Due to the asymptomatic nature of the early stages, chronic kidney disease (CKD) is usually diagnosed at late stages and lacks targeted therapy, highlighting the need for new biomarkers to better understand its pathophysiology and to be used for early diagnosis and therapeutic targets. Given the close relationship between CKD and cardiovascular disease (CVD), we investigated the associations of 233 CVD- and inflammation-related plasma proteins with kidney function decline and aimed to assess whether the observed associations are causal.We included 1140 participants, aged 55–74 years at baseline, from the Cooperative Health Research in the Region of Augsburg (KORA) cohort study, with a median follow-up time of 13.4 years and 2 follow-up visits. We measured 233 plasma proteins using a proximity extension assay at baseline. In the discovery analysis, linear regression models were used to estimate the associations of 233 proteins with the annual rate of change in creatinine-based estimated glomerular filtration rate (eGFRcr). We further investigated the association of eGFRcr-associated proteins with the annual rate of change in cystatin C-based eGFR (eGFRcys) and eGFRcr-based incident CKD. Two-sample Mendelian randomization was used to infer causality.In the fully adjusted model, 66 out of 233 proteins were inversely associated with the annual rate of change in eGFRcr, indicating that higher baseline protein levels were associated with faster eGFRcr decline. Among these 66 proteins, 21 proteins were associated with both the annual rate of change in eGFRcys and incident CKD. Mendelian randomization analyses on these 21 proteins suggest a potential causal association of higher tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) level with eGFR decline.We reported 21 proteins associated with kidney function decline and incident CKD and provided preliminary evidence suggesting a potential causal association between TNFRSF11A and kidney function decline. Further Mendelian randomization studies are needed to establish a conclusive causal association.The online version contains supplementary material available at 10.1186/s12916-023-02962-z. Chronic kidney disease (CKD), which is characterized by a progressive loss in kidney function over months or years , affecteIt has been well documented that CKD is strongly related to cardiovascular diseases (CVD), and they share common mechanisms such as oxidative stress and inflammation , 4. ThusAn increasingly large number of studies investigating the associations of urinary and circulating proteomic biomarkers with kidney function and the progression of kidney disease have been published in the past decade –16. We hThe present study aimed to investigate the associations of 233 CVD- and inflammation-related plasma proteins with longitudinal changes in kidney function in a community-based prospective cohort of middle-aged and older adults to uncover biomarkers and pathways involved in longitudinal kidney function decline and CKD development. Furthermore, we aimed to investigate whether the observed associations were potentially causal by using a two-sample Mendelian randomization (MR) design.N = 1653). The flow chart of study participants is presented in Fig. n = 19) or complete proteomics measurements (n = 68) at KORA S4 were excluded, leaving a total of 1566 participants at baseline. For the longitudinal analysis, participants without follow-up information on eGFRcr at both F4 and FF4 (n = 426) were further excluded. Finally, a total of 1140 participants were included, with a median follow-up time of 13.4  years  were further excluded when investigating the associations of proteomic biomarkers with incident CKD. The KORA S4, F4, and FF4 studies were approved by the local ethical committee (Number: 99186) and all participants gave written informed consent.This study was based on the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4/FF4 cohort study , 18. A tPlasma samples of baseline participants aged 55–74 years were used to measure proteomic biomarkers. Three Olink panels, including the Proseek Multiplex CVD II, CVD III, and Inflammation panels , each covering 92 proteins, were measured using proximity extension assay technology , 20. A t2 [The primary outcomes in the present study were the annual rate of change in eGFRcr and incident eGFRcr-based CKD, given their availability at KORA S4, F4, and FF4. Creatinine was assessed in fresh serum using an enzymatic method at S4 , a modified kinetic rate Jaffe method at F4 and the first part of FF4 , and a Jaffe method for the second part of FF4 . Serum creatinine at KORA F4 and FF4 part 1) were Isotope-Dilution Mass Spectrometry standardized. Kidney function was primarily assessed by eGFRcr calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Eq. 2009 . A CKD c were Iso2  was used2  and usedIn all surveys, standardized face-to-face interviews were conducted by trained staff , gatheriContinuous variables were reported as mean  for normally distributed data and median (interquartile range) for skewed data. Categorical variables were presented as total numbers with the corresponding percentage.n = 1140), the annual rate of change in eGFR was calculated as β coefficients from linear regression of eGFR regressed against age at the time of eGFR measurement for each participant, and thus, each participant had 1 annual rate of change in eGFR , exclusion of participants who had CKD at baseline (n = 54), exclusion of participants who had an increase in eGFRcr during follow-up (n = 151), or further adjusted for UACR at F4 to control for the confounding effect of albuminuria . To partially address bias caused by loss to follow-up , which was defined as the annual rate of change in eGFRcr < -3 ml/min/1.73 m2/year , was use2 at the following follow-up , or participants free of CKD at S4 had to have more than 50% decline in eGFRcr together with eGFRcr < 60 ml/min per 1.73m2 at FF4 [2 at S4, F4, and FF4.The 66 proteins significantly associated with the annual rate of change in eGFRcr were taken to investigate their associations with eGFRcr-based incident CKD, using interval-censored Cox regression models , adjusted for the same covariates in the above model 2, using R package “icenReg v.2.0.15” . Cox pro2 at FF4 . The conhttps://platform.opentargets.org/) [The proteins consistently associated with the annual rate of change in eGFRcr, the annual rate of change in eGFRcys, and incident CKD were further investigated regarding their associations with UACR at F4 using linear regression. To annotate druggable targets of the identified proteins, related information  was gathered from Open Targets Platform (ts.org/)  based onWe applied a two-sample MR design using the largest genome-wide association studies (GWAS) results to date. Additional file To characterize biological pathways that are enriched for the identified proteins, a Gene Ontology enrichment analysis was performed, using R package “clusterProfiler v.4.0.5” . To inveAll analyses were conducted by R version 4.1.0  and RStudio version 1.4.1717 .2/year  ml/min/1.73 m2 at FF4. Figure Table 67.6 SD, 5.3 ml/mi67.6 SD, 5.3 ml/mi2/year. When calculating eGFRcr using the 2021 equation, the correlation coefficient between the annual rate of change in eGFRcr-2009 and eGFRcr-2021 was 0.998 , which means that in comparison to participants with lower levels of biomarkers at baseline, participants with higher levels of biomarkers had a faster decline in eGFRcr  with faster eGFR decline . HoweveA total of 254 pathways that reached statistical significance (FDR < 0.05) were identified when using 21 biomarkers Table . The topP-value = 0.030, FDR = 0.463).In this prospective cohort study, we investigated the associations of 233 proteins with longitudinal change in kidney function and incident CKD among 1140 participants. A total of 66 biomarkers were associated with the annual rate of change in eGFRcr in discovery analysis, and 21 biomarkers out of these, were found to be also associated with both the annual rate of change in eGFRcys and incident CKD. Using a two-sample MR approach, we provided preliminary evidence suggesting a potential causal association between TNFRSF11A and kidney function decline , which has been shown to be a reliable biomarker for diagnosis of heart failure and prognostic evaluation among patients with heart failure . In the 2). Thus, we mainly focused on the annual rate of kidney function decline as an outcome rather than severe eGFR decline  or ESKD. Of note, our sensitivity analyses on rapid kidney function decline and redefinition of incident CKD cases show robust results . A previous GWAS in 583 coronary patients observed an association of a polymorphism located within the genomic region of TNFRSF11A with kidney function decline [p < 3.4E-11, each protein had only 1 cis-SNP as instrument, which limited the possibility to test the robustness of our results in sensitivity analyses and may have reduced our statistical power [In MR analysis, our results show preliminary evidence suggesting a potential causal association of TNFRSF11A with eGFR decline ( decline  reportedal power . Additioal power , althoug2 persists for more than 3 months. Thus, because our data may not be ideally suited for predictive analysis due to various limitations, such as a suboptimal CKD diagnosis and lack of external validation cohorts, we did not develop a prediction model for the development and progression of CKD. Our primary aim was to identify potential biomarkers related to kidney function decline, which may contribute to the development of predictive models, diagnostic strategies, and therapeutic targets in the future. Third, there may be selection bias due to loss to follow-up, but the results of sensitivity analysis with inverse probability weights suggest that this may not affect our result remarkably. Finally, although we adjusted for multiple confounders, we were unable to adjust for albuminuria at baseline due to lack of data.Study strengths include the assessment of a large number of proteomic biomarkers and the use of a large prospective cohort study, with a median follow-up time of 13.4 years and two follow-up visits for most participants. The Strengthening the Reporting of Observational Studies in Epidemiology checklists for cohort studies and MR studies are presented in Additional file In conclusion, we found 21 known proteins to be associated with kidney function decline and incident CKD in a Caucasian community-based population and provided further evidence regarding new diagnostic or prognostic biomarkers and therapeutic targets for CKD. Although the current underpowered MR analysis failed to find convincing evidence for causal associations of the 21 proteins with kidney function decline, our results provide preliminary evidence suggesting a potential causal association between TNFRSF11A and kidney function decline and a role of TNF signaling pathways in the pathophysiology of CKD. Further MR studies are needed to establish and validate a conclusive causal association.Additional file 1: Table S1. Normalized expressionvalues for proteomic biomarkers at baseline; Table S2. SNPs-traitsassociations retrieved from PhenoScanner V2 for proteins-related SNPs; Table S3. Harmonized summary statisticsused in Mendelian randomization analysis; TableS4. Characteristics of participants over the study period; Table S5. Baseline characteristics forparticipants with and without follow-up information on eGFRcr; Table S6. Longitudinal associationsbetween 233 proteomic biomarkers and the annual rate of change in eGFRcr; Table S7. Longitudinal associations between 233 proteomicbiomarkers and the annual rate of change in CKD-EPI Equation 2009-based andCKD-EPI Equation 2021-based eGFRcr;Table S8. Sensitivity analyses oflongitudinal associations between 66 proteomic biomarkers and the annual rateof change in eGFRcr; Table S9. Sensitivityanalyses of association of 66 proteomic biomarkers with rapid decline in eGFRcrand CKD incidence; Table S10. Associationof 66 proteomic biomarkers with the annual rate of change in eGFRcys and CKDincidence; Table S11. Longitudinalassociations between 233 proteomic biomarkers and the annual rate of change ineGFRcys; Table S12. Longitudinal associationsbetween baseline characteristics and the annual rate of change in eGFRcr andeGFRcys; TableS13. Association of 21 proteomic biomarkers with UACR; Table S14. Summary of druggable targetsand their corresponding disease of the 21 identified proteins; Table S15. Proteomic biomarkersassociated with kidney function and/or chronic kidney disease in previouscross-sectional or longitudinal proteomic studies; Table S16. Evaluation of bias due to participant overlap intwo-sample Mendelian randomization analysis; Table S17. STROBEStatement—checklist of items in reports of observational studies; Table S18. STROBE-MR checklist of recommended items in reports of Mendelianrandomization studies.Additional file 2: Text S1. Assessment of kidneyoutcomes; TextS2. Inverse probabilityweighting; Text S3. Mendelianrandomization analysis; Figure S1. Exampleof the annual rate of change in eGFR for each participant; Figure S2. Flowchart of statistical analyses; Figure S3. Genetic instrument selection and data harmonization forMendelian randomization analysis; FigureS4. Distribution and correlation between the annual rate of change ineGFRcr and eGFRcys; Figure S5. Overlapof proteomic biomarkers between biomarkers associated with the annual rate ofchange in eGFRcr in several sensitivity analyses; Figure S6. Longitudinal associations between 66 proteomicbiomarkers and the annual rate of change in eGFRcys; Figure S7. Association of 66 proteomic biomarkers with eGFRcr-basedCKD incidence; Figure S8. Pairwisecorrelation matrix between the 21 identified proteomic biomarkers; Figure S9. Pathway enrichment analysisof the 21 identified biomarkers showing top biological processes related tokidney function.


