Mycobacterium tuberculosis infection continues to be a major global challenge. All patients with pulmonary tuberculosis are treated with a standard 6-month treatment regimen. Historical data suggest that even with shortened treatment, most patients achieve long-term remission. Risk stratification is a goal for reducing potentially toxic prolonged treatment. This study aimed to determine the factors associated with the early clearance of sputum acid-fast bacilli (AFB). A total of 297 freshly diagnosed patients with pulmonary tuberculosis were included and enrolled in this study. Information related to their ethno-demographic and anthropometric characteristics was collected. We also assessed their complete blood counts, and blood iron, folate, and vitamin B12 levels. We found that the presence of higher levels of acid-fast bacilli (AFB) in diagnostic sputum microscopy was the single most significant prognostic factor associated with early clearance of sputum AFB after 2 months of treatment. All of our patients achieved treatment success after 6 months of treatment and were disease free. Our results support the data obtained from previous studies indicating that AFB clearance at 2 months is unlikely to be a clinically useful biomarker or indicator for therapeutic stratification. Furthermore, demographic, anthropometric, and nutritional factors are not clinically useful biomarkers. Mycobacterium tuberculosis, continues to be one of the leading infectious diseases despite the global efforts that are exerted for its prevention and treatment /[(d2/Z21 − α/2 × (N − 1) + p × (1 − p)]. We estimated the frequency of slow response to be 20%, and with a confidence limit of 5%, design effect of 1, confidence level of 95%, and drop-out rate of 20%, we calculated a sample size of 297. Adult (aged 18 years and above) patients who were freshly diagnosed with pulmonary tuberculosis were included and enrolled in this study. The participant information sheet was provided to all the participants to read and was also verbally explained in their native language. Written informed consent was obtained from the participants. Patients with a previous history of tuberculosis or antituberculosis therapy; diagnosed with multidrug-resistant or extrapulmonary tuberculosis; and those with associated comorbidities such as COPD, asthma, ILD, and lung cancer were excluded from the study. Tuberculosis diagnosis was based on sputum smear positivity of at least two sputum samples, collected on the same day for acid-fast bacilli (AFB) using Zeil-Neelson staining. Based on the number of AFB present, the patients were grouped as either scant (1–9 AFB/100 field), + (10–99 AFB/100 field), ++ (1–9 AFB/field), or +++ (10–99 AFB/field) as per the American Thoracic Society guidelines.2).A structured questionnaire was used to collect information about socio-demographic characteristics such as age, sex, ethnicity, education, occupation, household income, and smoking status from all the participants. Anthropometric measurements were recorded by trained data collectors and followed standard guidelines. To measure height, the participants were asked to stand still with their backs to a wall-mounted stadiometer  and head in the Frankfurt plan position. Height was measured to the nearest 0.1 cm by lowering the measuring device until it gently rested on the scalp without putting pressure. To measure weight, the participants were instructed to remove their shoes, added clothes and any extra weight, and stand on a precalibrated electronic scale . Weight was recorded in kilograms to the nearest 0.1 kg. For consistency, all the measurements were taken three times and the average was recorded. Body mass index (BMI) was calculated as the fraction of weight to the squared height  analyzer. The total iron-binding capacity (TIBC) was calculated by summing up the UIBC and serum iron concentration.Laboratory investigations included the complete blood count (CBC) and a range of hematological parameters. The CBC was immediately performed after blood collection on the Sysmex hematology analyzer  following manufacturer instructions and including different parameters such as hemoglobin (g/dL), red blood cells count, mean corpuscular volume, mean corpuscular hemoglobin, hematocrit, white blood cells, and platelets count. Serum iron, ferritin, transferrin, unsaturated iron-binding capacity (UIBC), and C-reactive proteins were analyzed by the electrochemiluminescence (need to confirm) method using a CobasAll the patients received free, first-line standard drug therapy per guidelines from the national TB control program . The treData were entered using Microsoft Excel 2016  and exported to Statistical Package for Social Sciences (SPSS) version 25 . g for continuous variables and frequencies for discrete variables. Multivariate regression was used to calculate OR for response at 2 months of ATT, adjusting for the following potential confounding factors: age, sex, BMI, monthly household income, income spent on food, smoking history, AFB burden at diagnosis, Hb levels, WBC counts, serum ferritin, iron, TIBC and transferrin levels, vitamin B12 and folate levels, and serum CRP levels.Early clearance of sputum AFB in pulmonary TB appears to be directly correlated with at-presentation sputum AFB levels and is unlikely to be useful for therapeutic stratification. The level of sputum AFB at diagnosis is unlikely to be a clinically useful predictor of treatment response. Other demographic, anthropometric, and laboratory variables, although perhaps individually important, are not independently associated with early clearance.


