48.09]) and women (45.45% [95% CI 42.99–47.92]). The prevalence of ePP in population aged <65 was 20.98% (95% CI 19.86–22.12), which was significantly different (p < 0.001) in men (24.50% [95% CI 22.73–26.28]) and in women (18.16% [95% CI 16.74–19.58]).The distribution of specific rates of ePP prevalence by 10-year age groups increased with age in a clear way  more frequent in patients with HTN (41.65% [95% CI 40.09–43.20]) than in patients without HTN (19.28% [95% CI 18.09–20.48]) (OR: 2.99 [2.70–3.30]), and mainly in patients with SBP/DBP ≥140/90 mmHg (64.66% [95% CI 62.34–66.98]) as compared with those who had SBP/DBP <140/90 mmHg (24.99% [95% CI 23.20–26.78]) (OR: 5.49 [4.78–6.31]). Among the population with HTN, the proportion of patients who had ePP was similar (p = 0.678) in men (41.32% [95% CI 39.12–43.52]) and in women (41.98% [95% CI 39.75–44.20]). The other CVRF and comorbidities which showed greater degree of association were LVH, HF, low eGFR (<60 ml/min/1.73m2) and DM  and smoking . The ePP) and DM . In the ) and DM .66.27% (95% CI 64.38–68.15) of patients with ePP had a high or very high CVR, as against the patients without ePP, of whom 36.57% (95% CI 35.31–37.83) had a high or very high CVR (OR: 3.41 [95% CI 3.08–3.77]) .This subanalysis of the cohort of the IBERICAN study describes the characteristics of the population according to the presence of ePP, with a prevalence adjusted for age and sex of 23.5%. This prevalence increases with age, is higher in men, and is more frequently associated with HTN, DM, low eGFR, LVH and HF, which increases the CVR of patients with ePP.After a detailed revision of bibliography, our results represents the first time that are described the prevalence of ePP and its associations with other cardiovascular risk factors, TOD and CVD simultaneously in the same cohort, using a clínica population, recruited in primary care.The prevalence of ePP observed in our study (23.5%) are similar to observed in other studies as NHANES survey 26.91%) using PP > 55 mmHg in a sample with 5,771 subjects  or 12.1%.91% usinThe relationship between ePP and other variables as HTN o LVH was described by Vasan et al. that described the association of these TOD with central PP . In the These relationships with other cardiovascular risk factor, TOD and CVD describes the ePP as a early risk marker and the importance of and early identification to introduce changes in the treatment of the patients and improve their prognosis. In really, maybe we need more studies, and clinical trials, that confirm that this reduction of PP would reduce the cardiovascular events and mortality.This subanalysis of the IBERICAN study has certain limitations derived from its very design and from the interpretation of some of the variables. The study sample has the bias of being a clinical cohort between the age of 18 and 85 seen in Primary Care with a possible accumulation of risk factors and comorbidities as compared with the rest of the population. Thus, the results obtained could be only extrapolated to the clinical population, despite the validity of the associations found. This study does not differentiate whether the ePP was detected during the day or at night, even though the ePP is associated with LVH regardless of the moment of detection whereas the greatest increase of ventricular mass has been associated with ePP during night time. Like SBP and DBP, PP is a continuous variable, so the decision to establish the ePP at an easy-to-remember threshold of 60 mmHg is an arbitrary one, though justified by the available literature , 29. TheAmong the strengths of this study are the large sample of the IBERICAN cohort, the adjustment for age and sex of the prevalence rates (which makes it easier to compare the results with other populations), the assessment of the association of ePP with numerous cardiovascular, cardiometabolic and renal variables, and the presentation of relevant results on ePP which did not exist in Spain before.There are no well-designed intervention studies which assess the potential cardiovascular benefits of specific therapeutic strategies for ePP. This may justify the fact that no PP objectives or appropriate treatment has been established. It has been found that the levels of PP reached with antihypertensive treatment form a curved (J-shaped) association for most cardiovascular events, and a linear one when it was associated with myocardial infarction, setting the optimum level of PP at 50 mmHg . A stricThe observational multicentre IBERICAN study, recruited in primary care in Spain, showed that near a quarter of the patients had ePP, and this prevalence increases with the age of the patients.The prevalence of ePP showed an independent association with other cardiovascular risk factors, as HTN, diabetes, abdominal obesity and alcohol consumption; other TOD, as LVH and low eGFR; and CVD.This association with other cardiovascular determinants and the higher cardiovascular risk associated become the ePP in the interesting risk marker to identify in the clinical practice to introduce more intensive treatments to improve the cardiovascular prognosis. However, this affirmation needs to be confirmed in a prospective observational studies and clinical trials.


Diabetic kidney disease (DKD) is the one of the leading causes of end-stage kidney disease. Unraveling novel biomarker signatures capable to identify patients with DKD is favorable for tackle the burden. Here, we investigated the possible association between urinary metabolites and the presence of DKD in type 2 diabetes (T2D), and further, whether the associated metabolites improve discrimination of DKD and mediate the effect of inflammation on kidney involvement was evaluated.Two independent cohorts comprising 192 individuals (92 DKD) were analyzed. Urinary metabolites were analyzed by targeted metabolome profiling  and inflammatory cytokine IL-18 were measured by ELISA. Differentially expressed metabolites were selected and mediation analysis was carried out.Seven potential metabolite biomarkers  were identified using the discovery and validation design. In the pooled analysis, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid were markedly and independently associated with DKD. The composite index of 7 potential metabolite biomarkers (CMI) mediated 32.99% of the significant association between the inflammatory IL-18 and DKD. Adding the metabolite biomarkers improved the discrimination of DKD.In T2D, several associated urinary metabolites were identified to improve the prediction of DKD. Whether interventions aimed at reducing CMI also reduce the risk of DKD especially in patients with high IL-18 needs further investigations.The online version contains supplementary material available at 10.1007/s00592-023-02094-z. Diabetic kidney disease (DKD) is the major complication of type 2 diabetes (T2D)  and the In recent decades, studies have investigated the role of circulating metabolite biomarkers in predicting the incidence and outcome of T2D –7, and sHere we investigated the potential association between a variety of urinary metabolites and presence of DKD in individuals with T2D. Some metabolites were unraveled and validated as independently and robustly associated. Whether these metabolites contribute to the effect of inflammatory cytokine on DKD were also explored. We further investigated whether a total of metabolites and inflammatory cytokine improved the diagnosis of DKD.2. eGFR was calculated using the chronic kidney disease epidemiology collaboration equation (CKD-EPI equation).Two cohorts of patients with T2D from Nanjing, east China, were analyzed. T2D was diagnosed according to American Diabetes Association 2018 criteria. The discovery cohort included 77 patients, and the validation cohort included 115 patients. DKD was diagnosed as urinary albumin-to-creatinine (ACR) ≥ 30 mg/g or estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 mBlood pressure (BP), height, and weight were measured by a trained nurse. BP was assessed using an arm electronic sphygmomanometer. Two separate measurements were taken for systolic and diastolic BP, and the average was recorded. In cases where there was a BP difference of 10 mmHg for systolic BP or 5 mmHg for diastolic BP, a third measurement was taken. The two closest BP measurements were then averaged and recorded. Hypertension was defined as systolic BP > 140 mmHg or diastolic BP > 90 mmHg or on antihypertension medication. Weight was measured using a calibrated digital weight scale , while height was measured using a wall-mounted and adjustable tape. Body mass index (BMI) was then calculated using weight (kilogram) divided by the square of height (meter). The biochemical parameters including albumin, hemoglobin A1c (HbA1c), fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), serum creatinine, uric acid and urinary ACR were measured. All participants were categorized as smokers or non-smokers, and alcohol consumption or not based on their responses in a standard questionnaire. Information on drug therapy was obtained from electronic medical record of each participant.Blood and morning urine samples at baseline were stored at −80 °C until analysis. We performed the metabolomics analysis by Q300 Kit . Urinary