Acute large vessel occlusion due to underlying intracranial atherosclerotic stenosis (ICAS-LVO) increases the difficulty of revascularization, resulting in frequent re-occlusion. The establishment of its pathogenesis before endovascular treatment (EVT) is beneficial for patients. We aimed at developing and validating a clinical prediction model for ICAS-LVO patients before EVT.Patients with acute large vessel occlusion at Jining No. 1 People’s Hospital from January 2019 to September 2021 were retrospectively included as the training cohort. The 70 patients who met the inclusion and exclusion criteria were included in the validation cohort (October 2021 to May 2022). Demographics, onset form, medical history, digital subtraction angiography (DSA) imaging data, and laboratory test data were collected. Preprocedural parameters for the ICAS-LVO risk prediction model were established by stepwise logistic regression controlling for the confounding effects. Then, we constructed a nomogram model and evaluated its performance via the Hosmer-Lemeshow goodness-of-fit test, area under the ROC curve (AUC) analysis.p = 0.451) and good discrimination . The optimal cut-off value for the ICAS-LVO scale was 2 points, with 86.5% sensitivity, 91.1% specificity, and 90.5% accuracy. In the validation cohort, the discriminative ability was promising with an AUC value of 0.897, implying a good predictive performance.The 231 acute LVO patients were included in the final analysis, 74 (32.3%) patients were ICAS-LVO. A preoperative diagnosis prediction model consisting of five predictors for ICAS-LVO, including fluctuating symptoms, NIHSS < 16, atrial fibrillation, tapered sign, and ASITN/SIR score ≥ 2. The model depicted an acceptable calibration (Hosmer-Lemeshow test, The established ICAS-LVO scale, which is composed of five predictors: fluctuating symptoms, NIHSS < 16, atrial fibrillation, tapered sign, and ASITN/SIR score ≥ 2, has a good predictive value for ICAS-LVO in Chinese populations. Globally, acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is among the leading causes of mortality and disability. Several randomized controlled trials –5 have sLarge vessel occlusion due to intracranial atherosclerosis (ICAS-LVO) is prevalent among Asians, and the incidences are higher than those found in other areas of the world . CompareUnique pathogenesis is associated with more complex and time-consuming surgical procedures, which present significant challenges in ICAS-LVO intervention , 17. TheWe retrospectively evaluated patients who had been subjected to emergency EVT due to acute large vessel ischemic stroke at Jining No. 1 People’s Hospital stroke center from January 2019 to September 2021. The EVT procedures included stent retrieval, aspiration, angioplasty, stenting or a combination of these techniques.ICAS-LVO was defined as: (1) intracranial artery fixed stenosis of > 70% when successful reperfusion was achieved and (2) degree of intracranial artery stenosis > 50% in addition to either flow and perfusion impairment on angiography or evident re-occlusion tendency even after adequate treatment with stent retrievers. Embolic-LVO was defined as the absence of residual stenosis in occluded segments after successful reperfusion of the occlusion vessel. The exclusion criteria were: (1) the pathogenesis of occluded vessels due to failed recanalization cannot be reliably assessed, (2) when the cause of vascular occlusion was vasculitis, or moyamoya disease, (3) presence of tandem lesions associated with the carotid or vertebral arteries in the extracranial segment  and (4) DSA image information is missing. This retrospective, observational study was approved by the Ethical Committee of No. 1 People’s Hospital of Jining.Immediately after admission, all patients were subjected to routine blood tests, serum biochemistry tests, blood coagulation tests, electrocardiogram, brain CT NIHSS, mRS, and GCS. Data on demographics, onset form, medical history, digital subtraction angiography (DSA) imaging and laboratory tests were retrospectively collected. Then, data were double entered using the EpiData Entry software v3.1 . To eliminate selection bias, radiologic assessments were conducted by two neuroradiologists and one neurologist.Fluctuating symptoms are defined as symptomatic fluctuations and progressive aggravation during the early course of neurologic deficits . The tapN (%) and compared using the χ2-testand Fisherʼs, exact test. Continuous variables are presented as mean ± standard deviation if normally distributed and as medians and interquartile ranges (IQR), if not normally distributed. The Mann-Whitney U test and the t‑test were used to compare continuous variables between groups.Multiple sixfold imputation was performed using the chained equations method to fill the missing blood test results . Baseline characteristics were compared between the ICAS-LVO and embolic LVO groups. Categorical variables are presented as numbers and percentages p < 0.05 in the univariate regression analysis. Cut-off values were determined using the maximum of Youden index. Continuous variables were translated into categorical variables. Collinearity diagnosis was performed using the variance inflation factor (VIF). Binary logistic regression  was used to evaluate the predictors and to generate the regression model as well as its related odds ratio (OR), 95% confidence interval (CI), beta coefficient and p values. The beta coefficients were rounded to the closest integer to generate a brief ICAS-LVO scale. The ROC curve was used to calculate the optimal cut-off value of the area under the curve (AUC) to assess the predictive accuracy of the scale and discriminatory ability of the model. The Hosmer-Lemeshow test was performed to assess calibration. A nomogram was built on the brief predictive model as a graphical presentation.Multivariable logistic regression analysis was performed for variables with Analyses were performed using the SPSS software package, version 22  and R software, version 4.1.3 .Tables n = 2, tandem lesions associated with the carotid or vertebral arteries in the extracranial segment n = 42, including extracranial stenosis of the vertebral or carotid artery carotid dissection n = 35, extracranial carotid dissection n = 7) were excluded. Finally, 231 patients were analyzed ; diabetes ; CHD n = 67 (29.00%); AF n = 87 (37.66%); VHD n = 19 (8.25%); ICAS n = 14 (6.06%); ischemic stroke n = 50 (21.65%); ICH, n = 6 (2.60%); smoking n = 72 (31.17%); and drinking 72 (n = 31.17%). Based on findings from DSA, patients were divided into two groups: ICAS-LVO group 74 (32.04%) and embolic-LVO group 157 (67.96%).Baseline characteristics for the training cohort are presented in Table p = 0.016, DBP: 93.50 mmHg  vs. 85.00 mmHg  p = 0.001; VLDL, very-low-density lipoprotein ; TG, triglyceride , p = 0.001) current smoking and drinking (40.50% vs. 26.90%), p = 0.037; 40.50% vs. 26.90%, p = 0.035), and had lower baseline NIHSS scores 15 vs. 19 p = 0.001; better collateral circulation ASITN/SIR score 2.00 vs. 1.00, p < 0.001. The embolic-LVO group had more cases of atrial fibrillation  and heart valve disease ; INR ; PT, ; WBC, ; neutrophils, ; NLR  and a lower proportion of ICAS history  when compared to the ICAS-LVO group.The ICAS-LVO and embolic-LVO groups differed in various aspects Tables  and 2. CThe internal carotid artery siphon, and the trunks before bifurcation in the M1 segment of the middle cerebral artery (MCA), mid-lower segment of the basilar artery are the most common intracranial sites of stenosis . In thisp = 0.451) and good discrimination . The β‑coefficients of the five predictors are shown in Table After excluding factors with collinearity or clinical relations with others, there were five more variables in the prediction model: fluctuating symptoms, NIHSS < 16 , AF, tapered, ASITN/SIR score ≥ 2 . The model depicted acceptable calibration  the discrimination ability was still promising with an AUC value of 0.897 and a good predictive performance Fig. ; Table 4% the disEarly and accurate diagnosis of ICAS-LVO before interventional surgery is particularly important to help select the most appropriate device . It is wTapered sign is defined as the appearance of a tapered beak-like or flame-like sign on DSA imaging –33. TapeCollateral circulation plays an important role in preserving perfusion and stabilizing cerebral blood flow in acute occlusion . ChronicWe included variables that were associated with ICAS-LVO as predictors into the analysis. Binary logistic stepwise regression analysis was performed to evaluate the predictors and generate the ICAS-LVO scale, which had 5 predictors; fluctuating symptoms, NIHSS < 16, AF, tapered sign, and ASITN/SIR score ≥ 2. These 5 predictors are easily available clinically. This scale was shown to have the ability to identify the pathogenesis of intracranial vascular occlusion before interventional therapy and to enhance the identification of acute cerebral infarction due to ICAS-LVO. It is important for neurointerventionalists to perform optimal revascularization strategies to reduce the difficulty of surgery and shorten the vascular recanalization time, although, the preferred initial treatment during interventional therapy for ICAS-LVO patients has yet to be established; however, the identification of ICAS-LVO before EVT may improve recanalization rates with more targeted revascularization techniques and shorten recanalization times with early remedial measures , 36, 41.There are several limitations in this study. First, as a retrospective observational study conducted in a single center, there may be information bias. Second, the clinical prediction models drawn from this study are limited by the relatively small sample size. Our findings should be verified via further external validation and their generalizability evaluated using large sample, multicenter datasets.The predictive scale comprising of fluctuating symptoms, NIHSS < 16, atrial fibrillation, tapered sign, and ASITN/SIR score ≥ 2 has a promising predictive value for ICAS-LVO before EVT in ischemic stroke due to acute large-vessel occlusion patients.


