This retrospective study aimed to explore the relationships between electrolytes and osmotic pressure homeostasis with contrast-associated acute kidney injury (CA-AKI) risk in patients with percutaneous coronary intervention or coronary angiography. We totally enrolled 4386 hospitalized patients, who were categorized into five groups based on the predetermined cutoff values of electrolytes and osmotic pressure. CA-AKI was defined as an increase in serum creatine by 0.5 mg/dL (44.2 mol/L) or a 25% increase of the highest level post-operation compared to baseline. Multivariable logistic analysis was used to examine the association of CA-AKI incidence with electrolytes and osmotic pressure levels. Piecewise linear regression models and restricted cubic spline analysis were further utilized to determine the nonlinear relationship. The results showed U-shaped relationships between sodium, chloride, magnesium, and osmotic pressure levels and CA-AKI incidence. The lowest incidence was observed in the categories of 139–141.9 mmol/L, 107.0–109.9 mmol/L, 0.91–1.07 mmol/L, and 290.0–299.9 mOsm/kg, respectively. J-shaped associations were observed for potassium and phosphate levels and CA-AKI incidence, with the lowest incidence in the categories of 3.50–4.09 mmol/L and 0.96–1.28 mmol/L, respectively. A negative correlation was observed between calcium level and CA-AKI incidence, with the lowest CA-AKI risk in the category of ≥ 2.58 mmol/L. In conclusion, abnormally higher or lower sodium, chloride, magnesium, phosphate, and osmotic pressure levels on admission were associated with increased risks of CA-AKI. While for potassium and calcium, the status of hyperkalemia and hypocalcemia on admission showed more susceptibility for CA-AKI. The incidence of CA-AKI is about 3.3% in the general population2, and patients with concomitant diseases such as chronic kidney disease, diabetes mellitus, and heart failure are at much higher risk4. Although CA-AKI is generally reversible, patients have a five times higher risk of in-hospital mortality than those without CA-AKI6. Understanding the CA-AKI mechanism and its risk factors is urgently needed to minimize the potential risks for patients undergoing percutaneous coronary intervention (PCI) and coronary angiography (CAG).Iodized contrast medium (CM) is indispensable for interventional cardiac procedures. Iodized CM use is one of the most common causes of contrast-associated acute kidney injury (CA-AKI). It is the third leading cause of acute kidney injury (AKI) following renal hypoperfusion and drug-induced acute kidney injury during hospitalizations7. Plasma osmotic pressure balance is critical to maintaining the fluid distribution across the cell membrane. Disturbance of electrolytes and osmotic pressure could induce significant clinical disorders, such as water intoxication, edema, neuromuscular dysfunction, and arrhythmia8. Electrolytes and osmotic pressure disturbances are prevalent in patients with cardiovascular disease (CVD)9. Abnormalities in these factors have been linked to poor prognosis in patients. Emerging evidence has proved that baseline electrolyte levels were independently associated with acute kidney injury for the hospitalized patients14. However, only one study described the association between the baseline electrolyte levels, specifically chloride levels, and CA-AKI10. Therefore, this is the first multicenter cohort study to explore the relationship between admission electrolyte and osmotic pressure levels with CA-AKI incidences.Electrolytes, such as sodium, chloride, potassium, calcium, magnesium, and phosphate, play crucial roles in regulating plasma osmolality, acid–base homeostasis, cellular metabolism, cellular membrane potentials of nerve and muscle cellsP < 0.001). Besides, they have a higher proportion of diabetes mellitus (DM) compared with patients in the non-CA-AKI group , as well as a higher HbA1c level observed in the CA-AKI group . They were also more likely presented with myocardial infarction  and had lower ejection fraction levels . The NT-proBNP levels were also significantly higher in the CA-AKI group (1522.00 (480.50–3634.00) vs. 513.00 (129.00–1681.00) pg/ml, P < 0.001). For the lipid profiles, the patients who developed CA-AKI had lower levels of total cholesterol (TC) (3.96 (3.13–4.61) vs. 3.96 (3.31–4.74) mmol/L, P = 0.006), high-density lipoprotein (HDL) (0.95 (0.76–1.12) vs. 0.98 (0.83–1.16) mmol/L, P < 0.001), very-low-density lipoprotein (VLDL) (0.58 (0.38–0.81) vs. 0.60 (0.41–0.88) mmol/L, P=0.002), and triglyceride (TG) (1.22 (0.89–1.63) vs. 1.28 (0.97–1.82) mmol/L, P < 0.001) than the non-CA-AKI patients. Patients in two groups had a similar distribution of low-density lipoprotein (LDL) (2.08 (1.54–2.72) vs. 2.08 (1.59–2.71) mmol/L, P = 0.485). Patients in the CA-AKI group have a slightly lower estimated glomerular filtration rate (eGFR) levels than those in the non-CA-AKI group . Potassium , phosphate , and osmotic pressure  levels were higher in the CA-AKI group than the non-CA-AKI group. In contrast, the levels of sodium , chloride , calcium , and magnesium  were lower in the CA-AKI group compared with the non-CA-AKI group.A total of 5211 patients were enrolled in this study. About 785 patients were excluded according to the criteria of enrollment. Finally, 4386 patients (age 67.10 ± 10.77 years) were enrolled for further analysis, of whom 787 (17.9%) were diagnosed with CA-AKI. The flow diagram of enrollment is shown in Fig. To explore the relationships of baseline electrolyte and osmotic pressure levels with CA-AKI incidence, we first divided all patients into five groups based on the predetermined values of each kind of electrolyte and osmotic pressure. Figure 15. Other correlation coefficients of each pair were all shown in Fig. Since we studied seven different independent variables simultaneously, a correlation matrix was first conducted to detect hidden patterns among these seven variables. As shown in Fig. P-value for trend, as shown in Table Since we have found the segmentation characteristics of CA-AKI incidence among different electrolytes and osmotic pressure, we further performed logistic regression analysis for each variable to determine whether different concentrations acted as influential factors for CA-AKI. A multivariate logistic model was utilized by adjusting for potential confounders. We used three different models to calculate the odds ratios, 95% CI, and P for trend were < 0.001, 0.001, < 0.001, and 0.090, respectively). Then the risk increased with the rise of concentrations . For potassium and phosphate, the lowest CA-AKI incidence was observed in the second category, showing overall J-shape association patterns. For potassium, the risk for CA-AKI was relatively flat until the category of 3.50–4.19 mmol/L (P for trend was 0.288), and then the risk started to rise rapidly afterward (P for trend was < 0.001). For phosphate, levels lower or higher than the category of 0.96–1.28 mmol/L increased the risk of CA-AKI significantly (P for trend were 0.008 and < 0.001). Uniquely, a negative correlation of calcium level with CA-AKI incidence was observed when the concentration was lower than the category of 2.25–2.40 mmol/L (P for trend was < 0.001). The curve then became relatively flat, indicating that the risk of CA-AKI did not significantly increase with the rise of calcium concentration when it was more than 2.40 mmol/L (P for trend was 0.330). The specific odds ratio values of each category compared with the reference group are presented in Table To flexibly model and visualize the relation of these electrolyte and osmotic pressure levels with CA-AKI incidence, we performed restricted cubic splines to visualize the data of Model 3 Fig. . The lev2, a higher potassium level significantly increased the risk of CA-AKI. In addition, hypomagnesemia and hyperphosphatemia showed unique higher risks of CA-AKI compared with patients with eGFR < 90 ml/min/1.73m2  level is a critical reference parameter for the kidney injury evaluation and diagnosis of CA-AKI. However, it can be affected by several factors such as age, the dose of contrast agent, eGFR, and DM. So we conducted subgroup analysis stratified by these factors and presented them as restricted cubic splines in Supplemental Figs. 17. However, it is unclear whether the distribution of electrolytes could predict CA-AKI. Up to our knowledge, this is the first study focusing on the associations between admission electrolyte and osmotic pressure levels and risk of CA-AKI. The main finding of this study is that CA-AKI incidence showed different patterns of associations with electrolytes and osmotic pressure homeostasis; U-shaped associations with serum sodium, chloride, magnesium, and osmotic pressure, J-shaped association with potassium and phosphate, and an inverse relationship with calcium levels.Previous studies have revealed that AKI could induce abnormal electrolyte levels since the kidney is the primary organ for maintaining the homeostasis of electrolytes15, evidenced by the highest correlation coefficient in the correlation matrix of our research. The risk patterns of sodium and osmotic pressure were also similar, both as U-shapes. Similar to our results, a recent study by Chen et al.18 revealed that hypernatremia and hyponatremia were both associated with increased risk for AKI. The mechanism for hypernatremia inducing AKI might be due to its effect on intravascular dehydration and vasoconstriction by tubuloglomerular feedback20.Several studies have reported the significance of these electrolyte and osmotic pressure levels on the incidence of acute kidney injury. In this study, we firstly performed a correlation matrix to explore the underlying relations among these variables. Although most correlations between two variables were statistically significant, the low correlation coefficients, except for the one of sodium and osmotic pressure and the one of sodium and chloride, indicated that the different electrolytes and osmotic pressure affected the incidence of CA-AKI in their unique roles. Since prior studies mainly focused on reporting the links between these electrolytes and AKI, but not with CA-AKI, we can only compare our findings with previous studies of AKI. Sodium is the primary electrolyte responsible for osmolarity21. Oh et al.10 reported that both patients with hypochloremia and hyperchloremia have higher CA-AKI rates than patients with normal chloride levels. This result is in agreement with our multivariable logistic regression analysis and subgroup analysis. The impact of chloride on AKI might be due to the regulating role of chloride for tubuloglomerular feedback and renin secretion21.Chloride is another important contributor to osmotic pressure, with a normal range of 96.0–114.0 mmol/L. The extracellular chloride levels are proved to be crucial for the constriction of the afferent arteriole, mesangial cells, and juxtaglomerular cells.11 found serum potassium at baseline over 4.0 mmol/L was a significant risk factor for in-hospital acute kidney injury, which was similar to our results. We found that hypokalemia did not significantly increase the risk for CA-AKI. However, higher baseline potassium levels over 4.1 mmol/L significantly increased the risk for CA-AKI compared with the reference group. This result mainly emphasizes the risks of hyperkalemia for CA-AKI. It might be that hyperkalemia is regarded as a sign of renal dysfunction and some comorbid diseases.The imbalance of potassium homeostasis is prevalent in patients with impaired renal function. Park et al22. Calcium is a critical mineral required for several physiologic functions, such as intracellular messenger transduction and hormonal activity12. Also, calcium affects the vascular tone of the kidney. The imbalance between renal vasoconstriction and vasodilatation due to the