Background and Objectives: The effect of individualized hemodynamic management on the intraoperative use of fluids and other hemodynamic interventions in patients undergoing spinal surgery in the prone position is controversial. This study aimed to evaluate how the use of individualized hemodynamic management based on extended continuous non-invasive hemodynamic monitoring modifies intraoperative hemodynamic interventions compared to conventional hemodynamic monitoring with intermittent non-invasive blood pressure measurements. Methods: Fifty adult patients  who underwent spinal procedures in the prone position and were then managed with a restrictive fluid strategy were prospectively randomized into intervention and control groups. In the intervention group, individualized hemodynamic management followed a goal-directed protocol based on continuously non-invasively measured blood pressure, heart rate, cardiac output, systemic vascular resistance, and stroke volume variation. In the control group, patients were monitored using intermittent non-invasive blood pressure monitoring, and the choice of hemodynamic intervention was left to the discretion of the attending anesthesiologist. Results: In the intervention group, more hypotensive episodes (3 (2–4) vs. 1 (0–2), p = 0.0001), higher intraoperative dose of ephedrine (0 (0–10) vs. 0 (0–0) mg, p = 0.0008), and more positive fluid balance (680 (510–937) vs. 270 (196–377) ml, p < 0.0001) were recorded. Intraoperative norepinephrine dose and postoperative outcomes did not differ between the groups. Conclusions: Individualized hemodynamic management based on data from extended non-invasive hemodynamic monitoring significantly modified intraoperative hemodynamic management and was associated with a higher number of hemodynamic interventions and a more positive fluid balance. Hemodynamic management during anesthesia is crucial to prevent fluid overload and hypovolemia. Fluid overload is potentially associated with pulmonary complications and worsened wound healing ,2. HypovSpine surgery in the prone position represents a particularly challenging setting from a hemodynamic point of view ,7,8. Perioperative hemodynamic instability may occur due to the prone position-induced changes in preload, afterload, and, in patients with pre-existing heart disease, decreased left ventricle ejection fraction ,7,8,9,10The impact of individualized hemodynamic management on the intraoperative use of fluids and other hemodynamic interventions in patients undergoing spinal surgery in the prone position is controversial. In a recent non-randomized study, the use of individually tailored approaches based on stroke volume variation (SVV) was shown to reduce blood loss and the use of transfusions, improve postoperative respiratory functions, and accelerate postoperative recovery in comparison to the liberal fluid strategy approach . In contCurrently, continuous non-invasive extended hemodynamic monitoring is possible using the ClearSight System/EV 1000 platform . This system continuously measures blood pressure using a special finger cuff and calculates stroke volume, SVV, and other derived hemodynamic parameters . The CleThis study aimed to evaluate how intraoperative hemodynamic interventions are modified using individualized hemodynamic management based on continuous non-invasive blood pressure measurements, heart rate (HR), cardiac output, systemic vascular resistance, and stroke volume compared to conventional hemodynamic management based on intermittent non-invasive blood pressure measurements. Intraoperative fluid balance was used as the primary outcome measure, whereas the intraoperative dose of norepinephrine, length of postoperative oxygen therapy, rate of wound complications, number of admissions to the intensive care unit, and length of hospital stay were considered secondary outcome measures.ClinicalTrials.gov (NCT03644654). No changes in the study protocol were made after trial commencement.This single-center, prospective, parallel, two-arm, open randomized controlled pilot trial was approved by the ethical committee  of the University Hospital Hradec Kralove, Hradec Kralove, Czech Republic  on 23 October 2018. This trial has been registered at Adult patients scheduled for elective spinal surgery with an expected length of <3 h were considered. The inclusion criteria were as follows: age >18 years, preoperative Glasgow Coma Scale score of 15, American Society of Anesthesiologists (ASA) physical status I–III, elective spinal surgery in the prone position, and sinus rhythm on preoperative electrocardiography (ECG). The