This association was independent from other foods whose consumption is associated with the high legume intake. Conclusions: In people with T2D and hypertension, three servings of legumes per week are associated with significantly better BP control. This gives further support to current dietary guidelines in recommending the frequent consumption of legumes, as a “ready-to-use” dietary strategy to achieve optimal BP control.Background: Our aims were to evaluate the relationship of habitual legume consumption with blood pressure (BP) control in a large cohort of people with T2D and hypertension, and to investigate whether specific nutritional components of legumes or other foods may contribute to regulate BP levels. Methods: We studied 1897 participants with T2D and hypertension. Dietary habits were assessed through a validated food frequency questionnaire. Sex-specific quartiles of legume consumption were created. Results: Higher legume consumption was associated with a lower intake of energy, carbohydrates, glycaemic load, alcohol, and sodium, and a significantly greater intake of proteins, fat, monounsaturated, polyunsaturated, fibre, potassium, and polyphenols. Significantly lower systolic and diastolic BP values were observed in the highest vs. lowest quartile of legume consumption (132.9 ± 6.7 vs. 137.3 ± 7.0 mmHg,  Hypertension is a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, and chronic kidney disease . To dateData from observational studies show that high blood pressure levels cause a significant increase in the risk of vascular complications in individuals with diabetes and predispose to a higher incidence of chronic kidney disease, ischemic cerebrovascular disease, retinopathy, and cardiovascular mortality ,6,7,8. TPharmacological treatment is required in the management of most patients, but lifestyle modification, including a better quality of diet, and weight management, are key components to control both blood glucose and blood pressure. Previous studies have shown that the consumption of specific foods, such as fruit and vegetables, dairy products, and whole grains, or the adherence to specific dietary patterns, such as the Mediterranean diet, or the low glycaemic index diet, can improve blood pressure control in diabetes patients ,11,12. TAmong plant-based foods, legumes contain various components linked to lower blood pressure, including dietary fibre, bioactive peptides, and flavonoid polyphenols ,17, but Therefore, the aims of the present study were to evaluate the association between habitual legume consumption and systolic and diastolic blood pressure control in a large cohort of people with type 2 diabetes and hypertension, and to investigate whether specific nutritional components of legumes, or other foods associated with a legume rich dietary pattern, may contribute to modulate blood pressure levels in real life conditions.clinicaltrials.gov (accessed on 31 May 2023) NCT00700856), a randomized clinical trial designed to assess the cardiovascular effects of two different hypoglycaemic drugs. The TOSCA.IT study complied with the Declaration of Helsinki and was granted the approval of the Ethics Committee of the coordinating centre and of each participating centre; written informed consent was obtained from all participants. Details on the study protocol, inclusion and exclusion criteria have been published elsewhere [We analysed the baseline data from the TOSCA.IT trial  was calculated as kg/mFasting blood sample were analysed in a central laboratory. High-performance liquid chromatography (HPLC) was used to measure HbA1c. Lipid profile  were measured by standard methods. The LDL-cholesterol was calculated by the Friedewald equation for people with triglycerides values < 400 mg/dL . The stuDietary habits during the past 12 months were assessed by the validated EPIC food frequency questionnaire (FFQ)  for a toThrough the use of a specifically designed software developed ad hoc by the Epidemiology and Prevention Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan , questioData are given as numbers and percentages, or mean values (M) and standard deviation (SD) for continuous variables, as appropriate.To correct for the different energy intake between subjects, the intake of legumes was expressed as g/1000 kcal/day. The sex specific quartiles of legume consumption were created to assess the relation of legume consumption with blood pressure, anthropometric variables, glucose control, and plasma lipids.2 test was used to compare proportions. To compare variables across the quartiles, the analysis of variance with a test for a linear trend was used for the continuous variables, and the χMultivariate linear regression analysis was used to estimate the separate and combined association of legumes and other dietary factors with the variables of interest  and results were expressed as regression coefficients (β). The explored dietary factors were cereals, wholegrains, potatoes, vegetables, fruits, nuts, fish, meat, eggs, dairy products, milk and yogurt, olive oil, animal fat, alcoholic beverages, sweeteners beverages, coffee and tea, and cakes and pastries. Multivariate linear regression analyses were performed to explore the impact of nutrients or bioactive compounds of legumes  on systolic and diastolic blood pressure.p values of less than 0.05 were considered to indicate statistical significance.The statistical analyses were performed with IBM version 28.0. Statistical tests were two-sided, and 2. Most participants were taking anti-hypertensive medications (95.6%) and 22% of total population had micro-albuminuria (The study population consisted of 1079 men (56.9%) and 818 women (43.1%) with a history of type 2 diabetes 8.7 years (±5.7 years) and hypertension of about 7.2 years (±6.4 years). The mean age was 62.8 years (±6.4 years), and BMI 30.8 ± 4.5 Kg/muminuria .p < 0.001; 78.9 ± 4.1 vs. 81.0 ± 4.2 mmHg, p = 0.002; respectively). Accordingly, the percentage of people on target for systolic and diastolic blood pressure significantly increased across the quartiles of legumes intake   and diastolic (<80 mmHg) blood pressure across the sex-specific quartiles of legume consumption are reported in  < 0.01) .No significant differences were observed across quartiles regarding age, diabetes duration, BMI, waist circumference, HbA1c, total cholesterol, LDL- and HDL-cholesterol, triglycerides, C-reactive protein, and percentage of people with micro-albuminuria . The samp < 0.05), and a lower intake of refined cereals, animal fat , alcoholic beverages, and cake and pastries (p < 0.05). No significant differences were detected for potatoes, nuts, meat, dairy products, milk and yogurt, sweetened beverages, and coffee and tea consumption (The specific food pattern associated with legume consumption is shown in sumption .p < 0.001) (p < 0.05). The intake of saturated fat, cholesterol and added sugar, and the glycaemic index of the diet did not change across the quartiles (As compared to subjects with lower legume intakes (Q1), participants reporting higher legume consumption (Q4) had significantly lower intake of energy, total carbohydrates and starch, glycaemic load, alcohol, and sodium (< 0.001) . Signifiuartiles .p < 0.001; β = −0.061, p = 0.014, respectively) independently of any other dietary item; none of the other foods consumed by the study participants was associated with blood pressure . This association disappeared when legumes were included in the model and was replaced by a significant inverse association between systolic and diastolic blood pressure values with legume consumption, thus suggesting that dietary fibre plays a significant role in modulating the relationship between legume consumption and blood pressure control.In addition, in order to evaluate which nutrients linked legume consumption to systolic and diastolic blood pressure values, separate linear regression models were used. As reported in This study investigated, for the first time, the association between legume consumption and blood pressure in a large cohort of people with type 2 diabetes, in the context of real-life conditions, where the amount of legumes intake was that habitually consumed by the study population and substantially lower than in the intervention trials conducted so far ,19,30. NLegume consumption in relation to blood pressure has been studied in people with or without type 2 diabetes in intervention studies exploring the beneficial effects of high legume intakes. Jenkins et al.  reportedA feature shared by all these studies is the high amounts of legumes used within dietary interventions which is unfeasible for the long term in real life conditions. Yet, our study confirms the association of legumes with lower systolic and diastolic blood pressure for a lesser amount of consumption (70 g three times a week), which is more feasible and in line with that recommended for the general population and suggested by the dietary guidelines for people with type 2 diabetes.Prior population studies in non-diabetic people have also reported that an increased legume intake is associated with a reduced risk of developing hypertension. A meta-analysis of five observational studies reported a ~5% risk reduction to develop hypertension for about 70 g/day of legume consumption . A subseAll these previous observational studies were performed in people without diabetes; conversely, we performed our study in a large cohort of individuals with type 2 diabetes; it is of interest that our population was almost entirely under anti-hypertensive pharmacological treatment. This means that legume consumption can represent an additional tool—besides medications—to lower blood pressure, allowing a larger proportion of people with type 2 diabetes to reach the target. Among several legume components potentially involved in the beneficial relationship observed with blood pressure in people with type 2 diabetes, like proteins, fibre, sodium, potassium, and polyphenols, only fibre showed a significant association with lower levels of systolic and diastolic blood pressure according to our results. This can be due, at least in part, to the demonstrated role of fibre in reducing inflammation ,38 and iHowever, the possible contribution of other macro- and micro-nutrients present in legumes in explaining the association between consumption of this food group with a better blood pressure control should also be considered. In this respect, the vasodilatory effect of arginine in legume proteins via converting into nitric oxide has been demonstrated in animal and in vitro models and proposed as a potential mechanism driving the relationship observed ,41. OtheThe health benefits of polyphenols from legumes in relation to blood pressure control were summarized in a recent comprehensive review by Ganesan et al.  demonstrThere are several strengths of this study. This is the first large cohort of people with type 2 diabetes in which the links between legume intake and blood pressure were investigated in real-life conditions. Furthermore, the study was able to control for medications, metabolic parameters, and dietary components, which can play a significant modulating effect on blood pressure. Finally, the use of a central laboratory for biochemical analyses ensures good quality standards for the measurements. Our study also has limitations, the most relevant being the cross-sectional study design which does not enable the establishing of a cause–effect relationship. Residual confounding cannot be ruled out, even though our findings are independent of (1) other dietary items and their components, such as mono- and poly-unsaturated fatty acids, glycaemic load, sodium, and alcohol intake; and (2) the main potential confounders, such as age, BMI, and smoking habit, were controlled. Furthermore, we did not analyse the role of different types of legumes consumed, as legume intake was aggregated into total amount. In this regard, we cannot exclude that different types of legumes may have different effects due to their distinct nutritional characteristics. Finally, we cannot exclude that individuals eating a healthier diet and consuming less alcohol may be more adherent to their medication.Our findings in people with type 2 diabetes showed that the association of legume consumption with lower systolic and diastolic blood pressure values is already present for an intake of approximately three servings per week, which is feasible and in line with the current dietary recommendations for people with diabetes. This gives further support to current dietary guidelines in recommending the use of legumes  for people with type 2 diabetes.


The gold standard is invasive measurement and monitoring via ventricular drainage or a parenchymal probe. In recent decades, numerous methods for non-invasive measurement have been evaluated but none have become established in routine clinical practice. The aim of this study was to reflect on the current state of research and shed light on relevant techniques for future clinical application. (2) Methods: We performed a PubMed search for “non-invasive AND ICP AND (measurement OR monitoring)” and identified 306 results. On the basis of these search results, we conducted an in-depth source analysis to identify additional methods. Studies were analyzed for design, patient type , statistical evaluation , number of included measurements, and statistical assessment of accuracy and reliability. (3) Results: MRI-ICP and two-depth Doppler showed the most potential (and were the most complex methods). Tympanic membrane temperature, diffuse correlation spectroscopy, natural resonance frequency, and retinal vein approaches were also promising. (4) Conclusions: To date, no convincing evidence supports the use of a particular method for non-invasive intracranial pressure measurement. However, many new approaches are under development. Measurement of intracranial pressure (ICP) is a pillar for the management of patients in intensive care units. The hypothesis known as the Monro–Kellie doctrine ,2 statesIn principle, the ICP can be measured invasively in three different ways: via lumbar drainage  , externaAll invasive methods carry a risk of infection or intracranial bleeding ,17,18,19Although the ICP is usually given as a static value, in reality, it corresponds to a pulsatile wave, which is influenced by arterial and venous blood pressure, body position, and peritoneal pressure , given tFor decades, scientists and physicians have searched for a reliable, non-invasive method for ICP monitoring. To date, although many methods have shown promising results, the necessary measurement precision and reliability according to a Bland and Altman analysis with ground-truth invasive measurements  has not In this review, we describe the current status of non-invasive intracranial pressure measurement and provide an overview of the numerous new methods to identify procedures that may be used in intensive care units in the future.Our report is a narrative review of methods for non-invasive ICP estimation. This set of heterogeneous measurement concepts can be subdivided according to the device used, the physical properties, or the anatomy of the underlying structures.To provide an overview, we first performed a PubMed search for (“non-invasive” AND “ICP” AND (“measurement” OR “monitoring”)). The 306 results consisted of 68 optic nerve sheath diameter (ONSD) studies, 41 reviews, 22 transcranial Doppler (TCD) studies, 22 other vascular method studies (without TCD), 21 otic method studies, 15 computed tomography (CT)/magnetic resonance imaging (MRI) studies, and 14 other ophthalmic studies (without ONSD). Of the results, 57 studies did not match the content of our search and were excluded. If a study compared two or more methods, it was counted as the rarest method. A pie chart of the included studies is shown in The main techniques used were ultrasound/Doppler for transcranial or transorbital measurements, CT, MRI, near-infrared spectroscopy (NIRS), tympanic membrane displacement systems ,36, ear The measured anatomic structures were vessels, eyes, ears, and the entire skull. The target structures and methods are presented in Six major measurement methods were found: (i) methods based on physiological parameters, (ii) ultrasound/Doppler, (iii) CT/MR imaging-based methods, (iv) di-/electric methods, (v) ophthalmic methods, and (vi) otic methods. The studies were carried out on phantoms, animal models, and healthy subjects, as well as patients with hydrocephalus and in intensive care units. Patient populations varied widely from infants to adults and from those who were healthy to those with traumatic brain injury (TBI) or hypoxic brain ischemia. Several of these methods were tested. However, there remains a strong need for better techniques, particularly for point-of-care use .A much-discussed Lancet article in 1997 postulated a relationship between intraocular pressure and ICP . A correA review of intracranial compliance as a reserve capacity for maintaining ICP stability highlighted the additional potential of this metric in monitoring .In a review from 2012, it was found that non-invasive measurements did not sufficiently and accurately measure the ICP . A recenAnother review found that no non-invasive methods were suitable on their own and recommended the use of a flow chart to evaluate the various non-invasive methods to avoid the placement of cranial pressure probes . Many otIn a recent study, the neurologic pupillary index was found to have the highest prognostic value for short-term unfavorable outcomes in patients with TBI but recommended a combination of several methods overall .In a meta-analysis of critically ill patients from 2019 , the pooA study of hypoxic brain ischemia indicated a moderate correlation with the ICP . The stuIt must be noted that most studies only report correlations. Although the Pearson’s correlation coefficient is a useful statistical method, it provides only a rough estimate and may not represent a reliable determination of the accuracy and reliability of a measurement method. Therefore, more stringent statistical methods  should be used instead.The importance of monitoring multiple values in the complex treatment of patients in intensive care has been confirmed by the measurement of the cerebral perfusion pressure (CPP), which can be calculated according to the difference in the mean systemic arterial blood pressure and the ICP . In the A refractory elevated ICP is associated with significantly elevated odds ratios (OR) for death  .Correlations between the ICP and single physiological parameters have been evaluated but have not shown promising results. For example, a waveform analysis of the radial arterial blood pressure has indicated a good correlation with ICP waves in approximately one-third of patients. Because of the high variance, this approach is not reliable in clinical practice .The concept of an increasing ICP correlating with changes in transcranial propagation of ultrasonic impulses was described in the late 1980s ,64 and iA review found a broad range of prediction accuracies  from 0.62 to 0.92 in the detection of elevated ICPs (≥20 mmHg) . The maiAn advantage of TCD measurements is that they are easy to obtain and perform, but only an optimal ultrasound window through the cranial bones can be found rapidly. The results also depend on the ultrasound operator. The quality of ultrasound devices has substantially improved in recent decades .A retrospective evaluation found a moderate correlation (r = 0.51) between the ICP and non-invasive ICP, calculated using the middle cerebral artery blood flow velocity and arterial blood pressure . An algoA fuzzy logic algorithm has also been applied to TCD and arterial blood pressure , and supIn a recent prospective study, the diastolic flow velocity showed a good correlation (r = 0.72) with the ICP . 2O) [A study of patients with suspected idiopathic intracranial hypertension demonstrated excellent results for detecting increased ICPs, with a sensitivity and specificity of 0.92 for a cutoff of approximately 15 mmHg (20 cmH2O) . Current and r = 0.07 (no correlation) in an analysis of subgroups with normalized vs. non-normalized slow-wave activity .2 = 0.86 for NIRS and r2 = 0.91 for diffuse optics) were shown in a recent study of primates under controlled conditions [Even better results with an optimized wave analysis and an increased correlation , and a combination of both methods showed even better performance (r = 0.8) . A review of minimally invasive multimodal monitoring was conducted .A recent study  observedMost methods can be improved by regular calibration  based onA multiparameter fusion model using vital and hemodynamic parameters, TCD, and FVEP found an excellent correlation with an invasive ICP (r = 0.931) .Software called ICM+ was developed by Cambridge University to handle the complexity of intensive care monitoring, including the estimation of CSF dynamics and ICP .2 > 0.9990) [A special case for measuring the ICP exists in newborns, whose fontanelles provide an additional possibility for measuring pressure. In 1980, the first non-invasive measurements of the ICP in infants via the anterior fontanelle were performed ,107,108. 0.9990) .The hypothesis that CO₂ levels influence the ICP and can be used for non-invasive measurements was tested through combined exposure to CO₂ and head-down tilt. The results indicated only small effects on an increasing ICP .The concept of the waves of the ICP reaching the skull and causing expansion and retraction, which can be measured as a pulse, was first described by Ueno . A novelAnother similar device , a specially developed pillow for detecting micromotions/head tremors, also achieved good results (r = 0.74) in initial clinical testing . 2 = 0.96) as a surrogate for the ICP. An interesting study from Japan [2 + 0.0842 × NRF), with an excellent correlation (R2 = 0.9952). Therefore, the individual NRF depends only on the ICP value. The (acoustic/vibration) natural resonance frequency (NRF) spectrum and its modal damping characteristics were successfully used to estimate the ICP in an experimental study in rabbits . An exceom Japan  suggesteInnovative approaches based on microwaves  and highIn a prospective study, cerebrovascular autoregulation was monitored invasively and non-invasively using arterial blood pressure and intracranial blood volume slow waves , detected by a pair of ultrasonic transducers on either side of the patient’s head .CT imaging plays a minor role in non-invasive ICP studies. Although bleeding and a midline shift can be detected, which primarily reflect an increased ICP, the absence of these two findings does not indicate the absence of an increased ICP. In a meta-analysis , the folMR technologies have been used to estimate the CSF velocity in the aqueduct and foramen magnum so that craniospinal CSF pressure gradients can be calculated. An additional parallel measurement of cranial fluid flows during a cardiac cycle  enables the estimation of cranial compliance and elasticity. This method was introduced in 2000 and was called MR-ICP . It indiThe main idea, which is based on Bernoulli’s principle and a Fourier transform, was demonstrated by Muehlmann et al. , who shoIn a pilot study, the pulse pressure gradient of the spinal canal at level C2 assessed using phase-contrast MRI (using a simplified Navier–Stokes equation) demonstrated no correlation with the pulsatile ICP .New real-time MRI technologies  suggest In 1932, Atzler and Lehmann  introducThe intracranial electrical impedance method  measures blood flow through an alternating current and was introduced for neurologic diseases in the early 1960s by Jenkner . InitialIn the early 1990s, a model device (headband) for measuring dielectric properties was described by Russegger and Ennemoser  and showA novel, high-precision electrical impedance tomography method introduced in 2018 ,149 usesA study from