abnormality of calcium finally induces AKI23. Thongprayoon et al.12 observed a U-shaped association between admission serum ionized calcium and in-hospital AKI. Both hypocalcemia and hypercalcemia on admission were associated with an elevated risk of in-hospital AKI. However, our study found a negative linear association between serum calcium levels and CA-AKI incidence. The highest CA-AKI incidence was presented in the categories of serum calcium < 2.00 mmol/L. Compared with the reference group, higher calcium levels did not significantly increase the risk, which might be due to the limited patients in the groups of hypercalcemia.Electrolytes like calcium, magnesium, and phosphate are essential minerals for many physiological functions of the body, including maintaining normal cardiac function, neuronal activity, and bone health24. It can counteract vasoconstriction by endogenous catecholamines and potentiate the action of endogenous vasodilators25. In a study by Shen et al.13, they found that low serum magnesium was an independent risk factor for AKI in patients with malignancy, while Cheungpasitporn et al.26 revealed that both admission hypomagnesemia and hypermagnesemia increased the risk for AKI. A U-shaped association between magnesium levels and CA-AKI incidence was also found in our study. The underlying mechanism for hypomagnesemia and hypermagnesemia causing AKI is that they dysregulate vascular tonicity homeostasis by overstimulated vasoconstriction and vasodilation effects, respectively26.Magnesium is an essential catalyst in multiple cellular function27. Besides, hyperphosphatemia was proved associated with increased AKI incidence and higher risk for end-stage renal disease (ESRD)28. The potential mechanisms may involve the calcification of smooth muscle cells and disrupted endothelial function by the hyperphosphateimia29. In our study, both hypophosphatemia and hyperphosphatemia showed a significantly increased risk of CA-AKI. The overall relationship showed a J-shaped pattern. It provides new evidence on the risks of hypophosphatemia for CA-AKI.The kidney is the primary organ regulating phosphate levels. In a study investigating the predictive effect of serum phosphate for AKI in pediatric cardiac surgical patients, serum phosphate level was a reliable predictor of AKI with an AUC of 0.8631. So we further performed subgroup analyses according to the presence of DM or not and baseline HbA1c levels. The results showed that intensive attention on hyponatremia, hypochloremia, and hypoosmolaemia should be paid to the DM patients to prevent CA-AKI. In addition, for the patients with HbA1c ≥ 6.5%, hyponatremia, hypermagnesemia, hypoosmolaemia, and hypoosmolaemia showed unique higher risks of CA-AKI compared with those patients with HbA1c < 6.5%.Diabetes is a critical risk factor both for the CA-AKI and imbalance of electrolytes32. Such strategies lie in the oral or intravenous infusion with isotonic saline or sodium bicarbonate34. By adding the fluid, hydration increases the renal blood flow and decreases CM concentration in renal tubules, thus effectively reducing the toxicity of CM35.All these studies combined with ours show the significant association between the electrolyte and osmotic pressure homeostasis and CA-AKI. The effective therapy to prevent CA-AKI is hydration, an inexpensive and beneficial treatment38. Debates mainly focused on the choice of intravenous normal saline infusion or intravenous sodium bicarbonate infusion. Intravenous hydration of sodium chloride is the most commonly used strategy to prevent CA-AKI in clinical practice, including our study. However, some researchers proposed that sodium chloride is a chloride-rich solution. According to our findings, hyperchloremia is a significant risk factor for CA-AKI. Hence, intravenous sodium bicarbonate infusion has been proposed. Another theoretical benefit of sodium bicarbonate is that alkalization with bicarbonate perfusion could decrease the formation of reactive oxygen species in the renal medulla39. However, whether an intravenous infusion of sodium bicarbonate is superior to sodium chloride in preventing CA-AKI still needs further large sample studies as proof43.Although the effectiveness of hydration therapy has been well recognized, the agents, timing, dose, and velocity of optimal hydration strategy remain inconclusiveThere are two main applications for this study. First, our findings remind the clinicians to pay close attention to the patients with electrolyte or osmotic pressure imbalance before PCI or CAG. Close monitoring and timely correction of the electrolyte and osmotic pressure imbalance are indispensable and beneficial to minimize the incidence of CA-AKI. We also provided optimal intervals of the lowest risk of AKI for each type of electrolyte and osmotic pressure. Second, the associations between sodium, chloride, and osmotic pressure and CA-AKI incidence revealed that the middle interval of the normal range was the lowest for the CA-AKI risk, indicating that osmotic normal saline hydration therapy might be the optimal strategy to prevent CA-AKI in normal patients. Applications of intravenous hydration strategies with isotonic or half iso-osmolar normal saline are left to the discretion of clinicians according to the baseline sodium, chloride, and osmotic pressure levels of each individual.There were several limitations to this study. First, this is a retrospective observational study, and hence inherent bias was unavoidable. Second, our study did not provide data about the previous treatment that could influence electrolyte levels, such as diuretics, nor did we bring these confounding factors into our analytical model. Third, we only assessed data of total calcium concentration rather than ionized calcium in this study. It would be more scientific and reasonable to determine the relation between ionized calcium levels and CA-AKI. Besides, since the categories were predetermined according to the normal range, the number of patients across categories was unequal. One major consequence was that the number of patients in the first and fifth categories was limited. Although the numbers were sufficient to provide a trend of the odds ratio, they were insufficient to reflect a more solid odds ratio of this category. Lastly, we only have information on single serum electrolyte and osmotic pressure levels on admission. Therefore, we could not determine the time-course of changes of these levels that might influence the risk of CA-AKI.In conclusion, admission electrolyte and osmotic pressure levels are associated with the incidence of CA-AKI in patients who underwent PCI or CAG. Abnormally higher or lower sodium, chloride, magnesium, phosphate, and osmotic pressure levels on admission were associated with increased risks of CA-AKI. While for potassium and calcium, the status of hyperkalemia and hypocalcemia on admission showed more susceptibility for CA-AKI.It is a multicenter retrospective observational study. Consecutive hospitalized patients, who underwent PCI or CAG procedure at Sir Run Run Shaw Hospital and its medical consortium hospitals from December 2006 to December 2019, were enrolled in this study. For this study, our exclusion criteria included: (1) allergic to contrast medium; (2) contrast medium use within two weeks prior to PCI or CAG; (3) nephrotoxic medication within two weeks, including cisplatin, acyclovir, aminoglycoside antibiotics, and non-steroidal anti-inflammatory drug (NSAIDs) et al.; (4) subjects with end-stage renal disease (ESRD) or diabetic nephropathy requiring hemodialysis; (5) a history of myocardial infarction or stroke; (6) incomplete laboratory results. Patients were then divided into two groups according to their CA-AKI status. The study was performed following the criteria set by the Declaration of Helsinki involving experimenting on human subjects and approved by the Institutional Ethics Committee of Sir Run Run Hospital (20200803-34). Informed consent was obtained from all participants. The present study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.44. The amount of contrast medium used in the procedure was left to the discretion of the cardiologists according to the progress of the operation. Before the procedures, all patients received 500 ml 0.9% normal saline (100 ml/h) intravenously for hydration therapy. Serum creatinine levels of patients were measured on admission and monitored at least three times within 72 h post-procedure. The highest level of serum creatinine after the procedure was recorded and used for comparison with the one on admission. CA-AKI was defined as an increase in serum creatine by 0.5 mg/dL (44.2 mol/L) or a 25% increase of the highest level within 72 h after the procedure compared to baseline45.CAG or PCI procedures were performed by experienced interventional cardiologists according to the current standard guidelinesThe blood samples of the enrolled patients were collected on admission and post-procedural for blood chemistry tests. The serum electrolyte, osmotic pressure, and creatinine levels were measured by the clinical chemistry analyzer . The demographic information of each patient was recorded, including age, gender, body mass index (BMI), comorbidities, smoking status, alcohol drinking status, the history of cardiovascular and renal diseases, and the history of PCI and coronary artery bypass grafting (CABG). The features of coronary lesions and procedural characteristics during the CAG or PCI, and the concomitant medications before admission, were also recorded. Proteinuria was defined as the urinary protein detected higher than 150 mg/d. eGFR was calculated by the value of creatine and patients’ age and weight. The formula is as follow: eGFR = (140-age) × weight / (72 × Cr) for male and eGFR = 0.85 × (140-age) × weight / (72 × Cr) for female.The categorical variables were expressed as numbers and percentages, while continuous variables were expressed as mean ± standard deviation (SD) or median and interquartile range. Categorical variables between groups were compared using chi-square tests, while continuous variables were compared with non-parametric Mann–Whitney U test.P-value for the trend (P for trend) was calculated by treating the categories as continuous variables. Underlying non-linearity association was estimated by using a likelihood ratio test, and P-value for non-linearity was shown. Exploratory analyses were performed in subgroups stratified by age, eGFR, contrast volume, DM, and HbA1c levels. The results of subgroup analyses were all adjusted with the same clinically relevant variables above.The correlation matrix plot was used to evaluate the correlations among different electrolytes and osmotic pressure. Considering the normal ranges of electrolyte and osmotic pressure and characteristics of data distribution, patients were categorized into five groups according to predetermined cutoff points: sodium , chloride , potassium , calcium , magnesium , phosphate , and osmotic pressure . Multivariate logistic regression analyses were used to examine the associations of pre-procedural electrolyte and osmotic pressure levels with CA-AKI incidence. The adjusted variables were age, eGFR, gender, diabetes, hypertension, smoking, drinking, type of contrast agent, pre-admission of furosemide injection, and pre-admission of dopamine. Restricted cubic spline analysis was used to fit and visualize these associations with 4 knots flexibly. Additionally, the piecewise P < 0.05 was considered statistically significant. The statistical analyses were performed by SPSS  and R .A two-tailed The study was conducted according to the Declaration of Helsinki, and was approved by the ethics committee of Sir Run Run Shaw Hospital (NO. 20200803-34).Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Supplementary Information 5.Supplementary Information 6.


