Background and Objectives: Functional capacity (FC) assessed via cardiopulmonary exercise testing (CPET) is a novel, independent prognostic marker for patients with coronary artery disease (CAD). Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are two readily available predictors of systemic inflammation and cardiovascular event risk, which could be used as cost-effective predictors of poor FC. The purpose of this study was to evaluate the utility of NLR and PLR in predicting poor FC in patients with CAD and recent elective percutaneous coronary intervention (PCI). Materials and Methods: Our cross-sectional retrospective analysis included 80 patients with stable CAD and recent elective PCI  who were referred to a cardiovascular rehabilitation center from January 2020 to June 2021. All patients underwent clinical examination, cardiopulmonary exercise testing on a cycle ergometer, transthoracic echocardiography and standard blood analysis. Results: Patients were classified according to percent predicted oxygen uptake (% VO2 max) in two groups—poor FC  and preserved FC . There was no significant difference between groups regarding age, gender ratio, presence of associated comorbidities, left ventricular ejection fraction and NLR. PLR was higher in patients with poor FC . A PLR cut-off point of 139 had 74% sensitivity and 60% specificity in predicting poor FC. After multivariate analysis, PLR remained a significant predictor of poor functional status. Conclusions: Although CPET is the gold standard test for assessing FC prior to cardiovascular rehabilitation, its availability remains limited. PLR, a cheap and simple test, could predict poor FC in patients with stable CAD and recent elective PCI and help prioritize referral for cardiovascular rehabilitation in high-risk patients. Coronary artery disease (CAD) is a significant public health problem, with a substantial contribution to global morbidity and mortality, especially in low- and middle-income countries ,2. CurreFunctional capacity (FC) is a strong, independent prognostic factor in heart failure (HF)  and CAD Systemic inflammation plays a major role in CAD etiopathogenesis  and routWe conducted a retrospective cross-sectional study of all patients with stable CAD and recent elective PCI, referred for phase II CR in the Cardiovascular Unit of the Clinical Rehabilitation Hospital in Iași over a period of 18 months (January 2020–June 2021). The Cardiovascular Unit of the Clinical Rehabilitation Hospital in Iași is a nationally ranked dedicated rehabilitation center specializing in phases II and III of cardiovascular rehabilitation ,48. Incl2. High blood pressure (HBP) was defined as current BP lowering treatment, prior diagnosis of HBP, resting systolic blood pressure (SBP) greater than 140 or resting diastolic blood pressure (DBP) greater than 90 mmHg [All patients were under optimal CAD treatment, according to current guidelines . Obesity 90 mmHg . Diabete 90 mmHg ,52,53.® . Biochemistry was processed using the Transasia XL 1000 Fully Automated Biochemistry Analyzer . We recorded the following parameters: platelet count, neutrophil count, lymphocyte count, C-reactive protein (CRP), low-density lipoprotein (LDL) and glycated hemoglobin (HbA1c). NLR was calculated using the absolute neutrophil (N) and lymphocyte (L) values from the complete blood count, using the formula: NLR = N/L. PLR was calculated using the absolute platelets (P) and lymphocyte (L) values from the complete blood count, using the formula: PLR = P/L. According to hospital protocol, blood samples were collected a jeun, in the morning upon admission, by qualified medical professionals. All blood samples were processed in the hospital’s laboratory. Complete blood count was processed using the Pentra DF Nexus Hematology SystemStandardized transthoracic echocardiography  was performed by experienced sonographists according to current EACVI guidelines  . According to hospital protocol, CPET was performed in the morning of the second day of hospitalization, in order to establish functional capacity and target heart rate for exercise rehabilitation. Each patient signed a written informed consent before the test. The test consisted of a 2 min resting period followed by 3 min warm up at 0 W followed by standard incremental exercise protocol of 15 W/min. The CPET was performed under continuous heart rate (HR), 12-lead ECG (electrocardiographic) and pulse oximetry (SpO2) monitoring. Blood pressure was recorded every 2 min. Indications for exercise termination included exhaustion, myocardial ischemia, complex ventricular arrythmia, grade 2 or 3 atrio-ventricular block, a sudden drop in BP levels > 20 mmHg, extreme BP elevation , SpO2 < 80%, confusion or severe dizziness. We recorded the following parameters: resting SBP and DBP , resting HR (recorded on the resting ECG performed immediately prior to the CPET), % peak HR ), % peak WR  and % VO2 max  relative to predicted normal according to age and sex, automatically calculated by the ergospirometer software). Functional capacity was assessed according % VO2 max, using a convention proposed by Cooper et al., as follows: >80%—normal, 71–80%—mildly reduced, 51–70%—moderately reduced and ≤50%—severely reduced . Due to p < 0.05 in the univariate analysis were included in the multivariate logistic regression model, to assess the independent predictors of poor FC (% VO2 max ≤ 70). The results are presented as odds ratio (OR) with 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curve analysis was done to determine the optimum cut-off value of PLR in predicting poor FC of CAD patients and recent PCI. Correlation analyses, calculating Pearson correlation coefficients, were assessed considering normally distributed and linearly related variables. A two-sided p value < 0.05 was considered significant for all analyses.Data analysis was performed using SPSS 20.0 . For continuous data, the normality of distribution was assessed by Shapiro–Wilk test. Data are presented as mean ± standard deviation (SD) for continuous variables with normal distribution, or as median with interquartile range for non-normally distributed continuous variables. Categorical variables are presented as number of cases with percent frequency. An independent samples T-test was used to compare continuous variables with normal distribution. A non-parametric Mann–Whitney’s U test was applied to compare the variables not satisfying the assumption of normality. Categorical comparisons were performed using Chi-square test or Fisher’s exact test . Variables with The study was approved by the Review Board/Ethics Committee of the Clinical Rehabilitation Hospital Iași (number 28567/21.12.2020) and complied with the Declaration of Helsinki. The Clinical Rehabilitation Hospital Iasi Review Board/Ethics Committee considered informed consent unnecessary owing to the characteristics of this study .p = 0.003, p = 0.003) and reached a higher peak HR during exercise (p = 0.006). CRP, platelet, neutrophil and lymphocyte count, as well as resting HR and blood pressure values, were similar between the two subgroups.Our analysis included 35 patients with % VO2 ≤70 and 45 patients with % VO2 >70. Among the hematological parameters, the PLR was higher in the group of % VO2 max ≤70 than in the group of % VO2 max >70  [Functional capacity is an independent prognostic factor in CAD patients ,58,59,60= 0.002) . Indeed,= 0.002) . In a pr= 0.002) . In anot= 0.002) . FC was Elevated blood and plasma viscosity have been associated with an increased risk of CAD. CAD patients have increased platelet and monocyte aggregates in their bloodstream, which are associated with plaque instability, worse in-hospital outcomes and an increased risk of future cardiac events ,83. Exerp = 0.003, p < 0.05; p = 0.009) after multivariate analysis. Using a cut-off point of 139, the PLR predicted poor FC with a sensitivity of 74% and specificity of 60% . To our knowledge, this is the first study that evaluated whether PLR can predict FC assessed by CPET in stable CAD with recent PCI.This study has several limitations. Most importantly, this single-center retrospective analysis included a relatively small number of patients and did not include measurement of other important cardiac biomarkers such as troponin and natriuretic peptides. Furthermore, although all patients had a negative COVID-19 PCR upon admission, we were not able to accurately exclude prior COVID-19 infection (we did not perform antibody testing and we did not take into consideration vaccination status). Previous COVID-19 infection can negatively impact functional capacity and could influence our results. The retrospective structure of our study and the small number of cases, our multiple regression was limited to only a few covariates. Residual covariates and additional risk factors (for example smoking status) could significantly impact our results. Considering these limitations, our conclusions need to be validated in larger cohort analyses. Furthermore, larger prospective studies are needed to evaluate whether PLR can also predict FC improvement after cardiovascular rehabilitation programs.PLR is higher in patients with recent PCI for stable CAD and poor FC compared to those with preserved FC. FC is an independent predictor of long-term prognosis in CAD. Although CPET is the gold standard test for assessing FC prior to cardiovascular rehabilitation, its availability remains limited. PLR, a cheap and simple test, could predict poor functional capacity in patients with stable CAD and recent elective PCI and help prioritize referral for cardiovascular rehabilitation in high-risk patients.


