Background: Cerebral autoregulation is the mechanism that allows to maintain the stability of cerebral blood flow despite changes in cerebral perfusion pressure. Maneuvers which increase intrathoracic pressure, such as the application of positive end-expiratory pressure (PEEP), have been always challenged in brain injured patients for the risk of increasing intracranial pressure (ICP) and altering autoregulation. The primary aim of this study is to assess the effect of PEEP increase (from 5 to 15 cmH2O) on cerebral autoregulation. Secondary aims include the effect of PEEP increase on ICP and cerebral oxygenation.Material and Methods: Prospective, observational study including adult mechanically ventilated patients with acute brain injury requiring invasive ICP monitoring and undergoing multimodal neuromonitoring including ICP, cerebral perfusion pressure (CPP) and cerebral oxygenation parameters obtained with near-infrared spectroscopy (NIRS), and an index which expresses cerebral autoregulation (PRx). Additionally, values of arterial blood gases were analyzed at PEEP of 5 and 15 cmH2O. Results are expressed as median (interquartile range).Results: Twenty-five patients were included in this study. The median age was 65 years (46–73). PEEP increase from 5 to 15 cmH2O did not lead to worsened autoregulation  to 0.18 (0.01-0.24), p = 0.83). Although ICP and CPP changed significantly (ICP: 11.11 (6.73–15.63) to 13.43 (6.8–16.87) mm Hg, p = 0.003, and CPP: 72.94 (59.19–84) to 66.22 (58.91–78.41) mm Hg, p = 0.004), these parameters did not reach clinically relevant levels. No significant changes in relevant cerebral oxygenation parameters were observed.Conclusion: Slow and gradual increases of PEEP did not alter cerebral autoregulation, ICP, CPP and cerebral oxygenation to levels triggering clinical interventions in acute brain injury patients. A large number of patients with brain damage require mechanical ventilation when admitted to the intensive care unit (ICU). The goal of mechanical ventilation is to optimize oxygen delivery and minimize lung and brain injury . The use2) resulting in cerebral vasodilation. Thus, strategies involving the use of elevated PEEP are still controversial in brain-injured patients  and hemodynamic instability with reduction of cerebral perfusion pressure (CPP). On the other hand, alveolar overdistension can lead to an increase in arterial partial pressure of carbon dioxide  approved this study, and written consent was obtained from patients’ next of kin. We adhered to the “Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)” statement guidelines for observational cohort studies   older than 18 years-old; 2) admitted to ICU for acute brain injury, i.e., traumatic brain injury (TBI), subarachnoid hemorrhage (SAH) or intracranial hemorrhage (ICH); 3) required invasive ICP monitoring and mechanical ventilation at ICU admission, and 4) underwent multimodal neuromonitoring  including ICP, cerebral autoregulation and cerebral oxygenation during a PEEP test from 5 to 15 cmHElectronic medical records were used to collect patients’ information, and included admission demographics , pre-injury comorbidities , reason for ICU admission , neurological status at admission as for Glasgow coma scale (GCS) and pupils characteristics , ICU complications (acute distress respiratory syndrome (ARDS), ventilator-associated pneumoniae, acute kidney injury, sepsis, vasospasm) and patients’ clinical outcomes, such as ICU length of stay, number of days with mechanical ventilation, ICU mortality and neurological status (as for Glasgow Outcome Score-Extended (GOSE)), type of ICP monitoring .2) and of carbon dioxide (PaCO2) and multimodal neuromonitoring data before and after PEEP test were also collected.Data on ventilatory mechanics, i.e., tidal volume, plateau pressure, and arterial blood gases  and/or midazolam (0.03–0.2 mg/kg/h) and fentanyl (0.1–0.8 μg/kg/min), intubated and mechanically ventilated in pressure or volume-controlled ventilation. Tidal volume was targeted to 6–8 mL per kg of predicted body weight (PBW), but higher values of tidal volume were tolerated, if driving pressure was maintained below 15 cmHidelines , as wellThe decision to perform a PEEP test was based on clinicians’ evaluation if optimization of mechanical ventilation was required, to set the best PEEP level, according to local protocol  and our 2O, about 2 cmH2O every minute, evaluating the changes in respiratory mechanics and cerebral hemodynamics, with the aim to set the best PEEP value. Our local protocol is based on our previous clinical experience which suggested that these PEEP values are safe in brain injured patients  after allowing 5 min for stabilization, as previously described (2O) represent the standard levels of PEEP used to estimate response to PEEP in general ICU patients (Data were obtained at PEEP of 5 (T0) and at 15 cmHescribed , and thepatients .2) and of carbon dioxide (PaCO2), tidal volume (VT), plateau pressure (Pplat), respiratory system compliance (CRS), driving pressure (DP), arterial saturation of oxygen (SaO2), as well as neuromonitoring data, i.e., ICP, pressure reactivity index , and data on cerebral oxygenation derived from near-infrared spectroscopy (NIRS).Data collected at T0 and T1 included respiratory mechanics and arterial blood gases parameters including arterial partial pressure of oxygen . In patients with head elevation, no corrections were made for hydrostatic pressure differences.® with O3® regional oximetry device , with a bilateral sensor applied in the frontotemporal region. Final values of cerebral oxygenation measurements at T0 and T1 were calculated as the mean between single instant measurements obtained from the right and left frontotemporal sensors. Different parameters of cerebral oxygenation can be obtained from this monitor: a) rSO2, which represents the regional cerebral oxygen saturation, and is derived as the ratio of the concentration of oxyhemoglobin (O2Hb) and total hemoglobin ; b) ΔO2Hbi, which is an index associated with changes of concentration of oxyhemoglobin, thus representing predominantly changes in the arterial component of regional oxygen saturation; c) ΔHHbi, an index reflecting changes in concentration of deoxyhemoglobin, approximately representing changes in the venous component of the oxygen saturation; d) ΔcHbi, an index representing the sum of ΔO2Hbi and ΔHHbi components   .https://icmplus.neurosurg.cam.ac.uk) (2O) periods.All continuous physiological data were collected simultaneously and analyzed using ICM+  , a clinim.ac.uk) . A presem.ac.uk) . PRx wast-test for normally distributed variables, while non-normally distributed variables were compared by paired Wilcoxon signed-rank test. Graphical representations of these comparisons are presented as boxplots. Dependent variables were expressed as a change from baseline (T0) in absolute terms (Δ change = T1-T0). The correlations coefficients between systemic and the different neuromonitoring variables were verified using Pearson’s or Spearman’s method, for parametric and non-parametric variables, respectively. All statistical analyses were performed using RStudio software (version 4.1.1). A p-value <0.05 was considered statistically significant.The Shapiro-Wilk test was used to test the normality of the distribution of the variables. Continuous variables are reported as median and interquartile range (IQR = 25th −75th percentiles). Comparisons between different variables at T0 and T1 were made by repeated measures (paired) During the study period, a total of 110 patients were considered for inclusion. Fifty-two patients were excluded as they did not undergo multimodal neuromonitoring and 33 patients were not allocated to a specific bed with ICM+. A final number of 25 patients were included in the analysis. The characteristics of the patients are presented in p = 0.83, After PEEP test, changes in PRx were not statistically significant, from 0.17 (−0.003-0.28) to 0.18 (0.01–0.24), p = 0.003, as well as ABP and CPP (from 83.38 (74.69–92.24) to 78 (72–87) mm Hg, p = 0.02, and from 72.94 (59.19–84) mm Hg to 66.22 (58.91–78.41) mm Hg, p = 0.004, respectively) (ICP significantly changed (from 11.11 (6.73–15.63) mm Hg to 13.43 (6.8–16.87) mm Hg, ctively) . On the ctively) , apart fctively) .2 also increased, from 87 (79–93) to 93 (88-98) mm Hg, p = 0.03), without causing changes in PaCO2 (from 40 (39-43) to 41 (38–43) mm Hg, p = 0.89) (Systemic PaO = 0.89) .p = 0.003), increased plateau pressure (20 (18-22) to 26 (24-28) cmH2O, p < 0.0001), reduced driving pressure (15 (13–17) to 11 (9–13) cmH2O, p < 0.0001), and improvement of respiratory system compliance (from 31.88 (30.24–37.88) to 41.29 (35.51–49.69) mL/cmH2O, p < 0.001)  to 460 (431.00–493.50) mL, < 0.001) .p < 0.0001, and r = −0.48, p = 0.01) .No significant correlations were observed between the changes in ICP and other parameters , except  = 0.01) . Changes2, without causing changes in PaCO2. Respiratory system compliance was improved.In our cohort of mechanically ventilated brain injured patients we found that: 1) ICP, CPP and ABP significantly changed after the PEEP test, however, PEEP increase did not worsen PRx; 2) No changes in cerebral oxygenation parameters related to arterial or venous components were observed; 3) There was an increase of systemic PaOThe use of high PEEP has been challenged in the ABI population, as it can potentially increase intrathoracic pressure, reduce jugular vein outflow, decrease venous return, and lead to a drop in cardiac output and blood pressure. This may potentially cause hemodynamic instability with consequent detrimental effects on CPP and cerebral blood flow. When cerebral autoregulation is intact, extreme reduction of CPP can lead to cerebral vasodilation and an increase in cerebral blood volume that can potentially exacerbate ICP; on the other hand, when autoregulation is impaired, decreased CPP may lead to cerebral ischemia . The tra2O and 15 cmH2O using hemodynamic parameters and recorded cerebral and respiratory function parameters. After the PEEP test, we observed an increase of PaO2 and improvement of CRS. PEEP increase in