This cross-sectional study describes the administration and outcome of a short screening tool for assessing executive function, memory, language, and perceptual motor function of adults with sickle cell disease. What is the prevalence of and which factors are associated with suspected dementia in adults with sickle cell disease (SCD)?In this cross-sectional study of 252 adult patients with SCD, participants underwent screening using the Rowland Universal Dementia Assessment Scale (RUDAS). The RUDAS scores that were suggestive of dementia were found in 29 patients (11.5%) and were associated with lower kidney function and older age, although they were not associated with sex, SCD genotype, or disease severity.Results of this study suggest that adult patients with SCD may be at an increased risk for dementia and should be offered cognitive screening; the RUDAS is a promising screening instrument that is undergoing further validation. Adults with sickle cell disease (SCD) disproportionally experience early cognitive decline; however, guidance on the optimal screening strategy for cognitive dysfunction is lacking, and several available tools are biased by language, educational level, socioeconomic status, and race/ethnicity. The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically designed for cognitive screening in multicultural populations.To ascertain the prevalence of suspected dementia in adults with SCD using the RUDAS, and to identify whether age, sex, educational level, several biological variables, and SCD complications were associated with RUDAS scores.This multicenter, bilingual, cross-sectional study was conducted in 2 SCD comprehensive care centers in Canada . Participants were adults aged 18 years or older and were enrolled in the study between July 1, 2018, and July 30, 2019. All outpatients were eligible and offered study participation, unless they had an acute medical condition that required inpatient care or they were unable to follow study instructions.The RUDAS was administered by trained personnel in either French or English, according to the patient’s language preference. A questionnaire on social determinants of health was also administered, and participants underwent screening for anxiety and depression.Proportion of participants with RUDAS scores that were suggestive of dementia and the RUDAS score. Any score lower than 23 points was suggestive of dementia, a score between 23 and 27 points indicated a possible association with mild neurocognitive disorder, and a score higher than 27 points was normal.2 = 0.02; 95% CI, 0.00-0.07; P = .02). In a multivariable analysis, lower glomerular filtration rate  and increasing age , but not SCD genotype or disease severity, were associated with lower RUDAS scores.A total of 252 adult patients with SCD were included . Overall, 29 patients (11.5%) had RUDAS scores that were suggestive of dementia, and this proportion increased with age . The RUDAS scores were not associated with sex, language, SCD genotype, and SCD complications. The highest level of education was significantly associated with the RUDAS score; however, the association was small (ηThis study found that using the RUDAS revealed a high prevalence of suspected dementia in adult patients with SCD that was associated with worsening kidney function and age. Cognition should be screened in all adult patients with SCD, regardless of age, disease severity, and SCD genotype; further validation of the RUDAS is ongoing. This sickling leads to anemia, pain crises, and systemic vasculopathy that can culminate in stroke, silent cerebral infarcts, reduced cerebral vascular reserve, and cognitive dysfunction.6 Precise estimates on the prevalence of dementia and mild neurocognitive disorder (NCD) in adults with SCD are lacking, but they could be as high as 33%.3 In comparison, 564 000 persons (<2% of the population) in Canada were estimated to live with dementia in 2016.7 The cognitive domains associated with SCD are perceptual reasoning, verbal reasoning, executive function, working memory, attention, and processing speed.8 These deficits can have implications for quality of life, social functioning, school performance, and employment.9Black individuals in the United States are at an increased risk for dementia.10 A brief and easy screening tool is, therefore, urgently needed to aid in the rapid identification of potential dementia as well as to facilitate referral for in-depth neurocognitive evaluation and access to much-needed rehabilitation and assistive services. Existing screening tools, such as the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), can be biased by educational attainment, race/ethnicity, socioeconomic factors, and language.16 The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically developed for dementia screening in a multicultural population.17 The RUDAS evaluates executive function, memory, language, and perceptual motor function. It was designed to minimize educational bias and can be administered in 6 minutes, even for patients with low literacy. In a meta-analysis of 11 studies (involving 1236 patients) in the general aging population, a low RUDAS score (<23 of 30 points) had a specificity of 85.9% and a sensitivity of 77.2% in identifying dementia.11 Compared with the MMSE outcomes, the RUDAS results were not associated with preferred language, age, and educational level.11Despite the high prevalence of cognitive dysfunction in adult patients with SCD, no standardized approach for screening exists. In addition, race/ethnicity-based disparities have been associated with delays in diagnosis, more severe presentations, and suboptimal access to care and research.In this cross-sectional study, our primary aim was to ascertain the prevalence of suspected dementia in adults with SCD using the RUDAS. A secondary aim was to identify whether age, sex, educational level, several biological variables, and SCD complications were associated with RUDAS scores. We hypothesized that the prevalence of suspected dementia in adult patients with SCD estimated by RUDAS is similar to previous studies that used different neurocognitive screening instruments.STROBE) reporting guideline.This study was reviewed and approved by the ethics committee of both participating centers. Written informed consent was obtained from all study participants. We followed Strengthening the Reporting of Observational Studies in Epidemiology  in Montréal and from the University Health Network (UHN) in Toronto. Between July 1, 2018, and July 30, 2019, we offered study participation to consecutive adult patients (aged ≥18 years) with SCD who attended the outpatient clinic or received blood transfusions at either CHUM or UHN. We excluded participants with an acute medical condition that required inpatient care or with any condition that, according to physician judgment, prevented a valid consent from being obtained and/or compromised the ability of the participant to follow study instructions.The RUDAS was administered by trained personnel  in either French or English, according to the patient’s language preference. A questionnaire on education and employment was administered, and patients’ blood pressure was measured. One of us (S.F.) trained the test administrators in person according to the RUDAS administration guide. Unplanned monitoring visits were performed to verify the quality of test administration. Two of us (S.F. and D.S.) assessed the quality of test scoring.The RUDAS scores were abstracted from the questionnaires. Demographic data, SCD complications, laboratory results, and radiographic findings were abstracted from the electronic patient record systems at both CHUM and UHN. Abstractors were provided with data collection manuals and training to standardize the data collection process. Calibration was done through regular meetings and ongoing communications.18 any score lower than 23 points was suggestive of dementia, and participants with such scores were referred for further neuropsychological testing. Scores higher than 27 points were considered normal. Scores between 23 and 27 points indicated a possible association with mild NCD. Clinical variables collected were age, sex, SCD genotype, α-thalassemia sequence variation status, previous or current blood transfusion, and hydroxyurea therapy. Complications were identified according to the definitions described by Sebastiani et al.19 Stroke was confirmed by medical history and imaging. Patients were noted to have dementia, depression, or anxiety disorder only if they were formally diagnosed with this condition by a health care practitioner. The SCD severity score was calculated using the online calculator developed by Sebastiani et al.20The RUDAS scores were defined according to the RUDAS manual for scoring. According to the definitions described by Basic et al,Socioeconomic factors included mean household income (expressed as a continuous variable), which was estimated from postal codes data on the CensusMapper website, a resource based on the 2016 Canadian census data. Highest level of education was ranked according to the highest completed educational program . Occupational status was dichotomized as either working and/or studying or not working and not studying. No differentiation was made between part-time vs full-time employment or studies.The most recent laboratory values of bilirubin, lactate dehydrogenase, hematocrit, reticulocyte count, mean corpuscular volume, fetal hemoglobin fraction, white blood cells, and glomerular filtration rate (GFR) within 1 year of enrollment were collected. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease Study equation. To ensure that laboratory parameters were not confounded by acute medical events, such as painful episodes, we used only the laboratory results from more than 3 weeks from an emergency department or inpatient admission.3) was required, assuming an area under the curve of 0.9 for the RUDAS and an SE of 0.02348. This SE was the most conservative estimate derived from all previous studies on the RUDAS that provided an SD.23An estimated sample size of 255 participants (of whom 85 [33.3%] were estimated to have cognitive dysfunctionSummary statistics of continuous variables were presented as either a mean (SD) or a median (range), whichever was appropriate. For categorical variables, frequencies were calculated. Mean RUDAS scores were stratified by age group , and the proportions of participants with RUDAS scores lower than 23 and higher than 27 were calculated for each stratum.z scores and 29 variables of interest. For discrete variables, we used independent unpaired, 2-tailed t test or 1-way analysis of variance. Effect sizes were quantified using Cohen d and η2. For continuous variables, we computed Pearson correlations. Multiple imputation of all missing variables was performed using the mice package in R .24 Five iterations were used. Holm correction was used to correct for multiplicity.The RUDAS score was standardized by subtracting every score from the mean and dividing by the SD. Skewness was assessed to be moderate. First, we investigated the association between these RUDAS z scores. Twelve independent variables were chosen a priori: age, sex, highest level of education, mean household income, SCD genotype, hematocrit, GFR, reticulocyte count, stroke, depression, anxiety, and pain. Statistical significance was defined as 2-sided P < .05. Multicollinearity was assessed using variance inflation factor (VIF). Cohen f2 was reported to measure the effect size of the regression model. Statistical analyses were performed with R.24Second, we produced linear multiple regression to identify the independent variables associated with the RUDAS Between July 1, 2018, and July 30, 2019, we enrolled 252 participants, of whom 92 were from CHUM and 160 were from UHN. Of these patients, 136 were women (54.0%) and 116 were men (46.0%), with a mean (range) age of 34.8 (18-75) years. Overall, we offered study participation to a total of 260 patients; 1 candidate was excluded because of inability to follow study instructions and 7 candidates declined the invitation. All participants at UHN chose the English questionnaires, whereas 85 participants (94.6%) at CHUM preferred the French questionnaire.0) in 152 (60.4%), SC in 79 (31.3%), Sβ+ in 9 (3.6%), and other sickle genotypes in 12 (4.8%). Two patients (0.8%) had a clinical diagnosis of dementia, and 24 patients (9.5%) had a stroke history. Pain (192 [76.2%]) and acute chest syndrome (110 [43.7%]) were the most frequent complications. The median (interquartile range [IQR]) Sebastiani SCD severity score was 0.17 (0.09-0.24) points, an estimated 17% chance of death within 5 years. Overall, 177 patients (70.2%) were on a disease-modifying therapy (hydroxyurea and/or regular transfusions).A significant proportion of patients (69 [27.4%]) was in the 40 to 59 age group . The SCDThe mean RUDAS score was 25.9 (2.9) points, and the median (IQR) RUDAS score was 26 (24-28) points . French-z scores, whereas the highest level of education had a small but statistically significant association with the RUDAS z scores . The mean difference was 0.8 points higher in those with at least a bachelor’s degree (26.6 [2.4] points) vs those without a bachelor’s degree (25.8 [3.1] points). On post hoc analysis, significant difference in RUDAS performance was observed only between those without any diploma, certificate, or degree and those with at least a bachelor’s degree .On univariate analysis , sex, stz scores . On post hoc analysis, the RUDAS scores in those who were both studying and working were 3.4 points higher or those who were studying were 1.9 points higher (post hoc Tukey HSD P = .009) than the scores in those neither studying nor working (post hoc Tukey HSD P < .001). Studying and working status was associated with a 2.1-point higher RUDAS score compared with only working .Similarly, occupational status had a small but statistically significant association with the RUDAS z scores . Stroke was not associated with the RUDAS z scores  (The association of a history of dementia diagnosis with the RUDAS score was not measured because only 2 patients with such history were included. A diagnosis of depression or anxiety disorder was not associated with the RUDAS P = .71) .z scores decreased significantly with increasing age . The RUDAS z scores also decreased significantly with lower GFR  and decreased more modestly with increasing systolic pressure  and lower reticulocyte count . The SCD genotype, complications, and severity score did not correlate with the RUDAS z scores , highest level of education , and GFR  were independently associated with the RUDAS z scores. Our model accounted for 24% of the variability in the RUDAS scores . Collinearity was overall acceptable  and was highest for age (VIF = 1.70) and GFR (VIF = 1.58). The result did not differ significantly when missing data were imputed , is still unclear. Recruitment for a future study is ongoing to ascertain the reliability and to further validate the ability of the RUDAS to detect clinically significant cognitive dysfunction in adult patients with SCD.Findings of this study are in line with the recommendation by the American Society of Hematology.37 A comprehensive clinical assessment, including the implication for independence and the subjective experience, is needed to confirm the diagnosis. Given that access to comprehensive clinical assessment for dementia is limited because of its specialized and cumbersome nature, the RUDAS can potentially fill the niche as a screening tool that allows the identification and channeling of patients with suspected dementia for formal assessment. Certain deficits observed in the RUDAS testing may reflect the neurodevelopmental impact of SCD early on in life, but the increased prevalence between age groups suggests the presence of an additional neurodegenerative process during adulthood. Third, the optimal threshold to flag a patient with SCD as having likely dementia or mild NCD will need to be established in future studies. Fourth, selection bias was also a potential concern. Convenience sampling was applied to recruit successive patients from ambulatory care settings in CHUM and UHN. Patients with dementia may have difficulties attending clinic visits. However, for these patients, clinicians may already have sufficient suspicion and indirect evidence of cognitive dysfunction for referral to the appropriate resources, and a screening tool may not be needed to unmask cognitive dysfunction. Fifth, although GFR was associated with the RUDAS scores, we cannot exclude the presence of additional confounders, such as diabetes, heart failure, medications, and other unknown factors.This study has several limitations. First, its cross-sectional design precluded our ability to use the RUDAS to detect the development of dementia at this time. Second, major vascular cognitive disorder diagnosis according to the International Society for Vascular Behavioral and Cognitive Disorders guidelines requires a decline from previous function; therefore, we can only suspect such a diagnosis.Cognitive dysfunction screening using the RUDAS revealed a high prevalence of suspected dementia in adult patients with SCD that was associated with worsening kidney function and age. The results of this study suggest that all adult patients with SCD, regardless of age, disease severity, and SCD genotype should be screened for cognitive dysfunction. A study is underway to ascertain the reliability and validity of the RUDAS to detect clinically significant cognitive dysfunction in adult patients with SCD.


However, other variables related to the quality of emergence from anesthesia did not different significantly between groups. Similarly, neurologic deficits, and PONV during postoperative day 3 showed no significant differences. (4) Conclusions: ICP elevation detected by ultrasonographic ONSD measurement was associated with a transient, inadequate emergence from anesthesia.(1) Background: Robot-assisted laparoscopic prostatectomy (RALP) is preferred over open prostatectomy because it offers superior surgical outcomes and better postoperative recovery. The steep Trendelenburg position and pneumoperitoneum required in Robot-assisted laparoscopic prostatectomy, however, increase intracranial pressure (ICP). The present study aimed to evaluate the effects of elevated ICP on the quality of emergence from anesthesia. (2) Methods: Sixty-seven patients undergoing RALP were enrolled. We measured optic nerve sheath diameter at four timepoints during surgery. Primary outcome was inadequate emergence in the operating room (OR). Secondary outcomes were postoperative neurologic deficits of dizziness, headache, delirium, cognitive dysfunction, and postoperative nausea and vomiting (PONV). (3) Results: A total of 69 patients were screened for eligibility and 67 patients completed the study and were included in the final analysis. After establishing pneumoperitoneum with the Trendelenburg position, ONSD increased compared to baseline by 11.4%. Of the 67 patients, 36 patients showed an increase of 10% or more in optic nerve sheath diameter (ONSD). Patients with ΔONSD ≥ 10% experienced more inadequate emergence in the OR than those with ΔONSD < 10% (47.2% vs. 12.9%,  However, the Trendelenburg position combined with a pneumoperitoneum adversely influences cardiovascular hemodynamics, respiratory mechanics, and cerebrovascular perfusion during surgery. In particular, significant changes in cerebral hemodynamic physiology leading to increases in intracranial pressure (ICP) and intraocular pressure have been noted [Robot-assisted laparoscopic prostatectomy (RALP) is the preferred alternative to open prostatectomy because it offers superior surgical outcomes and rapid postoperative recovery . To secuen noted . A few pen noted ,6,7,8,9.Optic nerve sheath diameter (ONSD) using ultrasonographic measurement correlated well with directly measured ICP. It is also known as a method of accurately and quickly monitoring changes in ICP ,11,12,13The present study aimed to evaluate the effect of elevated ICP due to position and pneumoperitoneum on quality of emergence from anesthesia. Primary outcome was the occurrence of inadequate emergence according to elevated ICP. Secondary outcomes were other variables associated with emergence quality such as time to eye opening, time to extubation, and inadequate emergence in post-anesthesia care unit (PACU). Additionally, we investigated whether elevated ICP was associated with postoperative nausea or vomiting, and neurologic deficits including dizziness, headache, delirium, and cognitive dysfunction.https://cris.nih.go.kr, accessed on 20 November 2020; registration number KCT 0005665). This study is a single center prospective observational study. The study was approved by the institutional review board of Samsung Medical Center, Seoul, South Korea  and registered at CRIS ; increased intracranial pressure ; and current medications known to influence emergence from anesthesia . We initially planned to enroll either female or male participants undergoing robotic pelvic surgery. However, there were no eligible female participants because surgeons at our hospital overwhelmingly prefer open surgery or simple laparoscopic surgery for elderly female patients. Therefore, only male patients undergoing RALP were enrolled during the study period. A total of 69 patients were screened for eligibility. After obtaining informed consent, we enrolled 67 patients scheduled for elective RALP.