samples were treated, and the metabolites were quantitated using an ultraperformance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system  by Metabo-Profile Biotechnology (Shanghai) Co., Ltd.. Serum aP values. The Z-score indicates standard deviations concerning the mean of the control group. Variable importance in projection (VIP) was obtained based on the orthogonal partial least squares discriminant analysis (OPLS-DA) model. Differentially expressed metabolites (DEMs) were selected with VIP ≥ 1 and P value < 0.05.Metabolite data were processed using iMAP platform . Principal component analysis (PCA) was performed. The V plot integrates the fold change and t test or Wilcoxon signed-rank test after checking for normality and Chi-squared test for class variables. IL-18 concentrations were logarithmically transformed because of skewed distribution. The associations between seven potential metabolic markers as well as IL-18 and DKD were tested using logistic regression models. To facilitate comparison of results, all ORs were reported per SD units. Mediation analysis was carried out for causal interpretation and exposure–mediator interactions detection [P value < 0.05 was considered statistically significant. All analyses were performed using SPSS 25 (process procedure for SPSS version 3.4) and R software.Baseline characteristics of the enrolled subjects were reported as mean ± SD or median (interquartile range) for continuous variables and frequency (percentage) for categorical variables. Differences between groups in continuous variables were tested by etection . A P valClinical features of patients from discovery and validation cohorts are summarized in Table The absolute concentrations of 160 metabolites were targeted measured using UPLC-MS/MS system in a total of 192 participants .P < 0.05, |log2FC|≥ 0 in univariate statistics as the threshold value, 64 out of the 160 analyzed metabolites in the discovery cohort were selected as differential metabolites, with their value shown in supplemental Table 3.Using both VIP ≥ 1 in multi-dimensional statistics and We carried out Boruta analysis to find out candidate biomarkers from differential metabolites. Plot of feature selection result by Boruta is shown in supplemental Fig. 1. Among the 64 differential metabolites identified in discovery cohort, 19 metabolites labeled as “Confirmed”  in the plot could serve as candidate biomarker.In the totally independent validation cohort, 31 differential metabolites out of the 160 analyzed metabolites matched the threshold value are shown in supplemental Table 4. Venn plot of 7 potential biomarkers  from the 19 candidate biomarkers in discovery cohort and 31 differential metabolites of validation cohort are shown in supplemental Fig. 2.P > 0.05).The seven validated associations were then analyzed using data from the two independent cohorts comprising a total of 192 individuals and 92 DKD  are shown in supplemental Table 5.As a matter of fact, urinary IL-18 was associated with CMI . Urinary IL-18 was also associated with the presence of DKD in the fully adjusted model  of the association between IL-18 and DKD were through CMI , 79.0% (95% CI 70.8%–87.2%), and 82.0% (95% CI 76.2%–87.9%), respectively Table . The effIn summary, our data consistently suggested that levels of urinary metabolites improved the discrimination of DKD in patients with type 2 diabetes.In this study, we rigorously evaluated the association between 160 metabolites measured through targeted metabolomics and incidence of DKD in 192 people with type 2 diabetes using a discovery and validation design. Seven potential urinary metabolite biomarkers were identified by metabolomics analysis. Among them, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid were independently associated with DKD in the pooled cohort of patients with T2D. Of note, taking into account of eGFR, a strong indicator of DKD, did not diminish the relationship between metabolites and the presence of DKD. This study suggested that the associations were independent of blood glucose level, BMI, or diabetes duration.The seven potential metabolite markers met the selection threshold of both multi-dimensional statistics and univariate statistics in both discovery and validation cohorts. Some of the them have been previously reported, and others are newly discovered. Propionic acid, isovaleric acid, and isobutyric acid, all short-chain saturated fatty acid, have been previously associated with the development and progression of kidney damage in diabetes patients , 18. LeuInflammation mediates hyperglycemia-induced series of intracellular processes to promote kidney damage in diabetes , 25. AltGrowing evidence has indicated that metabolic and inflammatory profiles of kidney proximal tubule were influenced by various injuries and further alterations occurred with damage progression or repairment . ActivatIn the two independent cohorts, patients with DKD have higher blood pressure but similar blood glucose and lipid levels compared to those without DKD. To date, the only proven primary prevention interventions for the development of DKD are blood glucose and blood pressure control . Intensi2) including diabetes subjects, the continuation of RAS inhibitors was not associated with a significant attenuation of the decrease in eGFR [Several medications influence the progression of DKD . The blo in eGFR . The use in eGFR , 53 or e in eGFR . There i in eGFR . Recentl in eGFR . Previou in eGFR . As compOur study has several strengths, especially the study design with two independent discovery and replication cohorts analyzed with standardized clinical evaluations. Few previous studies have addressed the association of urinary metabolites with DKD –18. InstIn conclusion, in patients with T2D, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, indole-3-carboxylic acid, and SAH were potential biomarkers of DKD and performed well in discrimination of the presence of DKD. This study may pave the way for different precision medicine approaches in T2D, albeit with different in kidney involvement. Before been practicable in clinical settings, the DKD-associated metabolites require to be validated in larger cohorts. Further, it is necessary to investigate whether directing metabolism might reduce the risk of DKD in patients with T2D, particular their roles in inflammation, before a novel therapeutic approach can be implemented.Supplementary file1 (TIF 1004 KB) Supplemental figure 1. Feature importance calculated by Boruta. The Boruta algorithm is a wrapper built around the random forest classification algorithm. It tries to capture all the important, interesting features might have in the dataset with respect to an outcome variable. Maximum iteration time is 1000. At every iteration, the algorithm compares the Z-scores of the shuffled copies of the features and the original features to see if the latter performed better than the former. If it does, the algorithm will mark the feature as important. In essence, the algorithm is trying to validate the importance of one feature by comparing with random shuffled copies, which increases the robustness. This is done by simply comparing the number of times a feature did better with the shadow features using a binomial distribution. A total of 19 Metabolites labeled as “Confirmed” (Green box) in the plot above can serve as biomarker for subsequent model building and prediction.Supplementary file2 (TIF 2662 KB) Supplemental figure 2. Venn plot of potential biomarkers. Venn plot of 7 potential biomarkers from the 19 candidate biomarkers in discovery cohort and 31 differential metabolites of validation cohort was shown. Blue: 64 differential metabolites in the discovery cohort; Yellow: 31 differential metabolites in the totally independent validation cohort; Green: 19 candidate biomarkers in discovery cohort.Supplementary file3 (XLS 294 KB) Supplemental Table 1. List of the absolute concentrations of 160 metabolites targeted measured using UPLC-MS/MS system in discovery cohort of 77 participants.Supplementary file4 (XLS 396 KB) Supplemental Table 2. List of the absolute concentrations of 160 metabolites targeted measured using UPLC-MS/MS system in validation cohort of 115 participants.P < 0.05 and |log2FC| >= 0 in univariate statistics.Supplementary file5 (XLS 42 KB) Supplemental Table 3. List of the 64 differential metabolites match the threshold value in the discovery cohort. Threshold value for differential metabolite selection here is: (1) VIP > 1 in multi-dimensional statistics, and (2) P < 0.05 and |log2FC| >= 0 in univariate statistics.Supplementary file6 (XLS 35 KB) Supplemental Table 4. List of the 31 differential metabolites match the threshold value in the validation cohort. Threshold value for differential metabolite selection here is: (1) VIP > 1 in multi-dimensional statistics, and (2) Supplementary file7 (DOCX 16 KB) Supplemental Table 5. IL-18 and CMI in the discovery and validation cohorts.n = 192; 92 DKD).Supplementary file8 (DOCX 15 KB) Supplemental Table 6. Correlation between IL-18 and CMI in the pooled sample (Supplementary file9 (DOCX 16 KB) Supplemental Table 7. Mediation analysis in the pooled sample.Below is the link to the electronic supplementary material.