exclusion criteria were as follows: weight >120 kg, prolonged preoperative fasting >12 h, expected postoperative mechanical ventilation, preoperative hypotension  <65 mmHg), severe respiratory comorbidity with assumed pulmonary hypertension, other than sinus rhythm on ECG, known valvular disorder, peripheral vascular disease, and assumed perioperative blood loss >1500 mL.Potential participants were identified on the operating list, and a screening visit was performed the day before surgery. All the patients provided written, informed consent for participation and were recruited between February and June 2019. Randomization (1:1) was performed using a computer-generated random list of patients in sealed envelopes that assigned individuals to the control or intervention group.2; S/5 monitor; GE Healthcare, Helsinki, Finland), was initiated in the operating room of the Department of Neurosurgery, University Hospital, Hradec Kralove, Czech Republic. In the intervention group, a non-invasive hemodynamic monitoring probe (ClearSight system/EV 1000 platform) was used.Standard monitoring, including non-invasive blood pressure, three-lead ECG, and pulse oximetry (SpO−1), and no additional muscle relaxants were administered during surgery. The lungs were ventilated with a tidal volume of 8–9 mL kg−1 predicted body weight to an end-tidal carbon dioxide (ETCO2) concentration of 35–40 mmHg. The depth of anesthesia was monitored using an entropy sensor and analgesia was monitored using the surgical plethysmographic index (SPI).Anesthesia management was standardized. General anesthesia was induced with titrated intravenous propofol up to 2 mg/kg  and sufentanil  depending on body weight  and maintained with desflurane. Tracheal intubation was facilitated using atracurium  at a standard dose  20 mL boluses were administered to flush the medication. Both groups received approximately 120 mL of PlasmaLyte at the beginning of anesthesia. Blood loss was compensated using PlasmaLyte with a crystalloid-to-blood volume ratio of 1.5:1.0; blood loss >1 L was compensated for through blood transfusion.−1 of PlasmaLyte infused within 5 min.Hemodynamic interventions were targeted to maintain the MAP in the range of ±15% of the patient’s preoperative level in both groups. Hypotension was defined as a MAP <25% of the patient’s preoperative value and could be treated with the fluid bolus, norepinephrine infusion, ephedrine, or atropine (0.5 mg) in cases of bradycardia (heart rate <45 beats per minute with suspected hemodynamic impact). The fluid bolus was defined as 2 mL kgIn the control group, the choice of hemodynamic intervention was left to the discretion of the attending anesthesiologist. Non-invasive blood pressure was measured at 5 min intervals, and it was recommended to shorten this interval to 2 min in cases of expected or proven blood pressure instability.−1 m−2  of at least 2.1 L min−1 m−2 . Atropin−1 min−1) with the initial intravenous bolus of 5–10 µg was used to keep the systemic vascular resistance index (SVRI) >1900 dyn s cm−5 m−2. A fluid bolus was used in patients with a stroke volume variation (SVV) ≥9% if the CI was <2.1 l min−1 m−2 and/or hypotension occurred or persisted despite corrected SVRI. Ephedrine (10 mg intravenously) was administered to patients with hypotension or a low cardiac index and SVV <9%. Hemodynamic interventions were repeated every 5 min if the target was not reached.Norepinephrine infusion ; comorbidities; duration of procedure; cumulative intraoperative doses of norepinephrine, atropine, and ephedrine; intraoperative doses of propofol, sufentanil, and atracurium; the number of episodes of hypotension (an episode was defined as a maximum of 5 min of MAP <25% of the preoperative level); intraoperative fluid intake and balance; duration of postoperative oxygen administration; wound complications; length of postoperative hospital stay; and outcome. Additionally, the CI, stroke volume index (SVI), SVRI, MAP, and SVV were noted before and after anesthesia induction and after prone positioning. The complete protocol is available upon request from the authors.t-test  was calculated to be 80 patients. A sample size of 100 patients was considered to compensate for potential dropouts and possible inaccuracies in the power analysis with a planned interim analysis after the first 50 patients with predefined stopping rules . All statistical analyses were performed by a blinded person.A power analysis based on an error of 0.05 and an error of 0.1 was performed using G*Power 3.0.9 . A difference of 30% in the intraoperative fluid balance with an expected fluid