Scotland examined the relationship between electrical impedance and ICP and concluded that electrical impedance is not suitable for reliably estimating the ICP . An artiWhen electromagnetic waves pass through the head and brain, they are influenced by the dielectric properties of the CSF, brain, and blood. On the basis of this idea, a pilot study in rabbits revealed the potential of broadband antennas to detect intracranial hemorrhage, with an accuracy of 77% . AnotherIn retrospective feasibility studies, a strong causal relationship between EEG and the ICP was identified ,156 and In a swine model, the best estimation of single-channel EEG signals with ICP was found using a support vector machine , with a Reviews of methods of non-invasive measurements of ICP via ocular measurements highlighted the limitations and potential of specific applications ,159 but Another review  reportedRagauskas et al. ,163,164 The frequency of the oculocardiac reflex as a disturbance variable in measurements  in ophthAnother approach in 2020 using fundus photography to calculate the ratio of the arteriole and venule diameter was described , revealiOphthalmodynamometry was introduced by Bailliart in 1917 . ElliottVenous ophthalmodynamometry was successfully tested for ICP estimation on Mount Everest (r = 0.85)  and in iA novel method for objective detection of venous vessel pulsation through high-resolution video recordings was introduced in 2015. This method may help to improve current measurement methods . An autoA model for a better mathematical understanding of these pulsations was described by Morgan et al. . A model based on zero retinal vein pulsation measured by photoplethysmography showed an excellent correlation with an invasive ICP (r = 0.91) .The mechanism underlying the effects of an increased ICP on retinal veins consists of increasing the cerebral venous pressure, elevating the CSF pressure in the optic nerve sheath, and developing papilledema. Therefore, changes in retinal veins can be used to indicate an increased ICP .Multi-layer perceptron neural networks with input vectors of retinal vein pulsations and intraorbital pressure demonstrated excellent accuracy and reliability  for the Larger prospective studies on these promising mechanisms are needed. The mean diameter of the optic nerve in healthy patients is 3 mm and the optic nerve is surrounded by a small subarachnoid space (0.1–0.2 mm thickness) and a leptomeningeal sheath (0.3 mm thickness) ,184. A dONSD is position-dependent . In mostIn 1987, increased ONSD was observed in patients with intracranial hypertension . In 2002In a meta-analysis, ONSD was found to have an ROC AUC of 0.932 in detecting increased ICPs (>20 mmHg), with a sensitivity of 88–95% and a specificity of 74–96% .An interesting study on asymmetric ONSD suggested that this method lacks significant diagnostic value .A study of children indicated a sensitivity of 93% and a specificity of 74% in detecting increased ICPs with a threshold ONSD of 5.5 mm , with excellent inter-rater reliability ,200. TheIn adults, ONSD demonstrated a good correlation with invasive ICP measurements of r = 0.71 , r = 0.5In one review, the typical cutoff values were summarized as 5.0 mm in adults (>15 years of age), 4.5 mm in children 1–15 years of age, and 4.0 mm in infants <1 year of age .Case reports have described the successful clinical application of ONSD-only monitoring under various conditions, including anticoagulation , intraop2 level was correlated with a decrease in ONSD. Another study of awake patients with ICP reported a threshold of 5.05 mm, with a sensitivity of 92% and a specificity of 90% [Under general anesthesia, the strong effects of carbon dioxide levels were observed in children  and aduly of 90% .An experimental study revealing that ONSD decreases with lumbar puncture also demonstrated the ability to collect real-time ONSD measurements . SimilarIn a swine model with intracranial balloons, excellent correlations between ONSD and balloon volume, as well as invasively measured ICP, were found .A study of patients with idiopathic intracranial hypertension indicated a correlation between ONSD and body mass index .In a pilot study, the measurement of (only) the subarachnoid space of the optic nerve achieved better results than ONSD .Pocket-sized ultrasound devices have also been evaluated ,225 and In the future, the standardized automated assessment of ONSD  is expecOwing to the transport risk in patients in intensive care, monitoring using MRI or CT is scientifically interesting but clinically less important. In MRI, the optic nerve appears isointense to cerebral white matter in T1- and T2-weighted images and is surrounded by the optic nerve sheath containing the pia, CSF, arachnoid, and dura . In geneBeyond an optic nerve sheath with increased diameter, several other properties of revealed ICP have been found: (i) a flattening of the posterior sclera, (ii) papilla protrusion, and (iii) kinking or tortuosity of the optic nerve .In principle, MRI is superior to CT in detecting optic nerve sheath diameter owing to the better representation of soft tissue and water. However, a substantial agreement (r = 0.959) between measurements of the optic nerve sheath diameter using CT and MRI was demonstrated in patients with craniosynostosis .High-resolution MRI indicated an additional correlation with body mass index and demonstrated a sensitivity of 70% and a specificity of 72% in the prediction of increased ICPs using a model based on MRI and the body mass index (BMI) .An ophthalmoscopic study revealed excellent sensitivity (100%) in the detection of elevated ICPs but poor specificity of only 32% . SeveralOptical coherence tomography can be used to detect a thickening of the retinal nerve fiber layer and, therefore, can be used as a quantitative tool to detect early papilledemas  and, conVisual-evoked potential latency can be delayed in patients with idiopathic intracranial hypertension and can detect optic nerve damage or increased ICP . Hence, The main clinical application of portable pupillometry, which was introduced in 1989, remains the assessment of brain stem function .A neurological pupil index measuring pupillary reactivity was introduced in 2012  but has The idea of using intracochlear fluid pressure as a possible monitoring device was described in 1987 , and theTympanic membrane displacement initially showed excellent results in patients with ventriculo-peritoneal shunts , as wellOther pilot studies analyzed otoacoustic emissions ,254,255,2 = 0.93) [A new system based on tympanic membrane temperature was developed and indicated excellent results for predicting increased ICPs and a correlation with invasive ICP monitoring (r = 0.93) . Approaches for non-invasive ICP measurements via the tympanic membrane have been pursued for more than 35 years but remain clinically inapplicable; therefore, doubts have been cast regarding its feasibility.The idea of ear-to-ear ultrasound waves is strongly related to a previously mentioned concept  and was In the 1970s, invasive measurement probes were used for non-invasive purposes in infants through the fontanelle. Later, software tools (such as ICM) were developed for multimodal monitoring, which were able to estimate missing parameters, e.g., ICP curves. In the late 1980s, the flow parameters of transcranial Doppler were analyzed and correlated with the ICP. In Austria, a dielectric approach was tested in neurosurgical patients.In 2005, the two-depth Doppler method was introduced. In the past decade, new technologies have increasingly been developed but most require further evaluation. The selected methods are listed in What levels of accuracy and reliability would be acceptable for a non-invasive method to be considered appropriate for routine clinical use? The main problem is that reliability is necessary for critical events, such as cerebral hemorrhage, seizure, or hydrocephalus. A reliability of 99% in an unremarkable intensive care stay is useless if the method would miss these critical events. Fear among intensive care physicians is one reason these procedures have not yet been incorporated into everyday clinical practice. Whether a long-term test under physiological conditions would enable a method for detecting pathological changes in a system as complex as the human body remains unclear. However, even with the established invasive test procedures, these critical events are sometimes overlooked or considered measurement errors.MRI-ICP and two-depth Doppler (the most complex methods) show the most promising accuracy but are not always applicable. Tympanic membrane temperature, diffuse correlation spectroscopy, and natural resonance frequency are also techniques of interest, although whether the excellent correlations observed in pilot studies can be sustained remains to be seen. The retinal vein approach appears to remain an insider tip despite promising results. The comparison of approaches is often hindered by the use of different statistical evaluations . Many techniques have been evaluated only in healthy people or compared with other non-invasive techniques. Such comparisons are insufficient for clinical proposes.Selectivity studies of novel techniques, as well as clinical applications and comparisons with the gold standard of invasive ICP measurement, are lacking. Many studies have assessed feasibility or have been performed in research institutions rather than in clinical settings.In addition, many studies have not stated the exact inclusion and exclusion criteria for participants, thus making the studies only slightly comparable overall and introducing bias.An exception is the studies of ONSD, which were conducted in large numbers and, in some cases, were of high quality.Overall, there appears to be insufficient basic research, and physically oriented approaches using other parameters  are notably lacking. Most approaches have focused on physiological concepts, which may have risks  or insufficient accuracy and reliability, possibly because physicians in many specialist disciplines  have a narrow research focus that sometimes loses sight of the bigger picture.For example, several anatomical norm variants of the CSF coupling of eyes and ears exist given that different manifestations of visual impairments in astronauts have been observed after long-duration space flights . In partAnother point is the existence of unpredictable events (power blackouts or seizures), which may de-calibrate a method, leading to inaccurate measurements. Almost all researchers consider their methods to be excellent, although comparisons to the gold standard or other relevant methods are often lacking. In addition, evaluations regarding real-world applicability are lacking, such as determining the number of people the method can be used on or the frequency of non-realistic errors.Even if no convincing non-invasive ICP measurement currently exists, many physical properties of the head remain to be evaluated for these pressure measurements. The best solution according to current viewpoints, will probably involve combining several methods and calibrating them at intervals . The continuing development of non-invasive methods with suitable feedback mechanisms is necessary to strengthen the confidence of physicians and further improve the methods.