Aneurysmal subarachnoid hemorrhage is a medical emergency that necessitates direct transfer to a tertiary referral center specialized in the diagnosis and treatment of this condition. The initial hours after aneurysmal rupture are critical for patients with aneurysmal subarachnoid hemorrhage, both in terms of rebleeding and combating the effect of early brain injury. No good treatment options are available to reduce the risk of rebleeding before aneurysm occlusion. Lowering the blood pressure may reduce the risk of rebleeding but carries a risk of inducing delayed cerebral ischemia or aggravating the consequences of early brain injury. Early brain injury after aneurysmal rupture has an important effect on final clinical outcome. Proper cerebral perfusion is pivotal in these initial hours after aneurysmal rupture but threatened by complications such as neurogenic pulmonary edema and cardiac stunning, or by acute hydrocephalus, which may necessitate early drainage of cerebrospinal fluid. Aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency that necessitates direct transfer to a tertiary referral center specialized in the diagnosis and treatment of this condition. Twelve percent of patients die immediately before reaching the hospital , 2. On aThe most important determinants of outcome are early brain injury, rebleeding of the ruptured aneurysm, and delayed cerebral ischemia (DCI) , 4. OtheEarly brain injury includes all processes leading to brain injury between the moment of aneurysm rupture and up to 72 h after ictus. Although early brain injury is the most important determinant of poor functional and cognitive outcome, it has attracted limited attention until recently. Most studies focused on the prevention and treatment of arterial narrowing (“vasospasm”) and DCI. Only after several studies showed that treatments that reduced the incidence of vasospasm did not improve functional outcome, focus started to shift from DCI toward early brain injury .During rupture, blood spurs into the subarachnoid space under arterial pressure, leading to an acute rise in intracranial pressure. Blood in the ventricles and basal cisterns may lead to cerebrospinal fluid outflow obstruction and a further increase of intracranial pressure. As a result, the cerebral perfusion pressure decreases, and cerebral circulation may even become absent, which, depending on its severity and duration, may lead to global cerebral ischemia . CessatiCurrently, no treatment exists for early brain injury other than treatment of acute hydrocephalus and evacuation of an intracerebral or subdural hematoma to reduce intracranial pressure. Because cerebral edema is a common feature in patients with early brain injury, it may be tempting to consider treatment with steroids. Although the effect of steroids has been studied in a few small trials in patients with aSAH, the results were conflicting and steroid treatment was not focused on diminishing early cerebral edema but rather on the prevention or treatment of DCI or hyponatremia . In concA recently ruptured aneurysm has a 40% risk of rebleeding in the first 6 weeks after ictus, and rebleeding substantially increases the risk of poor outcome . AlthougShortly after aneurysm rupture, the tear in the aneurysm is sealed by a blood clot. The process of hemostasis depends on a balance between the hemostatic and fibrinolytic system. Especially in the early hours after aneurysm rupture, the blood clots that seals the tear in the aneurysm is unstable, which makes the aneurysm prone to recurrent bleeding. The rationale of treatment with antifibrinolytic drugs after aSAH is to improve clot stability and thereby decrease the risk of rebleeding. Several studies investigated the effect of antifibrinolytic drugs, such as tranexamic acid and epsilon-aminocaproic acid, on the incidence of rebleeding and functional outcome. Here, we will discuss the results of the major multicenter, randomized-controlled trials in this field –21.In 1984, it was shown that long-term administration of tranexamic acid (given up to 4 weeks until aneurysm treatment) reduced the risk of rebleeding but did not improve functional outcome . AlthougHypertension after aSAH is associated with rebleeding of the aneurysm, which can be explained by an increase in aneurysmal transmural pressure, and with poor functional outcome . AlthougBecause all data on the value of blood pressure treatment in patients with aSAH come from low-quality studies, it is not surprising that the guidelines of the European Stroke Organization, American Heart/Stroke Organization, and Neurocritical Care Society have different recommendations , 29, 30.A randomized clinical trial is required to answer the question of whether blood pressure lowering before aneurysm occlusion, and to which target, decreases the risk of rebleeding and improves outcome after aSAH. However, because strict blood pressure control does not eliminate the risk of rebleeding, several thousands of patients would need to be included in such a trial.At least 20% of patients with aSAH have or develop hydrocephalus within the initial days after aneurysmal rupture. This so-called acute hydrocephalus is defined as a decreased level of consciousness combined with enlarged ventricles on imaging. The typical clinical picture is a gradual decrease in consciousness developing over hours. This deterioration in consciousness may be accompanied by small, fixed pupils and impaired upward gaze, although this latter sign cannot be investigated in patients with a severely depressed level of consciousness. These ocular signs may help in making the diagnosis of acute hydrocephalus, but absence of these signs does not exclude hydrocephalus as cause of the decreased level of consciousness. If acute hydrocephalus develops before the patient comes under medical attention, and the patient is already unconscious, the diagnosis can only be made based on enlarged ventricles on imaging. In individual patients with hydrocephalus as the only cause of a decreased level of consciousness, there is a good relation between the level of consciousness and the size of the ventricles, but at the group level the relation between level of consciousness and ventricular size is less clear.Acute hydrocephalus may result from intraventricular obstruction through intraventricular extension of the hemorrhage, from compression of the ventricular system by an intracerebral hematoma or from obstruction of the flow of the cerebrospinal fluid at the level of the tentorial hiatus in patients in whom all cisterns around the brainstem are filled with blood .The enlargement of the ventricles leads to increased intracranial pressure and reduced cerebral blood flow , and cerAround one in every ten patients with aSAH has a seizure at time of aneurysmal rupture or shortly thereafter, but in many of these patients the clinical manifestation is more an epiphenomenon of a major neurological complication rather than an epileptic seizure . SeizureHyperglycemia is found in one third of patients with aSAH during their clinical course and is associated with a poor clinical condition on admission . The maiPulmonary edema is a severe nonneurological complication after aSAH, which is most common in patients with a poor clinical condition on admission . PulmonaThe management of neurogenic pulmonary edema after aSAH consists of supportive care and is focused on volume correction and avoidance of hypervolemia . HypovolStress-related cardiac abnormalities present with electrocardiogram changes, left ventricular dysfunction, and cardiac-specific serum enzyme and protein elevation. The characteristic finding on echocardiography is an aneurysm-shaped apex and hyperdynamic base, which resembles a takotsubo, a Japanese octopus (“tako”) trap (“tsubo”). In a systematic review of the literature including ten studies, one in every 20 patients with aSAH had a takotsubo cardiomyopathy . Other dNo antifibrinolytic drugs or corticosteroids.Upper blood pressure limits are based on individual factors. In general, we accept any systolic blood pressure after treatment of the aneurysm. In elderly patients, those with a history of cardiac disease, or those without hypertension prior to ictus, a blood pressure cutoff can be considered (for example systolic blood pressure below 220 mm Hg). If it is decided to give blood pressure lowering drugs, we prefer continuous infusion of short-acting drugs, such as labetalol. Diuretic drugs should be avoided to maintain normovolemia. Care should be taken that the blood pressure reduction will be gradual  to decrease the risk of DCI.Nimodipine 60 mg every 4 h.Antiepileptic drugs only after documented seizure is not related to (re)bleeding.Insulin therapy if fasting glucose > 10 mml/L, and regular glucose control with oral antidiabetic drugs and/or insulin therapy in patients with diabetes.Treatment of acute hydrocephalus with one or more lumbar punctures. We pursue external ventricular drainage only in case of complete filling of the third or fourth ventricle with blood if repeated lumbar punctures are not effective in restoring consciousness. External ventricular drainage is also applied if the neurosurgeon wants to decrease intracranial pressure prior to clipping of the ruptured aneurysm.The authors’ practice is as follows Table :No antifIdentify novel treatments that improve recovery from early brain injury and thereby improve functional and cognitive outcome after aSAH.Determine the optimal blood pressure prior to aneurysm occlusion.Define the type and duration of cerebrospinal fluid drainage in patients with hydrocephalus.Determine the optimal treatment strategy for patients with takotsubo cardiomyopathy after aSAH.The initial hours after aneurysmal rupture are critical for patients with aSAH, both in terms of rebleeding and combating the effect of early brain injury. Unfortunately, no good treatment options are available to reduce the risk of rebleeding until the patient is admitted in a tertiary care center where the aneurysm can be occluded. Lowering the blood pressure may reduce the risk of rebleeding but carries a risk of inducing DCI or aggravating the consequences of early brain injury. The notion that early brain injury has an important effect on final clinical outcome has emerged over the last decade, but this process is, until now, poorly understood, and treatment strategies to reduce the effects of this injury need to be developed. Proper cerebral perfusion is pivotal in these initial hours after aneurysmal rupture but is threatened by complications such as neurogenic pulmonary edema and cardiac stunning, for which currently only supportive care is available. Cerebral perfusion can also be compromised by acute hydrocephalus, and early drainage of cerebrospinal fluid may improve perfusion and thereby final clinical outcome. The optimal type, duration, and extent of the drainage are uncertain, in particular before aneurysm occlusion. Supportive care to minimize secondary brain injury, prevention and treatment of cerebral and systemic complications, and initiation of oral nimodipine should be priorities in all patients presenting with aSAH.