balance of 500 mL in the control group was considered significant for the power analysis. The sample size required for the t-test  or Mann–Whitney test was used to compare results between groups based on the results of the Kolmogorov–Smirnov test. The hemodynamic variables recorded before and after anesthesia induction and after prone positioning were compared using the Friedman test with pairwise comparisons and the Conover post-hoc test. Fisher’s exact test was used to examine the differences between categorical variables. Statistical significance was set at p <0.05. Statistical analyses were performed using MedCalc 18.6.3 .Continuous variables are presented as the mean ± standard deviation or as the median with interquartile ranges (IQR) based on the results of a test for normality of the distribution using the Kolmogorov–Smirnov test. The A total of 54 patients undergoing elective spinal surgery were screened, and 50 patients (25 patients in each group) were enrolled in the study . The stuDuring the procedure, the use of individualized hemodynamic management resulted in higher hypotension recognition and was associated with more interventions, namely, the total intake of fluids and the use of ephedrine . InterveThis study showed that the use of individualized hemodynamic management based on continuous non-invasive blood pressure, heart rate, cardiac output, and systemic vascular resistance monitoring significantly modified intraoperative interventions in patients with restrictive fluid management. Its use was associated with a higher number of detected episodes of hypotension and a higher number of hemodynamic interventions, including the administration of both fluids and adrenergic agonists. No differences in postoperative outcomes were observed between the control and intervention groups.Higher use of adrenergic agents to control episodes of hypotension was recently reported in patients monitored with the ClearSight system/EV1000 platform . SimilarThe observed higher total fluid intake and more positive fluid balance in the intervention group corresponded to the results of studies on perioperative goal-directed therapy that used restrictive fluid therapy in the control arm ,24. In c−1 of predicted body weight was lower than the commonly cited cut-off value of 14% [−1 lean body mass in the prone position [−1 of predicted body weight questioned the usability of SVV to predict fluid responsiveness in the prone position. These studies found that the use of either a tidal volume challenge [The cut-off values used for SVV and CI could also have influenced the obtained results. The cut-off value for SVV of 9% using tidal volumes of 8–9 mL kge of 14% . This cuposition . The neeposition . In contposition . Recentlhallenge  or a lunhallenge  improved−1 m−2, our approach was in line with a recently published expert opinion [−1 m−2.The CI value used to indicate hemodynamic interventions may have also influenced our results. Although some studies  used a h opinion , which s2 <90%) or postoperative wound complications, revealed that at least 200 patients per group must be included in a possible definitive trial aimed at modifying postoperative outcomes.No differences in the postoperative outcomes were observed in the present study. In a recent meta-analysis, no mortality benefit with perioperative hemodynamic goal-directed therapy (PGDT) was observed in studies with mortality <10% . A systeOur study had several limitations. First, the hemodynamic management of patients in the control group was based on non-invasive blood pressure monitoring, which limits our ability to distinguish between the effects of continuous blood pressure monitoring and the effects of extended hemodynamic monitoring. Second, the values of hemodynamic parameters used to trigger hemodynamic interventions may be affected by the prone position, and the best cut-off values for patients in the prone position are still under debate. Other methods of fluid responsiveness assessment  should be considered in future studies. This study was not powered to assess changes in postoperative outcomes. Finally, the single-center nature and the patient population may have limited the generalizability of our results.Individualized hemodynamic management based on data from extended non-invasive hemodynamic monitoring significantly modified intraoperative hemodynamic management and was associated with a higher number of hemodynamic interventions and a more positive fluid balance. Further studies are needed to determine the role of individualized hemodynamic management in the modification of postoperative outcomes.