−1 and propofol and remifentanil via target-controlled infusion . Attending anesthesiologist used the following ventilator settings: tidal volume of 8 mL·kg−1 of ideal body weight, FiO2 0.4, and zero positive end tidal pressure. Respiratory rate was adjusted to maintain an inspiratory peak pressure less than 30 cmH2O and an EtCO2 between 35 and 38 mmHg. After establishing pneumoperitoneum, ventilator setting was adjusted to a target PaCO2 of 32–35 mmHg. Effect site concentrations of propofol and remifentanil were adjusted to achieve bi-spectral index (BIS) values of 40 to 50 and to maintain mean blood pressure and heart rate at within 20% of pre-induction values. Neuromuscular blockade monitoring was performed with an NMT device . Continuous infusion of rocuronium was adjusted to maintain two counts of train of four (TOF) and stopped at least 30 min before the end of surgery. Palonosetron 0.075 mg and propacetamol 1 g were administered for pain control and as antiemetics. When the surgeon started suturing subcutaneous tissue, the propofol infusion was stopped or decreased by targeting a BIS of 60–65. After surgery, residual neuromuscular blockade was reversed with pyridostigmine (250 mcg·kg−1) and glycopyrrolate (10 mcg·kg−1). Independent anesthetic provider checked the patient’s consciousness and evaluated if the patient met the pre-determined extubation criteria of (1) sufficient reflexes to protect the airway; (2) adequate gas exchange ; (3) TOF ratio ≥ 0.9; and (4) Observer Assessment of Alertness/Sedation Scale (OAA/S) ≥ 2. Patients were extubated in the operating room (OR) and transferred to a post-anesthesia care unit (PACU).During standard monitoring of patients per protocol, general anesthesia was induced with intravenous rocuronium 0.8 mg.kgA single experienced investigator who has performed > 50 scans measured ONSD using a portable US unit  with a 5–10 Hz linear probe . When geUltrasonographic images were reviewed using a picture archival and communication system  and ONSD was measured 3 mm behind the globe by the blinded two clinicians. After obtaining the mean ONSD of each eye, the mean value of ONSD in both eyes was calculated. We defined ∆ONSD as follows: ∆ONSD = 100 × (maximum ONSD at any time point—ONSD at baseline)/ONSD at baseline.We recorded physical characteristics, intraoperative variables, and length of stay (LOS) by review of medical records. All patients underwent the Mini Mental State Exam (MMSE) prior to surgery as a baseline examination. The primary outcome was inadequate emergence in OR. The variables related to quality of emergence from general anesthesia, namely time to eye opening, and time to extubation were collected. Inadequate emergence was evaluated using the Richmond Agitation and Sedation Scale (RASS) after extubation by the attending anesthesiologist. Inadequate emergence was classified as agitated emergence or hypoactive emergence. Agitated emergence was defined as a RASS score > 1; hypoactive emergence was defined as a RASS score < −2 ,18. TimeSample size was calculated based on a previous study. Inadequate emergence incidence reported in the literature is 8.2% . The meap-value < 0.05. All analyses were performed using SAS version 9.4 .Data are presented as means (standard deviations (SD)) or as medians (inter-quartile ranges (IQR)), as appropriate. The Shapiro–Wilk test was used to explore normality. Significance of differences between groups was assessed using the chi-square test or Fisher’s exact test for categorical variables and T tests or Wilcoxon’s rank sum test for continuous variables as appropriate. Post hoc analyses were also performed. Statistical significance was defined as a A total of 69 patients were screened for eligibility. After excluding two patients, 67 patients completed the study and were analyzed . Patientp = 0.003). p = 0.005). Other variables related to the quality of emergence did not different significantly between groups  immediately before discharge from OR. We considered that this might be a unique characteristic of the elderly that occurs in the process of emergence from general anesthesia. However, it is necessary to introduce more stringent extubation criteria to perfectly exclude residual effects of anesthetics. Last, neurological outcomes were collected up to POD 3 so we were not able to determine the association between an increase in ONSD during surgery and long-term neurologic deficits after surgery. We evaluated postoperative cognitive impairment using only MMSE, but a more detailed neurocognitive battery is required for accurate diagnosis.The present study showed a potential link between elevated ICP and inadequate emergence. To assess other effects of elevated ICP on neurological outcomes, further research is needed, including more detailed neurologic tests and long term follow-up.The patients undergoing RALP showed an increase in ONSD during surgery. ICP elevation detected by ultrasonographic ONSD measurement was associated with inadequate emergence from anesthesia in the OR. We suggest that ICP monitoring using sonographic ONSD measurement is helpful to identify patients who may be at increased risk of inadequate emergence or morbidity due to increased ICP.


FSGS recurrence was defined as having proteinuria of ≥3 g/g or urinary creatinine of ≥3 g/day. All patients received an induction therapy; maintenance immunosuppressive therapy at post-transplantation relied on tacrolimus/mycophenolate mofetil/steroids. In order to prevent or treat FSGS recurrence, patients received apheresis sessions plus rituximab. Results: FSGS recurrence rate was 47%. All patients that relapsed with a first graft also relapsed with subsequent grafts. Median time to recurrence was 3  days, despite rituximab/apheresis prophylaxis. Mean age was significantly lower in the relapsers (group 1) than in the non-relapsers (group 2); i.e., 47 ± 11 vs. 58 ± 9 years (p = 0.04). Time to progression to stage 5 chronic kidney disease (CKD) and young age at FSGS diagnosis were lower in group 1 compared to group 2; i.e., 5  vs. 2  years, and 16  vs. 34  years, respectively. There was no difference between the two groups in terms of progression to CKD stage 5 on the native kidneys, averaging 7 years in both groups (p = 0.99). In group 1, seven patients received rituximab/apheresis prophylaxis, although this did not prevent the recurrence of FSGS. Conclusion: pretransplant prophylaxis with plasmapheresis/rituximab did not appear to reduce the risk of recurrence of primary FSGS on the graft, but could allow remission in the event of recurrence.Background: Primary focal segmental glomerulosclerosis (FSGS) is associated with a high risk of recurrence after kidney transplantation with a major risk of graft loss despite preventive or curative treatments. Aim: to assess graft survival in FSGS kidney-transplant recipients and to compare those that had a relapse with those that had no relapse. Patients/Methods: we included 17 FSGS kidney-transplant recipients between January 2000 and January 2020, separated retrospectively into two groups (recurrences:  Primary focal segmental glomerulosclerosis (FSGS) is a diagnosis of exclusion, because the histological lesion does not allow guiding the pathogenesis. It is a glomerular lesion characterized by the presence of sclerotic and hyaline lesions, which may be associated with deposits of immunoglobulin M (Ig M) and the C3 complement fraction . The incWhether primary, secondary, or genetic, FSGS progresses to chronic kidney disease (CKD); kidney transplantation is then the treatment of choice in stage 5 CKD. Primary FSGS is associated with a high risk of recurrence in a graft after kidney transplantation, reaching 30% after a first transplant and 80–100% after a second kidney transplant [Recurrence on the graft is defined by the reappearance of glomerular-type proteinuria, with or without nephrotic syndrome, and the absence of other causes that may be the origin of this proteinuria. It usually occurs very quickly, within hours or days after kidney transplantation . The patThis single-center retrospective study included 17 kidney-transplant recipients with primary FSGS that attended our hospital between January 2000 and January 2020.Diagnosis of primary FSGS was retained after kidney biopsy and in absence of other etiologies. Only a single patient whose diagnosis of FSGS was made at the age of 4 years was able to benefit from the genetic study, which came back negative.FSGS recurrence was defined as having proteinuria of ≥3 g/g or urinary creatinine of ≥3 g/day, whatever the time of onset after transplantation. It was mandatory to eliminate other causes of early de novo proteinuria, including acute humoral rejection . Kidney graft biopsy was not systematic; i.e., it was only performed when recurrence occurred late after transplantation or in the event of presence of a donor-specific alloantibody .The time to recurrence was defined according to Cameron’s classification : immediaComplete remission was defined as having proteinuria < 0.5 g/day for at least 2 consecutive weeks. Partial remission was defined as a reduction in proteinuria to 0.5–3 g/day or having decreased proteinuria of >50% from the baseline value for at least 2 consecutive weeks.The main objective was to assess the survival of the renal transplant according to FSGS relapse, which was then treated by apheresis and/or rituximab.All patients received an induction therapy before transplantation of either antithymocyte globulins or basiliximab. Maintenance immunosuppressive therapy at post-transplantation relied on tacrolimus (aiming at trough levels of 5–8 ng/mL), mycophenolate mofetil (1 g/day), and steroids (prednisone).In order to prevent recurrence of FSGS, patients received one plasma exchange before transplantation, and then three plasma exchanges per week during the first 2 weeks post-transplantation. It was only performed in 7 patients due to a recurrence on a previous kidney graft.®  or Spectra Optia®  separators. The plasma volume was treated as 1.5 times the plasma volume calculated using Kaplan’s formula [However, in the event of an FSGS relapse immediate or early after transplantation the previous schedule was modified accordingly; i.e., apheresis sessions were intensified. Plasma exchanges were carried out by centrifugation using Comtec formula : PV = 0.