CKD patients demonstrated a greater periodontitis severity and higher inflammatory burden than non-CKD patients. Additionally, CKD patients with CP showed a good response to NSPT. Therefore, CKD patients’ periodontal health needs to be screened for early dental interventions and monitored accordingly.Chronic kidney disease (CKD) and chronic periodontitis (CP) contribute to the increased level of inflammatory biomarkers in the blood. This study hypothesized that successful periodontal treatment would reduce the level of inflammatory biomarkers in CKD patients. This prospective study recruited two groups of CP patients: 33 pre-dialysis CKD patients and 33 non-CKD patients. All patients underwent non-surgical periodontal therapy (NSPT). Their blood samples and periodontal parameters were taken before and after six weeks of NSPT. The serum level of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and periodontal parameters were compared between groups. On the other hand, kidney function indicators such as serum urea and estimated glomerular filtration rate (eGFR) were only measured in CKD patients. Clinical periodontal parameters and inflammatory markers levels at baseline were significantly higher ( Chronic periodontitis (CP) is a chronic inflammatory disease caused by bacteria and affects the periodontium’s stability . Accordi2 and/or kidney damage for at least three months. Based on the degree of GFR reduction, CKD can be classified into five stages (stages I-V). The fifth stage (stage V) is considered an end-stage renal disease (ESRD), with a GFR value of less than 15 mL/min/l.73 m2 and persistent bilateral damage of the nephrons, which are the basic functional units of the kidney  × 1.159 [if Black] .Exclusion criteria for both groups were (a) patients taking antibiotics, corticosteroids, statin, immunosuppressants, and aspirin which can affect the level of inflammatory markers in the past month, (b) pregnant women or lactating mothers, and (c) patients with a history of rheumatic fever, congenital heart disorders, prosthetic heart valves or any other condition that required them to have antibiotic prophylaxis prior to dental treatment.A proforma was used to collect patients’ demographic details, such as age, gender, ethnicity, and other comorbidities. A coding system was used for patient identification to ensure that only the researchers had access to their information. Only one examiner was assigned for clinical periodontal examination. Clinical data acquired by the clinical examiner were calibrated by senior specialists. The intra- and inter-examiner observations indicated about 90% of the recording being reproduced within a ±1.0 mm range. Briefly, the clinical periodontal examination was performed by assessing the CAL and PPD. The assessments were done by measuring six points for every tooth (except the third molar) using the Michigan probe with Williams marking.Five mL of blood samples were drawn from the median cubital vein and collected in a plain tube for the analyses of inflammatory markers (hs-CRP and IL-6) and kidney function indicators (serum urea and serum creatinine).Patients subsequently underwent NSPT, including SRP and oral hygiene instructions. Full mouth SRP using an ultrasonic , and curettage at PPD sites with 5 mm or greater using hand scalers  were performed under local anesthesia . All treated sites were then irrigated with 0.2% chlorhexidine. Patients were also given oral hygiene instructions to brush their teeth at least twice a day using fluoridated toothpaste and a soft-bristled toothbrush and floss once daily. Patients from both groups were followed up six weeks after the NSPT. Clinical periodontal parameters and blood samples were analyzed.The collected blood samples were centrifuged at 3000 rpm, and the blood serum was stored at −80 ℃ until they were analyzed. The serum hs-CRP level was measured using the latex particle-enhanced immunoturbidimetric method in a COBAS INTEGRA 400 plus . On the other hand, the IL-6 was measured using the electrochemiluminescence immunoassay method in the COBAS 6000 analyzer . Serum creatinine and urea levels were measured using a spectrophotometric method in the Architect C8000 analyzer .t-test and Chi-squared test were used for comparing the CKD and non-CKD groups. Repeated-measures analysis of variance was used for comparing the periodontal parameters from the baseline to six weeks and between the groups. Analyses were carried out using IBM SPSS 24.0 Armonk, NY, USA with the significance level set at 5%.The summary statistics were obtained using mean (SD) and frequency (percentage) for all variables. The independent p < 0.05) than for the  participated in this study (33 patients in each group). The mean age of patients in the non-CKD and CKD groups was 49.18 ± 8.58 years and 55.96 ± 11.26 years, respectively. In total, 89.3% (n = 59) of the patients were Malay, and only 10.6% (n = 7) were Chinese. In the CKD group, 12 and 21 patients were in stages Ⅲ and Ⅳ, respectively. Most of the patients were non-smokers, followed by ex-smokers and active smokers. The mean teeth count was significantly higher for the non-CKD group ( for the .p < 0.05) for the CKD group than the non-CKD group at the baseline level. Both groups showed significant improvement (p < 0.05) in the mean PPD and CAL after six weeks of NSPT. Nevertheless, there were no significant differences between groups when considering the mean of all periodontal variables during follow-up (p > 0.05). The mean baseline PPD for the non-CKD group was 4.76 ± 0.52 mm, while the mean PPD after NSPT was 2.97 ± 0.74 mm. On the other hand, the mean baseline PPD for the CKD group was 5.02 ± 0.50 mm, while the mean PPD after NSPT was 2.74 ± 0.50 mm. Apart from that, the mean CAL for the non-CKD group was 4.79 ± 0.52 mm and 3.20 ± 0.78 mm at baseline and post-treatment, respectively. In contrast, the mean CAL for the CKD group was 5.34 ± 1.06 mm and 3.26 ± 0.94 mm, respectively. Both groups demonstrated significant improvement in the plaque and gingival indicators after six weeks (The PPD and CAL were significantly higher (ix weeks .t-test showed that the mean baseline for hs-CRP and IL-6 were significantly higher (p < 0.05) in the CKD group than in the non-CKD group. Analyses revealed a significant reduction (p < 0.05) in inflammatory marker levels when both groups are considered. For the CKD group, post-treatment measurements for hs-CRP and IL-6 were 1.50 ± 1.38 mg/L and 2.93 ± 1.47 pg/mL, respectively. For the non-CKD group, post-treatment measurements for hs-CRP and IL-6 were 0.82 ± 0.71 mg/L and 1.89 ± 0.63 pg/mL, respectively. Apart from that, kidney function indicators (eGFR and serum urea) showed improvement during the study’s timeframe. However, these indicators did not show significant changes (p > 0.05) after NSPT.The results for hs-CRP and IL-6 are tabulated in The NSPT was the first recommended approach to control periodontal infections. Notwithstanding its advancement over the years, NSPT remains the “gold standard” for which all treatment methods are compared. The main aim of NSPT is to restore gingival health by eliminating the factors responsible for gingival inflammation, such as endotoxins, plaque, and calculus in the oral cavity. This debridement procedure was carried out using hand instruments  and staged in different sessions . SeveralIn this study, males were dominant in the CKD group since males are more susceptible to the disease than females . This geOur study highlighted that CKD patients had a more severe form of periodontal disease than non-CKD patients. Overall, higher periodontal disease severity in CKD patients than in non-CKD patients can be associated with many risk factors, such as malnutrition, uremic syndrome, xerostomia, compromised immunity, and low oral health awareness ,38. In aAll periodontal aspects, such as PPD, CAL PS), and GBI, showed significant improvement in both groups after NSPT. The results were consistent with previous research that showed NSPT significantly improved CAL levels and reduced PPD in moderate or severe periodontitis ,41. NSPTThe findings from this study were similar to those reported by Artese et al. (2010), where periodontal therapy outcomes for CKD patients were analyzed . The resInflammatory markers (IL-6 and CRP) were elevated in both CP and CKD conditions ,37. Our As observed in this research, the significantly poor periodontal condition could also be related to the elevated production of IL-6 and hs-CRP in CP subjects. Several studies have documented CP as an infectious condition and a non-traditional risk factor for CKD due to high systemic inflammation loads. The high systemic inflammation loads arise from periodontal inflammation, locally generated inflammatory mediators, and acute phase reactants , and CRP) ,37,50.p < 0.05).It was hypothesized that the control of local inflammation could result in a reduced systemic acute-phase response [Accompanying the improvement in periodontal parameters after NSPT, both groups were observed to have significantly decreased serum inflammatory markers (response . This maFindings on inflammatory markers were also consistent with other studies ,52. By cThese findings highlighted that periodontal therapy might have delayed CKD progression. Usually, CKD is progressive and associated with a sustained decline in renal function, as reflected by the reduction in eGFR. Its progression depends on CKD causes, albuminuria levels, acute kidney injury, uncontrolled blood sugar levels, and blood pressure dysregulation . Hence, This study provides a useful approach to the future management of CKD patients, focusing on the importance of monitoring oral hygiene which has often been neglected. Periodontal therapy should be part of the treatment in retarding the progression of CKD patients in the future. More studies should be performed to further enhance our knowledge in this research area to support the study findings.Pre-dialysis CKD patients demonstrated good clinical periodontal and inflammatory responses after NSPT. Hence, an understanding of periodontal health and its benefits for pre-dialysis CKD patients should be emphasized. Multi-centered research with a large sample size is required to evaluate periodontal treatment effects on periodontal parameters, eGFR status, and inflammatory markers.