Differences between the 2 groups were analyzed for demographic features, FENO values, and predictive correlations between FENO and BD. Both groups of patients showed an increase in the eosinophil count  and FENO values (P = .015 for both) with an increase in the asthma severity from step 3 to step 5 of the global strategy for asthma management and prevention. The correlations of FENO and eosinophils as well as FENO values and BD + were 0.127  and 0.696 , respectively. Measuring FENO levels may be useful for identifying patients with BD+.Nitric oxide (NO) is an important product of eosinophilic metabolism, and its increase is associated with bronchial remodeling and airway hyperresponsiveness. Fractional exhaled NO (FENO) in the expired air of patients with suspected or diagnosed asthma has been used as a marker for eosinophilic inflammation. This cohort study included asthmatic patients classified under steps 3, 4, or 5 of the global strategy for asthma management and prevention. In the morning of the same day, all patients underwent blood collection for eosinophil counts, followed by FENO measurement and spirometry. We considered 2 groups based on the bronchodilation (BD) response on spirometry (>10% of FVC or FEV FENO has become a diagnostic indicator and a tool for prognostic and therapeutic evaluations.,5 Moreover, the advent of immunobiology has brought great advances in the treatment of asthma, with predominantly immunological and pathophysiological approaches. Therefore, using FENO to identify the predominant inflammatory mechanism has become essential for assessing severely ill patients refractory to inhaled and systemic treatments. However, some gaps are yet to be addressed, such as their correlation with bronchial reactivity and flow variability, which are essential for the diagnosis of asthma. Thus, the main objective of this study was to analyze FENO values in a cohort of patients classified under steps 3, 4, and 5 of the global strategy for asthma management and prevention (GINA) and to correlate these values to positive bronchodilation (BD) results on spirometry. In addition, these findings could identify patients who would potentially demonstrate bronchodilator test positivity.Nitric oxide (NO) is an important free radical produced during the arginine cycle. It functions as a messenger that interferes with several inflammatory cascades. In patients with asthma, NO is an important product of eosinophilic metabolism, and its increase is related to bronchial remodeling and airway hyperresponsiveness.This prospective cohort study included patients treated at the Severe Asthma Center of the Rio de Janeiro State University. The inclusion criteria were age > 18 years, taking ≥ 800 µg of budesonide, and classified under steps 3, 4, or 5 of the GINA 2022. Patients underwent blood collection for eosinophil count, spirometry, and FENO measurements in the morning of the same day. The exclusion criteria were history of smoking and coexisting chronic obstructive pulmonary disease. All participants provided free and informed consent. This study was approved by the Committee for the Ethics of Research (CAAE-94348718.8.0000.5259).All patients underwent blood collection, followed by 2 FENO measurements and spirometry to minimize the influence of spirometry and the BD maneuver on NO measurements. In addition, an epidemiological questionnaire was used to collect data on variables such as age, sex, time since diagnosis, medications used, number of attacks in the previous year, body mass index (BMI), and asthma control assessment using the GINA questionnaire.,10 Forced vital capacity (FVC)%, forced expiratory volume in 1 second (FEV1)%, and the FEV1/FVC ratio (%) of predicted were determined before and after 20 minutes of using the inhaled bronchodilator . BD values were calculated according to the ATS/European Respiratory Society for 2022 and an increment above 10% of the predicted FEV1 or FVC value was considered a response to the bronchodilator.,10Spirometry tests were performed using an HD CPL apparatus  following the American Thoracic Society (ATS) criteria. NO levels were measured in a single breath exhaled directly into the analyzer at 50 mL/s for at least 6 seconds. The exhalation was repeated, and the reproducibility was verified. The exhaled NO levels were measured in parts per million (ppm) and obtained in real time.FENO levels were measured using the NIOX VERO device according to the technique recommended by the ATS and European Respiratory Society.t tests with significance levels (type I error probability) of 0.05 and sample sizes (in each group) for the calculation of effect sizes. The Mann–Whitney U test was used for continuous numerical variables to compare the demographic, clinical, and immunological characteristics and baseline pulmonary function tests between the BD test groups with negative and positive results. The Fisher’s exact test was used to evaluate the frequency independence between categorical nominal variables and disease severity. For intra-rater agreement in the FENO measurements, the average intraclass correlation coefficient for the two-way random-effects (patients and raters) analysis of variance model  was used as an index of intra-rater reliability, consistency, and agreement. F tests and one-sided 95% confidence intervals (CIs) were used to assess statistical significance. Moreover, Bland–Altman plots were drawn to illustrate the 95% CIs for bias and limits of agreement. Pearson’s correlation coefficient was used to compare continuous variables. Multiple linear mixed-effects models were used to evaluate the log-transformed repeated FENO measurements, either between the BD test groups or among the levels of bronchial responsiveness and GINA, and patients were considered random effects. In addition, we introduced any clinical/phenotypic features associated with FENO as confounders to eliminate any possible bias introduced by convenience sampling. The fixed systematic component of the models was adjusted for the confounding variables of age, BMI, sex, time since asthma diagnosis (in years), number of exacerbations in the previous year, severity (GINA steps), and current use of topical corticosteroids. The Tukey honest significant difference method was used to correct p-values using the number of comparisons whenever necessary. Estimated mean marginal effects and their 95% CIs are presented graphically, whereas all other variables in the multiple linear mixed models are presented as means or equal proportions using contrasts constructed from these estimated mean marginal effects. Statistical significance was set at P < .05. The software R version 4.1.1 , packages “lme4” and “emmeans,” and their dependencies were used to perform statistical analysis.The estimated statistical power for pairwise mean differences between groups of 2 repeated measures of FENO were 100% for both Gina step 4 to 5 and sex. Other contrasts had a lower statistical power, between 0.05 and 0.53, assuming paired two-tailed http://links.lww.com/MD/J341).Outpatients from the Severe Asthma Center were invited to participate and 30 of them were recruited; however, one was excluded due to difficulty in performing the FENO measurement technique. Thus, the data of 29 patients were analyzed; 82% were women and 18% were men. Most patients were obese or overweight (65.5%), with a median age of 43 years and an average time since diagnosis of 30 years. Approximately 41.4% of the patients had GINA step 3, 44.8% had GINA step 4, and 13.8% had GINA step 5. The mean dose of inhaled budesonide was 800 µg/d. The mean number of exacerbations in this cohort in the previous year was 4, and the median concentration of exhaled NO was 34 ppm. Table P = .03).Statistical analysis of the samples revealed no correlation between the FENO values and the presence or absence of a BD response on spirometry. However, there was a slight tendency for the FENO values to be higher in the BD+ group than in the BD− group Fig. . FurtherP < .001) with a mean agreement of 0.12 (–0.146 to –0.273) between the first and second FENO measurements. Thus, it is acceptable and reasonable to conduct only one measurement for each patient  , and dose of inhaled corticosteroid used, the GINA step 5 patients had higher mean FENO values than the GINA step 4 patients (15) Fig. .P = .714, R = 0.098 ) and FENO with all patients   did not demonstrate statistical significance.The cohort was divided into BD+ and BD− groups, comprising patients with positive and negative BD test results, respectively, on spirometry. The BD+ and BD− groups had a mean age of 40 years and 42 years, respectively, and a mean time since diagnosis of 26 and 29 years, respectively. The FENO values were 46.9 and 41.8 ppm, respectively, and predominantly comprised GINA step 3 (56.2%) and step 4 patients (61.5%). There was a strong positive correlation between FENO and BD+ group values (Fig.  Recently, with the advent of immunobiological drugs, identifying the most prevalent inflammatory pathway has become increasingly important in the improvement of treatment in patients. Thus, biomarkers, such as FENO, help identify the eosinophilic inflammation profile, which is of fundamental importance not only in the diagnostic evaluation but also in the therapeutic follow-up of these patients.,6 The findings of this study show that FENO has the potential to help physicians in therapeutic orientation, as high values might be associated with a bronchodilator response.Asthma is a chronic inflammatory airway disease with multiple pathophysiological mechanisms. According to the ATS consensus, an FENO level >50 ppm is suggestive of eosinophilic inflammation, with a likely response to inhaled corticosteroids. However, values between 25 and 49 ppm must be interpreted with caution and should be correlated with other biomarkers.,12 In this cohort, the mean FENO value was 34 ppm, and higher exhaled NO values were suitable for predicting bronchial reactivity. It is expected that patients with detectable bronchial responsiveness on spirometry would have increased inflammation and high exhaled NO levels.,14FENO values must be interpreted while considering certain technical and patient-related aspects. it is not sufficient to establish an eosinophilic inflammation profile. Indeed, this cohort predominantly included patients with a prolonged time of diagnosis who probably had more than one inflammatory mechanism and not necessarily an eosinophilic mechanism. This could have contributed to the lower-than-expected FENO value. Furthermore, the process of bronchoreactivity and BD response is multifactorial and not exclusive to the eosinophilic pathway of inflammation.,16 FENO is applicable not only for identifying patients with severe asthma but also for those at a higher risk of exacerbations, serving as a guide for the clinical management of this group of patients.The median FENO value in our study was 34 ppm, and according to the ATS,,2 In this cohort, FENO values were significantly higher in men than in women despite the small number of participants. The relationship between FENO values and sex is controversial and not well-established. Some studies have shown that women are mainly predisposed to allergic asthma, mostly due to hormonal effects; however, this report contradicts the reports of international literature.,17 In contrast, there are cohorts in post hoc analyses that show that NO levels are higher in men than in women.The assessment of FENO in the airways depends on several factors, such as the use of medications and cigarettes. Despite being well-established for the diagnosis of severe asthma, its use in low-resource developing countries is restricted for financial reasons. This study showed good reproducibility and repeatability of results. Therefore, only one measurement per patient was considered satisfactory. These results are relevant because they demonstrate a reduction in the number of tests conducted and an increase in the availability of tests, regardless of the service expertise in the method.Although the FENO methodology is simple from a practical viewpoint, it requires continuous exhalation at a flow of 0.05 L/min.The main limitation of this prospective cohort study was its small sample size, which affected the distribution of the results and resulted in great variability in the values obtained. Other limitations of the study were that it was carried out in a single center and it used a convenience sample.Advances in technology and discoveries regarding the pathophysiology of eosinophilic asthma have expanded the scope and applicability of FENO in the evaluation of patients with diagnosed or suspected asthma. Measuring FENO can be helpful in identifying eosinophilic asthma and disease exacerbation as well as predicting the bronchodilator response. However, we observed that FENO was higher in step 4 and 5 patients, even in those who had lower eosinophil values in the peripheral blood. Our findings present the possibility of using FENO to predict BD.We would like to thank the Pulmonology Service, Department of Chest Diseases, Medical Sciences Faculty, Rio de Janeiro State University, Brazil.Conceptualization: Thiago Prudente Bartholo, Kennedy Martins Kirk, Mario Fritsch Neves.Data curation: Bruna Cuoco Provenzano, Kennedy Martins Kirk, Ana Paula Ramos Barreto, Nadja Polisseni Graça, Paulo Roberto Chauvet Coelho.Formal analysis: Thiago Prudente Bartholo, Marcelo Ribeiro-Alves, Rogerio Rufino.Funding acquisition: Claudia Henrique da Costa, Rogerio Rufino.Investigation: Bruna Cuoco Provenzano, Kennedy Martins Kirk, Mario Fritsch Neves, Ana Paula Ramos Barreto, Nadja Polisseni Graça, Paulo Roberto Chauvet Coelho.Methodology: Thiago Prudente Bartholo, Kennedy Martins Kirk, Mario Fritsch Neves, Marcelo Ribeiro-Alves, Claudia Henrique da Costa.Resources: Mario Fritsch Neves.Supervision: Thiago Prudente Bartholo.Writing – original draft: Bruna Cuoco Provenzano, Thiago Prudente Bartholo, Claudia Henrique da Costa, Rogerio Rufino.Writing – review & editing: Thiago Prudente Bartholo, Claudia Henrique da Costa, Rogerio Rufino.