® columns  were used alternately for every 500 mL of treated plasma . The Globaffin® adsorber used synthetic peptide GAM ligands that bind the constant (Fc) portion of the immunoglobulins, particularly the Ig G1, 2, and 4 subclasses. The volume of treated plasma per session was 100 mL × body weight (kg).After January 2016, patients that experienced a post-transplantation FSGS relapse had plasma exchanges replaced with immunoadsorption. Two GlobaffinIn group 1, one patient received pretransplant immunoadsorption sessions in preparation for an incompatible HLA kidney transplantation, and another patient received eight plasma-exchange sessions after transplantation to avoid a relapse of FSGS upon request of his nephrologist.2, given as one or two injections at one week apart. In the prophylactic setting, rituximab was given in a single dose. In curative treatment, rituximab was administered twice 2 weeks apart, then every 6 months depending on the clinical–biological evolution .Rituximab was used to prevent and treat the recurrence of FSGS at a dose of 375 mg/mWhen combined with apheresis, rituximab was always given after an apheresis session.The next post-rituximab apheresis session was performed 72 h after the rituximab injection to minimize drug elimination during apheresis.Rituximab was administered as a pretransplant in 7 patients in group 1 due to recurrence of FSGS on a previous kidney graft, and in a single patient in group 2 in the setting of an incompatible HLA kidney with specific donor antibodies.2 of body surface area) at the 4th and 8th apheresis sessions.Treatment of FSGS consisted of intensified plasma exchange or IA sessions: i.e., every other day for 2 weeks, and was then adapted to proteinuria level. Patients also received either methyl-prednisone pulses (10 mg/kg for three consecutive days) or prednisone, which was increased at 1 mg/kg/day for 3 weeks and then slowly tapered. Rituximab was also given (375 mg/m2), albuminemia, serum protein, proteinuria, IgG, IgA and IgM, renal-allograft histology, infectious complications .The data collected included age, body mass index (BMI), and gender. Before kidney transplantation, we determined age at diagnosis of FSGS, time to progression to CKD stage 5, previous renal transplants , time on dialysis before transplantation (in months), magnitude of anti-HLA sensitization, and blood group. After kidney transplantation, we collected characteristics on the donor–recipient pair , time to recurrence of FSGS, induction and maintenance immunosuppressive treatments, and the use of renin–angiotensin system blockers. In addition, at regular intervals post-transplantation, we collected the following data: serum creatinine, estimated glomerular-filtration rate (GFR) . The biobank collection number is BRIF BB-0033-00069.All data are available upon request to the corresponding author.Quantitative data are presented as means ± standard deviations (SD) or medians and quartiles (Q1–Q3). Qualitative data are presented as absolute numbers with percentages. Differences were calculated using the chi-squared or Fisher’s exact test for categorical data, Student’s test and ANOVA were used for normally distributed numeric data variables, and the Mann-Whitney-U and Kruskal-Wallis tests for non-Gaussian variables.p-value of <0.05 was considered statistically significant. Analyses were conducted using R statistical software .A two-sided p = 0.04). The age at diagnosis of FSGS was also lower in group 1 than in group 2; i.e., 16  vs. 34  years (p = 0.12). There was no difference between the two groups in terms of progression to CKD 5 on the native kidney, averaging 7 years in both groups (p = 0.99). The patients’ demographic criteria are listed in We retrospectively separated the patients into two groups according to whether or not they had FSGS recurrence; i.e., FSGS recurrence (group 1: 8 patients), and no FSGS recurrence (group 2: 9 patients). Of the eight kidney-transplant recipients that had FSGS relapse, 75% had an early relapse. Median time to recurrence was 3  days. The mean age was significantly lower in group 1 than in group 2; i.e., 47 ± 11 years vs. 58 ± 9 years . No patient had donor-specific antibodies at the time of the transplantation.In group 1, CMV DNAemia was assessed weekly for the first month, and then before each apheresis session during the maintenance period. In group 2, CMV DNAemia was assessed every 2 weeks for the first 6 months post-transplantation. All the patients except those that were donor CMV seronegative/recipient seropositive underwent CMV prophylaxis for the first three months post-transplant with valganciclovir adapted to eGFR.If CMV, DNA level was >3 log copies/mL, treatment with valganciclovir was initiated (900 mg × 2/day) for 3 weeks and adapted to GFR. Overall, only four patients  presented with mild CMV reactivation.The rate of recurrence of primary FSGS on a renal graft was 20 to 40% for a first graft, but reached 80 to 100% recurrence on subsequent grafts if there was recurrence on the first graft ,18. In oIn our study, all patients that relapsed with a first graft also relapsed with subsequent grafts. The time to progression to stage 5 CKD and young age at diagnosis of FSGS were lower in the relapsers (group 1) compared to the non-relapsers (group 2); i.e., 5  vs. 2  years, and 16  vs. 34  years, respectively. Two of our patients received transplants from living donors.Despite rituximab and apheresis prophylaxis, group 1 patients had FSGS recurrence after a median of 3  days, and two subsequently lost their allograft. In general, renal transplantation from a living donor allowed better graft survival compared to transplantation from a deceased donor. However, in view of the significant risk of recurrence of primary FSGS, it was not advisable to propose a kidney transplant from a living donor in the event of primary FSGS, especially if there had been recurrence on a previous graft because, to date, there is still no effective prophylaxis that can prevent FSGS recurrence ,25.In group 2, no patient had FSGS recurrence in the kidney transplant. The mean age in this group at FSGS diagnosis was 34  years. The genetic study was not carried out in these patients. We did not find any secondary causes of FSGS, but we therefore could not rule out a genetic cause explaining absence of FSGS recurrence. Morello et al. , in a stIn our series, prophylaxis with rituximab and apheresis did not appear to reduce the risk of recurrence of primary FSGS. In fact, the combination of plasmapheresis and rituximab immediately before kidney transplantation in 87.5% of these patients did not prevent recurrence. However, after an average follow-up of 7 ± 3 years, this association of treatments seemed to be effective when recurrence occurred at post-transplantation; i.e., remission was induced in 50% of cases.Prophylaxis is based on the assumption of the existence of a soluble permeability factor ,5. This Several factors have been mentioned, such as suPAR, cardiotrophin-like cytokine-1 (CLCF-1), apolipoprotein A1, anti-tyrosine phosphatase antibody of the O receptor, CAsK, and sCD40L ,12,13,14p = 0.029). In contrast, Alasfar et al. [p = 0.21). Likewise, Verghese et al. [n = 57) and that had received a kidney transplant. They compared two groups (group 1: kidney transplant recipients after 2006 and that had received a PLEX before transplantation (n = 31); and group 2: kidney-transplant patients that received a transplant before 2006 and had not received a PLEX (n = 26)). They found no significant difference in the incidence  or the time until FSGS recurrence (p = 0.22) between the two groups.None of the preventive intervention measures showed any benefits in recurrence of primary FSGS after kidney transplantation. However, Kalliopi Vallianou et al.  found thr et al.  carried e et al.  retrospePlasmapheresis allowed complete or partial remission in 70% of children and 63% of adults when commenced soon after a recurrence , in a liIn addition to plasmapheresis, semispecific IA has been shown to be effective at causing remission. Lionaki et al.  reportedn = 31); i.e., after an average of 28 days. Complete remission was achieved in 46.6% of patients, and partial remission was achieved in 33.1%. Analysis of the propensity score showed no difference in the rates of complete remission and partial remission between G1 (82.6%) and G2 (71.8%) (p = 0.08). Following the addition of rituximab, 26.3% of patients had complete remission, and 31.6% had partial remission. The incidence of severe infection was similar between patients treated with or without rituximab. In multivariate analysis, infectious episodes were associated with hypogammaglobulinemia < 5 g/L.To assess the benefit of adding rituximab to plasmapheresis to treat a FSGS relapse after kidney transplantation, Lanaret et al.  identifiOur study had some limitations, including its relatively small sample size, retrospective nature, heterogeneity of treatments given, and absence of genetic testing. Indeed, only one of our patients underwent genetic exploration.We concluded that pretransplant prophylaxis with plasmapheresis and rituximab did not appear to reduce the risk of recurrence of primary FSGS on the graft, but potentially could allow remission in the event of recurrence, to be confirmed by randomized studies. Because recurrence can occur several years after transplantation, this justifies rigorous monitoring of patients with FSGS, more so than for other kidney-transplant recipients.


Asthma patients with obesity often have a high disease burden, despite the use of high-dose inhaled corticosteroids (ICS). In contrast to asthmatics with normal weight, the efficacy of ICS in patients with obesity and asthma is often relatively low. Meanwhile, patients do suffer from side effects, such as weight gain, development of diabetes, cataract, or high blood pressure. The relatively poor response to ICS might be explained by the low prevalence of type 2 inflammatory patterns (T2-low) in patients with asthma and obesity. T2-low inflammation is characterized by low eosinophilic count, low Fractional exhaled NO (FeNO), no clinically allergy-driven asthma, and no need for maintenance oral corticosteroids (OCS). We aim to study whether ICS can be safely withdrawn in patients with T2-low asthma and obesity while maintaining an equal level of asthma control. Secondary outcomes focus on the prevalence of ‘false-negative’ T2-low phenotypes (i.e. T2-hidden) and the effect of ICS withdrawal on parameters of the metabolic syndrome. This study will lead to a better understanding of this poorly understood subgroup and might find new treatable traits.2). Patients will be randomly divided into two arms (both n = 60). One arm will start with fixed-dose ICS (control group) and one arm will taper and subsequently stop ICS (intervention group). Patients in the intervention group will remain ICS naïve for ten weeks. After a washout of 4 weeks, patients will crossover to the other study arm. The crossover study takes 36 weeks to complete. Patients will be asked to participate in the extension study, to investigate the long-term metabolic benefits of ICS withdrawal.The STOP trial is an investigator-initiated, multicenter, non-inferiority, open-label, crossover study aiming to assess whether ICS can be safely withdrawn in adults aged 17–75 years with T2-low asthma and obesity (body mass index (BMI) ≥ 30 kg/mThis study yields valuable data on ICS tapering in patients with T2-low asthma and obesity. It informs future guidelines and committees on corticosteroid-sparing algorithms in these patients.Trial registration Netherlands Trial Register, NL8759, registered 2020–07-06, https://www.trialregister.nl/trial/8759.Protocol version and date: version 2.1, 20 November 2020. Asthma is a highly prevalent chronic pulmonary disease characterized by wheezing, shortness of breath, and cough. Asthma has a significant disease burden  and is cThese side effects can be prevented by minimizing ICS dosage. Dose reduction has been studied before, initially to induce asthma exacerbations and later to study dose optimization algorithms, but did not result in a successful ICS discontinuation strategy –22. HoweIn this trial, we withdraw ICS in patients with