Chronic kidney disease (CKD) is often accompanied by anemia. High-flux membranes contribute to a reasonable removal of uremic toxins which cause anemia in CKD. Inadequate data have described the efficiency of high-flux dialysis in promoting erythropoietin responsiveness in CKD patients in the Middle East. This study was conducted to compare the efficiency of maintaining high-flux hemodialysis versus low-flux dialysis for ≥1 year in promoting erythropoietin responsiveness and to show the factors associated with erythropoietin hyporesponsiveness in Arab chronic hemodialysis patients.  It was a retrospective cohort study that involved 110 subjects who were categorized into group 1  and group 2 . History taking, examination, and laboratory investigations were conducted for all patients every 3 months from January 2021 to January 2022. p=0.011), longer hemodialysis vintage , lower hemoglobin levels , and higher neutrophil-to-lymphocyte ratio .  Group 2 had significantly higher weight and body mass index than group 1 but lower cholesterol and intact parathyroid hormone levels than group 1. Erythropoietin resistance index levels did not differ between the two groups upon repeated measures over a 1-year follow-up. Significant risk factors for erythropoietin hyporesponsiveness on multivariate analysis were lower weight (Odds ratio (OR): 0.966; 95% Confidence interval (CI): 0.94–0.992;  High-flux dialysis was not superior to low-flux dialysis in improving erythropoietin responsiveness. Chronic renal impairment is often accompanied by anemia, which is linked to a higher risk of memory deficits, hospital admission, acute cardiovascular events, and shorter life expectancy. In addition, severe anemia is a poor prognostic factor for patients with chronic kidney disease (CKD) . In contThe principal reason for anemia in CKD patients is the accumulation of uremic toxins, which suppress erythropoietin production by renal interstitial fibroblasts . Other eDialyzers are generally categorized into low-flux dialyzers and high-flux dialyzers. Low-flux membranes eliminate small solutes via diffusion, but larger solutes are more poisonous and difficult to get rid of them via diffusion . The innThe research was executed following Helsinki Declaration's ethical regulations. Before joining the study, each participant provided a written informed consent form. The study was authorized by the Institutional Review Board of the Ethical Committee of Zagazig University (ZU-IRB #9321).Group 1: it involved patients who underwent regular hemodialysis with low-flux polysulfone dialyzers. There were 50 participants with a mean age ± standard deviation of 55.4 ± 15.3 years.Group 2: it involved patients who underwent regular hemodialysis with high-flux polysulfone dialyzers. There were 60 participants with a mean age ± standard deviation of 51 ± 12 years.This retrospective cohort study was conducted from January 2021 to January 2022. Criteria to recruit participants in our study were age 18 years or above, chronic kidney disease, regular hemodialysis for at least 1 year, and receiving erythropoietin therapy for 1 year or longer. We omitted patients with active malignancy, active infection, hemoglobinopathies, severe cardiovascular disease, or advanced cirrhosis. The patients were classified into two groups:β. The target hemoglobin level was 10–12 gm/dL. In addition, iron stores of the patients were replenished using intravenous iron sucrose when transferrin saturation was less than 30%, or ferritin was less than 500 ng/mL.Each study participant underwent a thorough medical history taking and clinical examination including the history of comorbid diseases, average interdialytic weight gain (IDWG), the type of vascular access either the permcath or the arteriovenous fistula, and dialysis vintage. In addition, laboratory investigations were collected predialysis except for urea which was collected before dialysis and after dialysis. Investigations consisted of liver function tests, bone profile, estimated glomerular filtration rate using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, urea reduction ratio, complete blood count, iron profile, lipid profile, serum folate level, serum vitamin B12 level, and erythropoietin resistance index (ERI). The ERI was calculated by dividing the average weekly erythropoietin (EPO) dose by body weight by the average hemoglobin over 3 successive months. Patients were administered a treatment protocol using intravenous epoetin 2 . Surface areas of high-flux dialysis membranes were 1.4 and 1.8 m2 . The selection of surface areas of dialyzers was adjusted according to the body surface areas of the patients. Dialysis sessions for all participants of the study were three times per week with the blood flow rate at 250–350 ml/min and dialysate flow rate at 500–600 mL/min in low-flux dialysis and 700–800 mL/min in high-flux dialysis.All hemodialysis sessions of the participants were exclusively performed using synthetic polysulfone dialyzers . In low-flux dialysis, surface areas of the dialysis membranes were between 1.0 and 1.8 mt-test was utilized to compare continuous parametric data, which were represented as means and standard deviations. The Mann–Whitney U test was utilized to compare nonparametric continuous data, which were represented as medians and interquartile ranges (IQR). Frequency counts and percentages were utilized to represent categorical variables. The average ERI over 1 year was classified into high ERI (ERI ≥18 IU/kg/week/g/dl) and low ERI (<18 IU/kg/week/g/dl). Independent predictors of erythropoietin hyporesponsiveness (high ERI group) were defined using univariate binary logistic regression analysis of the baseline variables at the start of the study. Then, variables with p ≤ 0.2 were analyzed using multivariate forward logistic regression analysis. Repeated measures of ERI and hemoglobin were analyzed using the general linear model (GLM) which considers within subject effects. SPSS software for Windows, version 26, was used to perform all statistical analyses.Continuous data were checked for normality by utilizing the Shapiro–Wilk test. The p=0.011), longer hemodialysis vintage , lower hemoglobin , and higher NLR  (p=0.045 (p=0.325 (Demographic data are demonstrated in p=0.004) . Repeate levels if they are less than 10 g/dL, but there is also a higher risk when Hb levels are 13 g/dl. Then, the Hb goal seems to be from 10 to 12 g/dl , and allIn addition, high-flux dialysis was associated with higher body weight and BMI. A higher BMI predicts a better outcome in chronic dialysis patients, as it indicates better nutritional status . In addiWe analyzed the probable predictors for high ERI, and we found that lower weight was a significant risk factor on multivariate analysis. Similar findings were recorded by Hejaili et al. . GeneralOther risk factors of high ERI included lower hemoglobin and high NLR. This is consistent with findings in 299 patients from a recent study by Zhang et al. . This maHigh-flux dialysis was not superior to low-flux dialysis in improving erythropoietin responsiveness and did not improve erythropoietin responsiveness in Arabic end-stage kidney disease patients even after the maintenance of hemodialysis for ≥1 year. It is apparent that high-flux dialysis may be better than low-flux dialysis regarding nutritional status, parathyroid hormone level, and blood cholesterol level, and further studies are required to evaluate that. Finally, erythropoietin resistance was associated with lower weight, longer hemodialysis vintage, lower hemoglobin, and higher NLR.


The new generation of nonvitamin K antagonists are broadly applied for stroke prevention due to their notable efficacy and safety. Our study aimed to develop a suggestive utilization of dabigatran through an integrated machine learning (ML) decision-tree model. Participants taking different doses of dabigatran in the Randomized Evaluation of Long-Term Anticoagulant Therapy trial were included in our analysis and defined as the 110 mg and 150 mg groups. The proposed scheme integrated ML methods, namely naive Bayes, random forest (RF), classification and regression tree (CART), and extreme gradient boosting (XGBoost), which were used to identify the essential variables for predicting vascular events in the 110 mg group and bleeding in the 150 mg group. RF  and XGBoost  had better area under the receiver operating characteristic curve (AUC) values than logistic regression . We then selected the top ten important variables as internal nodes of the CART decision tree. The two best CART models with ten important variables output tree-shaped rules for predicting vascular events in the 110 mg group and bleeding in the 150 mg group. Our model can be used to provide more visualized and interpretable suggestive rules to clinicians managing NVAF patients who are taking dabigatran. Non-valvular atrial fibrillation (NVAF) is a growing health issue in the aging society ,2. Elder2DS2-VASc and HAS-BLED scores have provided concepts of the risk of ischemic stroke and bleeding in patients with NVAF. In recent years, machine learning (ML)-based tools for analyzing data have shown efficacy in identifying the influence and interaction of important factors in the medical context [Traditional evaluation tools such as the CHA context ,16. Unli context ,18. ML m context ,22,23,24 context .However, the interpretability of ML is also a growing concern because many models work in “black boxes” . In clinA ML decision tree algorithm is a tree-based classifier composed of nodes representing selected variables; the division of the tree into prognostic outcomes shows rules regarding the combinations of these variables ,29. DeciOur research adopted an ML method for secondary analysis based on the dataset of the RE-LY trial. The Fu Jen Catholic University Hospital’s Research Ethics Review Committee examined and approved this study (IRB No. FJUH111180). Since the data solely contained de-identified content, informed permission was waived.Dabigatran 110 or 150 mg twice daily or an adjusted dose of warfarin were the three treatment options in the RE-LY trial. There were 18113 patients with newly diagnosed arrhythmia and evidence suggesting secondary prevention randomly assigned to receive one kind of anticoagulant with a median follow-up time of approximately two years. A history of severe