Hematopoietic cell transplant (HCT), used for treatment of many malignant and non-malignant pediatric diseases, is associated with serious complications, limiting this therapy’s benefit. Acute kidney injury (AKI), seen often after HCT, can occur at different stages of the transplant process and contributes to morbidity and mortality after HCT. The etiology of AKI is often multifactorial, including kidney hypoperfusion, nephrotoxicity from immunosuppressive and antimicrobial agents, and other transplant-related complications such as transplant-associated thrombotic microangiopathy and sinusoidal obstructive syndrome. Early recognition of AKI is crucial to prevent further AKI and associated complications. Initial management includes identifying the etiology of AKI, preventing further kidney hypoperfusion, adjusting nephrotoxic medications, and preventing fluid overload. Some patients will require further support with kidney replacement therapy to manage fluid overload and AKI. Biomarkers of AKI, such as neutrophil gelatinase-associated lipocalin can aid in detecting AKI before a rise in serum creatinine, allowing earlier intervention. Long-term kidney dysfunction is also prominent in this population. Therefore, long-term follow-up and monitoring of renal function  is required along with management of hypertension, which can contribute to chronic kidney disease. AKI is a relatively common complication after HCT, with a reported incidence rate of 21–84% ,7,8,9,10Common risk factors for kidney injury include myeloablative conditioning, older age, acute GVHD, and SOS . SatwaniOne reason that the incidence of AKI varies so widely (21–84%) is that non-standardized definitions of AKI were used in prior studies. More standardized and widely used AKI scoring systems have now been developed, the most recent and commonly used of which are the KDIGO guidelines. Diagnosis and staging of AKI relies mainly on two factors: serum creatinine (sCr) level and urine output . Howeverp = 0.04]) ) . Additio= 0.001) .Eculizumab is a monoclonal antibody against the complement component C5, which blocks the formation of the membrane attack complex (MAC or C5b-9) and thus prevents endothelial damage. In a cohort of 64 pediatric HCT patients with high-risk TA-TMA and multiorgan dysfunction, the survival rate improved dramatically with the use of eculizumab (66% in 1-year post HCT in treated vs 16.7% in a previously reported untreated cohort) . NotablyConsumptive and transfusion-refractory thrombocytopenia;Weight gain on 3 consecutive days despite the use of diuretics, or a weight gain of >5% above baseline weight within 72 h;Increase in bilirubin from baseline on 3 consecutive days, or bilirubin ≥ 2 mg/dL within 72 h;Hepatomegaly (best if supported by imaging) above baseline value;Ascites (best if supported by imaging) above baseline.Sinusoidal obstruction syndrome (SOS) is associated with multiorgan dysfunction and a high mortality rate . SOS occKidney injury in SOS is attributed to hypoperfusion and vasoconstriction and is associated with fluid overload. Managing the kidney injury requires fluid restriction and use of diuretics to reduce fluid overload. Renal replacement therapy may be necessary if fluid overload persists, and urine output remains inadequate despite diuretic treatment . In suchFluid overload (FO) is common in critically ill children and negatively affects outcome ,30. AddiFO is a new post-HCT toxicity category with the following proposed grading system :Grade 1: AKI Stage 0 or 1; fluid overload < 10%Grade 2: AKI Stage 0 or 1; fluid overload > 10%Grade 3: AKI Stage 2 or 3; fluid overload < 10%Grade 4: AKI Stage 2 or 3; fluid overload > 10%Close monitoring of daily fluid balance and weight is crucial to prevent FO. This allows for early recognition and prompt management of FO to reduce further kidney injury and improve survival. Unfortunately, even significant FO is often missed. Al-Lawati et al. found that clinicians did not recognize FO > 15% in 30% of pediatric patients . In addiChimeric antigen receptor (CAR) T-cell therapy, used for treatment of hematologic malignancies, involves the utilization of engineered cytotoxic T-cell to recognize specific tumor antigen. AKI occurs with this therapy secondary to cytokine release syndrome (CRS), a well described complication of this therapy which can lead to organ dysfunction. Hypoperfusion secondary to capillary leak and proinflammatory cytokines contribute to AKI encountered post CAR-T cell therapy. AKI is usually mild in these cases . In a coNearly one-third of patients with AKI require kidney replacement therapy (KRT) . CKRT isNo consensus exists on the optimal time for initiation of CKRT and whether early initiation can improve outcome. Most evidence is from adult randomized trials that compared the early initiation of CKRT to using a standard strategy. One of the largest adult trials, the STARRT-AKI trial, randomized 3019 critically ill adults with AKI to either an accelerated RRT strategy  or a standard strategy. The accelerated RRT strategy did not reduce mortality compared to the standard strategy, and survivors of the accelerated RRT strategy had a higher risk of adverse events and dependence on kidney replacement therapy . In cont2/h in children. However, the delivered dose is usually less than prescribed dose due to interruptions that occur during CKRT, such as circuit clotting, scheduled filter changes, and pauses for other procedures. Thus, KDIGO recommends a 25–30 mL/kg/h prescribed dose to achieve a delivered dose of 20–25 mL/kg/h [The recommended dose of CKRT is 20–25 mL/kg/h, or 2000 mL/1.73 m mL/kg/h . A CKRT  mL/kg/h . Anticoa mL/kg/h . TherefoThe optimal timing for successful discontinuation of CKRT or switch to IHD is difficult to predict. Renal recovery is usually preceded by an increase in urine output. Urine output > 500 cc/day is used in some adult patients as a criterion to discontinue KRT . Factorsp < 0.0001)) [ICU mortality in children post HCT requiring CKRT is estimated to be 52–65% . The 1-yGiven the potential shortcomings of sCr as a marker of AKI, several additional biomarkers of AKI have been developed and studied. These biomarkers measure either glomerular function or renal tubular damage and can aid in early detection of AKI . Cystatin C (CysC) is a low molecular weight protein which is present in all nucleated cells and inhibits cysteine proteases. It is freely filtered by the glomerulus, then reabsorbed by the proximal tubule epithelium and catabolized. It is present in urine only in instances of tubular injury. Serum CysC levels can be altered by several factors such as corticosteroids, inflammatory status, and chemotherapy. Levels may also be elevated in patients with leukemia without any documented AKI secondary to increased cell turnover . CysC caSeveral tubular injury markers have been described and investigated for their utility in early recognition of AKI. Neutrophil gelatinase-associated lipocalin (NGAL) levels are elevated in the urine early after ischemic, septic, or toxic injury and precede the rise in serum creatinine levels by 48 h . In addiFatty acid-binding protein 1 is another early biomarker of AKI and can predict the need for dialysis . An incrCKD in children post HCT has a reported incidence of 48%. CKD is defined by estimated GFR < 90 mL/min/1.73 BSA or presence of markers of kidney damage for >3 months . CKD can2 at the initial AKI episode [2 must be monitored closely for early detection of CKD. Similar to the approach to AKI noted previously, the management of CKD post HCT requires regular monitoring for long term changes in estimated GFR to identify patients with CKD, followed by preventive strategies that minimize nephrotoxic medication exposure, ensure adequate hydration and nutrition, optimize blood pressure control, and minimize proteinuria.The most common etiologies and risk factors for CKD development are TMA, total body irradiation, nephrotic syndrome, AKI, acute GVHD, and drug toxicity  . Estimat episode . TherefoAlbuminuria  is an important parameter to monitor in children post HCT during long-term follow-up for early recognition of CKD. Albuminuria is relatively common (detected in 50% of patients one-year post HCT) . FurtherAdditional long-term follow-up for HCT patients with CKD includes monitoring and treatment of other consequences of progressive CKD including electrolyte disturbances, such as metabolic acidosis, anemia of CKD, and CKD-related bone disease . Consult