T2-low asthma and obesity to determine the effects on asthma control. We hypothesize that ICS withdrawal is non-inferior to ICS continuation in patients with asthma and obesity. Additionally, this trial uses common T2-biomarkers to detect patients that become T2-high after ICS withdrawal; T2-hidden asthma.The STOP trial is initiated by the ‘STZ center of Excellence for Asthma and COPD’ of the Franciscus Gasthuis & Vlietland hospital, collaborating with the Maasstad hospital and the Albert Schweitzer hospital. This multicenter approach ensures a larger number of possible study subjects and decreases selection bias due to social-economical differences between regions of Rotterdam. Patients will be randomized into one of two study groups to avoid allocation bias. Both groups consist of a control period and an intervention period in a 2 × 2 crossover pattern that creates balanced groups maximizes statistical power, and allows for analysing a possible sequence effect. The study has a non-inferiority design, which tests the hypothesis that ICS tapering is not inferior to ICS continuation. This intervention trial has an open-label to determine the effects of ICS tapering in a real-life situation.2 and a confirmed T2-low asthma diagnosis will be recruited at the outpatient clinic of the pulmonary departments of three major hospitals in the region of Zuid-Holland, the Netherlands; Franciscus Gasthuis & Vlietland hospital (Rotterdam), Maasstad hospital (Rotterdam), and Albert Schweitzer hospital (Dordrecht). In- and exclusion criteria must be met before the start of the run-in period. A detailed description of the in- and exclusion criteria can be found in Fig. Adults aged between 18 and 75 years with a Body Mass Index (BMI) ≥ 30 kg/mPatients included in the study will be randomized into two groups: the first group with sequence Intervention-Control and the second group with sequence Control-Intervention. Randomization is performed by Castor Data Capturing software using variable block randomization with block sizes of 4/6/8 and stratification by study centre.All patients start with a run-in period of 4 weeks using a fixed dose of ICS (Fluticasone 1000mcg/day) as well as salbutamol 100mcg ‘as needed’ , while patients in arm 2 will continue with a fixed-dose ICS for 14 weeks (control). An abrupt stop of ICS might cause asthma flair-ups. Therefore, ICS-dose will be tapered in two steps (fluticasone 500mcg/daily and 250 mcg/daily) over 4 weeks  of ICS tapering. To study the long-term effects of ICS withdrawal in T2-low asthma patients with obesity, we will extend the study by 2 years in an open-label extension study. In this extension study, patients will remain ICS naïve. Patients may only participate in the extension study after successful discontinuation of ICS in the crossover period.The primary parameter is the ACQ-5, which is widely used in the Netherlands to monitor asthma control. The difference between the control and intervention periods will be analysed using the baseline ACQ-5 score as a reference .Anamnestic parametersExacerbation frequency (mild/intermediate/severe)MedicationSmoking status and exposure to drugs/vapors/fumes/gases/other chemicalsSocial-economic statusAge at asthma diagnosisCo-morbidity Birth weight and respiratory history during childhoodAdverse eventsAdherence to treatment regimen QuestionnairesACQ-5: In this study the ACQ-5 will be used, consisting of five patient self-reported questions. The recall time is one week with a score range of 0 to 6 . A higher score is associated with worse asthma control. The minimal clinically important difference of the ACQ is 0.5 [Q is 0.5 .AQLQ: The AQLQ consists of 32 items with a 3 week recall period. The score range per question is 1 to 7 . It is used to qualify the disease-specific health-related quality of life [ of life –26.MRC: The MRC  is a dyspnea scale, as a measure of disability in patients with respiratory disabilities. It consists of one question about the shortness of breath and six possible answers. The score range per question is 0 to 5 . A higher score is therefore associated with a high burden of disease [ disease .FSS: The FSS  measures fatigue severity. It has 9 items with are scored on a 7 point Likert scale. A higher score is associated with higher fatigue severity [severity .AnthropometricsBody Mass Index (BMI)Waist circumferenceBlood pressureBlood testsMetabolic and endocrine panel: Oral corticosteroids are none for their dysregulating effects on glucose homeostasis [eostasis . This dyeostasis . Howevereostasis –33. The Pulmonary panel: Inhaled corticosteroids suppress T2-high inflammatory pathways. Previous ICS tapering studies (mainly including patients with T2-high asthma) demonstrated increased blood eosinophils after ICS tapering or even used an ICS dosing algorithm based on blood eosinophils [inophils , 22. HowBlood Serum: Blood serum will be isolated and frozen at − 80 °C for analyses of inflammatory and endocrine biomarkers.Isolation of Peripheral Blood Mononuclear Cells (PBMCs): To study the effect of ICS withdrawal on T2-low inflammatory cells.Lung functionExpiratory flow assessment: A hand-held spirometer will be used to assure maintained lung function after ICS withdrawal by measuring the FEV1.FeNO: Patients in this study have a starting FeNO lower than 20 ppb. However, we postulate that the FeNO values may increase to a value larger than 20 after ICS withdrawal. These patients have become T2-high (e.g. T2-hidden), which is an important secondary outcome.eNose: The electronic Nose is a novel development that uses semiconductors to measure patterns of exhaled volatile compounds. A eNose test results in a so-called ‘breath print’. The eNose successfully predicted response to (lung-)cancer treatment and is also used to measures the effect of corticosteroids in patients with Asthma [h Asthma –37. We aOtherHair cortisol and cortisone: As parameters of long-term endogenous corticosteroid exposure.Empty canisters: To study treatment adherence.Data will be stored in an electronic database (Castor EDC) using the participant study number. A master file is available to link the study number with the corresponding patient number at every site. This master file is only accessible for the site investigators. Paper questionnaires and other relevant materials will be safely stored in a locked room. The material will be labelled with a study number, study site, date, and visit number. Data and materials will be monitored every year by an independent monitor.Safety is assured by close monitoring of the subjects using a weekly questionnaire and online diary. Additionally, the use of reliever medication  is monitored to keep track of asthma control. Loss of asthma control is defined as an increase in ACQ score of more than 0.5 points for at least 4 days or progressive dyspnea despite using 500mcg of salbutamol per day by pressurized metered-dose inhaler (pMDI) with spacer. Patients will be asked to contact the coordinating researcher in case of progressive dyspnea despite using ≥ 600mcg salbutamol by pMDI with spacer. A central telephone number (the STOP-telephone) is available for all patients included in this study. As a backup, patients may email (STOP-mail). As a second backup, the local investigators and the general practitioner will be notified of the subject’s study participation and supplied with helpful flowcharts , an allowable difference  of 0.5 ACQ points and a drop-out rate of 10%. The population variance Primary study parameterStudy data will be analysed according to the intention-to-treat approach. Results of the statistical analysis consist of descriptive univariable and multivariable analysis. Continuous parameters with (approximately) normal distributions will be summarized with means and SDs (or 95% CIs). Continuous primary study parameters with skewed distributions will be summarized with medians and interquartile ranges (IQR). Finally, nominal and ordinal primary study parameters will be summarized with numbers (percentages).Baseline: ACQ score at the first visit of period 1 or period 2Endpoint: ACQ at last visit of period 1 or period 2The primary endpoint is defined as the difference in ACQ between the intervention period and control period relative to the baseline ACQ score. Definitions:2.Secondary study parameter(s)The non-inferiority margin is 5% . Non-inferiority will be established if the lower limit of a one-sided 95% confidence interval for the mean difference in ACQ score between the intervention period and control period is within the absolute 5% non-inferiority margin of the mean in the control arm.The time to first exacerbation will be tested with Kaplan–Meier curves and log-rank tests to estimate the effect over time for both patient groups. Next, Cox regression will be used to measure the treatment effect adjusted for BMI and hospital as fixed covariates.The majority of secondary variables are continuous and will be described by descriptive compared between intervention group and control group.3.Interim analysisThe change in time of several secondary parameters will be estimated by repeated measurements analysis. Linear mixed modeling will be used for continuous variables. Generalized estimated equations for binary data with logit link function will be used for the categorical variables.No interim analysis has been planned to prevent alpha loss. An independent Data Safety Monitoring Board (DSMB) may conduct an investigation of adverse events when ≥ 12 exacerbations may have occurred.Obesity is more and more present among all asthma endotypes, often associated with T2-low endotypes and therefore not responsive to steroids. Nevertheless, guidelines advocate the use of ICS in all asthma patients, regardless of T2-endotype. As a result, obese T2-low asthma patients potentially suffer from the side effects of high dosed ICS while remaining poorly controlled.T2 low asthma can be classified as obesity-related asthma, paucigranulocytic asthma or neutrophilic asthma with overlap between phenotypes , 39. WitThe STOP trial is the first to investigate ICS tapering and discontinuation in the population of patients with T2-low asthma and obesity. Several trials on ICS tapering have been published in the past decades , 55, 56.The primary safety issue regarding this trial consists of patients worsening due to ICS tapering. Based on earlier trials and literature, we estimate the risk of severe exacerbations in patients with obese T2-low asthma as very low in patients with T2-low asthma and obesity , 17, 56.Current guidelines advocate the use of ICS in all asthma patients. The STOP trial investigates opportunities to taper ICS to zero in patients with obese T2 low asthma. Successful discontinuation of ICS will lead to decreased exposure to glucocorticosteroids. On the contrary, failed ICS tapering justifies exposure to glucocorticosteroids in this patients group, as benefits appear to outweigh risks. Either way, the outcomes of this trial are expected to influence future guidelines on T2 low asthma and obesity.