valvular heart disease, recent stroke, and renal failure was listed as exclusion criteria. A stroke or systemic embolism was the primary outcome, as major bleeding was the primary safety outcome . The RE-We proposed an integrated multi-step ML scheme  to constCART is a binary splitting decision tree method based on the Gini index, which could be a classifier or regression predictive tool with an optimal tree size by applying a cross-validation (CV) procedure . NB is aFirst step: Define variables and classify the study subgroups. Our study referred to the recommendations of the American Heart Association and the European Society of Cardiology ,2. The phttp://www.R-project.org; accessed on 27 October 2022; https://www.rstudio.com/products/rstudio/; accessed on 27 October 2022) with the required installed packages. NB, RF, CART, and XGBoost were implemented, respectively. The “caret” R package version 6.0–90 was used for each method to generate the importance values of individual variables. Averaging the importance values of predictive variables in the selected models, we chose the ten most important variables for vascular events and bleeding in the 110 mg and 150 mg groups, respectively, as nodes in the decision tree model.Second step: Construct an ML model to identify important variables of vascular events and bleeding in the two study subgroups. In our study, the dataset was randomly divided into an 80% training dataset for constructing the acceptable model with the best hyperparameter set and a 20% testing dataset for model testing. Our protocol applied a 10-fold CV method to enhance stability for tuning the hyperparameters for the best performance of NB, RF, CART, and XGBoost models based on the area under the receiver operating characteristic (ROC) curve (AUC) values. Tenfold CV involves the modifying the validation dataset ten times to generate the adequate validation performance . The perThird step: Develop decision rules using CART based on the selected important variables. Using the same model construction process in the previous step, the 10-fold CV was used to train the CART model. The CART decision tree model with the best performance was used to establish tree-shaped rules composed of the 10 selected variables for predicting vascular events and bleeding in the 110 mg and 150 mg groups, respectively.In the last step, the rules derived from the important variables in our scheme were used to clarify what clinicians should avoid when selecting the dabigatran dose for NVAF patients. The discussion of these rules may provide us with graphical information on the precise dose of dabigatran.Our study recruited 5869 patients who took 110 mg dabigatran twice daily and 5933 patients who took 150 mg dabigatran twice. The top ten important variables were used as inputs for rebuilding the CART decision-tree models. Interpreting the CART-generated rules in the 110 mg group, patients with a combination of a history of congestive heart failure (CHF), MI, diabetes mellitus (DM), kidney function abnormality, ethnicity, body mass index (BMI), and age feature had a tendency towards vascular events . PatientTo the best of our knowledge, our study is the first to apply an ML-based decision-tree model to NVAF patients taking dabigatran. Clinicians need to determine the balance point between preventing vascular events and avoiding bleeding. Although NOACs possess prior safety than warfarin, approximately 9–39% of patients had off-label low-dose NOACs in real-world research for concern about risk of bleeding or other side effects ,47,48. MAmong ML techniques, decision tree models are more able to demonstrate clear rules. Like in most clinical settings, this method recursively partitions the data into subsets based on the values of the input features. The final work generates a tree-like model that can be used to make predictions by traversing the tree from the root to a leaf node, and the decision rules are the conditions at each node that determine which branch to follow. This allows the establishment of personalized suggestions and protocols to achieve precision medicine. CART is a popular tool for creating tree-shaped medical rules with realistic visualization and interpretability. It is a classifier and decision tree algorithm, but it showed inferior prediction performance in the second step of our study. We improved its AUC value by selecting fewer important variables with our integrated ML feature selecting scheme. Thus, we obtained explainable tree rules with acceptable predictive values. 2DS2-VASc score. In many national cohort studies, most clinicians prescribed off-label reduced doses of NOACs in consideration of age, body weight, kidney function abnormality, and medical history. Our research offers another viewpoint that may help in the prescription of reduced-dose NOACs to patients with a low risk of vascular events. However, more critically, the decision tree demonstrated that patients with certain variables had an extremely high risk of vascular events while taking 110 mg dabigatran twice daily.In the tree-shaped rule, the most important variables may be used to classify patients into high-risk and low-risk groups. We may notice that it is challenging to predict patients who may be free from vascular events in the next year when taking dabigatran 110 mg. Most rules indicating freedom from events demonstrated accuracy of 60–90%. However, we may surmise that 110 mg dabigatran was a relatively acceptable dose in patients without a history of MI, CHF, and kidney function abnormality. The risk of stroke and vascular events in patients with NVAF is determined by coexisting systemic diseases and age. The annual stroke risk was approximately 2–3% in low-risk patients based on the CHA2 or kidney function abnormality (EGRF < 50 mL/min/1.73 m2). For those without a history of MI, a combination of CHF, history of DM, and kidney function abnormality was associated with a high risk of vascular events when on dabigatran 110 mg, especially in underweight persons (BMI < 18.5 kg/m2). Thus, applying intensive medical control and a standard dose of dabigatran 150 mg, if tolerable, is a more reasonable choice for clinicians.MI and CHF are important comorbidities and risk factors in NVAF patients, which greatly influence stroke and vascular death. This might be the result of different vascular risk factors, such as hypertension, DM, smoking, and dyslipidemia. In our tree model, NVAF patients with a history of MI and CHF had a higher risk of vascular events when taking dabigatran 110 mg twice daily. Furthermore, they had a greater risk of vascular events when they had low BMI < 18.5 kg/m2). The combination of kidney function abnormality (EGRF < 30 mL/min/1.73 m2) and smoking habits also increased bleeding risk, regardless of BMI. Otherwise, the rule also indicated that elderly patients (age ≥75 years) with smoking habits and underweight stature tended to bleed when taking 150 mg dabigatran. Adjusting the dose of dabigatran may be considered in these patients.When we consider safety with dabigatran 150 mg, The primary prevention of stroke in NVAF patients has been a prevalent issue in recent years due to the progression of NOACs. Intensive risk-factor control and the early application of anticoagulants in patients prone to vascular events are emphasized. This study provides an integrated multi-step ML scheme to assist in selecting the appropriate dose of dabigatran. In general, it is crucial to first determine if the patients have a history of MI, CHF, or kidney function abnormality with regard to the risk of vascular events, and if there is the contaminant use of drugs, kidney function abnormality, older age, and smoking habit with regard to the risk of bleeding. To confirm the most appropriate dose of dabigatran for the patient, clinicians may check the detailed classification information in our tree model.Our model might be extended to more medical issues with its good prediction ability and convenience. However, dose adjustments and patient selection guidelines may take time before confirmation according to cohort studies and expert opinion. Our integrated ML scheme with adequate detailed data should provide clinicians with personalized decision support and recommendations. Moreover, ML techniques have the advantage of remodeling and may improve their prediction efficacy with new dataset. In this way, experts may reinspect and utilize our model to construct medical guidelines.2DS2-VASc scores were 2.1 ± 1.1, which might be different from the real-world situation. Our results might be inappropriate for patients in the acute stage of stroke or other extremely high-risk conditions. Second, we conducted a subgroup analysis to evaluate bleeding and vascular event risk. This procedure decreased the dataset size, and we did not perform CV to confirm the influence of different choices. However, the prediction performance value remained consistent in the two subgroups, and we performed 10-fold nested CV to enhance stability and avoid overfitting. The application of anticoagulant agents in NVAF patients with risk of vascular events and the choice of NOACs as first-line drugs have been the consensus management modality. We only focused on the dose selection for dabigatran but did not compare the doses with warfarin. However, the limited dataset and lack of external validation with real-world information restrict the consistency of our decision tree rules. Further remodeling our model with broad information is indicated before the utilization.There are some limitations to this study. First, our study was a post-hoc analysis of the RE-LY trial and excluded patients with recent ischemic stroke, and the participants’ CHAThis study used an integrated ML-based decision tree scheme to predict vascular events and bleeding when NVAF patients took different doses of dabigatran. According to the integrated ML feature-selection tool, we utilized the performance of the CART method, which should provide clinicians with detailed and interpretable information. Our tree-shaped rules should demonstrate the interaction between factors and the most risk-prone combinations of variables. Appropriate dose selection of NOACs for balancing benefits and side effects is an art in medicine. Our results may help clinicians achieve the optimal treatment for NVAF with different characteristics.