our cohort did not lead to increase of PaCO2 and the effect on cerebral physiological parameters was minimal, with no significative changes in autoregulation. These preliminary results suggest that an increase in PEEP within the proposed range might be a safe maneuver in patients with ABI, provided this improves respiratory mechanics and does not affect importantly hemodynamic status.A multimodal approach for the assessment of cerebral hemodynamics, especially cerebral autoregulation, is therefore of great interest, and warrants clinical relevance in this context. We assessed a heterogeneous group of patients with ABI at fixed PEEP levels of 5 cmHSurvival after ABI is dependent on the control of intracranial hypertension and the provision of hemodynamic support to achieve an appropriate cerebral perfusion pressure . The curHowever, the idea of a single value or even a single range of CPP being suitable for the diverse group of ABI patients is an oversimplification. Age, comorbidities, and pre-injury arterial blood pressure are examples of factors likely to influence individual CPP targets, with elderly, hypertensive patients requiring a higher CPP compared with young, normotensive patients. In addition, in healthy, the ability to autoregulate occurs in a very wide CPP range, but after brain injury, this ability is impaired, and the risk of secondary damage increases dramatically .The examination of continuous autoregulation and the definition of optimal CPP, which is the CPP at which each patient autoregulates at best, requires sophisticated signal analysis. ICM + bedside software and pressure reactivity index (PRx) have already been extensively validated in the literature and allow an individualized assessment of the effect of respiratory manipulations on the brain . PRx–whiA multimodal approach of respiratory and cerebral parameters can therefore help with a better definition of the best individualized PEEP value to be applied in order to promote improvement of respiratory mechanics without altering cerebral dynamics.2Hb signals), the nature of HHb and HbO2 dependent on the unknown scattering coefficient likely differing on an individual basis, and the unknown contribution of venous and arterial components to the measured signals, particularly O2Hb, are potential confounders in our study. Furthermore, we did not assess any direct measures of CBF in these patients. Finally, all patients had relatively low ICP at the moment of measurement; moreover, we cannot exclude that different ventilator settings or the addition of a recruitment maneuver may have led to different results.This study has several limitations that need to be mentioned. Firstly, this is a single center study with a small sample, and heterogeneity of included patients, which limit the generalization of our results. The posteriori use of the data as presented in this study setting  can potentially delay the modification of interventions in clinical practice. Only two arbitrary levels of PEEP were investigated for technical reasons and patient safety concerns, and as for our local protocols. The application of this protocol may cause physiological changes in CPP after an increase in PEEP due to a decrease in ABP or increase in right pressures above ICP. High levels of PEEP are useful in ARDS patients in whom pulmonary compliance is low; in such patients the PEEP effects on cerebral hemodynamics likely differ from the changes observed in most patients. Known limitations of NIRS, such as the potential influence of extracranial contamination (particularly in HHb and O2 values. This led to the absence of detrimental effects on cerebral autoregulation, cerebral oxygenation and intracranial pressure.In this study, PEEP increase led to improvement of respiratory system compliance, without affecting importantly systemic hemodynamics and PaCOThese results suggest that the use of augmented PEEP can be safe in acute brain injured patients. Our findings are in line with the current recommendations for this patient population, which suggests applying the same level of PEEP as in the general ICU population. This study also highlights the applicability and feasibility of a multimodal approach for the individualization of lung and cerebral management in future studies.


Background and objectives: Arterial hypertension (HTN) is the leading preventable cause of atherosclerotic cardiovascular diseases (ASCVD) and death from all causes. This study aimed to determine the prevalence rates of HTN diagnosed according to the threshold diagnostic criteria 130/80 mmHg and 140/90 mmHg, to compare blood pressure (BP) control, and to evaluate their associations with cardiovascular diseases and cardiometabolic and renal risk factors. Materials and Methods: This was a cross-sectional observational study conducted in primary care with a population-based random sample: 6588 people aged 18.0–102.8 years. Crude and adjusted prevalence rates of HTN were calculated. BP control was compared in HTN patients with and without ASCVD or chronic kidney disease (CKD). Their associations with cardiovascular diseases and cardiometabolic and renal factors were assessed using bivariate and multivariate analysis. Results: Adjusted prevalence rates of HTN diagnosed according to 140/90 and 130/90 criteria were 30.9%  and 54.9% , respectively. BP < 130/80 mmHg was achieved in 60.5% of HTN patients without ASCVD or CKD according to 140/90 criterion, and 65.5% according to 130/80 criterion. This BP-control was achieved in 70% of HTN patients with ASCVD and 71% with CKD, according to both criteria. Coronary heart disease (CHD), heart failure, atrial fibrillation, stroke, diabetes, prediabetes, low glomerular filtration rate (eGFR), hyperuricemia, hypercholesterolemia, obesity, overweight, and increased waist-to-height ratio were independently associated with HTN according to both criteria. Conclusions: Almost a third of the adult population has HTN according to the 140/90 criterion, and more than half according to the 130/90 criterion, with a higher prevalence in men. The main clinical conditions associated with HTN were heart failure, diabetes, CHD, low eGFR, and obesity.  Arterial hypertension (HTN) constitutes a major global public health problem according to the World Health Organization (WHO)  and partHTN causes 10.4 million deaths annually worldwide ,5,6. In Epidemiological studies show that cardiovascular risk (CVR), renal morbidity or fatal events start from an office systolic blood pressure (SBP) > 115 mmHg and diastolic blood pressure (DBP) > 75 mmHg . The Eurhttps://www.who.int/es/news-room/fact-sheets/detail/hypertension [accessed on 31 August 2023]). Studies about the prevalence of cardiovascular risk factors (CVRFs) are necessary to improve cardiovascular prevention activities, to adequately plan the necessary health resources, and to monitor and evaluate the strategies aimed at achieving the objectives established by the WHO in the global action plan for the prevention and control of non-communicable diseases  years) and females (55.0 [18.0] years).The mean (SD) age was 55.1 (17.5), and the median (IQR) was 54.7 (41.7–68.1) years. Women represented 55.9% [95% CI: 54.7–57.1%]) of the sample. The median ages (IQR) were 55.0 (42.4–67.5) years in men and 54.5 (41.0–68.8) in women, with no significant differences (p < 0.001). The age- and sex-adjusted prevalence rate of HTN was 30.9% . The HTN-adjusted prevalence rates were 35.0%  in people between 40 and 69 years of age, and 75.0%  in people older than 69 years of age. The distribution of the HTN prevalence rates by ten-year age groups increased precisely with age (R2 = 0.971) according to the linear function y = 14.438x − 18.842, being significantly higher in males than in females (p < 0.001), except in the 70s, where the difference was not significant (p = 0.099), and in the age group in the 80s, whose proportion of females was significantly higher than that of males (p = 0.006) . The difference between males (42.2% [95%CI: 40.3–44.0%]) and females (35.9% [95% CI: 34.4–37.5%]) was significant (= 0.006) . p < 0.001). The age- and sex-adjusted prevalence rate of HTN was 54.9% . The HTN-adjusted prevalence rates were 63.5%  in people between 40 and 69 years of age, and 88.5%  in people older than 69 years of age. The distribution of the HTN prevalence rates by ten-year age groups increased precisely with age (R2 = 0.957) according to the linear function y = 12.707x − 10.087, being significantly higher in males than in females, except in the age groups from 70 onwards, in which there were no significant differences . The difference between males (70.3% [95% CI: 68.6–72.0%]) and females (56.0% [95% CI: 54.4–57.6%]) was significant (ferences . p < 0.001) (p < 0.001) in the population with HTN than in the population without HTN, except for total cholesterol, high-density lipoprotein cholesterol (HDL-C), and estimated glomerular filtration rate (eGFR), which were significantly (p < 0.001) higher in the population without HTN, and non-HDL-C and aspartate aminotransferase (AST), whose differences between both populations were not significant (The median (IQR) ages of the populations with and without HTN were 67.5 (58.2–77.9) and 46.0 (36.4–57.2) years, respectively. The age means difference (19.7 years) between both populations was significant (< 0.001) . The resnificant .p < 0.001) (p < 0.001) in the population without HTN, and total cholesterol, low-density lipoprotein cholesterol (LDL-C) and AST, whose differences between both populations were not significant (The median (IQR) ages of the populations with and without HTN were 62.2 (50.3–73.8) and 42.6 (33.4–53.9) years, respectively. The age means difference (17.0 years) between both populations being significant (< 0.001) . The resnificant .All comorbidities and CVRF were significantly associated with HTN according to both criteria, except for smoking and the low and moderate CVR categories, which were significantly associated with populations without HTN .The following variables showed a strong association (OR between 3.0 and 6.0) with HTN diagnosed according to 140/90 criterion: obesity, abdominal