Ninety-six eyes from 52 patients with hypertension were included in this analysis. Twenty patients (n = 37 eyes) were diagnosed with CKD. The mean age was 69 ± 11.7 years and 60.4 ± 9.2 years in the CKD group and in the control group, respectively. The univariate model revealed a significant difference in VD between patients without and with CKD in the superficial IR , the superficial OR , the deep OR , and the FD in the SVP  and DVP . After adjusting for age and sex, these differences did not remain statistically significant. Similar results were observed for the FD in the SVP and DVP. In our cohort, patients with hypertension and CKD did not differ from patients without CKD in regard to microvascular perfusion status in the macular area as assessed using OCTA.To compare retinal microvascular perfusion between the eyes of hypertensive patients with and without chronic kidney disease (CKD), the vessel density (VD) and fractal dimension (FD) of the superficial (SVP) and deep retinal vascular plexus (DVP) were analyzed on 6 × 6 mm fovea-centered optical coherence tomography angiography (OCTA) images of patients with hypertension. The retina was divided into an inner ring (IR) and outer ring (OR) according to the Early Treatment of Diabetic Retinopathy Study grid. The glomerular filtration rate (GFR) was determined and CKD was diagnosed (GFR < 60 mL/min/1.73 m Chronic kidney disease (CKD) is a worldwide public health concern with a rising incidence and prevalence. Although adverse outcomes can be prevented or delayed through early treatment, CKD remains underdiagnosed und undertreated .2 [It has been shown that the development and progression of CKD are associated with loss of the microvasculature ,3. To ev2 ,6,7,8,9.2 ,11. HypeVarious studies have investigated the relationship between vascular diameters and risk factors for cardiovascular diseases ,13,14, dA recently introduced deep learning algorithm showed good performance in detecting CKD on mydriatic color fundus photographs, highlighting the importance of retinal imaging as a non-invasive screening tool .Another potentially important method in screening for changes in retinal microvasculature is the analysis of fractal dimension (FD) as a global measure for vascular complexity expressed as a single variable, mostly evaluated from fundus photographs ,7,16,17.Hypertension and CKD are closely related in that they both cause changes in the microvasculature of the neuroretina, which can be detected with various imaging methods.The aim of this study was to evaluate changes associated with CKD in patients with hypertension by analyzing retinal microvascular parameters on OCTA en-face images in the superficial (SVP) and deep vascular plexus (DVP).In this cross-sectional study, patients with hypertension were recruited from the Clinic Landstrasse cardiology department . The study was conducted according to the guidelines of the Declaration of Helsinki. Approval was given from the Medical University of Vienna Ethics Committee. Written informed consent was obtained from all subjects prior to enrollment in the study. People with diabetes and other ocular diseases were excluded from this analysis.2 for a period of more than 3 months. GFR levels of ≥90 mL/min/1.73 m2, 60–89 mL/min/1.73 m2, 30–59 mL/min/1.73 m2, 15–29 mL/min/1.73 m2, and <15 mL/min/1.73 m2 were further defined as no CKD, mild, moderate, severe CKD, and kidney failure, respectively.GFR was calculated from serum creatinine concentration using the CKD Epidemiology Collaboration equation . PatientFovea-centered 6 × 6 mm optical coherence tomography angiography (OCTA) scans were acquired using a 200 kHz Plex Elite 9000 device . Automated segmented SVP and DVP en-face images were exported for further analysis of microvascular parameters.We calculated the VD as the percentage of vessel area with blood flow over the total area measured  and usedTo evaluate the microcirculation of the macula, larger vessels were excluded from the VD calculation. VD was calculated in all individual sectors of the 6 mm ETDRS grid centered around the fovea. To place the grid, the center of the foveal avascular zone (FAZ) was manually annotated on the en-face OCTA image using ImageJ . An automated algorithm developed by the Vienna Reading Center at the Medical University of Vienna was used to perform the VD calculations. The FAZ was measured on en-face images of the SVP.p-value was <0.05, a multivariable mixed model was applied with age and sex as additional independent variables. The mixed models were also calculated for each subarea  in the superior and deep plexus separately, whereby Bonferroni correction was applied to adjust for the number of subareas (4 subareas). Analyses were repeated with GFR (metric) instead of CKD as the independent variable. The effect of age on GFR was analyzed using a linear regression model. Statistical analyses were carried out with SAS 9.4. and R 4.1.3. The significance level was set to alpha = 0.05. Due to the exploratory character of the analyses, multiplicity correction was performed for the number of subareas, but not for the number of endpoints. Hence, the interpretation of the p-values is descriptive.Qualitative variables are reported as absolute frequencies and percentages. Metric variables are summarized as mean ± standard deviation (SD). Univariate mixed models (SAS Proc mixed) were calculated with the patient as a random factor to consider that some patients have measurements on both eyes. The number of degrees of freedom was calculated using Kenward–Roger approximation. The dependent variables were SVP VD in the inner ring  and the outer ring , DVP VD in the inner ring  and the outer ring , SVP FD, DVP FD, and FAZ size on the SVP. The independent variable was CKD (dichotomous). If the 2 and were therefore classified as having CKD. Thirty-two patients (59 eyes) had a GFR of ≥60 mL/min/1.73 m2 and thus composed the control group. The mean age was 69 ± 11.7 years (range 40–86 years) and 60.4 ± 9.2 years (range 42–78 years) in the CKD group and in the control group, respectively. The mean GFR was 41 ± 16.6 mL/min/1.73 m2 and 84.8 ± 14.4 mL/min/1.73 m2 in the CKD group and the control group, respectively. Age was significantly negatively associated with GFR , as shown in Ninety-six eyes (49% right and 51% left eyes) of 52 patients  were included in this cross-sectional study. The mean age of all patients was 64 ± 10.9 years (range 40–86 years). Twenty patients (37 eyes) had a GFR of less than 60 mL/min/1.73 mDetailed reports of VD, FD, and FAZ are specified in After assessment of GFR levels, no, mild, and moderate CKD and end-stage/kidney failure were determined for 11 (21%), 21 (40%), 17 (33%), and 3 patients (6%), respectively. However, no further analyses were performed using these subgroups due to the small sample sizes.p = 0.033) and outer ring . However, after adjusting for age and sex, these differences did not remain statistically significant in either the inner ring  or outer ring .The mean SVP VD (CKD vs. control) was 0.34 ± 0.04 vs. 0.36 ± 0.03 in the inner ring and 0.33 ± 0.04 vs. 0.35 ± 0.02 in the outer ring. In the univariate mixed model, we found significantly lower VDs in patients with CKD in the inner ring  but a significantly lower VD in patients with CKD in the outer ring . This difference did not remain significant after adjusting for age and sex The mean DVP VD (CKD vs. control) was 0.23 ± 0.03 vs. 0.24 ± 0.03 in the inner ring and 0.23 ± 0.02 vs. 0.24 ± 0.01 in the outer ring. The univariate mixed model revealed no significant difference in the inner ring  and DVP . After adjusting for age and sex, these differences did not remain statistically significant in the SVP  or DVP .The FD (CKD vs. control) was 1.86 ± 0.02 vs. 1.87 ± 0.01 in the SVP and 1.82 ± 0.01 vs. 1.83 ± 0.01 in the DVP. The univariate mixed model revealed a significantly lower FD in the SVP , which did not remain when adjusted for age and sex .The FAZ (CKD vs. controls) was 209.3 ± 73.9 µmp < 0.05) (as shown in p > 0.05).When including GFR instead of CKD in the mixed models, the results for VD and FD were similar, revealing a significant association of GFR with vascular parameters in the univariate model  . Wu et aPeng et al., assessed VD within the SVP and DVP using 6 × 6 fovea-centered OCTA images, revealing that patients with hypertension also exhibited a decreased DVP VD compared to those without hypertension. SVP density was only reduced in patients with signs of hypertensive retinopathy . In contIn our cohort, all patients had hypertension without signs of retinopathy. However, the differences between patients with CKD and the control group observed in the univariate mixed model were not statistically significant after adjusting for age and sex.In 1990, retinal branching patterns were first characterized as fractals, a geometrical pattern whose parts resemble the whole, providing a new measure of vascular geometry in ocular disease . This alSng et al., analyzed FD in patients with CKD using two 45° fundus photographs (optic disc and fovea-centered) and showed a reduced FD in patients with CKD compared to patients without CKD (1.43 ± 0.048 vs. 1.44 ± 0.042) . Lim et Zahid et al., were among the first to investigate FD on OCTA images in the eyes of patients with diabetic retinopathy without macular edema and found significant reductions in the SVP and DVP . HoweverIn our study, we found a reduction in the FD in the SVP (1.86 ± 0.02 vs. 1.87 ± 0.01) and the DVP (1.82 ± 0.01 vs. 1.83 ± 0.01), which did not remain significant after adjusting for age and sex.Age and sex both have an influence on microvascular parameters in OCTA analysis and have to be accounted for when interpretating data ,34. HoweOur cohort was small, consisting of only 96 eyes from 52 patients. However, patients with CKD showed a higher decrease in VD in the SVP than expected due to normal age-differences, as reported in a recent population-based study . Larger Macular microvascular perfusion in patients with hypertension and CKD did not show significant differences compared to in patients without CKD when assessed using OCTA.


NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks compared with matched placebo significantly reduced severe asthma exacerbations and improved forced expiratory volume in 1 s (FEV1) in patients with uncontrolled, moderate-to-severe asthma. This post hoc analysis explored the efficacy of dupilumab in patients with type 2 asthma enrolled in QUEST with or without elevated blood neutrophil counts.  Elevated neutrophil counts in blood, sputum, or lung have been associated with poor clinical outcomes and more severe disease in patients with type 2 asthma. In the phase 3 LIBERTY ASTHMA QUEST  ≥ 20 ppb; and eosinophils ≥ 300 cells/µL or FeNO ≥ 50 ppb) and low  or high  neutrophil counts.  Annualized severe exacerbation rates during the 52-week treatment period and least-squares mean change from baseline in FEVP < 0.0001 for all comparisons). Significant improvements in FEV1 versus placebo were observed as early as Week 2 and over the 52-week treatment period, irrespective of baseline neutrophil count . Safety findings were similar across all subgroups, regardless of neutrophil counts at baseline.  Dupilumab significantly reduced annualized severe exacerbation rates compared with placebo during the 52-week treatment period in patients with elevated type 2 biomarkers, irrespective of baseline neutrophil count (NCT02414854. Dupilumab treatment significantly reduced annualized severe exacerbation rates and improved lung function in patients with uncontrolled, moderate-to-severe, type 2 asthma, irrespective of baseline blood neutrophil count. This trial is registered with  Asthma is a heterogeneous and chronic inflammatory disease characterized by a spectrum of overlapping phenotypes –3. PatieNeutrophils may play a key role in asthma, attracting other immune cells and contributing to mucus hypersecretion and increased smooth muscle responsiveness –12. ElevIt has been suggested that non-type 2 mechanisms, including neutrophilic inflammation, may directly affect patient outcomes and the efficacy of asthma treatment , 21–23. NCT02414854), add-on dupilumab 200 or 300 mg every 2 weeks (q2w), compared with matched placebo, significantly reduced severe asthma exacerbations and improved prebronchodilator forced expiratory volume in 1 s (FEV1), and was well tolerated in the overall population of patients with uncontrolled, moderate-to-severe asthma [μL or FeNO ≥ 25 parts per billion (ppb)) [post hoc analysis of QUEST aims to assess the consistency of dupilumab treatment within the heterogeneous type 2 asthma populations to more precisely evaluate the potential impact of non-type-2 biomarkers such as neutrophils on the efficacy of dupilumab in patients with type 2 asthma with and without elevated blood neutrophil counts at baseline.Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, key and central drivers of type 2-mediated inflammation , 30 in me asthma . Greatern (ppb)) . This po1 ≤ 80% (≤90% if aged 12–17 years) predicted normal value, FEV1 reversibility of 12% and 200 mL, a score of ≥1.5 on 5-point Asthma Control Questionnaire (ACQ-5), and worsening asthma in the past year. Patients were eligible for enrollment irrespective of a minimum baseline blood eosinophil count or levels of type 2 inflammatory biomarkers. Key exclusion criteria included weight <30 kg, comorbid lung diseases, severe asthma exacerbation, and current smoking, smoking cessation <6 months prior to the study, or history of >10 pack-years. Full details of the study design and inclusion and exclusion criteria have been published previously [QUEST was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluating the safety and efficacy of dupilumab in patients aged ≥12 years with uncontrolled, moderate-to-severe asthma. Dupilumab is approved in the USA as an add-on maintenance treatment in patients with moderate-to-severe asthma aged ≥6 years with an eosinophilic phenotype or with oral corticosteroid-dependent asthma, and in Europe to treat patients with uncontrolled, severe asthma aged ≥6 years , 33. Beteviously . The stuµL and/or FeNO ≥ 20 ppb per Global Initiative for Asthma (GINA) guidelines [Only patients with type 2 asthma  AND low or high neutrophil count or eosinophils ≥ 300 cells/µL or FeNO ≥ 50 ppb (type 2-300/50) AND low or high neutrophil count. It should be noted here that the cutoff of eosinophils ≥ 150 cells/µL includes all patients with blood eosinophils ≥ 150 cells/µL (and not only those with 150–300 cells/µL), and FeNO ≥ 20 ppb refers to all patients with FeNO of 20 ppb or greater, and not only those with FeNO 20–50 ppb; thus, patients in type 2-300/50 subgroups were by definition also included in the less strict type 2-150/20 subgroup. The threshold for high and low neutrophil count was set at ≥4,000 and <4,000 cells/µL, respectively, based on previous studies and the recent Severe Asthma Research Program (SARP) analyses [µL threshold in the current study population, median ) blood neutrophil counts were analyzed and the number of patients in different neutrophil count categories at baseline  was assessed in the intention-to-treat (ITT) population and in patients with eosinophils ≥ 150 cells/µL or FeNO ≥ 20 ppb .Safety was measured in terms of treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) throughout the study. Safety data were evaluated by treatment (dupilumab or placebo) for patients with or without clinically defined treatment-emergent neutropenia , baseline eosinophil strata, baseline ICS dose level, visit, treatment-by-visit interaction, baseline prebronchodilator FEV1 value, and baseline-by-visit interaction as covariates. Additional covariates—the subgroup, subgroup-by-treatment interactions, and subgroup-by-treatment-by-visit interaction—were added for the interaction P-value model. A P value of <0.05 was considered statistically significant for the comparisons between dupilumab and placebo. The number of type 2 patients by neutrophil count categories at baseline and the safety results were summarized descriptively. In addition, restricted cubic spline regression models with a maximum of 4 knots (k) regressions were implemented to explore the relationship between the outcomes  and baseline biomarker (blood eosinophils and FeNO) levels. The spline models for the annualized severe exacerbation outcome used a penalized negative binomial model, with the pooled treatment groups, age, region (pooled country), baseline ICS dose level (medium or high), number of severe exacerbation events within 1 year prior to the study, baseline biomarker (eosinophils or FeNO), and baseline biomarker-by-treatment (eosinophils or FeNO) interaction as covariates, and log-transformed standardized observation duration as an offset variable. Similarly, the spline models for the change from baseline in prebronchodilator FEV1 at Week 52 outcome used a penalized regression with the pooled treatment groups, age, sex, baseline height, region (pooled country), baseline ICS dose (medium or high), and baseline prebronchodilator FEV1, baseline biomarker (eosinophils or FeNO), and baseline biomarker-by-treatment (eosinophils or FeNO) interaction as covariates. The negative binomial model and mixed-effects model with repeated measures were analyzed using SAS v9.4, and spline regression analyses were performed using R-3.6.2.For this analysis, data were pooled within treatment types (combined dupilumab 200 and 300 mg q2w and combined matched placebo groups). Annualized severe exacerbation rates over the 52-week treatment period were assessed using a negative binomial model, with the total number of events with onset from randomization up to visit 18 or the last contact date (whichever came earlier) as the response variable. The pooled treatment groups, age, region (pooled country), baseline eosinophil strata, baseline ICS dose level, and the number of severe exacerbation events within 1 year prior to the study were included in the model as covariates and the log-transformed standardized observation duration as an offset variable. Change from baseline in FEVµL) , and the mean number of severe exacerbations in the previous year ranged from 1.91 to 2.32. Approximately half of the patients in each of the analyzed subgroups were taking high-dose ICS at baseline. Baseline blood eosinophil and FeNO levels were broadly similar across treatment groups, regardless of neutrophil count at baseline.In total, 1,582 patients were included in the current analysis. Patients' mean age was similar across the analysis subgroups; however, a higher proportion of adolescents were included in the subgroups with low neutrophil counts  . BaselinµL  and 4,060 cells/µL  in the placebo and dupilumab treatment arms, respectively, with similar blood neutrophil counts in the type 2-150/20  cells/µL; dupilumab: 4,050  cells/µL) and type 2-300/50  cells/µL; dupilumab: 4,115  cells/µL) groups, further confirming the appropriateness of the chosen cutoff of 4,000 neutrophils/µL.Overall, median (95% CI) blood neutrophil counts in the QUEST ITT population were 4,050 cells/P < 0.001) annualized severe exacerbation rates were observed in patients treated with dupilumab versus placebo across the type 2-150/20 and type 2-300/50 subgroups, irrespective of neutrophil count .Over the 52-week treatment period, significantly lower (il count . In patiP < 0.001) in the least squares (LS) mean change from baseline in prebronchodilator FEV1 were observed for dupilumab versus placebo at all assessed timepoints, irrespective of baseline eosinophil, FeNO, or neutrophil level .Significantly greater improvements  and dupilumab (81.0%) groups . The most frequent AE occurring in ≥5% of patients and at higher rates among patients who received dupilumab was injection-site reaction (16.8% of patients in combined dupilumab vs. 7.9% in combined placebo groups). Viral upper respiratory tract infections (URTI) were the next most frequent AE in all groups . PneumonµL and in 17.7% versus 18.7%, respectively, in patients with neutrophils ≥1,500 cells/µL. In patients with neutrophils <1,500 cells/µ/L, any-class SAE was reported in four patients (2.7%) in the combined dupilumab group and one patient (1.3%) in the combined placebo group, and in patients with neutrophils ≥1,500 cells/µL, in 36 patients (3.2%) in the combined dupilumab group and 23 (4.1%) in the combined placebo group. The most frequent SAE was pneumonia, which occurred in one patient (0.7%) with neutropenia and three patients (0.3%) without neutropenia in the