We then performed head-up tilt table testing with incremental lower body negative pressure while recording beat-by-beat blood pressure and heart rate. The primary endpoint was orthostatic tolerance defined as time to presyncope. Time to presyncope during combined head-up tilt and lower body negative pressure did not differ between hypercaloric and normocaloric dieting . Heart rate, blood pressure, heart rate variability, and blood pressure variability in the supine position and during orthostatic testing did not differ between interventions. We conclude that 4 days of moderate hypercaloric nutrition does not significantly improve orthostatic tolerance in healthy individuals. Nevertheless, given the important interaction between energy balance and cardiovascular autonomic control in the brain, caloric intake deserves more attention as a potential contributor and treatment target for orthostatic intolerance.Reduced-caloric intake lowers blood pressure through sympathetic inhibition, and worsens orthostatic tolerance within days. Conversely, hypercaloric nutrition augments sympathetic activity and blood pressure. Because dietary interventions could be applied in patients with syncope, we tested the hypothesis that short-term hypercaloric dieting improves orthostatic tolerance. In a randomized crossover trial, 20 healthy individuals (7 women, 26.7 ± 8 years, 22.6 ± 2 kg/m Neurally mediated syncope is a common reason for emergency room admissions , but can2 and a resting heart rate > 55 beats per minute (bpm) were eligible for this study. Main exclusion criteria were recent body mass changes > 3 kg, history of syncope or cardiac arrhythmia, smoking, and alcohol or drug abuse. We ruled out preexisting diseases by obtaining a detailed history, and performing a physical examination, a 12-lead electrocardiogram, blood pressure recordings, and taking blood samples for routine laboratory tests. Subjects on medication that might impact study outcomes were excluded. We obtained written informed consent before inclusion in the study. The study was approved by the ethics committee of the Medical Board North Rhine (Nr. 2018071) and was performed in accordance with the declaration of Helsinki (2013). We prospectively registered the study on DRKS  (registration number: DRKS00020750).Healthy people aged 18–40 years, with a body mass index between 18 and 25 kg/mThis randomized cross-over study was conducted at the Institute of Aerospace Medicine of the German Aerospace Center in Cologne, Germany. Participants followed hypercaloric or normocaloric nutritional plans over 4 days, with a washout period of at least 23 days between interventions Fig. . In the We determined individual total energy expenditure based on individually measured resting metabolic rate and estimated physical activity level. We assessed resting metabolic rate and substrate oxidation through indirect calorimetry . We determined individual energy requirements over 24 h via the Freiburger questionnaire. Caloric content of the normocaloric diet corresponded to individual total energy expenditure. Caloric intake was increased by 25% above total energy expenditure during the hypercaloric diet. We increased energy content by raising fat intake, while carbohydrate, fiber, and protein were kept constant. Fluids, as well as dietary sodium and potassium intake, were kept constant during both dietary phases. Both dietary plans included commercially available food. To ensure compliance to the dietary intervention during the outpatient phases, we provided all food items as well as nutritional protocols. Food had to be weighed by study participants to the nearest gram and noted in the protocol. These logs were then analyzed  to calculate nutrient intake , each lasting 10 min. The test was terminated when brachial systolic blood pressure decreased below 80 mmHg (or < 90 mmHg and rapidly decreasing), when finger blood pressure and heart rate decreased simultaneously, when participants reported presyncopal symptoms, when syncope occurred, or when subjects requested to abort the test. We defined orthostatic tolerance as time to presyncope expressed in minutes .The primary endpoint of the study was the change in time to presyncope. Exploratory endpoints included blood pressure, heart rate, heart rate variability, and baroreflex sensitivity before and during orthostatic testing.In a previous study in a similar sample, the improvement in time to presyncope had a standard deviation of 4.8 min . In the t-test. Differences were considered significant with p < 0.05. Data are reported as mean ± SEM.According to a prospective data analysis plan, we used a general linear model to assess the effect of the hypercaloric intervention and linear regression analyses to detect correlation among variables. Within-individual differences were tested with a paired We screened 39 people Fig. . Of thosp = 0.85). Fluid intake was adjusted to the individual needs of each participant and kept constant during the two phases.Dietary energy content and composition during normocaloric and hypercaloric dieting are presented in Table p = 0.50, diastolic p = 0.28). Supine heart rate was 64.0 ± 8.2 bpm on the normocaloric and 64.1 ± 8.6 bpm on the hypercaloric diet (p = 0.96). Moreover, the hemodynamic response during the initial phase of orthostatic testing did not differ between interventions .Time to presyncope during combined head-up tilt and lower body negative pressure, the primary endpoint of the study, did not differ between hypercaloric and normocaloric diets . The same is true for heart rate before test interruption, which was 112.0 ± 33.1 bpm on the normocaloric and 118 ± 35.0 bpm on the hypercaloric diet (Dietary caloric intake did not affect heart rate variability, blood pressure variability, or baroreflex sensitivity in the supine or in the upright position Table .Table 3HThe important finding of our study is that a moderate increase in caloric intake for 4 days compared with normocaloric nutrition does not significantly improve orthostatic tolerance in healthy subjects. Moreover, blood pressure and heart rate regulation at rest and during orthostatic stress did not differ between normocaloric and hypercaloric nutrition.The combination of a carefully controlled dietary intervention and a rigorous methodology for assessing orthostatic tolerance is a strength of our study. We determined orthostatic tolerance through head-up tilt testing combined with lower body negative pressure . This meOur findings have to be reconciled with previous investigations showing intense cross talk between metabolic and cardiovascular control through the autonomic nervous system, with effects on orthostatic tolerance. In animal studies, high-fat feeding elicited sympathetic activation , 27, 32.An important limitation of our study is that orthostatic tolerance in the laboratory may not always translate to orthostatic symptom load in daily life. Moreover, changes in orthostatic tolerance in healthy people cannot be simply extrapolated to patients with neurally mediated syncope. However, previous studies using a similar approach, such as studies on salt or water intake, elicited similar improvements in orthostatic tolerance in healthy people and in patients with syncope , 11, 30.Despite these issues, we suggest that modestly increasing caloric intake for a few days is unlikely to improve orthostatic tolerance in normal weight individuals prone to neurally mediated syncope. However, given the intense cross talk between energy balance and cardiovascular autonomic control, influences of more pronounced increases in energy balance on orthostatic tolerance deserve to be studied, particularly in patients who are malnourished and underweight, such as patients with anorexia nervosa or in frail elderly people who are prone to fall-related injuries.


Medical device‐related pressure ulcers are increasingly common in critical care units. These ulcers can be complicated due to the necessity of the device for diagnosis or treatment.To determine the prevalence of and risk for medical device‐related pressure ulcers in critical care units in Jordan in addition to identifying the preventive measures for those ulcers as well as identifying the most frequently used medical devices that cause ulcers and to assess the relationships between prevention measures and developing ulcers.A cross‐sectional survey was used to assess ulcers among 318 patients who were elder than 18 years old. Data collection was based on an outline published by the European Pressure Ulcer Advisory Panel, Braden Scale, and an author‐developed specific checklist.The prevalence rate of medical device‐related pressure ulcers was 38.1%. Most affected sites were sacrum and heel, and most affected were those with old age, being admitted to public hospitals, and with a prolonged hospital stay. About half of the patients (46.3%) had severe risk. Only 17% of the patients who were at risk got adequate preventive measures. Face masks, endotracheal tubes, pulse oximetry probes, and intravenous catheters were associated with almost half of the ulcers.Medical device‐related pressure ulcers are threats to patient safety and quality of nursing care in hospitals, which require determining appropriate preventive measures. Key messages:Medical device‐related pressure ulcers are common among patients in critical care units, which raise the need to evaluate the prevalence of such type of ulcers in those patients.Three hundred and eighteen patients were investigated for the prevalence of medical device‐related pressure ulcers through a cross‐sectional survey.Patients in critical care units in Jordan had a high prevalence rate for medical device‐related pressure ulcers, which require the need to apply appropriate preventive measures. Using medical devices (MDs) in physically compromised critically ill adults, children and trauma/orthopedic patients are pervasive in sustaining life and promoting healing during patients' hospital stay.Pressure ulcers (PrUs) are the main health alteration, which results in decreased value of life and increased demands on healthcare systems globally. However, PrUs are largely preventable when available clinical guidelines available are applied by clinicians.Few studies have captured information on MDRPrUs among critically ill patients. Coyer et al.The MDRPrUs were mostly caused by noninvasive ventilation masks (NIV) and NGT and were associated with a longer stay in intensive care units (ICU). In a closer figure to the Jordanian population, Amirah et al.Other researchers reported that the percentage of PUs could reach up to 49% of the ICU patientsIt is challenging to compare the prevalence and incidence of MDRPrUs due to variations in the population under investigation, the location, and stage of ulcers, and the MDs used. For instance, 35% of MDRPrUs developed on the earsRegarding the devices that cause the MDRPrUs, ET tube and Foley's catheters,In the Middle East, evidence has revealed that common types of PrUs lack adequate documentation, risk assessment, training, prevention, and treatment guidelines for nurses.22.1A cross‐sectional survey design was used to describe the prevalence of MDRPrUs and common MDs causing MDRPrUs in critically ill patients in Jordan.2.2Hospitals having CCUs, and a capacity of 200 beds or more were surveyed as such hospitals contained more patients who were vulnerable to acquiring MDRPrUs in their CCUs. Of the 50 invited hospitals, 11 met the inclusion criteria and 10 gave permission to access critically ill adult patients including three public hospitals (816 beds) (9 CCUs comprised 100 beds), four private (794 beds) (10 CCUs comprised 130 beds), one‐non‐profit (442 beds) (two CCUs comprised 30 beds), and two university hospitals (1099 beds) (nine CCUs comprised 100 beds). The occupancy rate of CCUs in Jordan is almost 100%.2.3Ethical authorization was obtained from the institutional review board committee in the university where the principal researcher works; additional approvals were obtained from ethical research committees in the participating hospitals. Each patient or his first‐degree relative  was asked to sign a consent form for participation in the survey. The patient's right to withdraw from the research study at any stage was guaranteed.2.4A list of patients was obtained from the Directors of Nursing of each targeted hospital on the assigned day for data collection. A critically ill patient is defined as a patient with severe respiratory, cardiovascular, or neurological alterations, often in