obesity, increased waist-to-height ratio (WHtR), hypercholesterolemia, erectile dysfunction, and albuminuria. The variables diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), CHD, stroke, peripheral arterial disease (PAD), atrial fibrillation (AF), low eGFR, CKD, and very high CVR showed a very strong association (OR > 6.0) with HTN, highlighting MetS (OR: 11.0) and heart failure (HF) (OR: 15.6). A total of 80.1% (95% CI: 78.5–81.6) of the HTN patients had a high or very high CVR .On the other hand, the following variables also showed a strong association with HTN diagnosed according to 130/80 criterion: obesity, abdominal obesity, high WHtR, DM, ASCVD, ictus, stroke, PAD, AF, erectile dysfunction, albuminuria, and CKD. The variables CHD, HF, low eGFR, and very high VR showed a very strong association (OR > 6.0) with HTN, highlighting MetS (OR: 11.4). A total of 62.8% (95% CI: 61.3–64.3) of the HTN patients had a high or very high CVR .The comorbidities and clinical conditions that were best independently associated with HTN according to both criteria were HF, DM, CHD, low eGFR, and obesity. Other variables that were also independently associated with HTN according to both criteria were stroke, AF, hypercholesterolemia, hyperuricemia, high WHtR, prediabetes, and overweight. Albuminuria and PAD also showed an independent association with HTN, but only according to the 140/90 criterion .p < 0.001), differences both in the percentage of HTN patients with BP control target < 140/90 mmHg or <130/80 mmHg, according to both diagnostic criteria  and was slightly and significantly higher (p = 0.009) in patients with CKD. The mean daily number of drugs was similar, although significantly higher in patients diagnosed with ASCVD or CKD according to the 140/90 criterion. There were no significant differences in percentages of BP control targets < 140/90 mmHg or <130/80 mmHg according to both diagnostic criteria . According to these BP values, the age-standardised prevalence of HTN in high-income European countries was 20.6%  . Follow-Age plays a fundamental role in the increase in BP throughout life and in determining the HTN prevalence rates. In our study, HTN prevalence rates increased with age with an almost perfect linear correlation using both diagnostic criteria. However, in the adult population, the adjusted prevalence of HTN defined according to the 140/90 criterion was 24.0% lower than according to the 130/80 criterion (54.9%); conversely, the mean age of the population with HTN defined according to the 140/90 criterion was 5.7 years older than the 130/80 criterion.Considering the HTN diagnosis as BP levels ≥ 130/80 mmHg, the NHANES study showed than HTN prevalence was 46.7% in the adult population from the United States  , 86.2% iPrevious studies carried out in the Spanish population showed adjusted prevalence rates of HTN similar to the present study, such as the studies of Banegas et al.  33.3%);.3%;33]  to that of the American population (84.3%) , althougOn the other hand, a strong association of HTN with both AF and HF was observed. High BP is the most important risk factor for HF  and the The aggregation of CVRFs in patients with HTN is well known and increases their CVR . It is iThe guidelines for HTN management ,17 recomOn the other hand, the recommended thresholds for BP-lowering drugs are ≥ 130/80 mmHg in patients with CHD or CKD . In our study, BP control target < 130/80 in HTN patients with ASCVD or CKD was similar using both HTN diagnostic criteria (around 70%), although the percentage of patients treated with BP-lowering medications and the mean number of antihypertensive drugs per patient were slightly higher using the 140/90 criterion than with the 130/90 criterion. The study limitations were the sampling bias due to the recruitment response rate, the inability to estimate incidence rates or to determine causality, inter-interviewer variability, possible heterogeneity of the measurement and laboratory equipment, and the HTN underdiagnoses due to the per protocol exclusion of terminally ill, institutionalised, or cognitively impaired patients and pregnant women. BP control of HTN patients was excellent, probably due to the study selection bias of excluding subjects without the clinical or laboratory data necessary to be evaluated, who are the subjects with the worst follow-up. Strengths of the study include a large population-based random sample aged 18.0–102.8, the determination of both crude and adjusted prevalence rates of HTN according to two BP threshold values defined by main international guidelines for the HTN management, and the assessment of the association of HTN with renal and cardiometabolic factors.The high prevalence of HTN has serious healthcare and socioeconomic consequences by increasing cardiovascular morbidity and mortality. Assessing the epidemiological magnitude of HTN is essential to better plan prevention policies aimed at reducing the HTN burden, to improve medical care and quality of life for patients, and to optimise available health resources. In order to compare HTN prevalence rates with other populations, they should always be age-adjusted because HTN is strongly associated with increasing age.The early identification of HTN patients has some important implications. In our study, almost two thirds of the population with HTN diagnosed according to the 130/80 criterion had a high or very high CVR; hence, the early identification of these patients would facilitate starting a comprehensive management not only of BP but also of other comorbidities and clinical conditions that are frequently associated with HTN. In addition, the implementation of the 130/80 diagnostic criterion would imply that almost a quarter more of the HTN population could be identified almost 6 years earlier and start counselling on changes to healthy lifestyles and pharmacological treatment when indicated, in order to delay the increase in BP, decrease CVR, and avoid cardiovascular complications.We hope that this study updates the knowledge of the HTN prevalence rates and contributes to emphasising the importance and magnitude of the clinical conditions and comorbidities that are associated with HTN to promote the comprehensive diagnostic and therapeutic management of this disease.Almost a third of the adult population with HTN were diagnosed according to the 140/90 criterion and more than half according to the 130/80 criterion. The use of the 130/80 criterion for HTN diagnosis compared to the 140/90 criterion means that the HTN prevalence rates increase almost 20 percentage points from 29.7% in women and more than 30 percentage points from 32.9% in men. The distribution of the HTN prevalence rates increases linearly with age using both criteria.The intensity of BP-lowering drug treatment and the proportion of HTN patients achieving the BP control target < 130/80 mmHg was similar in both ASCVD and CKD patients, regardless of the diagnostic criteria used. The clinical conditions that were most strongly associated with HTN according to both diagnostic criteria were HF, DM, CHD, low eGFR, and obesity. Stroke and PAD also maintain a strong association with HTN according to the 140/90 criterion. The proportion of HTN patients with elevated CVR was higher in those diagnosed according to the 140/90 criterion (80.1%) than in those diagnosed according to the 130/80 criterion (62.8%). The high cardiovascular burden of HTN justifies the need to implement measures to achieve the BP control objectives recommended by the guidelines and to optimise the comprehensive management of clinical conditions and comorbidities associated with HTN.WHAT IS KNOWN ABOUT THE TOPIC?The proportion of adults with HTN doubled between 1990 and 2019 worldwide.Primary health care is the setting where HTN is usually detected.There is a continuous relationship between BP and cardiovascular or renal morbid or fatal events starting from SBP/DBP values >115/75 mmHg.The American guidelines recommend that the threshold values for SBP/DBP to consider HTN should be 130/80 mmHg, which are different from the classic threshold values (140/90 mmHg) recommended according to other international guidelines for the HTN management.The discrepancy with these threshold levels raises differences, not only diagnostic, but also in the determination of the HTN prevalence and in the assessment of the clinical conditions and comorbidities that can be associated with HTN.Early initiation of antihypertensive treatment can effectively control hypertension and prevent its progression and associated cardiovascular, metabolic, and renal complications.WHAT DOES THIS STUDY ADD?The mean age of the HTN patients diagnosed according to the 140/90 criterion was 5.7 years older than those diagnosed according to the 130/80 criterion (61.5 years).The age- and sex-adjusted prevalence rate of HTN was 30.9% according to the 140/90 criterion and was 54.9% according to the 130/80 criterion.The proportion of HTN patients with high or very high CVR was higher in those diagnosed according to the 140/90 criterion (80.1%) than in those diagnosed according to the 130/80 criterion (62.8%).The proportion of HTN patients without ASCVD or CKD who achieved the BP control goal < 130/80 mmHg was 60.5% in those diagnosed according to the 140/90 criterion and 65.5% according to the 130/80 criterion.The proportion of HTN patients according to both diagnostic criteria who achieved the BP control target < 130/80 mmHg was similar in patients with ASCVD (70%) and in patients with CKD (71%).The intensity of treatment with BP-lowering drugs in HTN patients without ASCVD or CKD decreased by half when using the 130/80 diagnostic criterion than when using the 140/90 criterion, and instead, it was similar for both HTN patients with ASCVD and with CKD.The following comorbidities and clinical conditions showed, from greater to lesser intensity, an independent association with HTN according to both criteria: HF, DM, CHD, low eGFR, obesity, stroke, AF, hypercholesterolemia, hyperuricemia, high WHtR, prediabetes, and overweight. Albuminuria and PAD showed an independent association only with HTN according to the 140/90 criterion.