Moreover, elevated pretransplant serum creatinine and need for kidney replacement therapy is associated with nonresolution of HRS-1 after liver transplant.2 Treatment of HRS-1 often necessitates admission into the intensive care unit (ICU) for the administration of vasopressor support. In patients with HRS-1, the mean length of ICU stay is 10 days, with an average total hospital stay of 30.5 days.3 The diagnosis of AKI in patients with cirrhosis is independently associated with ICU admission, in addition to increased duration of hospital stay, development of multiple organ failure, and increased in-hospital mortality and 90-day mortality.4 Despite the significance of AKI in cirrhosis, several treatment questions remain, such as appropriate treatment parameters like mean arterial pressure (MAP) goals and urine output, to duration of treatment and weaning parameters, to more challenging questions such as when to consider renal replacement therapy or the effect of HRS-1 on liver transplantation evaluation, all leading to substantial resource allocation to these patients in the ICU.Hepatorenal syndrome type-1 (HRS-1) is a frequent cause of AKI in cirrhosis and is associated with significant mortality. The median survival in HRS-1 is 8–12 weeks, with a 30-day survival of 25%.Kidney360, Velez and colleagues attempt to identify factors associated with improved kidney function in patients with HRS-1 and whether differences could be observed between norepinephrine and octreotide/midodrine. Of particular interest was determining whether kidney function improved with varying MAP increases of 5, 10, or 15 mm Hg or whether fixed titration parameters  was sufficient. The retrospective cohort included 77 hospitalized patients with cirrhosis diagnosed with HRS-1 and treated with vasopressor therapy. The primary endpoint was defined as >30% reduction in serum creatinine on cessation of vasopressor support without the need for RRT or death. A significant reduction in serum creatinine was identified in patients with MAP increases of ≥15 mm Hg compared with those with increases of 5 or 10 mm Hg. No differences in serum creatinine was identified when patients were stratified by a fixed absolute parameter. The duration of vasopressor therapy needed to demonstrate evidence of therapeutic response also yielded interesting findings. Of the 25 patients who met the primary end point, 22 (88%) had improvements in serum creatinine within the first 48 hours, with 96%  by 72 hours, suggesting a fairly rapid response to vasopressor therapy in those who saw a significant improvement in kidney function.In this issue of 5 As a result, absolute parameter goals, such as a MAP of 85 mm Hg, may be difficult to achieve or require high doses of vasopressor support, whereas a targeted goal of ≥15 mm Hg is potentially a more reasonable approach. In addition, 96% of patients who experienced improvement in their kidney function demonstrated evidence within the first 72 hours of administration. This provides insight into a reasonable duration of time that can be expected to note if an improvement in kidney function is seen but also identifies an extremely at-risk population for morbidity and mortality among those who do not have any improvement within 72 hours.These findings provide useful observations regarding the treatment goals and expectations for improved kidney function in patients with HRS-1. Patients with advanced cirrhosis typically have lower MAPs and decreased systemic vascular resistance at baseline, largely attributed to imbalance of compensatory homeostatic and vasoactive mechanisms.This study does have several notable limitations. Only a third of the patients enrolled in the study met the primary study end point, limiting the studies' power to compare differences among the differing MAP parameters. In addition, drug administration was not uniformly executed as part of institutional protocols. In most instances, the goal of therapy was to achieve a rise in MAP of ≥5–15 mm Hg, an absolute MAP target of 85 mm Hg, or a range of absolute MAP of 80–85 or 85–90 mm Hg, making comparison difficult between the groups. Given the varying individual MAP response to vasopressor therapy, it is possible that the study identified a subgroup that was more responsive to vasopressor therapy and that this responsiveness provided therapeutic benefit, rather than the actual increase in MAP itself. Furthermore, the mean MAP of 70 seems high for this critically ill population, and an increase of 15 mm Hg in this instance interferes with the absolute targets that were specified. It would be interesting, for instance, to see whether an increase in MAP from 55 to 70 mm Hg was similarly efficacious.6 or terlipressin7 but remains the primary treatment outside of the ICU in the United States. Norepinephrine was the only vasopressor therapy available in the United States that had demonstrated improved kidney function in HRS8 before terlipressin was US Food and Drug Administration–approved for use in HRS in September 2022.9 Norepinephrine and terlipressin may have provided a more effective comparison, but terlipressin was notably associated with significant respiratory complications in a recent randomized trial.10 Of further note, serum creatinine is an imperfect marker for kidney function in patients with cirrhosis because it underestimates renal function due to reduced muscle mass, impaired hepatic production of creatine, and the increased tubular secretion of creatinine. The limitations of serum creatinine highlight the importance of identifying novel biomarkers of kidney function that may more accurately reflect changes in kidney function and facilitate earlier recognition of declining function before the development of HRS-1.In this study, 36% of the cohort received midodrine and octreotide, which has been shown to be less efficacious in the management of HRS-1 when compared with norepinephrineIn conclusion, the results of this retrospective cohort study provide interesting insights into the MAP parameters and duration of time that should be targeted to maximize the likelihood for improved renal function. Future considerations might include a randomized trial that can better stratify MAP parameters to overcome the potential for confounding within the study or the administration of stable doses of norepinephrine to patients on lower acuity services outside of the ICU to determine whether a similar safety profile and improvement in kidney function can be identified.