combination, and are reflected in abnormal physiological observations.Each patient was assessed by a wound care nurse assigned in each hospital selected, so 10 nurses assisted in the data collection procedure. Those nurses were trained about how to use the data collection measures in assessing the target patients . The training program lasted for 2 days, then each nurse was asked to use the data collection measures clinically on two patients  therefore the pilot study sample was 20 patients. These nurses displayed almost 0.90 interclass correlation coefficient in grading results of risk assessment and Braden scale and were consistent with the assessment done by one of this study's investigators who is a tissue viability nurse specialist.Observations for patients selected for the study by the assigned nurses to collect data were managed in unscheduled visits through the day and night shifts. Assessment of patient skin was carefully performed and each patient was assessed for PrUs on daily basis during the data collection period identified below. PrUs from stage I (nonblanchable erythema) to stage IV (widespread destruction of the skin and underlying tissue), deep‐tissue injury, and unstageable ulcers were identified according to the NPUAP, EPUAP classification system.2.5n = 10) from a university teaching hospital. This improved the content validity of the form, the level of comprehensiveness, clarity, and reduced ambiguity. The modified survey form included data across five categories: general patient data, risk assessment (The Braden score), MDs used, skin inspection, and utility of pressure ulcer prevention interventions. The first category describes the patients' age, gender, duration of stay (from admission until the survey time), previous hospitalization, and the patient's diagnostic category. It also includes details of the hospital including sector, the total number of beds, and the unit's number of beds. The second category includes patients' assessment using the Braden scale to identify their risk of PU development. Risk assessment of PU development using the Braden scale is based on six subscales  and scores on each of these six subscales range from 1 to 4 except for friction/shear which ranges from 1 to 3; lower scores indicate a high risk for PU development. Scores of 15 to 18 indicate mild risk, scores of 13–14 indicate moderate risk, scores of 10–12 indicate high risk, and scores of 9 or less indicate very high risk.Data were collected using a modified form based on the EPUAP pressure ulcer prevalence survey form, which has been validated and showed high interrater reliability.The third category includes a checklist developed to observe and record (MDRPrUs). The checklist included 26 MDs that are associated with PU development and were informed by literature, as follows: antiembolic stockings;2.6Descriptive analysis of data was accomplished using IBM SPSS 24.0.3The number of patients congruent with the inclusion criteria in the selected hospitals was 348 critically ill patients, 13 patients dropped and 17 patients were not obtainable at the time of screening to give a final sample of 318 patients. The demographic characteristics are shown in Table 3.1n = 39, 29.5%), lips , and cheeks . Excluding stage I PU, the prevalence rate was 8.4% (n = 27), a higher rate of MDRPrUs was recorded among critically ill adult patients from public , private , and university  compared with lower rate in nonprofit‐hospital   of them were evaluated as having a mild risk of PU while the remaining were considered vulnerable to PrUs at different levels including severe, high, and moderate risk. On the other hand, of the patients who had (MDRPrUs) (n = 121), 56 (46.3%) patients had severe risk, 24 (19.8%) high risk, 13 (10.7%) moderate risk, and 28 (23.1%) mild risk (see Table p < 0.001) relationship between the Braden scores and the MDRPU development.All patients involved in this study were at risk of PrUs using the Braden scale. While 197 patients of the study sample were free of MDRPrUs, 55.3% . Although patients who had MDRPrUs were evaluated at risk of PU, no single patient received planned frequent relocation of the MD since implemented. Other components of the prevention program were relatively implemented such as the use of PU clinical guidelines , frequent skin inspection , and using skin barrier creams . The results in Table α = 0.05 using the chi‐squared test. As all prevention and treatment variables were not significant, performing regression analysis to elucidate a prediction model among those who developed MDRPUs was useless and therefore the study results were dependent mainly on correlations.Table 3.4n = 242), noninvasive blood pressure amplifier (n = 240), urinary catheters (n = 233), cardiac monitoring cables and temporary pacemakers (n = 197), and patient identification bands (n = 179) were frequently used in critically ill patients, they were poorly associated with MDRPrUs.Our study indicated the use of 26 MDs in CCUs in Jordan. The frequently used MDs are shown in Table 4The overall prevalence of MDRPrUs was 38.1% and declined to 8.4% when excluding stage one PU. MDRPrUs (stages II–IV) are responsible for one‐third of all PrUs in this sample. Stages I and II MDRPrUs were the most communal; while unstageable PrUs and deep tissue injury were not found. Hence, MDRPrUs is a growing problem and required the need for future research and consensus.It is hard to compare our data with that of other studies. Only two studies identified MDRPrUs in critically ill patients.M = 60.5) in Jordan and the USA and Australia,M = 69.6) in Saudi Arabia.M = 13 days) among patients who had MDRPrUs in Jordan, USA, and Australia.M = 10.5) compared with patients from USA and Australia (M = 14).Compared to other studies in the USA, Australia, and Saudi Arabia which employed similar methods, Jordan shows similar findings related to male gender, age, and length of stay. Despite younger Jordanian patients, the mean age of patients found with MDRPrUs was almost similar across studies. It was similar (n = 132) were stage I while serious ulcers of stage III or deeper were not present. The percentage of reported stage I MDRPrUs might reflect the fact that mucosal PrUs were not reported and/or staged in this study as researchers did not include this option to mark mucosal PrUs, however, data collectors may have marked them as stage I PUs. Our findings were consistent with several studiesIn the present study, 77.3% of screened MDRPrUs  in our set of data were serious, and so the number of MDRPrUs would be considerably undervalued if only serious PrUs were considered. Furthermore, Apold and Rydrych's reportOur study data indicate how essential it is to evaluate, determine and commence early prevention for potential MDRPrUs. However, stating CCUs data by PrUs rather than by patients impedes computing the prevalence and as a result, restricts comparison within sites and studies.Although prevention of MDRPrUs is the main goal, earlier detection of MDRPrUs could result in a better prognosis and lower the financial impact of this disease. This can be done with a routine physical examination by the medical team and taking proper precautions. However, unfortunately, there are no clear guidelines in this regard and a consensus has yet to be reached.The hands and arms of patients in the study sample were the most frequent site of MDRPrUs (29.5%). On the other hand, ulcers of the lips (15.2%), cheeks (12.1%), and other sites of the head and neck taken collectively make MDRPrUs of the head and neck the most common site. This is consistent with the study done by many researchers. This may be attributed to the number of MDs used in this region, ranging from Nasal cannulas, and NGT to ET tubes and tracheostomy tubes.Forthcoming research is required to discover the relationship between the type of MD and the depth of tissue included in the MDRPrUs; certain MDs might be related to advanced PU numerical stages. The results of this present study are different from ICU studies stated by both Coyer et al.In this study, ET tubes and NGT encompassed 7.5% and 5.0% of the MDRPrUs, respectively, among all health care settings. Of the MDRPrUs seized in this study, 28% were reported in CCUs settings, as divergent to the aforesaid studies,BRADEN risk tool was used to assess the threat of acquiring MDRPrUs in our study. It was found that 46.3%, 19.8%, 10.7%, and 23.1% of MDRPrUs patients had a severe, high, moderate, and mild risk, respectively. Although the BRADEN risk tool was related to the prevalence of MDRPrUs in our study, it is a tool used to evaluate the threat of acquiring PrUs in general and other studies have deemed it unreliable.This study showed that 35.5% of the patients with MDRPrUs were treated in public hospitals in comparison with 30.6%, 27.3%, and 6.6% at private, teaching, and non‐profit hospitals, respectively. This difference can be attributed to the different devices, settings, types of patients, and procedures performed in each sector. Different protocols and documentation processes can be employed to minimize this difference present among types of hospitals.We aim to standardize these protocols to provide the best care across the country. As MDRPrUs are a growing problem, we advise further research in the hope of reaching a consensus on prevention strategies, detection, and treatment of this disease. Although we excluded patients who were younger than the age of 18 years, we cannot deny the high prevalence of MDRPrUs in the younger age group, which was found to be 10% for children.4.1The participants in the current study included patients from different centers across Jordan, which adds strength to this study. In addition, the use of the EPUAP grading system facilitated homogenizing the results throughout the study population.4.2The exclusion of certain patients, such as those younger than 18 years, can alter the true prevalence of MDRPrUs in Jordan. In addition, the absence of a specific risk tool for developing MDRPrUs made it difficult to assess properly the risk in our patients. Only adult patients were involved in this study, and additional research is necessary in pediatric patients.The survey concentrates on acute care health care settings, and as a result, the size of the sample from each setting was fairly small, making it unattainable to study variances in features of MDRPrUs among health care settings. Eventually, the current study was limited to self‐reported data from health care facilities that chose to take part in the MDRPrUs survey. Studies using considerable samples from non‐acute health care settings are required to know if these results can be generalized outside acute care.5This study found that the prevalence of MDRPrUs was high, and male patients were the most vulnerable to MDRPrUs. The most communal anatomic locations for MDRPrUs were the hands/arms, and the most frequently associated MDs were the face‐ mask for noninvasive positive pressure ventilation. Due to the absence of assessment and prevention protocols in hospitals, several cases reported during this study did not receive adequate care. This study found the foremost communal anatomic locations for MDRPrUs were the hands/arms, and therefore the most typically related MDs were masks for noninvasive positive pressure ventilation.Conceptualization: Mohammad Y. Saleh, Yahya W. Najjar. Data curation: Mohammad Y. Saleh. Formal analysis: Mohammad Y. Saleh. Funding acquisition: Mohammad Y. Saleh. Investigation: Zeinab M. Hassan. Methodology: Zeinab M. Hassan, Mohammad Y. Saleh. Project administration: Zeinab M. Hassan. Software: Zeinab M. Hassan, Mohammad Y. Saleh. Supervision: Zeinab M. Hassan, Yahya W. Najjar. Validation: Yahya W. Najjar. Writing—original draft: Mohammad Y. Saleh, Zeinab M. Hassan. Writing—reviewing and editing: Yahya W. Najjar.The authors declare no conflicts of interest.Ethical approval to conduct the study was obtained from the university in which primary investigators works and from the hospitals selected as settings for the study.Medical device‐related pressure ulcers are a crucial marker of patient safety and nursing quality in providing care to patients. Hence, crucial preventive measures for MDRPrUs are needed in Jordanian hospitals, and a scientific approach to MDRPrUs before and when occurred is nonetheless to be devised in Jordanian hospitals. We encourage further research in this field to raise awareness of this problem among the healthcare team.The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.