The reversible maneuver that mimics the fluid challenge is a widely used test for evaluating volume responsiveness. However, passive leg raising (PLR) does have certain limitations. The aim of the study is to determine whether the supine transfer test could predict fluid responsiveness in adult patients with acute circulatory failure who do not have intra-abdominal hypertension, by measuring changes in cardiac index (CI).. Thirty-four patients who presented with acute circulatory failure and were scheduled for fluid therapy. Every patient underwent supine transfer test and fluid challenge with 500 mL saline for 15–30 min. There were four sequential steps in the protocol: (1) baseline-1: a semi-recumbent position with the head of the bed raised to 45°; (2) supine transfer test: patients were transferred from the 45° semi-recumbent position to the strict supine position; (3) baseline-2: return to baseline-1 position; and (4) fluid challenge: administration of 500 mL saline for 15–30 min. Hemodynamic parameters were recorded at each step with arterial pulse contour analysis (ProAQT/Pulsioflex). A fluid responder was defined as an increase in CI ≥ 15% after fluid challenge. The receiver operating characteristic curve and gray zone were defined for CI.Single-center, prospective clinical study in a 25-bed surgery intensive care unit at the Fudan University Shanghai Cancer Centerr value of the linear correlations was 0.73 between the supine transfer test- and fluid challenge-induced relative CI changes. The relative changes in CI induced by supine transfer in predicting fluid responsiveness had an area under the receiver operating characteristic curve of 0.88  and predicted a fluid responder with 76.5%  sensitivity and 88.2%  specificity, at a best threshold of 5.5%. Nineteen (55%) patients were in the gray zone (CI ranging from -3 and 8 L/min/m2).Seventeen patients were fluid challenge. The The supine transfer test can potentially assist in detecting fluid responsiveness in patients with acute circulatory failure without intra-abdominal hypertension. Nevertheless, the small threshold and the 55% gray zone were noteworthy limitation.https://www.chictr.org.cn/showproj.html?proj=166175.Predicting fluid responsiveness with supine transition test (ChiCTR2200058264). Registered 2022–04-04 and last refreshed on 2023–03-26, The online version contains supplementary material available at 10.1186/s12871-023-02280-0. Fluid administration is a cornerstone of treatment in critically ill patients. Fluid challenge is the gold standard for assessing fluid responsiveness , 2; howePassive leg raising (PLR) mimics a fluid challenge in which blood is transferred from the splanchnic vasculature and lower limbs to the right heart . Howeverhttps://doi.org/10.1186/s13054-019-2545-z).Arterial pulse contour analysis (ProAQT/Pulsioflex) is a dynamic and fast-response method used to measure CI in real-time. It is particularly suitable for measuring the response of a fluid-challenge when compared to other methods . While the device may off less accurate CI measurements compared to transpulmonary thermodiltion , it can This study aimed to determine whether the supine transfer test can predict fluid responsiveness by measuring changes in the CI using uncalibrated arterial pulse contour analysis in patients without intra-abdominal hypertension.This single-center, prospective clinical study was conducted in a 25-bed surgery intensive care unit (ICU). It was performed in accordance with the Declaration of Helsinki. The study was approved by the institutional review board of our hospital. All patients that were enrolled in the study provided written informed consent approved the study . For patient who is unable to provide consent, informed consent is obtained from the authorized relatives. The study was registered in ChiCTR.gov (ChiCTR2200058264).Inclusion criteria were as follows: (1) All adult patients (> 18 years) equipped with radial arterial catheter, (2) presented with acute circulatory failure with a systolic blood pressure below 90 mmHg, or experienced a decrease of more than 40 mmHg who previously hypertensive, (3) presented with other signs of acute circulatory failure .Patients with arrhythmia, hip pain and mobility deficits, intra-abdominal hypertension  > 12 mmHg measured by intrabladder pressure , pulmonaEvery patient underwent a supine transfer test and fluid challenge with 500 mL saline for 20 min, as previously described . To avoiInformation on the demographic and clinical characteristics, mechanical ventilation and its parameters, and dosage and use of vasopressors were collected. Hemodynamic variables at each step were also collected.The protocol consisted of four sequential steps , the variables were collected when the CI reached the maximal value during the supine transfer test. Finally, the last step  was performed immediately after the fluid challenge. For each enrolled patient, data on the heart rate, CVP, CI, PPV, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were collected.Following the protocol, patients were considered as fluid responders or non-responders. Fluid responders were defined as those with an increase in CI ≥ 15% after a fluid challenge , 17; othAll patients were equipped with a special transducer, ProAQT/Pulsioflex, for CI through a radial arterial catheter. The initial CI value was estimated using a proprietary algorithm through an “autocalibration” with ProAQT/Pulsioflex, and values from the next steps were determined by pulse contour analysis with ProAQT/Pulsioflex. The data displayed by proAQT/Pulsioflex system is averaged over a 12-s rolling period. We track short-term changes in CI, and the data is automatically displayed by devices after processing, filtering, and averaging. The average of three consecutive measurements was used for analysis.The central venous pressure is assessed by inserting a central venous catheter through the internal jugular veins. Monitoring of the central venous pressure can be done using a pressure transducer. The pressure transducer will be securely placed near the tricuspid valve on the right chest wall, and should be calibrated to atmospheric pressure before collecting the data .The arterial pressure was calibrated using a 5-step approach . After phttps://www.medcalc.org; 2019) was used to estimate the sample size. As per the null hypothesis at 0.50, assuming an α error of 0.05, power of 0.9, and allocation ratio of 1, the area under the receiver operating characteristic (ROC) curve (AUC) was expected to be 0.80. Seventeen fluid responders and 17 nonresponders were included in this study.MedCalc Statistical Software , median (interquartile range), or number (frequency in %), as appropriate.Continuous variables were evaluated between groups using the Wilcoxon or Friedman rank-sum test, whereas the Bonferroni post-hoc test was used for multiple pairwise comparisons. The Fisher’s exact test was used to compare categorical variables. The Pearson method was used to test linear correlations between the percent change in CI induced by the supine transfer test and fluid challenge.The supine transfer-induced changes in continuous variables  and ROC curves were calcualted. The diagnostic performances of the tests were assessed by calculating the AUC . The 95%The gray zone approach establishes a range of values where no conclusion can be made regarding the potential responsiveness to fluid . The besP < 0.05 is considered to be statistically significant. Statistical analysis was performed using the MedCalc Statistical Software version 19.0.4.A two-tailed 2O, and a plateau pressure of 18 (17–18) cmH2O. These patients were mechanically ventilated throughout the study protocol. Eight (24%) patients received norepinephrine at a dose of 0.30 (0.18–0.33) µg/kg/min. The results also showed that there were more hypotensive and tachycardia patients in the responders group than in the non-responders group, even though the p-value was greater than 0.05 in both groups.From April 2023 to June 2023, thirty-four patients were consecutively enrolled in this study  during the supine transfer test in responders, while no significant change was observed in non-responders , while no significant change was observed in non-responders     Table b. The PPThis is the first study to evaluate the ability of the supine transfer test in detecting fluid challenges in patients with acute circulatory failure without intra-abdominal hypertension. In addition, results showed that an increase in CI greater than 5.5% during supine transfer test can predict fluid responsiveness with a gray zone between -3 and 8%.The supine transfer test can be recommended for patients contraindicated to PLR. The supine transfer test transferred the blood from the splanchnic territory, as the “first part” of the PLR test. Compared with the PLR test, the supine transfer test involves lowering the trunk. Moreover, no special bed equipment is required . The bedThe present study showed that 55% of the patients fell into the gray zone, meaning that the data of only 45% of the patients were sufficiently accurate to guide fluid loading according to the changes in CI induced by the supine transfer test. A possible explanation for this finding may be that the supine transfer test causes smaller changes in the CI than the fluid challenge. However, the cut-off is also small (5%) in the tidal volume and mini-fluid challenges, which are popular tests for predicting fluid responsiveness; however, the percentage of patients included in the gray zone is approximately 14–20% . Another. conducted an evaluation of the least significant changes of PPV derived from pulse contour analysis, the results revealed that the least significant changes for PPV ranged from 10 to 4.9% [PPV is an accurate predictor in critically ill patients with mechanical ventilation, however, it is not applicable in various clinic scenarios . Changes to 4.9% . These eTo date, there is no easy and reliable method for predicting fluid responsiveness in patients with an elevated IAP. The PLR may lead to false-negative results , 32, whiOur study has some limitations. When the supine position was changed, the joints of the body moved. Movement was restricted in patients with inconvenient hip joints. Second, joint rotation might provoke adrenergic stimulation and cause false positives; however, for the enrolled patients, the heart rate change was not significant; hence, the results were reliable. Third, this was a single-center study with a small sample size; further studies with larger sample sizes are required. Fourth, the supine transfer induced only small changes in the CI and an analysis of the least significant change was not conducted. Therefore, this limits the interest in this test and external validity of the results, as a low threshold value will limit the use of this test in patients under noninvasive hemodynamic monitoring, such as echocardiography, given the precision and variability of measurement with this device . Fifth, The supine transfer test can potentially assist in detecting fluid responsiveness in patients with acute circulatory failure without intra-abdominal hypertension. Nevertheless, the small threshold and the 55% gray zone were noteworthy limitation.The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Delaration of Helsinki (as revised in 2013). The study (ChiCTR2200058264) was registered on 2022–04-04, and last refreshed on 2023–03-26. The study  was approved by the ethics committees of Shanghai Cancer Center, Fudan University, China, and written informed consent was taken from all individual participants.Additional file 1: Table E1. Demographic and clinical information of included population. Figure E1. Study protocol. Figure E2. Study flowchart. Figure E3. Individual values of systolic blood pressure (SBP) , diastolic blood pressure (DBP) , and pulse pressure variation (PPV)  in each step of the responders and non-responders. Figure E4. Receiver operating characteristic curve and gray zone analysis of the changes in the pulse pressure variation (PPV) , systolic blood pressure (SBP) , and diastolic blood pressure (DBP)  that were induced by the supine transfer test to predict fluid responsiveness. The blue dashed lines represent 95% confidence bounds.