Background: Although sleep respiratory disorders are known as a relevant source of cardiovascular risk, there is a substantial lack of trials aimed to evaluate the eventual occurrence of associations between sleep apnea (SA) and valvular heart diseases (VHD).Methods: We recruited 411 patients referring to our sleep disorder unit, among which 371 had SA. Ninety-three subjects with SA also suffered from VHD. Physical examination, echocardiography, nocturnal cardio-respiratory monitoring, and laboratory tests were performed in each patient. Patient subgroups were comparatively evaluated through cross-sectional analysis.Results: A statistically significant increase in the prevalence of VHD was detected in relation to high apnea hypopnea index (AHI) values (p = 0.011). Obstructive sleep apnea occurrence was higher in SA patients without VHD (p < 0.0001). Conversely, central and mixed sleep apneas were more frequent among SA patients with VHD . We observed a direct correlation between AHI and BMI values (p < 0.0001), as well as between AHI and serum uric acid levels (p < 0.0001), high sensitivity C-reactive protein (p < 0.0001), and indexed left ventricular end-diastolic volume (p < 0.015), respectively. BMI and VHD resulted to be the main predictors of AHI values (p < 0.0001).Conclusions: Our study suggests that a significant association can occur between SA and VHD. It is clinically relevant that when compared to SA patients without VHD, higher frequencies of central and mixed apneas were found in subjects with SA and VHD. Moreover, after elevated BMI, VHD represented the second predictor of AHI values. Respiratory sleep disorders in adults represent an extensive and heterogeneous group of clinical conditions of varying severity which include snoring, increased upper airway resistance syndrome, obstructive sleep apnea (OSA), central sleep apnea (CSA), mixed sleep apnea (MSA), and obesity-hypoventilation syndrome . AlthougSA is defined as a respiratory dysfunction or alteration that occurs during sleep, characterized by repeated episodes of either reduction (hypopnea) or total cessation (apnea) of airflow through the airways. The estimated prevalence of this disease is around 5–15% of the general population, with a peak incidence between the sixth and seventh decade of life; it mainly affects males, and to a lesser extent females . Indeed,SA can be associated with rheumatic and non-rheumatic VHD . In patiOn the basis of the above considerations, the aim of our present study has been to evaluate, in a large cohort of patients with breathing-related sleep disorders, the association between SA and VHD.The study population consisted of consecutive patients referring to the Sleep Disorder Unit of the Geriatrics Division, located at “Mater Domini” University Hospital of Catanzaro, Italy, from January 2018 to January 2020. We recruited 411 outpatients, including 303 men (73.7%) and 108 women (26.3%). None of them took drug therapy or substances that could interfere with sleep. Patients suffering from HF with either preserved or reduced ejection fraction, ischemic heart disease, atrial fibrillation, severe renal and hepatic failure, moderate to severe respiratory failure or anemia were excluded. All patients underwent evaluation through the Epworth sleepiness scale, a questionnaire which identifies the probability of falling asleep under certain circumstances, based on the following score: 1–6 , 7–8 (mean sleepiness), and 9–24  . Complet2), and a gravity sensor able to localize patient's position. Heart rate (HR) values were also measured. All the recordings were examined by the same operator, and each event was judged to be either obstructive, central and/or mixed, apnoic and/or hypopnoic, according to the criteria of the American Academy of Sleep Medicine  , equipped with five cables utilized to record electrocardiogram through two bipolar leads, a nasal cannula used to detect the flow-meter trace, a microphone which records snoring, two piezoelectric belts measuring thoraco-abdominal movements, a digital pulse oximeter assessing peripheral arterial oxyhemoglobin saturation , corresponding to the number of episodes of desaturation >3% per hour of sleep. Furthermore, we also measured time below 90% (TC90), corresponding to the percentage time of saturation below 90%  were performed with an aneroid sphygmomanometer at level of the left arm in supine position, after 5 min of quiet rest. Three or more BP evaluations were performed on three different occasions, separated by at least 2 weeks. Systolic and diastolic BP values were registered at the first appearance (phase I) and disappearance (phase V) of Korotkoff sounds, respectively. Baseline BP values were obtained from the mean of the last two of three consecutive recordings, performed at intervals of 3 min. Pulse pressure (PP) values were also calculated. Patients with systolic BP (SBP) >140 mmHg and/or diastolic BP (DBP) >90 mmHg, as well as those with normal BP values under treatment with antihypertensive agents, were considered to be hypertensive according to current guidelines .All laboratory measurements were carried out after at least 12 h of fasting. Glycemia was determined by the glucose oxidase method . Diabetes was diagnosed using the oral glucose tolerance test (OGTT), based on administration of a 75 g glucose load, followed by measurement of 2-h post-load blood glucose levels. Blood levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured by enzymatic methods . Serum insulin levels were determined in duplicate by chemiluminescence tests . Insulin resistance was assessed using the homeostatic model assessment (HOMA), based on the concentrations of fasting glucose and insulin, according to the following formula: blood glucose (mmol/L) × insulin (mU/mL)/22.5. The aforementioned index was used because of its good correlation with the euglycemic clamp, which represents the gold standard of insulin sensitivity . CreatinAll subjects underwent standard left ventricular ultrasonography in both M-mode (motion mode) and B-mode , according to the recommendations of the American Society of Echocardiography . RecordiEchocardiographic examinations were carried out by the same expert operator to minimize measurement errors. However, the operator was not aware of patient's clinical data, and the values represented the average of at least three measurements. According to our ultrasonographic methods, the intra-operative variability coefficient is 3.85% for posterior wall thickness (PWd), 3.70% for interventricular septal thickness (IVSd), 1.50% for left ventricle internal diameter at end diastole (LVEDD) and end systole (LVESD), and 5.10% for left ventricular mass (LVM), respectively. Devereux's formula was used to calculate LVM, which was subsequently indexed for BSA (LVMI) .2. In addition to EF, left atrial diameter (LAD) was measured using M-mode or two-dimensional echocardiography, from the posterior aortic wall to the posterior left atrial wall, in the parasternal long-axis view at the end-ventricular systole. Right ventricular systolic parameters were also assessed, by calculating the systolic pulmonary arterial pressure (S-PAP) estimate. The diameter and collapsibility of the inferior vena cava during the inhalation-expiratory phase, in subcostal projection, were used to estimate the right atrial pressure. Tricuspid regurgitant velocity (TRV) was assessed by continuous Doppler at level of the atrioventricular plane of the tricuspid valve, in projection with the four apical chambers or, in the case of eccentric jets, in parasternal short axis: therefore, S-PAP was derived through the Bernoulli equation. Diastolic dysfunction was evaluated by recording pulse-wave Doppler patterns at the mitral valve, in order to obtain early (E) and late (A) diastolic filling velocities from the 4-chamber view. The echocardiographic study of VHD and their grading was carried out according to guidelines, utilizing continuous doppler through a multi-parametric approach and apical window, using off axis approaches when appropriate (Left ventricular ejection fraction (LVEF) was calculated by the Simpson biplane method according to the following formula: LVEF = [left ventricular end-diastolic volume (LVEDV)-LV end-systolic volume (LVESV)]/LVEDV ×100 as mean of two measures in four and two apical chambers. Both volumes were subsequently indexed for BSA and expressed in mL/mropriate . Only mopost-hoc test for multiple comparisons. Student's t-test for unpaired data was used to compare continuous variables between patients with or without VHD. Chi-square test was used for nominal data. Differences were considered to be significant for p-values < 0.05. A linear regression analysis was performed on the SA population, with the aim of investigating the eventual correlation between AHI values, (considered as a dependent variable) and different covariates. Subsequently, the variables significantly related to AHI were included in a stepwise multiple regression model. Statistical analysis was carried out using SPSS V20.0 program for Windows .The differences in terms of anthropometric, clinical and biological parameters among the four different AHI groups, stratified with respect to their severity, were evaluated by one-way ANOVA for continuous variables followed by Bonferroni 2 values (p < 0.0001). With regard to metabolic and biochemical parameters, high AHI values were associated with elevated fasting insulin levels (p < 0.0001), HOMA values (p < 0.027), serum UA concentrations (p < 0.0001), and hs-CRP levels (p < 0.0001). Furthermore, patients with severe SA had lower eGFR values (p < 0.001). Bonferroni's post-hoc analysis confirmed that patients who suffered from severe SA had worse BMI and WC, as well as worse renal function and metabolic profile. p = 0.011). On the contrary, there was no statistically significant difference among groups with regard to the different VHD subtypes.In regard to the 411 enrolled patients, 40 subjects were characterized by normal AHI values, 93 suffered from mild SA, 116 had moderate SA, and 162 were found to have severe disease. 2 were lower. There were no differences between SA patients with or without VHD in regard to the occurrence of AH, smoking habit, and diabetes. Furthermore, also drug treatments were not significantly different. In particular, the intake of antihypertensive, antiplatelets, antidiabetic, and lipid lowering drugs was similar between the two groups. In regard to the overall study population, 123 (29.93%) patients were taking loop diuretics, 8 (1.95%) spironolactone, 287 (69.83%) renin–angiotensin–aldosterone system inhibitors, 205 (49.88%) calcium antagonists, and 82 (19.95%) beta-receptor blockers. No patient was taking sacubitril-valsartan, anticoagulants, cardiac glycosides, ivabradine, or other antiarrhythmic drugs. Because COPD was more frequent in SA patients with VHD, obviously inhaled drugs were significantly more used in this group (data not shown). When considering echocardiographic parameters, SA patients with VHD had higher values of LVEDD, LVESD, and LVEDV/BSA. Moreover, LVMI, LAD, S-PAP, EF, and E/A ratio were significantly higher in SA patients with VHD.Subsequently, the analysis was conducted only in the SA population, including 93 patients with VHD and 278 without VHD, respectively. The two groups were compared for the different variables. This population sample approximately reflects the main rate of VHD patients, detected among all subjects referring to our center for sleep-related respiratory disorders during a 2-year period. In particular, within the group of 93 subjects with VHD, 15  had severe disease, and 78  suffered from moderate disease, respectively. p < 0.0001). On the contrary, CSA and MSA were more frequent among SA patients with VHD  , or CSA (19), or MSA (13). The 278 SA patients without VHD included subjects with either OSA (245), or CSA (20), or MSA (13) . OSA occctively) .r = −0.091; p = 0.040), as well as between AHI and eGFR . We also found a direct and statistically significant correlation between AHI and BMI values , as well as between AHI and serum UA levels , hs-CRP , and LVEDV/BSA  respectively. Conversely, no significant correlation was detected between AHI and either HOMA or PP  below the apneic threshold (35 mmHg), thereby preventing the stimulation of brainstem breath centers, and causing CSA. Breath arrest increases PaCO2 and decreases arterial oxygen partial pressure (PaO2), thus leading to a compensatory resumption of breathing . The patients/participants provided their written informed consent to participate in this study.All authors contributed to design and carry out the study protocol, as well as to write the text and draw the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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