Neurovascular coupling (NVC) is a key process in cerebral blood flow regulation. NVC ensures adequate brain perfusion to changes in local metabolic demands. Neuronal nitric oxide synthase (nNOS) is suspected to be involved in NVC; however, this has not been tested in humans. Our objective was to investigate the effects of nNOS inhibition on NVC in humans.We performed a 3-visit partially randomized, double-blinded, placebo-controlled, crossover study in 12 healthy subjects. On each visit, subjects received an intravenous infusion of either S-methyl-L-thiocitrulline (a selective nNOS-inhibitor), 0.9% saline (placebo control), or phenylephrine (pressor control). The NVC assessment involved eliciting posterior circulation hyperemia through visual stimulation while measuring posterior and middle cerebral arteries blood velocity.P=0.049), and a reduced rate of increase  in posterior cerebral artery velocity . The overall magnitude of posterior cerebral artery response relative to placebo control or pressor control was not affected. Changes in BP parameters were well-matched between the S-methyl-L-thiocitrulline and pressor control arms.nNOS inhibition blunted the rapidity of the NVC response versus pressor control, evidenced by a reduced initial rise in mean posterior cerebral artery velocity (−3.3% , Neuronal NOS plays a role in dynamic cerebral blood flow control in healthy adults, particularly the rapidity of the NVC response to visual stimulation. This work opens the way to further investigation of the role of nNOS in conditions of impaired NVC, potentially revealing a therapeutic target. Neurovascular coupling (NVC) is an important mechanism in neurovascular regulationNitric oxide (NO) is an important mediator of NVC responsesnNOS  is known to play a role in cerebrovascular regulation, but its precise role in NVC is unclearnNOS (as a source of NO) has a role in the regulation of the rapidity of NVC responsesnNOS does not affect the magnitude of NVC responsesNeurovascular coupling (NVC) is a key process in cerebral blood flow regulation, ensuring adequate brain perfusion to changes in local metabolic demands. NO is known to be involved in NVC responses, but the contribution of specific nitric oxide synthase (nNOS) isoforms was previously unclear. This is the first human study to demonstrate the role for nNOS in the regulation of NVC responses, particularly the rapidity of the NVC response to visual stimulation.949In This Issue, see p 950Meet the First Author, see p 1The central nervous system’s voracious energy consumption and lack of substrate storage capacity necessitates sophisticated cerebral blood flow regulation to ensure appropriate perfusion. One of the primary regulatory pathways involved in neurovascular control is neurovascular coupling (NVC).2 and has been identified in neurological diseases such as Alzheimer’s disease and spinal cord injury4 as well as cardiovascular pathologies such as hypertension and atrial fibrillation.7 Briefly, modulated neuronal activity, and the ensuing changes in glutamate levels, cause changes in local blood flow by adjusting vascular tone via pial arteries, penetrating arterioles, and pericytes enveloped around capillaries.9 These adjustments in vascular tone are thought to be elicited through rapid and transient direct neuronal-to-vascular cascades, as well as indirect slower and sustained astrocyte-mediated pathways. Although NVC is a well-established physiological response, with altered blood pressure playing a key role, a comprehensive mechanistic understanding is lacking. Studies in anesthetized animals indicate that more than half of the neurovascular cascade is driven by nitric oxide (NO), a powerful vasodilator that activates soluble guanylate cyclase in vascular smooth muscle.10 Emerging preclinical work indicates that the early phase direct neuronal-to-vascular cascade is modulated by neuronal production of NO through neuronal nitric oxide synthase (nNOS).10 It is not currently clear if this effect is translatable to humans. Although it is well-established that NO is involved in the regulation of basal central nervous system blood flow in humans,12 studies have not to date identified the individual NOS isoform that is responsible, nor its effect on NVC.NVC represents the relationship between neuronal activity and local central nervous system blood flow, allowing the brain to match regional perfusion levels to the metabolic demand. Dysfunctional NVC is associated with early vascular cognitive impairment,The role of nNOS in NVC has not previously been studied in humans, but it is important to define since many cerebrovascular disorders are associated with abnormalities in this fundamental regulatory mechanism. Therefore, the mechanisms underpinning NVC responses could represent novel therapeutic targets for these conditions. Accordingly, in addition to furthering understanding of patho-mechanisms and the interplay of cardiovascular and neurovascular disease, there is clear translational potential in identifying the mechanisms of dysfunctional NVC responses.In this study, we have undertaken the first direct investigation of the role of nNOS in NVC in healthy humans, using a 3-visit double-blinded, placebo-controlled, crossover study design. We tested NVC during intravenous administration of a well-characterized selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC). The responses during SMTC infusion were compared with those during a control condition where blood pressure was matched using titrated phenylephrine or to saline placebo.The data that support the findings of this study are available from the corresponding author upon reasonable request.This study adhered to the standards outlined in the Declaration of Helsinki. Ethical approval for this study was obtained from the Conjoint Health Research Ethics Board (REB19-1613) at the University of Calgary and the London-Dulwich Research Ethics Committee (18/LO/2064). Written informed consent was obtained from all volunteers prior to commencing any protocol-related procedures. The study was performed at a single site; the NIHR Biomedical Research Centre, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK.Figure S1 for recruitment flow chart and Table S1 for participant characteristics). Participants were healthy adult volunteers with normal blood pressure (systolic blood pressure <140mmg and diastolic blood pressure <90 mm Hg) without any recent illness, or regular systemic medication . Exclusion criteria included altered circadian rhythms ; active menstruation, pregnancy, or breastfeeding; current/past neurological or psychiatric diagnosis; use of recreational drugs within the last 12 months; current or regular opioid medications. Participants were required to abstain from a number of agents prior to each testing visit: alcohol (24 hours), caffeine (12 hours), NSAIDs/paracetamol (24 hours), tobacco/nicotine (4 hours).A total of 12 participants completed all 3 visits . One participant had a vasovagal response during experimental set-up and therefore is excluded from the final analysis , we also used a pressor control . SMTC is a synthetic L-arginine analogue strongly selective for nNOS versus endothelial nitric oxide synthase (eNOS).19 Rodent studies suggest that SMTC is 17-times more specific for nNOS in brain tissue than endothelial nitric oxide synthase in vascular endothelium.20 SMTC also crosses the blood brain barrier, as demonstrated through use of 11C-labeled SMTC in rat and primate models.21 SMTC was prepared to Good Manufacturing Practices standard for human use by Guy’s and St Thomas’ NHS Foundation Trust aseptic pharmacy. SMTC was infused at a dose of 3.0 µmol/kg for 10 minutes as a bolus, followed by 0.05 µmol/kg/min maintenance dose until the protocol was completed.14 The preparation of the SMTC infusion was calculated based on weight to allow for a standard rate of infusion for all participants . The placebo control was infused at a rate identical to the SMTC. The pressor control was infused at a dose of 25–100 µg/min at a rate titrated to achieve a rise in MAP corresponding to that seen with SMTC (~7 mm Hg from our previous work).14 During the pressor control condition, we aimed to match MAP to the SMTC condition; therefore randomization between these conditions was not possible. However, at all points, the participants and the members of the research team performing NVC data collection remained fully blinded to the contents of the infusion. There was a minimum of 48 hours washout between study visits.We performed a 3-visit randomized, double-blinded, placebo- and pressor-controlled, crossover study to assess the effect of intravenous administration of S-methyl-L-thiocitrulline , an nNOS inhibitor, on measures of NVC. Intravenous infusion of SMTC is associated with a rise in mean arterial pressure (MAP) due to systemic nNOS inhibition.22 Cerebral blood flow velocities were assessed and recorded using software . End-tidal carbon dioxide and oxygen levels were monitored via the RespirAct, . The breathing circuit was connected to the participant via a soft plastic mask custom-fitted to each participant. The mask was sealed to the participants face using transparent dressing film .Brachial blood pressure was obtained by standard noninvasive oscillometric methods . Finger plethysmography  was used to provide estimations of the following hemodynamic variables: blood pressure, systemic vascular resistance (SVR), and cardiac output (CO). Heart rate was measured by placement of 3 electrocardiogram electrodes in a 3-lead bipolar arrangement and collected at a sampling rate of 1000 Hz. Cerebral blood flow velocity was assessed using 2 MHz transcranial Doppler probes  inserted into an adjustable headpiece and positioned bilaterally against the temporal bones to insonate the middle cerebral artery (MCA) on the 1 side and posterior cerebral artery on the other as previously described.23 The research team members performing data collection of NVC responses were blinded to the contents of the infusion , as were the volunteers. A separate member of the research team was responsible for preparation and administration of the infusion. In our hands, the test-retest reliability of NVC assessments is 0.95 .On each visit, pre- and postdrug assessments of NVC were performed. The standardized NVC assessment involved using a visual task to activate the visual cortex, resulting in hyperemia in the posterior circulation. This involved 10 cycles of 30 seconds with eyes closed, followed by 30 seconds of eyes open where the participant tracked a pendulum moving laterally, back and forth across the screen  on a 24-inch computer monitor, with the participant