We investigated the accuracy of CEUS for characterizing cystic and solid kidney lesions in patients with chronic kidney disease (CKD). Cystic lesions are assessed using Bosniak criteria for computed tomography (CT) and magnetic resonance imaging (MRI); however, in patients with moderate to severe kidney disease, CT and MRI contrast agents may be contraindicated. Contrast-enhanced ultrasound (CEUS) is a safe alternative for characterizing these lesions, but data on its performance among CKD patients are limited. We performed flash replenishment CEUS in 60 CKD patients (73 lesions). Final analysis included 53 patients (63 lesions). Four readers, blinded to true diagnosis, interpreted each lesion. Reader evaluations were compared to true lesion classifications. Performance metrics were calculated to assess malignant and benign diagnoses. Reader agreement was evaluated using Bowker’s symmetry test. Combined reader sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignant lesions were 71%, 75%, 45%, and 90%, respectively. Sensitivity (81%) and specificity (83%) were highest in CKD IV/V patients when grouped by CKD stage. Combined reader sensitivity, specificity, PPV, and NPV for diagnosing benign lesions were 70%, 86%, 91%, and 61%, respectively. Again, in CKD IV/V patients, sensitivity (81%), specificity (95%), and PPV (98%) were highest. Inter-reader diagnostic agreement varied from 72% to 90%. In CKD patients, CEUS is a potential low-risk option for screening kidney lesions. CEUS may be particularly beneficial for CKD IV/V patients, where kidney preservation techniques are highly relevant. Patients with chronic kidney disease (CKD) are subject to routine kidney imaging and are especially susceptible to incidental findings. Patient-dependent management strategies include no intervention, active surveillance, ablative therapy, or surgery ,2,3. IncContrast-enhanced ultrasound (CEUS) has emerged as an alternative to CECT and CEMRI. It has many attractive attributes including low cost, lack of ionizing radiation, real-time imaging capabilities, portability, accessibility, and patient tolerability, including in those with kidney dysfunction ,12,13,14Clinically, CEUS is used to diagnose lesions by qualitatively assessing features concerning for malignancy ,15. In t2), presence of albuminuria or proteinuria > 30 mg/g, dialysis, an active kidney transplant, or a biopsy-proven disease; (2) one kidney lesion based on imaging in the past 6 months suspected for malignancy or warranting follow-up imaging, including Bosniak IIF cystic lesions and greater; and (3) ability to provide consent and comply with study protocol. Exclusion criteria were the following: (1) any contraindications to the contrast agent, including hypersensitivity; (2) severe pulmonary hypertension or adult respiratory distress syndrome; (3) critical illness or intensive care unit status; (4) right-to-left cardiac shunt ; (5) active cardiac disease defined as severe congestive heart failure class IV NYHA, unstable angina, severe arrhythmia, myocardial infarction within 14 days, or severe hypertension (systolic > 180 mmHg or diastolic > 100 mmHg), (6) unstable neurologic disease  within 3 months; (7) invasive kidney procedure  between lesion identification and CEUS; (8) medical condition that would decrease data reliability ; (9) pregnancy or lactation; and (10) obesity limiting acquisition of quality images. After obtaining informed consent, patients underwent CEUS per a standardized study protocol using flash replenishment imaging , in accordance with ethical standards outlined in the Helsinki declaration. Written informed consent was obtained from all participants. Patients were recruited from Nephrology clinics at University of North Carolina Hospital. Patients that met study criteria were offered participation. Inclusion criteria were the following: (1) presence of kidney disease . A 50 mL saline solution mixed with 1.3 mL of Perflutren Lipid Microspheres was infused at 4, 6, or 8 mL/min based on patient body mass indices <21, 21–30, or >30 kg/m2, respectively, using a Medfusion® 4000 syringe pump . Two flash replenishment clips and a sagittal kidney sweep were collected in either CPS only or split-screen CPS and B-mode imaging (Ultrasound (US) images were acquired by registered sonographers using a Siemens Acuson Sequoia 512  and a curvilinear abdominal transducer (1–4 MHz) oriented over the lesion and part of the kidney parenchyma. Lesions were located using B-mode US at a standard mechanical index (MI = 1.9). CEUS imaging used a low MI Cadence Pulse Sequencing (CPS) mode to limit contrast disruption during acquisition. CPS MI (0.18), dynamic range (80 dB), capture rate (10 Hz), flash duration (<1 s) and frequency (1.5 MHz) were kept constant across patients. Gain, depth, and infusion rate were optimized per patient. Flash sequences used acceptable MI ranges (0.7–0.8 depending on depth) for Perflutren Lipid Microspheres . Readers were radiologists with 0.25–3 years of experience interpreting CEUS images. Prior to interpretation, readers reviewed UI operating instructions and viewed a lecture on kidney CEUS imaging [Cases were de-identified and stripped of clinical information before being interpreted by four readers using a custom user interface (UI)  develope imaging . BosniakTrue lesion diagnosis was confirmed by tissue pathology or follow-up imaging when pathology was unavailable. The follow-up interval (≥12 months) and modality  were determined by the patient’s clinician. The most recent exam was used when patients had multiple follow-up examinations. Pathology samples were either malignant or benign for disease. Follow-up imaging diagnoses were (1) stable for lesions with no change, regression, or no concerning features, (2) suspicious for lesions with stable, but persistent concerning features, or (3) progressed for lesions with progression of concerning features. Suspicious lesions were likely malignant, but the patient and treatment team opted for active surveillance. Concerning characteristics included enhancing or thickened septations, calcifications, mural thickness, irregularity, nodules, or solid enhancing masses.n = 31; II: 10, III: 21), CKD IV/V , and end-stage kidney disease . Diagnostic performance was assessed through sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) for individual and combined reader interpretations. Combined reader measures were estimated using functions of the logistic regression parameters fitted via Generalized Estimating Equations to account for the correlation of measurements made on the same patient [p-value of 0.05 was considered statistically significant; p-values closer to one indicated greater agreement between readers. Analysis was completed using the open-source R statistical software environment v4.0 and SAS v9.4 .CEUS diagnostic accuracy for characterizing malignant and benign lesions was evaluated by comparing reader interpretations to true lesion diagnoses using the full lesion dataset, only cystic lesions, and by grouping lesions according to CKD stage. Groups were CKD II/III  were imaged and 63 lesions (53 patients) were included in the final analysis after excluding 10 lesions due to data inadequacies . Among i 3 vs. 4 .In total, 14 lesions were malignant and 49 were non-malignant . CombineOverall, 41 lesions were benign and 22 were non-benign . For diaThis study evaluated CEUS diagnostic accuracy for suspicious cystic and solid kidney lesions in CKD patients. We showed that flash replenishment CEUS could be used to qualitatively characterize kidney lesions with moderately high sensitivity and specificity . CEUS pePrevious studies have compared the sensitivity of CEUS for diagnosing complex cystic kidney lesions to CECT, CEMRI, and unenhanced ultrasound. Quaia et al., 2008 demonstrated that CEUS had a diagnostic sensitivity between 86% and 95% for three different readers, while unenhanced ultrasound only achieved a sensitivity between 43% and 48% for those same readers . SimilarWe performed sub-analyses to further investigate CEUS performance. Specificity for characterizing benign lesions was higher than for malignant lesions, indicating more true negative and less false positive results through benign dichotomization, i.e., only classifying as benign those without suspicious features. PPV also increased, suggesting a decrease in false positive results with benign over malignant criteria. By grouped CKD stage performance metrics were notably highest for CKD IV/V  when determining lesion malignancy. When characterizing benignity, CKD IV/V had a sensitivity, specificity, and PPV of 81%, 95%, and 98%, respectively. The superior performance of CEUS in CKD IV/V patients with kidney lesions compared to patients with other CKD stages suggests that CEUS could be utilized as a diagnostic tool in this patient population. This is fortuitous as kidney preservation is an important consideration in CKD IV/V patients and the use of CECT/CEMRI can sometimes be limited in patients at this stage. As such, CEUS could play a key role in safely diagnosing kidney lesions in patients with deteriorating kidney function.Challenges with accurately characterizing kidney lesions resulted from decreased CEUS sensitivity to malignant lesions in ESKD patients  Table 4Table 4, Lack of experience reading CEUS images was a limitation in this study and may be partially responsible for decreases in performance. Reader experience interpreting CEUS images ranged from 0.25 to 3 years. This and minimal CEUS training likely disadvantaged less experienced readers, influencing their ability to accurately evaluate kidney lesions with CEUS. We would expect reader accuracy to improve with additional training and experience , but accContrast imaging modalities use CT Bosniak criteria to interpret cystic lesions ,27. CEUSn = 12). Surveillance imaging was used when pathology was unavailable, but lesion characterization was less definitive by imaging. This study also suffered from a small number of malignant lesions (n = 14), affecting sensitivity and specificity [This study was limited by the small number of available pathology results  when assessing lesion malignancy, correspondingly high PPV 91%) for lesion benignity, and the diagnostic performance in CKD IV/V patients. To reduce surgical overtreatment ,26,32, r% for les0% when a