combined dupilumab group and two patients (0.4%) in the combined placebo group (both patients without neutropenia).In patients with and without neutropenia, as analyzed here, overall rates of TEAEs and SAEs also were similar between dupilumab and placebo  [To our knowledge, this is the first analysis that describes the efficacy of a biologic that targets underlying type 2 inflammation by baseline neutrophil count in patients with asthma. Within the spectrum of asthma, elevated neutrophils can occur with or without type 2 inflammation. In a cluster analysis of patients in the SARP program, type 2 asthma patients with severe asthma who had the poorest lung function, frequent hospitalization, and uncontrolled symptoms despite high-dose oral corticosteroid use also had elevated blood neutrophils . In a sess index , 23. Givss index , 35. It nalysis) , 36, altpost hoc, and the study was not specifically designed to assess the differences in efficacy across neutrophil counts. Therefore, sputum, which could provide more direct insight into neutrophilic airway inflammation and its potential interaction with airway eosinophils, was not collected. Smaller studies may be better tailored to evaluate sputum and other mechanistic outcomes. Our findings suggest that it would be of interest to evaluate induced sputum in smaller mechanistic studies because of its relation to the effects of biological treatment in this patient population. Since this was a large regulatory clinical trial, collection and analysis of induced sputum was not feasible, as in most clinical settings, blood biomarkers were more readily obtainable.One limitation of the current analysis is that it was performed µL or FeNO ≥ 50 ppb at baseline and higher or lower blood neutrophil levels. As other new biomarkers are validated for non-type 2 asthma endotypes, future studies should evaluate predictive and prognostic outcomes after treatment with targeted type 2 biologics within overlapping asthma endotypes.In summary, type 2 asthma comprises a spectrum of heterogeneity that includes patients with and without elevated blood neutrophils. Treatment with dupilumab resulted in consistent improvements in lung function in patients with uncontrolled, moderate-to-severe asthma across the type 2 spectrum, irrespective of mixed heterogeneity as described by blood neutrophil levels. Comparable responses were observed in patients with blood eosinophils ≥ 300 cells/


Although reports vary, the prevalence of true resistant hypertension and apparent treatment-resistant hypertension (aTRH) has been reported to be 10.3% and 14.7%, respectively. As there is a rapid increase in the prevalence of obesity, chronic kidney disease, and diabetes mellitus, factors that are associated with resistant hypertension, the prevalence of resistant hypertension is expected to rise as well. Frequently, patients with aTRH have pseudoresistant hypertension . As the prevalence of WUCH is high among patients with aTRH, the use of out-of-office BP measurements, both ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM), is essential to exclude WUCH. Non-adherence is especially problematic, and methods to assess adherence remain limited and often not clinically feasible. Therefore, the use of HBPM and higher utilization of single-pill fixed-dose combination treatments should be emphasized to improve drug adherence. In addition, primary aldosteronism and symptomatic obstructive sleep apnea are quite common in patients with hypertension and more so in patients with resistant hypertension. Screening for these diseases is essential, as the treatment of these secondary causes may help control BP in patients who are otherwise difficult to treat. Finally, a proper drug regimen combined with lifestyle modifications is essential to control BP in these patients. High blood pressure (BP) is associated with increased cardiovascular complications, regardless of the type of prescribed antihypertensive medications . BP reduIn Korea, the overall control rate of hypertension is less than half of the hypertensive population, and the control rate in patients treated for hypertension is approximately 70% . PatientRH is defined as the failure to achieve the target BP despite the use of ≥3 antihypertensive drugs, commonly including dihydropyridine calcium channel blockers(CCBs), renin-angiotensin system (RAS) inhibitors, and diuretics, or the need for treatment with ≥4 antihypertensive medications to achieve the target BP . PatientThe reported prevalence of RH varies significantly according to specific studies. In the 2018 AHA scientific statement, the prevalence of RH among all patients with hypertension was 12-15% based on population studies and 15-18% for clinic based reports . In a poNoubiap et al. analyzed the prevalence of aTRH by region . They foRH is associated with an adverse prognosis compared with patients without RH. In a retrospective cohort of 205,750 patients with incident hypertension over a median follow-up of 3.8 years, RH was associated with an approximately 50% higher risk of cardiovascular events . In a poRH can be diagnosed by ruling out pseudoresistance, which is defined as a lack of BP control despite appropriate treatment in patients who do not have RH. Several factors, such as improper BP measurement, the “white-coat effect,” medication non-adherence, and treatment inertia, contribute to pseudoresistance. According to current guidelines, accurate BP measurement is the cornerstone of RH diagnosis , 22. The2 doubled the risk to have aTRH  [2 [More recent randomized controlled trials –143 (DEN=0.0059) . In the  0.0039) . The res022)]  and 24-hour DBP  at 12th week of treatment. However, this and other recent clinical trials using CPAP enrolled asymptomatic patients with OSA for obvious ethical reasons, while excluding subjects with symptomatic OSA ), major adverse cardiovascular events(HR:1.681.16-2.45]), cardiovascular mortality(HR:1.85[1.18-2.90]) and stroke(HR:2.14[1.17-3.93])  compared-2.45), cThe prevalence of the aTRH is approximately 10-15%. Among these patients, specific aspects, such as pseudo-resistance, WUCH, secondary hypertension, non-adherence, and inappropriate treatment regimens, must be ruled out to properly diagnose true RH. Comprehensive treatment approaches, including lifestyle interventions, pharmacological approaches, and systematic approaches to improve adherence, are needed to control RH. Device-based therapies aimed at sympathetic nervous system activity are currently used in patients with RH. Among device-based therapies, RDNs have been shown to be effective in some patients with RH; however, more research is needed to apply them to a larger number of patients with RH. Further studies are required to determine the long-term efficacy and safety of these devices. Refractory hypertension, defined as the failure to control BP below the target BP with the use of five or more antihypertensive agents, including thiazide-like diuretics  and spironolactone, is associated with a poor prognosis. Further research is warranted to develop better treatment options for refractory hypertension.


Background and Objectives: Central aortic pressure (CAP) can be measured through noninvasive methods, and CAP wave analysis can provide information about arterial stiffness. The objective of this study was to compare CAP in women with preeclampsia and normotensive postpartum women from an urban region in western Mexico. Materials and Methods: We recruited 78 women in immediate puerperium, including 39 with preeclampsia and 39 with normotension, who received delivery care in our hospital between September 2017 and January 2018. Pulse wave analysis was used to assess central hemodynamics as well as arterial stiffness with an oscillometric device. For this purpose, the measurement of the wave of the left radial artery was obtained with a wrist applanation tonometer and the ascending aortic pressure wave was generated using the accompanying software . Additionally, the systolic CAP, diastolic pressure, pulse pressure, heart rate, and rise rate adjusted for a heart rate of 75 bpm were determined. The radial pulse wave was calibrated using the diastolic and mean arterial pressures obtained from the left brachial artery. For all the statistical analyses, we considered p < 0.05 to be significant. Results: The results were as follows: a systolic CAP of 125.40 (SD 15.46) vs. 112.10 (SD 10.12) with p < 0.0001 for women with and without preeclampsia, respectively. Systolic CAP was significantly elevated in women with preeclampsia and could indicate an elevated risk of cardiovascular disease. Conclusion: CAP is an important parameter that can be measured in this group of patients and is significantly elevated in women with postpartum preeclampsia, even when the brachial blood pressure is normal. There is currently a range of conditions that include pregnancy-related hypertensive disorders, which are classified before and after the 20th week of gestation . ChronicHypertensive disorders in pregnancy are the second leading cause of maternal death, accounting for 14.0% of maternal deaths around the world, and they are an important cause of morbidity in this group of patients . RegardiPreeclampsia (PE) is defined as a disorder of pregnancy associated with new-onset arterial hypertension after the 20th week of gestation until the first 6 weeks postpartum, commonly accompanied by recent-onset proteinuria; however, this condition may present as other signs or symptoms in the absence of proteinuria . The maiThe diagnosis of PE is complex since it implies the involvement of different systems and not only the existence of arterial hypertension (>140/90 mmHg); for example, patients with PE can present with proteinuria (2+ on a test strip or >300 mg from a 24 h urine sample) and/or evidence of acute kidney injury, liver dysfunction, thrombocytopenia, hemolysis, neurological features, and fetal growth restriction . SymptomCardiovascular function during pregnancy is affected by important changes that allow for healthy fetal development, for example, a 20% increase in pulse rate, uterine artery blood flow, a 30–40% increase in cardiac output, blood flow microvascular, and blood flow at rest; likewise, blood pressure decreases at approximately 18 weeks gestation and then increases toward the end of pregnancy .In recent years, the association of PE with increased arterial stiffness during and after pregnancy, rather than gestational