seated in an upright posture approximately 0.75 m from the computer monitor. This visual stimulus has been shown to be the most selective for the posterior circulation in in-human NVC testing.24 All hemodynamic variables were sampled at 1000 Hz and extracted on a beat-by-beat basis. All NVC metrics were calculated as absolute or percent change relative to the 15−5 seconds prior to eyes open. Each participant’s NVC metrics were calculated as the average of all included trials from the 10 cycles of visual task for each condition. In addition to assessing PCA velocities and associated metrics across the entire 30 second period of the NVC response, to assess the effect of nNOS on rapidity of NVC responses, we also measured PCA velocity responses during the first 5 seconds, when the rate of change of PCA velocity is highest.NVC data were analyzed through iNVC software . This software automatically analyzes NVC data collected on a variety of data acquisition systems, calculating the classical metrics characterizing the hemodynamic response, as well as proprietary iNVC summary measures that capture the key features  within the neurovascular coupling response, and are stable within and across individuals.mean) was calculated in a similar fashion using MCA max velocity (MCAmax) and MCA minimum velocity (MCAmin) as ((⅓ MCAmax) + (⅔ MCAmin)). Mean PCA velocity was calculated in this exact fashion. Cerebrovascular conductance through the MCA (MCACVC) was calculated as MCAmean/MAP, and cerebrovascular resistance through the MCA (MCACVR) was taken as the inverse of this relationship. Cerebrovascular conductance and resistance values for PCA were calculated in this exact fashion.MAP was calculated from systolic blood pressure and diastolic blood pressure as ([⅓ systolic blood pressure] + [⅔ diastolic blood pressure]). Mean MCA velocity . In summary, with the exception of SV, cardiac output, and systemic vascular resistance, the hemodynamic effects of SMTC and pressor control were similar, compared with the placebo control condition.There were no statistically significant differences in steady-state pre-intervention hemodynamic variables between study visits (see Table P=0.0085). However, the MCA conductance index with SMTC was comparable to that seen in the pressor control group , nor the time to peak response (P=0.27). Additionally, metrics of rapidity  did not show statistically significant differences across baseline conditions .Across baseline conditions, mean PCA velocity increased from 38.6±1.3 to 45.6±1.5 cm/s during the eyes open period. Pre-intervention, there were no statistically significant differences in the PCA mean velocity response and peak velocity response to visual stimulation between conditions (P=0.46) or pressor control (P=0.32)  versus pressor control and −3.7% , (P=0.026) versus placebo control, with both maximal changes seen at T=4 seconds . Trends in PCA velocity changes remained consistent when corrected for changes in cardiac output and systemic vascular resistance .Considering the entire 30 second period of the NVC response, there was no statistically significant overall difference in the change in PCA velocity from SMTC compared with either placebo control . Neither was there a statistically significant difference between SMTC and pressor control in terms of iAmplitude1 and iAmplitude2 . See Figure There was no statistically significant difference in either the average or peak PCA mean velocity response with SMTC compared with pressor control  was well matched to that induced by SMTC, while the differences in pattern of change in cardiac output and systemic vascular resistance are consistent with those observed in studies comparing phenylephrine with nonselective NOS inhibition using N(G)-monomethyl-L-arginine.26 Previous human studies assessing the role of NOS in regulation of cerebral blood flow have used N(G)-monomethyl-L-arginine, which, due to the nonselective action of this drug, provides little insight into the role of specific NOS isoforms.28 In rodents, selective nNOS inhibition with 7-nitroindazole reduced basal CBF,30 while in humans, selective nNOS inhibition with SMTC decreases global and regional CBF as measured by brain MRI arterial spin labeling.13The systemic hemodynamic changes seen following selective nNOS inhibition with SMTC are consistent with prior published data, showing an increase in systemic vascular resistance and MAP, with a minor decrease in cardiac output and heart rate.30 Continuous, near-instantaneous vascular responses are vital to meet temporal neuronal metabolic demands in the human brain, which lacks capacity for energy substrate storage. Our results are consistent with data from the rat brain, suggesting that NO levels rise early in the NVC response (≈400 ms)31 and further supports the contention that although NO may be important for the early response, the steady-state elevation in blood flow during NVC may rely predominantly on NO-independent astrocytic inter-communication. Although data from anaesthetized animal models suggest a role for NO in steady-state elevation, in unanesthetized rats, NOS inhibition has no effect.33 The effect of nNOS on NVC in the early and direct phase of the response is consistent with a modulatory fine-tuning role rather than as the primary mediator of increases in blood flow. The latter role may be subserved by several additional neuronal sources of vasodilators, such as eicosanoids, adenosine, adenosine triphosphate , and oxygen . Changes in newly developed markers of rapidity (iRate1 and iRate2) followed the same trend, but differences between conditions were not statistically significant. This is the first human study, complementing preclinical work, to show that nNOS plays a role in the early transient direct neuronal-vascular component of NVC.n Figure .34 As our findings show no effect on peak NVC responses when using an established selective nNOS inhibitor, this previous work may suggest that peak NVC responses are due not to nNOS but other NOS isoforms, such as endothelial nitric oxide synthase. However, this deductive rationale should be interpreted with caution as the nonselective NOS inhibition condition was not compared with a matched pressor condition (+4 versus +15 mm Hg).34 More work is needed to consolidate these previous findings with our results.A recent study in healthy young humans showed that nonselective NOS inhibition reduced the peak NVC response by ~30%.35 This points to a role for NVC integrity as a disease biomarker, and also potentially identifies nNOS as a therapeutic target capable of improving function by enhancing NVC. Moreover, increasing nNOS activity may mitigate central nervous system hypoperfusion and hypoxia, such as that preventing neurological recovery in the acute phase of spinal cord injury.Dysfunctional NVC has been identified in a range of neurological conditions. In a preclinical model of Alzheimer’s dementia, tau induces dissociation of nNOS from postsynaptic density protein 95 (PSD95) in the post-synaptic neuron, impairing NVC.17 This consistent finding should be taken into consideration when interpreting prior studies and future study designs.37A relatively small increase in mean arterial pressure with phenylephrine, of approximately 10 mm Hg, increased NVC. This observation is aligned with our previous work showing that NVC is highly sensitive to changes in perfusion pressure.38 therefore providing another mechanism whereby local NO production may promote an enhanced NVC response.40 The interaction between nNOS and 20-HETE  in NVC is therefore a key area for future research.In this study, we hypothesize that the effects of nNOS in NVC are due to NO’s effect on vascular smooth muscle. However, this does not fully appreciate the complexity of downstream NO signaling. For example, NO inhibits cytochrome p450 and may therefore decrease cytochrome p450-incuded production of the potent vasoconstrictor 20-HETE from arachidonic acid,41 Previous human work has shown that local infusion of SMTC did not affect diameter of radial artery, and had only a small effect on basal epicardial/conduit vessel tone.19 However, the effect of SMTC on cerebral artery diameter is unknown, and should be addressed by future studies. We used phenylephrine as a pressor control condition; however, we are unable to rule out the possibility that some or all of the effect seen is by mechanisms other than change in cerebral perfusion pressure due to increased MAP .This study had a relatively small sample size of healthy volunteers, and as such the findings cannot be extrapolated to disease states without further study in specific patient groups. In female participants, we did not control for phase of the menstrual cycle. Consistent with a noninvasive study in healthy volunteers, several of the outcome variables are indirect estimates and not direct measures of NVC. Using transcranial Doppler to estimate cerebral blood flow assumes consistent cross-sectional area of the insonated vessel. We chose to insonate the P1 to mitigate potential changes in PCA diameter during visual stimulation.Neuronal NOS plays a fundamental physiological role in the regulation of cerebral blood flow, particularly the rapidity of the NVC response to visual stimulation. The role of nNOS in conditions of impaired NVC warrants further evaluation.We are grateful to Karen McNeill and the staff at the Biomedical Research Centre, Clinical Research Facility, Guy’s and St Thomas NHS Foundation Trust for supporting this study and to the team from Guy’s Hospital Aseptic Pharmacy for the production of SMTC. We are grateful to Dr David Vickers PhD, University of Calgary for his statistical advice.Funding: The laboratory of A.A. Phillips is supported by the Canadian Institutes for Health Research (Project Grant), Brain Canada, Compute Canada, Natural Sciences and Engineering Research Council , the Libin Cardiovascular Institute of Alberta, Hotchkiss Brain Institute, Campus Alberta Neuroscience, and Rick Hansen Institute. This work was supported by the National Institute for Health Research Biomedical Research Centre (NIHR BRC) at Guy’s & St Thomas’ NHS Foundation Trust and King’s College London [IS-BRC-1215-20006]. We also acknowledge support from the British Heart Foundation ; and a UK Medical Research Council Clinical Research Training Fellowship [MR/R017751/1] to KOG. Funding sources had no involvement in the study design, the collection, analysis, and interpretation of data, the report writing, or the decision to submit for publication.The iNVC software used in the data analysis is commercially available and was developed by Lam and Phillips.Tables S1–S4Figures S1–S4Major Resources Table