Nephronophthisis-related ciliopathies (NPHP-RC) have strong genotype and phenotype heterogeneity, and the transplantation strategy of Boichis syndrome is still controversial. Our purpose was to examine associations of genotype and phenotype in children with NPHP-RC and analyze the transplantation strategies of different phenotypes.The records of children with NPHP treated at our center from 01/2018 to 03/2021 were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received kidney transplantation, and received whole exome sequencing (WES) or nephropathy gene panel testing.NPHP1 mutations, and all presented with isolated nephropathy. Eighteen of 20 patients with non-NPHP1 mutations had compound heterozygous mutations, and 70% had extrarenal phenotype. Age at disease presentation (11.2 ± 1.94 years) and the development of kidney failure (12.4 ± 2.70 years) were later in children with NPHP1 mutations than those with non-NPHP1 mutations . Four of six children with NPHP3 mutations were diagnosed with Boichis syndrome due to liver fibrosis. Isolated kidney transplantation resulted in good outcomes for patients with mild or moderate liver fibrosis without portal hypertension, while cholestasis was common postoperatively and could be resolved with ursodeoxycholic acid.Twenty-nine children with NPHP were included. Nine children (31%) had NPHP1 mutations are the most common in children with NPHP, and the phenotype of NPHP1 mutation is significantly different from that of non-NPHP1 mutation. For NPHP patients with mild to moderate liver fibrosis without portal hypertension, timely treatment of cholestasis could prevent the rapid progression of liver function damage after isolated kidney transplantation.The online version contains supplementary material available at 10.1007/s00467-022-05763-3. Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by kidney corticomedullary cysts and extrarenal symptoms and are the most common genetic cause of kidney failure in children and young adults –3. NPHP-Most patients with NPHP-RC progress to kidney failure before the age of 30 years , 11. TypIn the aforementioned studies, most patients were in the chronic kidney disease (CKD) phase of the disease at the time of phenotype analysis, or only some patients had reached kidney failure during the follow-up period. As nephropathy progresses to the kidney failure stage, the involvement of extrarenal organs also progresses. Thus, the analysis of the phenotype of uremic patients is helpful for the perioperative management of kidney or other organ transplantation. For example, when there is liver involvement, the state of liver function plays a decisive role in perioperative management and the choice of transplantation strategy.When patients with NPHP-RC reach kidney failure, kidney transplantation is the first-choice treatment . Some stThe genotype and phenotype of children with NPHP-RC treated at our center from January 1, 2018, to March 31, 2021, were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received a kidney transplant or CLKT, received whole exome sequencing (WES) or nephropathy gene panel testing and were found to have a pathogenic gene mutation associated with NPHP, had complete medical records, and were ≤ 18 years of age. Diagnosis of NPHP was based on the clinical diagnostic criteria for NPHP proposed by Chaki et al. [The study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (IIT-2021–892).Data extracted from the medical records included medical history, including age at presentation of NPHP-RC and age when kidney failure was reached. Laboratory data extracted included serum creatinine (Scr), blood urea nitrogen (BUN), albumin (ALB), globulin (GLB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels. All children underwent abdominal ultrasound. A liver biopsy was performed if abdominal ultrasound indicated liver fibrosis when the informed consent was available. All the children underwent chest, extremity, and pelvis X-rays. All children received visual acuity and visual field evaluation, slit lamp examination if necessary, and optical coherence tomography and electrophysiological examinations in cooperative patients suspected of having retinitis pigmentosa. Each child underwent an echocardiogram to check for structural defects in the heart. Head MRI examinations were performed in children with neurological abnormalities found by physical examination to detect cerebellar vermis hypoplasia and other structural brain abnormalities. All patients were followed up through outpatient clinic and telephone after kidney transplantation. Postoperative eGFR, graft survival, patient survival, rejection, and recurrence of primary disease were obtained by follow-up.WES was performed using MyGenetics and Wuxi NextCODE. Genomic DNA was extracted from blood lymphocytes. Exon capture was performed using Agilent SureSelect Human all Exome V5 Kit, NimbleGen, or MyGenostics Gencap Capture techniques, and then NGS was performed on the Illumina HighSeq sequencing platform. At least 98% of the target sequences were sequenced at a 20 × reading depth.ALB gene as the internal reference gene, the copy number of exon 1–20 of NPHP1 was detected by fluorescence quantitative PCR with normal control samples and proband and family samples.After removing reads containing adaptor sequences and low-quality reads, clean data were mapped to the human reference genome assembly (NCBI build 37/hg19) using the Burrow–Wheeler Aligner (BWA). Single nucleotide polymorphisms (SNP) and small insertions and deletions (INDELs) were detected using a Genome Analysis Toolkit (GATK). Allele frequency was determined by annotating the variations using public databases , and the 1000 Genomes Project). Changes that represented synonymous and common variants  were discarded. SNP variant deleteriousness was predicted by SIFT, PolyPhen2, and MutationTaster. Mutation screening was prioritized based on known disease-causing genes and nephropathy-associated genes. Evidence of disease causality was assessed using ClinVar and HGMD, followed by a manual review of the cited primary literature. Copy number variation (CNV) analysis was performed using WES data, and then validated by PCR. Using the The nephropathy gene panel includes 162 genes causative or associated with nephropathy, as well as genes that may cause phenocopies in humans or related phenotypes in animal models  guidelines, mutations in known pathogenic genes whose pathogenicity levels are “pathogenic,” “likely pathogenic,” and “variant of unknown significance (VUS)” are defined as diagnostic variants. For variants of unknown significance, we regarded it as a diagnostic variation only when other causes of chronic kidney failure were excluded and there was a high correlation between phenotype and variants. All diagnostic variants were confirmed by Sanger sequencing with segregation.NPHP1 mutations were performed using the t-test. Kidney survival analysis between children with NPHP1 mutations and those with non-NPHP1 mutations was performed by Kaplan–Meier analysis. The level of statistical significance was defined as p < 0.05. GraphPad Prism 8 statistical software was used for all statistical analyses.Continuous data were expressed as mean ± standard deviation or median and interquartile range (IQR), and categorical data as count (percentage). Comparisons of patients with and without A flow diagram of patient inclusion is shown in Fig. IQR: 10–27 months). The median eGFR value post-transplant was 100 ml/min/1.73 m2 (IQR: 91–112). One child underwent CLKT, and the others received kidney transplantation only. Graft loss occurred in three patients due to acute thrombosis or acute kidney vein torsion. All three patients received second transplantation; two grafts survived well after the second transplant, and in one case, there was secondary acute thrombosis. There was no rejection or recurrence of primary disease, and there was no recipient death.The clinical data of the 29 children is summarized in Table NPHP1  were the most common genetic defects. Non-NPHP1 mutations included mutations in NPHP3 , TTC21B , WDR19 (n = 3), IFT140 (n = 2), IQCB1 (n = 2), NEK8 (n = 1), and CEP290 (n = 1) , 5 frameshift variants (13.2%), 2 inframe variants (5.3%), 8 splicing variants (21.1%), and 18 missense variants (47.4%)  Fig. . Of all iants 13.%, 5 framiants 13.%, 5 framNPHP1 mutations presented with isolated NPHP  (Table IFT140 (1/2), IQCB1 (1/2), and CEP290 (1/1) mutations  presented with isolated NPHP, while the other 14 48.3%) presented with an extrarenal phenotype. The most common sites of extrarenal involvement were the liver, eyes, and bones. All patients with % presentNPHP1 pathogenic mutations than in those with NPHP1 pathogenic mutations  in patients with NPHP3 mutations   Fig.  and F.NPHP3 mutations, and liver involvement was present in five of the six children with NPHP3 mutations. Three children underwent a liver biopsy, and a pathological examination of the tissue specimen showed mild to moderate fibrosis in all three children. Portal hypertension was present in one of the six children, and one had only mild liver enzyme elevations.The presentation of disease symptoms was earliest in patients with NPHP3 pathogenic mutations, four (66.7%) were diagnosed with Boichis syndrome, and these were the only patients with Boichis syndrome of the 29 patients. Of the six children with NPHP3 pathogenic mutations, five patients (5/6) with splice site mutations, truncation mutations, or frameshift mutations had liver involvement and rapidly progressed to kidney failure (mean age of reaching CKD stage 5: 4.3 years), while the patient (1/6) with only missense mutations had no extrarenal involvement and slow nephropathy progression (age of reaching CKD stage 5: 10.2 years).Of the six children with The liver findings of the four children with Boichis syndrome are described in Table Considering the possibility of rapid development of hepatic fibrosis to portal hypertension after isolated kidney transplantation, the three children have been followed closely with liver function testing. Although kidney function recovered well in the three patients . The mutated genes carried by patients with post-transplant embolism in our cohort were WDR19, NEK8, and IQCB1. Doreille et al. reported that thrombotic microangiopathy (TMA) was found in young adult NPHP patients with TTC21B and WDR19 mutations [TTC21B mutation and one patient was found to have TMA in the native kidney biopsy. However, no vascular thrombosis occurred in these five patients after transplantation. In addition, based on the findings during surgical exploration, we infer that vascular thrombosis initiated in the main renal vascular instead of microvascular circulation, and TMA was not reported in the pathological examination of removed allografts. Therefore, it is difficult to reasonably conclude that post-transplant thrombosis is related to these genes, while we believe this is a very noteworthy clinical phenomenon.Of the 184 patients in this cohort, four developed post-transplant thrombosis, of whom three were diagnosed with NPHP. The rate of renal vascular thrombois was higher in NPHP patients  than non-NPHP patients  Supplementary file2 (DOCX 17 KB)Supplementary file3 (DOCX 25 KB)Supplementary file4 (DOCX 44 KB)Below is the link to the electronic supplementary material.