Cricoid pressure, a manoeuver used to prevent pulmonary aspiration during rapid sequence induction, can result in deterioration of laryngeal view and increased haemodynamic changes. Its effect on laryngoscopy force remains unevaluated. The study aimed to assess the impact of cricoid pressure on laryngoscopy force and intubation characteristics during rapid sequence induction.Seventy American Society of Anaesthesiologists I/II patients, both sexes, aged 16-65, having non-obstetric emergency surgery were randomly assigned to the cricoid group, which received 30 N cricoid pressure during rapid sequence induction, and the sham group, which received 0 N pressure. Propofol, fentanyl, and succinylcholine were used to produce general anaesthesia. The primary outcome was the peak force of laryngoscopy. Secondary outcomes were the laryngoscopic view, time to execute endotracheal intubation, and intubation success rate.P  < .001. Without cricoid pressure, the intubation success rate was 100%, compared to 85.7% with cricoid pressure, P  = .025. The proportions of CL1/2A/2B patients with and without cricoid pressure were 5/23/7 and 17/15/3, respectively, with P  = .005. With cricoid pressure, there was a considerable increase in intubation duration, with a mean difference (95% CI) of 24.4 (2.2-19.9) seconds.With the application of cricoid pressure, the peak forces of laryngoscopy increased significantly, with a mean difference (95% CI) of 15.5 (13.8-17.2) N. With and without CP, the mean peak forces were 40.758 (4.2) and 25.2 (2.6) N, respectively, Cricoid pressure increases peak forces during laryngoscopy, resulting in worse intubation characteristics. This demonstrates the need of exercising care while performing this manoeuver. Cricoid pressure is often applied to prevent aspiration.It’s use resulted in significant increase in peak pressure applied during laryngoscopy.This warrants caution while applying cricoid pressure.1 in 1961 to prevent regurgitation of gastric contents while performing endotracheal intubation during rapid sequence induction in emergency settings. This age-old practice of applying CP has been surrounded with controversies regarding its efficacy in preventing regurgitation2 and potential risks associated with the technique.4Cricoid pressure (CP) is a manoeuver proposed by Sellick8Few studies have reported difficulty in mask ventilation, deterioration of laryngeal view, and difficulty in intubation with the application of cricoid force.9 Factors which result in increased force during laryngoscopy can accentuate these haemodynamic fluctuations, resulting in adverse cardiac events in susceptible individuals. The force of laryngoscopy is dependent on various patient- and performer-related factors. Patient factors include the age, body mask index (BMI), and presence of bucked or protruding teeth, while the performers factors include the experience and technique of the laryngoscopist.10 Therefore, it can be implied that factors which increase the difficulty of laryngoscopy can result in greater force of laryngoscopy. Previous studies reporting force of laryngoscopy observed greater peak force in patients with poor laryngeal view. The worsening of the laryngeal view with CP may warrant increase in the force of laryngoscopy.Laryngoscopy and intubation can induce haemodynamic perturbations in the form of tachycardia and hypertension.Till date, the effect of CP on laryngoscopy force remains unevaluated. We hypothesized that the application of CP would significantly increase the peak force of laryngoscopy. The primary objective was to measure the peak force generated during laryngoscopy with Macintosh laryngoscope in patients with and without CP. Time taken to intubate, glottic visualization, and haemodynamic response were recorded as secondary outcomes.This prospective randomized trial was conducted in the tertiary care Hospital of India after approval from the Postgraduate Institute of Medical Education and Research, Chandigarh, India (NK/6249/Study/131) dated May 8, 2020, and written informed consent from all study participants. The trial was commenced after being registered with Clinical Trial Registry (CTRI/2020/06/0025562). Seventy American Society of Anaesthesiologists (ASA) I and II patients between 16 years to 65 years of either sex were enroled in this prospective randomized trial. Patients with anticipated difficult airway, cardiovascular disease, symptomatic gastroesophageal reflux or reactive airway disease, and ASA >3 were excluded.−1 and fentanyl 1-2 μg kg−1. Succinylcholine 2 mg kg−1 was given for muscle relaxation. The patient was placed in sniffing position (extension of the head and flexion of the neck). Cricoid pressure or sham pressure was applied after induction of anaesthesia using 2 hand technique according to the group allocation. Patients were randomized using computer-generated random numbers into 2 groups in which tracheal intubation was performed with and without CP. In the CP group, 30 N pressure was applied by the trained resident, while 0 N was applied in the sham group. The allocation to the group was concealed in sequentially labelled opaque envelopes.In the operation theatre, standard monitors including pulse oximeter, non-invasive blood pressure, electrocardiograph, and capnograph  were applied. All patients were preoxygenated with 100% oxygen for 3 minutes. General anaesthesia was induced with propofol 2-2.5 mg kg11 who had tested this using custom-made weights and a regularly serviced electronic scale (Seca model 727). Only trained residents were allowed to perform the CP. In the sham group, a hand was placed on the cricoid cartilage without applying any pressure for blinding.Before the commencement of the trial, all the residents and paramedical staff posted in the emergency operation theatre were trained to apply the CP on a mannequin using a 50 mL syringe model for 3 consecutive days. They were instructed to reduce the volume of an air filled obtruded 50-mL syringe to 33 mL to apply 30 N pressure. This method of training to apply cricoid pressure had been successfully demonstrated by Kopka et alA specially designed laryngoscope equipped with strain gauge sensor placed between the blade and the handle to measure the force parallel to the axis of the handle was used to measure the peak force of laryngoscopy. It had a small display unit, which showed the peak force .Laryngoscopy and endotracheal intubation were performed by 2 investigators  with an experience of more than 100 intubations each. The screen of the display unit was kept facing the blinded observer, who recorded the parameters. The time taken to intubation was measured from the time the laryngoscope blade was inserted in the patient’s mouth till the first capnograph trace was seen. The grading of the laryngeal opening was done by the laryngoscopist using Cormack–Lehane (CL) grading. Peak force of laryngoscopy was recorded as primary outcome. Impulse force, laryngoscopic view obtained by CL grade, time taken to intubate, number of attempts taken to intubate, manoeuvers used and haemodynamic response such as heart rate (HR) and mean arterial pressure (MAP), and any desaturation (oxygen saturation <95%) observed were recorded as secondary outcomes.12 who observed applied peak force of 35 N (standard deviation: 12) using Macintosh blade in normal airway patients. Anticipating a 30% increase as clinically relevant increase in force, we calculated the sample size. For an alpha of 0.05 and power of 0.8, we required a sample size of 32 patients in each group. To account for the dropouts, 70 patients would be enroled in the study.Sample size calculation was based on the previous study by Bucx et alt-test. For skewed data, Mann–Whitney test was applied. Qualitative or categorical variables were described as frequencies and proportions. For comparison of tim-related variables, repeated measure analysis of variance (ANOVA) was used. All statistical tests were 2-sided and were performed at a significance level of α = 0.05.The statistical analysis was carried out using Statistical Package for Social Sciences version 22.0 software . Mean and medians were calculated for all quantitative variables. Normality of data was checked by Kolmogorov–Smirnov tests of normality. For normally distributed data, the means of 2 groups was compared using Eighty-four patients were assessed for eligibility out of which 10 did not meet the inclusion criteria and 4 declined consent. A total of 70 patients were randomized and analyzed . The demP  < .001. There was a significant increase in the peak forces of laryngoscopy with the use of CP with a mean difference (95% CI) of 15.5 (13.8-17.2) N. The mean peak forces with and without CP were 40.758 (4.2) and 25.2 (2.6) N, respectively, P  = .025. The proportion of patients with CL1/2A/2B with and without CP were 5/23/7 and 17/15/3, respectively, P  = .005. Two patients (5.7%) in CP group and 3 patients (8.5%) without CP group were intubated in the second attempt (P  = .65). Bougie was used in 6 patients (17%) in CP group and 2 patients (5.7%) in without CP group (P  = .139). Cricoid pressure resulted in a significant increase in the time taken for intubation with a mean difference (95% CI) of 24.4 (2.2- 19.9) seconds  in the CP group at 1 minute of post -ntubation, while increase in MAP was seen in the CP group at 1 minute (P  = .000) and 3 minutes (P  = .040) post-intubation (There was a significant increase in the heart rate (tubation .2 below 95%) was seen in 16 patients in CP group and 4 patients without CP. Minimal trauma was seen in 1 patient in both the groups.Minimum desaturation (SpO12 were one of the initial researchers to demonstrate the force required during laryngoscopy. Later, Hastings et al13 further elaborated that laryngoscopy is a complex procedure involving not just axial but torque forces as well. Their study highlighted that the axial force was a predominant force during laryngoscopy, whereas torque and other forces had minimal contribution to the force of laryngoscopy. An important observation in these studies was the increased force of laryngoscopy in patients with poor glottic view. However, none of the previous studies measuring the force of laryngoscopy included patients in whom CP was applied. Ours is the first study to document and quantify the increase in the force of laryngoscopy in patients whom CP is applied. Bucx et al13During CP application, the tissues that surround the vallecula are forced into closer contact with the laryngoscope blade and the pressure exerted on the laryngoscopy blade can be expected to increase. Another reason for the increase in peak force can be the hampered glottic visibility with the application of CP. To attain an optimal view of the glottis aperture for endotracheal intubation, greater axial force is required. This seems to be in line with the earlier reports by Hasting et al.14 Vanner et al15 showed improvement in the laryngeal view with CP. Contrary to these findings, a study evaluating the effect of CP on laryngoscopic view through endoscopic photography found marked deterioration of laryngeal view in 20% of the patients.16 Noguchi et al17 designed a study to compare the gum elastic bougie and stylet during endotracheal intubation with CP and found significant worsening the laryngeal view with CP.So far, there have been numerous published articles, with contradictory results, reporting the effect of CP on laryngeal view and tracheal intubation.16 reported complete loss of the glottic view in a group of patients with 30 N force.In the present study, we observed significant deterioration of glottic view in the CP group with application of 30 N force. Haslam et alIn contrast to the previous studies, we could not report the change in the glottis view with CP as laryngoscopy in the CP group was performed after the application of the CP.18 showed that the compression of laryngeal and perilaryngeal structures with the application of CP leads to stimulation of the autonomic nervous system resulting in increase in HR and BP, which is further accentuated during induction of anesthesia with laryngoscopy and intubation. Although we observed significant increase in the haemodynamic response during laryngoscopy and intubation in the CP group, there was no significant increase in HR or MAP postinduction of anaesthesia following application of CP. Saghaei et al18,19 Kopka et al11 and Flucker et al20 suggested the use of a 50‐mL syringe as a simple and economical method to be used in everyday clinical practice.Correct application of CP has also been a matter of concern. In this study, 30 N is considered sufficient enough to occlude the esophagus and reduce the risk of pulmonary aspiration. However, it is difficult for practitioners to accurately estimate this force in everyday practice. Various methods investigated to train the staff on the correct application of CP include the weighing scale method, simulation-based training, and use of a 50 mL syringe.The findings of our study highlight another implication of the CP in the form of increased peak force of laryngoscopy. The increased forced combined with the increased duration of laryngoscopy can be hazardous in patients prone to cardiac complications.The results of our study should be interpreted in the light of some limitations. Firstly, the laryngoscope was equipped to measure only the axial force. However, in the hands of trained personal, the effect of torque is minimal. The intubation was performed by the senior resident who had more than 4-5-year experience in anaesthesia. Secondly, as already discussed application of CP is relatively subjective, despite the training of the staff prior to the study. The skin compliance of a manikin is not the same as the patients; therefore, application of 30 N force might not be transmitted equally in a manikin and a patient. The use of a sensor to monitor 30 N force would have been ideal. Lastly, complete blinding of the laryngoscopist to the CP manoeuver was not possible despite the use of sham technique, in which the trained personnel placed a hand on the cricoid cartilage to mimic CP application.To conclude, our findings show significant increase in the peak forces during laryngoscopy with application of CP along with deterioration of intubation parameters. This highlights the need for caution while using this maneuver in susceptible individuals.