hypertension, has been documented ,8,9. On The evaluation of arterial function can be performed through invasive and noninvasive methods, where the latter are preferred since they are safe, easy, and reproducible procedures ,8,10,11.Specifically, the AIx is both an indicator of left ventricular work during systole and a direct measure of vasoconstriction, which is why it has been shown to be an independent predictor of cardiovascular risk, coronary disease, cerebrovascular events, cardiovascular mortality, and exercise tolerance ,12,13,14Given the high rates of PE in pregnant Mexican women and the fact that there are no studies that report its association with arterial stiffness, this descriptive study was proposed, with the aim of comparing CAP between women with preeclampsia and women with normotension from an urban region in western Mexico.This study was performed in the obstetrics department of the Fray Antonio Alcalde Civil Hospital from 1 September 2017 to 19 January 2018.For this study, a sample size of 78 subjects, 39 in each arm, is sufficient to detect a clinically important difference of 7.3 between groups, assuming a standard deviation of 11.25 using a two-tailed t-test of the difference between means with 80% power and a 5% level of significance (39 patients without preeclampsia and 39 patients with preeclampsia).The recruitment criteria for this study were as follows: women in immediate puerperium who were willing to participate in the study and who gave informed consent before any protocol procedures. All participants had no history of any other cardiovascular disease except PE at the time of inclusion.PE was defined as follows: a systolic blood pressure of 140 mmHg or more and diastolic blood pressure of 90 mmHg or more on two independent measurements taken at least 4 h apart in combination with proteinuria  in pregnant women who were previously normotensive for at least the first 20 weeks of pregnancy to through the first 6 weeks postpartum, according to the PE diagnostic criteria of the American College of Obstetricians and Gynecologists [Pulse wave analysis was used to assess central hemodynamics as well as arterial stiffness with the oscillometric device Omron HEM-9000 AI . For this purpose, the measurement of the wave of the left radial artery was obtained with a wrist applanation tonometer and an ascending aortic pressure wave was generated using the accompanying software . Additionally, the systolic central aortic pressure, diastolic pressure, pulse pressure, heart rate, and rise rate adjusted for a heart rate of 75 bpm were determined. The radial pulse wave was calibrated using the diastolic and mean arterial pressures obtained from the left brachial artery. All these procedures were performed in accordance with the instructions provided by the manufacturer ,15.The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Clinical Research and Bioethics Committee of the Hospital Civil de Guadalajara Fray Antonio Alcalde approved this study, and all patients signed informed consent forms.p < 0.05 to be significant.All data obtained were analyzed using GraphPad Prism version 9.3.1.471 . For the descriptive analysis, quantitative variables were analyzed with measures of central tendency and dispersion (the median and standard deviation). For inferential analysis, the differences between groups were analyzed using Student’s t test, and for nonparametric data, the Mann-Whitney U test was used. For all statistical analyses, we considered We recruited 78 women in immediate puerperium for our study, 39 patients with preeclampsia and 39 patients with normotension, who received delivery care in our hospital between September 2017 and January 2018.Of the included patients diagnosed with preeclampsia, 6 were diagnosed with early-onset preeclampsia (diagnosed before 34 weeks’ gestation), while 33 were diagnosed with late-onset preeclampsia (diagnosed after 34 weeks’ gestation). Patients were classified as having severe preeclampsia if, at the time of diagnosis, they presented pressures above 160/110 mmHg, proteinuria, and headaches accompanied by phosphenes.At the time of inclusion in this study, all the patients with PE (n = 39) were under antihypertensive treatment, of which 14 patients (35.89%) were treated with captopril and nifedipine; 12 patients (30.76%) with captopril alone; 8 patients (20.52%) with enalapril and nifedipine; and 5 patients (12.83%) with losartan and nifedipine. No other medications (both for women with and without preeclampsia) were taken during the collection of data for our study.p = 0.882 and a confidence interval (CI) of 0–5; weight, with a mean of 74.01  vs. 70.09 (SD ± 15.71) kilograms, with a value of p = 0.3088 and a CI of −3.70–11.55; body mass index (BMI) of 28.73 (SD ± 6.23) vs. 28.25 (SD ± 5.37) kg/m2 with a value of p = 0.7154 and a CI of −2.14–3.1; gestational age at delivery of 36.68 (SD ± 2.83) vs. 39.21 (SD ± 1.34) weeks, with a value of p < 0.0001 and a CI of −3–−1; serum hemoglobin of 12.77 (SD ± 1.50) vs. 12.70 (SD ± 1.75) g/dl with a value of p = 0.864 and with a CI of −0.67–0.80, respectively. In patients with preeclampsia, the mean urine protein collected per 24 h was 1076.12 mg/24 h (SD ± 1703.63).For our sample of patients, the following clinical characteristics were analyzed, comparing the group of women with preeclampsia with the group of women without preeclampsia: age, with a mean of 25.59  vs. 22.9 (SD ± 5.7) years, with a value of The comparison of the hemodynamic characteristics between women with and without preeclampsia can be seen in p < 0.001) in the comparison of both groups for the AIx, while Turi et al. showed an equal result in pregnant Romanian women in 2020 [In this study, we found that preeclampsia was characterized by an increase in systolic CAP; however, this increase was not observed in the AIx or in the AIx adjusted for a heart rate of 75 bpm in patients with preeclampsia compared to those without preeclampsia. In Austria in 2013, Franz et al.  reported in 2020 .p = 0.05) [p = 0.44) [p = 0.000) for both the AIx and the AIx adjusted for a heart rate of 75 bpm in the studied pregnant South African women [On the other hand, regarding the AIx adjusted for a heart rate of 75 bpm, Torrado et al. showed a relevant significant difference between the evaluated Uruguayan groups ( = 0.05) , and in  = 0.44) . Accordian women . In our an women . Althougan women ,19. Evenan women . In the Our study showed that the patients with preeclampsia in our sample presented a significant increase in central pressures, which suggests an increase in arterial stiffness in patients affected by preeclampsia compared to those without preeclampsia. Similarly, Torrado et al. found a significant elevation of this parameter in patients with preeclampsia . Polóniap = 0.115 and BMI, p = 0.067) [p < 0.001 for both variables in the three studies) [Regarding somatometry, our results for weight and BMI did not show statistical significance, in agreement with what was reported by Franz et al. in 2013 and by Namugowa et al.  ,18. Thisstudies) ,16,17.In our study, we observed a statistically significant difference in terms of gestational age at delivery, being lower in the case of women with preeclampsia. This can be explained due to the recommendations of international clinical guidelines regarding indications for induction of labor or caesarean section in women with preeclampsia, taking into account that our sample of patients was only women with severe preeclampsia .p = 0.22) and Torrado in 2015 (p = 0.844) [p = 0.006) and Namugowa et al. from 2017 (p = 0.000), significant differences in this parameter were not found [The heart rate in our study was not different between the groups examined, which was also reported by Savvidou et al. in 2011 (= 0.844) ,17. Convot found ,18.p = 0.36) [p = 0.041) and Namugowa et al. (p = 0.000) obtained statistical relevance in their respective populations [Pulse pressure did not show a difference between the groups in our study, similar to that reported by Savvidou et al. in UK patients ( = 0.36) . In contulations ,18.p = 0.000, for the three pressures), and although the averages of these variables reported in the publication were below the diagnostic blood pressures for hypertension, the rest of the endothelial function evaluations were altered [p < 0.001 for the three pressures), Franz et al., or Turi et al. (p < 0.001 in both studies), predominantly in systolic and diastolic pressures [In our study, pregnant patients with preeclampsia had higher systolic, diastolic, and mean arterial pressure (MAP) values than pregnant women with normotension. These results are similar to those found by Namugowa et al. in 2017 , CAP remained high ; therefoCAP can be measured with a noninvasive method that provides relevant data on short- and long-term therapeutic behaviors . It shouOne limitation of our study is that as it was a cross-sectional study, we cannot say whether the increase in systolic CAP in patients with preeclampsia was the cause of the disease or a consequence of the pathology.Even though the sample size of our study was relatively small, the means and standard deviations in our study are similar to those of other studies that have statistical significance, indicating that the sample of 78 patients was adequate to detect the effect of pregnancy status with at least 80% power.The measurement of systolic CAP in patients with preeclampsia who are given a subsequent clinical follow-up could be a more reliable indicator of the cardiovascular health of the patients and indicate the need for targeted interventions to avoid chronic cardiovascular changes or reduce the mortality associated with the lack of periodic medical check-ups in patients with high cardiovascular risk.In conclusion, women with preeclampsia in our study presented significantly higher systolic pressure, diastolic pressure, mean arterial pressure, and systolic CAP than women without preeclampsia. CAP is an important parameter that can be measured in this group of patients and is significantly elevated in women with preeclampsia, even when the BBP is normal. It can indicate an elevated risk of cardiovascular disease that warrants follow-up for possible therapeutic interventions, and its noninvasive measurement can be useful in a variety of clinical situations, such as early recognition of PE. Future longitudinal studies in this group of patients are needed to determine causality.