IntroductionImpairment of cognitive functions can commonly develop in patients with chronic kidney disease (CKD) and increase morbidity and mortality. The antioxidant activity of selenium reduces cognitive decline by protecting neurons from free radical damage. We aimed to explore the associations between serum selenium levels, cognitive impairment, and depression in CKD patients in this research.MethodsIn this prospective cross-sectional research, 100 participants between the ages of 20 and 65 were included, and four groups of 25 patients each were formed . The Standardized Mini Mental Test (sMMT) was used to measure cognitive skills, and the Beck Depression Inventory (BDI) was utilized to diagnose depression. Simultaneously, measurements of serum selenium levels were done from collected blood samples.ResultsCognitive impairment was detected in 4% of the control group, 16% of CKD patients (n=75), and 30% of the dialysis patients (n=50). Depression was found in 16% of the control group, 40% of the stage 3-4 CKD group, 50% of the PD group, and 44% of the HD group. In the control group, sMMT scores were higher than the other groups , while the BDI score was statistically significantly lower (p=0.003). Serum selenium levels were found to be higher than HD and PD groups in patients with non-dialysis CKD and control groups in the post hoc analyses .ConclusionDepression and cognitive impairment are particularly prevalent in CKD and dialysis patients. Our results indicate serum selenium insufficiency may be related to depression and cognitive impairment in this patient group. Nonetheless, these findings need to be confirmed by larger-scale studies. Chronic kidney disease (CKD) is characterized by an irreversible, progressive decline in kidney function, and is an important public health problem affecting the quality of life, morbidity, and mortality . It is kIt has been shown that selenium can influence the antioxidant process and neuromodulation against oxidative stress. It has been suggested that selenium may slow down cognitive deterioration by preventing the damage caused by free radicals in neurons . DietaryMany psychiatric and psychosocial problems are encountered during the course of CKD. Psychiatric disorders are associated with increased morbidity, mortality, frequency of hospitalization, and health expenditures in end-stage renal disease (ESRD) patients . There iTo the best of our knowledge, there are no published studies examining the associations between CKD patients’ blood selenium levels and cognitive impairment and depression. However, it is known that depression may also affect cognitive functions . TherefoThe study was started after the approval of the Hitit University Research Ethics Committee (Date/No: 08.01.2020/147). Participants were given detailed information about the study, and written consent was obtained in accordance with the Declaration of Helsinki.2), Group 4 as non-CKD patients. Participants in the dialysis treatment group had received HD or PD treatment for at least six months.A total of 100 participants followed in the nephrology clinic and dialysis unit between the ages of 20 and 65 were included in this controlled cross-sectional study. Volunteers were categorized into four groups: Group 1 as HD treatment patients, Group 2 as patients with continuous peritoneal dialysis (PD), Group 3 as patients with stage 3-4 CKD  and depression assessment tests, and individuals who can speak in the native language and are literate were included. Patients using any multivitamin or trace element supplements were also excluded. Somatometric and demographic characteristics of the participants, laboratory tests used in routine follow-up, accompanying additional diseases, medications, and habits were recorded. The education levels of the participants were questioned and recorded as primary school (1-5 years), middle school (6-8 years), high school (9-12 years), and university (over 12 years).urea was calculated to evaluate HD and PD qualifications.After overnight fasting, complete blood count, glucose, blood urea nitrogen, creatinine, GFR, albumin, calcium, phosphorus, uric acid, parathormone, ferritin, bicarbonate, lipid profile, and C-reactive protein (CRP) levels were analyzed. Blood samples were taken before the middle dialysis session of the week for HD patients, at outpatient clinic control for PD patients, and at the time of inclusion for the control group. Estimated glomerular filtration rate (eGFR) values were determined using the Chronic Kidney Disease Epidemiology Collaboration equation . Kt/Vureg for 10 minutes, and the separated serum was stored at -80 °C until analysis. Measurement of SSL was done by mass spectrometry method in ICP-MS (Agilent-7500) device [The blood sample taken into the vacutainer tube was kept at room temperature for 30 minutes, then centrifuged at 1.310 ) device .Application and interpretation of the sMMTIn the week following the collection of blood samples, sMMT was applied to HD patients before the mid-week dialysis session and PD patients under outpatient control to evaluate cognitive functions.sMMT assesses orientation, memory, attention, language, and visuospatial skills. It consists of 10 points of time and space orientation, 3 points of recording, 3 points of recall, 6 points of memory, 5 points of attention, 8 points of language, and 1 point of visual-spatial functions, as a total of 30 points. Normal cognitive function is defined as at least 24 points, while 23 or fewer points as dysfunction in sMMT .Application and interpretation of the Beck Depression InventorySince cognitive functions may be affected in the presence of depression, the Beck Depression Inventory (BDI) was applied to evaluate depression simultaneously with the application of the sMMT.It has been shown that the BDI can be applied reliably to detect symptoms of depression in people with CKD . Using tStatistical analysisThe SPSS package software  was used for the statistical analyses. For normally distributed continuous data, the descriptive statistics were reported as mean ± standard deviation; for non-normally distributed continuous data, the median (min-max) was used; and for categorical data, the numbers and percentages (%) were used. The normality distribution was analyzed by the Shapiro-Wilk test. In the comparison of continuous variables between two independent groups, the student’s t-test was used for normally distributed variables in independent groups, and the Mann-Whitney U test was used for variables not normally distributed. One-way analysis of variance (ANOVA) was used for normally distributed variables, and the Kruskal-Wallis test was used for variables not normally distributed in comparing continuous variables among more than two independent groups. For identifying the cause of the difference in ANOVA and Kruskal Wallis tests, multiple Mann-Whitney U post hoc comparison tests with Tukey or Bonferroni correction were used. Relationships between categorical variables were investigated with either the chi-square test or Fisher's exact test, depending on the number of data in the crosstab cells. Depending on the data distribution, Pearson's or Spearman's correlation coefficient was used to assess the relationships between numerical variables. The cause-and-effect relationship between two numerical variables with strong correlations was determined using simple linear regression analysis. The statistical significance level was determined as p <0.05.The mean age of 100 participants  was 48±11 years, and the male-female ratios and mean ages were statistically similar between the groups . Table sMMT scores were statistically significantly higher in the non-CKD group than in the HD, PD, and stage 3-4 CKD groups p<0.001 for all). sMMT scores were similar between HD and PD and stage 3-4 CKD groups . sMMT scores were similar between PD and stage 3-4 CKD groups (p=1.000). BDI scores in the HD and PD groups were statistically significantly higher than in the non-CKD group . BDI scores were similar between HD and PD and stage 3-4 CKD groups  Table . SSLs we for all.In correlation analysis, a statistically significant negative correlation was found between SSL and BDI scores  Table . A statiCognitive impairment is commonly observed in CKD patients but is usually diagnosed after clinical progression since its importance is not known enough. Early diagnosis of cognitive dysfunction is crucial because it has negative effects on morbidity, mortality, and quality of life of the patients . In one Cognitive impairment was detected in 20-87% of patients receiving HD treatment . In one Depression is very common in ESRD patients and is seen at a rate of 20-25% . In addiOxidative stress is known to play a role in neurodegenerative diseases such as Alzheimer's disease and cognitive impairment . It is kIn our study, SSLs of stage 3-4 CKD and control groups were statistically significantly higher than those of HD and PD groups. We also found a statistically significant positive correlation between SSL and sMMT scores. This finding suggests that selenium may be effective in preserving cognitive functions in CKD patients. In addition, a statistically significant negative correlation was found between SSL and BDI scores, which supports a relationship between low SSL and depression in the study population.When the literature was examined, it was seen that the relationship between selenium and depression could not be clearly revealed before . In someLimitationsOur study has some limitations due to the design of the study; it has a relatively small sample size and a single ethnic origin. Also, it was a single-center study. However, the study group's specificity increases the study's power.Both cognitive impairment and depression are common in patients receiving dialysis treatment for ESRD, and depression may affect cognitive impairment. Selenium deficiency is correlated to the emergence of cognitive impairment and depression in dialysis patients. Investigation of the effects of selenium supplementation and increasing dietary selenium intake on cognitive functions and depression in patients with the impaired renal function will increase the strength of our findings.


In individuals with complex underlying health problems, the association between systolic blood pressure (SBP) and cardiovascular disease is less well recognised. The association between SBP and risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD) was investigated.In this cohort study, 39 602 individuals with a diagnosis of COPD aged 55–90 years between 1990 and 2009 were identified from validated electronic health records (EHR) in the UK. The association between SBP and risk of cardiovascular end points  was analysed using a deep learning approach.In the selected cohort , 10 987 cardiovascular events were observed over a median follow-up period of 3.9 years. The association between SBP and risk of cardiovascular end points was found to be monotonic; the lowest SBP exposure group of <120 mm Hg presented nadir of risk. With respect to reference SBP (between 120 and 129 mm Hg), adjusted risk ratios for the primary outcome were 0.99 (95% CI 0.93 to 1.05) for SBP of <120 mm Hg, 1.02 (0.97 to 1.07) for SBP between 130 and 139 mm Hg, 1.07 (1.01 to 1.12) for SBP between 140 and 149 mm Hg, 1.11 (1.05 to 1.17) for SBP between 150 and 159 mm Hg and 1.16 (1.10 to 1.22) for SBP ≥160 mm Hg.Using deep learning for modelling EHR, we identified a monotonic association between SBP and risk of cardiovascular events in patients with COPD. In patients with chronic obstructive pulmonary disease (COPD), the relationship between systolic blood pressure and risk of cardiovascular events is poorly understood.One observational study using conventional statistical modelling, which requires manual confounder selection and is found to be inadequate in modelling high-risk cohorts, has shown a J-shaped association, with increased risk above and below an apparently optimal systolic blood pressure value.With recent access to comprehensive, routine electronic health records data and developments in causal deep learning modelling capable of extracting and adjusting for confounders both known and latent in medical history, our longitudinal cohort study on about 40 000 patients with COPD with and without prior cardiovascular disease captured a monotonic relationship between systolic blood pressure and risk of cardiovascular events rejecting the J-shaped curve hypothesis.While current guidelines recommend a systolic blood pressure target of 130 mm Hg (140 mm Hg in the elderly) in patients with COPD, our study demonstrates a nadir of risk at <120 mm Hg for cardiovascular outcomes in line with established knowledge concerning cardiovascular risk.Systolic blood pressure (SBP) is a well-known risk factor for cardiovascular diseases.In patients with chronic obstructive pulmonary disease (COPD), the relationship remains unclear. Independently, SBP and COPD have both been associated with a higher risk of cardiovascular disease (CVD).With the availability of comprehensive electronic health records (EHR) and the advancement of deep learning (DL) causal modelling, the opportunity for more accurate modelling of associations among subgroups with poorer health has arisen.In this study, we applied the T-BEHRT model to evaluate the association between SBP and risk of cardiovascular outcomes in a cohort of 39 602 patients with COPD.We used retrospective anonymised EHR data from Clinical Practice Research Datalink (CPRD), an EHR database representative of the UK population that has been validated for epidemiological research.10.1136/heartjnl-2023-322431.supp1Supplementary dataThis cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.The exposure variable in this study was SBP and was derived from the CPRD measurements dataset. Blood pressure measurement data are recorded by staff at the general practice (GP) during a visit/consultation.The primary outcome was fatal/non-fatal CVDs defined as a composite of ischaemic heart disease (IHD), heart failure, stroke and cardiovascular-related death. Secondary outcomes investigated in this study were individual components of the defined primary outcome: (1) IHD, (2) heart failure and (3) stroke. We identified cardiovascular events using three data sources in CPRD: (1) primary care, (2) secondary care (HES) and (3) the Office of National Statistics  using previously published phenotyping algorithms.For analyses of the primary and secondary outcomes, the DL model, T-BEHRT was implemented.et al, we adjusted for the same variables as those chosen in their research: sex, age, body mass index (BMI), smoking status , beta-blocker use, long-acting beta-agonist (LABA) use and inhaled corticosteroid use.In order to compare our DL approach against established statistical modelling, we implemented logistic regression (LR) modelling to investigate the association between SBP and risk of cardiovascular outcomes in those with COPD. The SBP exposure group was included as a categorical variable. Since we motivated our work with findings from the research conducted by Byrd Five sensitivity analyses were pursued in our studies using the T-BEHRT model. First, we investigated the association of SBP and cardiovascular risk in patients who had not taken antihypertensives during the follow-up period. Antihypertensives are established medications for lowering high blood pressure, thereby potentially attenuating cardiovascular risk; hence, we conducted this sensitivity analysis in order to investigate the undiluted association between SBP and risk of cardiovascular outcomes in patients with COPD.Patients were not involved in this research for the development of the research question, exposure definition or the outcome definition. They were not involved in any form for any possible recruitment, design or implementation of this study. There are no current plans to involve patients in the dissemination stage of this study.A total of 39 602 individuals with COPD at baseline were included in our analysis . The medet al) for the analysis of the primary outcome ? While guidelines for hypertension indeed endorse blood pressure lowering in patients with concomitant COPD and high blood pressure, the recommendations suggest a treatment target of <130 mm Hg (<140 mm Hg in the elderly).Naturally, our investigation does not answer questions relating to antihypertensive treatment effects. Hence, while our study in isolation is insufficient for recommending revisions of hypertension guidelines, our investigation sheds light on the aetiological nature of SBP and CVD in those with COPD—imperative, especially since randomised evidence of blood pressure-lowering therapies in patients with COPD is unavailable and likely to remain unavailable in the near future. While (1) external validation of the studied association would be prudent and (2) in-depth investigations of the association between antihypertensive and CVD  are needed to comprehensively capture all facets of the relationships between blood pressure, antihypertensives and CVD risk in patients with COPD, our investigation serves as one such source of well-adjusted evidence.First, in terms of data, the comprehensive information provided by CPRD is a strength of our research. The linkage capabilities of CPRD allow the capture of rich health encounters  from various sources including primary care, secondary care and mortality-based datasets. With access to rich EHR, our DL approach could better extract confounders, both known and latent in routine clinical data as shown in past investigations of SBP and CVD risk in high-risk patients.In terms of limitations, while EHR data in CPRD have some degree of diagnostic recording error, past studies have validated the primary care, secondary care and mortality-based sources within the CPRD database for observational research.We found that patients with COPD in the lowest category of SBP of <120 mm Hg has the lowest risk of cardiovascular events during follow-up. Our findings capture a monotonic relationship between SBP and risk of cardiovascular events in patients with COPD and were in line with the established clinical understanding of the monotonic relationship between SBP and cardiovascular risk in the general population.