Improving organ perfusion is the aim of shock resuscitation; therefore, improving organ blood perfusion is a direct indicator for shock resuscitation. During shock, different organs have different capacities for blood flow autoregulation. The kidney is an important organ with excellent ability to autoregulate the blood flow and with vulnerability to poor organ perfusion, which places kidney perfusion in a position of necessity and priority relative to that of other organs in shock. Critical-care ultrasonography provides the best evaluation of renal perfusion. Shock is an acute circulatory failure, the essence of which is failure to provide tissues with adequate oxygen, leading to cellular hypoxia and organ dysfunction. Shock resuscitation increases oxygen delivery to the tissues and organs by improving tissue perfusion. Oxygen is carried through blood flow, and direct monitoring of changes in the organ’s blood flow is vital in shock resuscitation. Improving organ blood flow is a direct objective in shock resuscitation . However1.Although the kidney accounts for only 0.4% of the body weight, it receives 20%-25% of the cardiac output (CO). The rationale behind this is not to maintain kidney viability but to filter systemic metabolites from the entire circulation, to regulate water, electrolyte, and acid-base balance, and to maintain internal homeostasis while performing other important functions such as blood pressure regulation. Clearly, normal blood perfusion is the key to ensuring renal function. Decreased renal perfusion reduces the amount of purified blood, the capacity to remove metabolites, and autoregulation by the kidneys. This may manifest as disorders in water, electrolyte, and acid-base balance. Once the damage reaches a certain level, it is clinically defined as an acute kidney injury (AKI).2.2.1.i.e., CO; (ii) the organ perfusion pressure, or the gap between the macrocirculatory pressure and the interstitial pressure; this can be replaced with the mean arterial pressure (MAP) when the organ’s interstitial pressure is unknown; and (iii) organ vascular resistance. When CO and MAP are constant, organ vascular resistance determines the organ perfusion and is mainly affected by the organ’s capacity for autonomic regulation of blood flow and by neuroendocrine factors. Except for the pulmonary circulation, which receives all CO without the need for autonomic regulation of blood flow [Organ perfusion is maintained by CO distribution as a function of organ vascular resistance and arterial blood pressure. The main factors that determine the blood flow perfusion of an organ are three-fold: (i) the level of macrocirculation, ood flow , all orgood flow .plateau period, in which the two ends of the plateau period are the lower limit of autoregulation (LLA) and the upper limit of autoregulation (ULA) (5). If the blood pressure or perfusion pressure is above the LLA, not only can the organ be effectively perfused but also the application of vasoactive drugs and fluids can be reduced. An organ with a strong capacity for regulation has a wide and flat plateau stage with a clear LLA, while one with a weak capacity for regulation has a narrow, steep, or even absent plateau period. Regardless of the organ type, the ULA is not easily determined. According to an organ’s capacity for autonomous blood flow regulation, it is classified into three levels: strong ; medium ; and weak  (5). In general, organs with weak regenerative capacity have strong blood flow autoregulation, which also indicates the importance of the autonomous regulatory capacity for organ function. In short, automatic regulation of blood flow, to a certain extent, determines the level of organ perfusion during shock.Autonomic regulation of blood flow refers to the maintenance of stable organ perfusion through the organ’s intrinsic capacity to self-regulate vascular resistance as blood pressure or perfusion pressure fluctuates. This reflects the connection between organ perfusion pressure and blood flow. Thus, the greater the regulatory capacity, the higher the probability of stable organ blood flow when blood pressure fluctuates. The stage at which the blood flow does not fluctuate with pressure changes is the Some studies have indicated that conditions with poor prognosis, such as multiple organ dysfunction syndrome and sepsis after cardiac surgery in critically ill patients, are correlated with blood pressure lower than the autonomically regulated LLA value for cerebral blood flow; this may serve as a guidance for blood pressure management in critically ill patients -8. Howev2.2.glomerular capillary network, which filters the entire blood volume and forms the second set of capillary networks. Both ends of the glomerular capillary network are the arterioles, which lead to a far greater forward perfusion pressure of the glomerular capillary network than in most other organs (approximately 60 mmHg vs. 10-15 mmHg). Hence, the kidney is more susceptible to MAP fluctuations, which is also why the LLA is relatively high. In addition, this feature keeps the renal resistance vessels in a state of constant high pressure; therefore, the kidney’s capacity for autonomous regulation of blood flow is easily impaired. In the setting of hypertension and diabetes, damage to the autoregulatory capacity is accelerated, so that the blood flow autoregulation curve shifts to the right and the LLA increases. The results of the SEPSISPAM study showed that compared with an MAP of 65-70 mmHg, that of 80-85 mmHg reduces the serum creatinine levels and renal replacement therapy requirements in patients with septic shock and pre-existing hypertension [The renal circulation is different from that of other organs, in which there are two sets of capillary networks corresponding to different renal functions. The first set is the rtension  discoverperitubular, and to reabsorb most of the glomerular filtrate, the intra-peritubular capillary pressure must be adequately low. In general, the effective glomerular filtration pressure is approximately 10 mmHg; if the intra-peritubular capillary pressure is above this, reabsorption stops. Due to the low pressure of this system, it is easily susceptible to ambient pressures, such as intra-abdominal pressure, renal interstitial pressure, and especially renal venous pressure. The renal venous pressure is the direct resistance of peritubular capillary blood flow back. If the renal venous pressure increases, which is approximately 3-4 mmHg normally, the peritubular capillary pressure increases and reabsorption from the renal tubule decreases. Through backward conduction of pressure, increased renal venous pressure can decrease glomerular filtration pressure, increase interstitial pressure, and decrease renal perfusion. A slight increase in renal venous pressure leads to an increase in renin release, resulting in increased renal vascular resistance and reduced renal perfusion [The second set of capillaries are erfusion . Under terfusion ,14. The erfusion ; hence, erfusion .2.3.Under normal circumstances, the autonomous regulation of organ blood flow is mainly through metabolism. Vasodilators generated by metabolism dilate the blood vessels  and incrIn summary, renal blood perfusion is more dependent on pressures such as MAP and CVP, and its LLA is high. During shock, the kidney is more susceptible to damage than are the other vital organs such as the heart, brain, and spinal cord. This characteristic indicates that changes in renal blood flow can better reflect macrocirculatory changes in the early stages. Determining the LLA is relatively straightforward and can help in the management of pressures and blood flow.3.The heart and lungs supply oxygen, and cardiopulmonary function and perfusion require special attention. Coronary angiography is a common method for assessing cardiac perfusion. Due to its invasiveness, its utilisation and promotion have been limited and mostly used in patients with coronary artery disease. Pulmonary perfusion is a direct measure of CO; however, as the pulmonary circulation receives all CO and lacks the ability to autoregulate blood flow, it is a poor indicator of perfusion of the other organs . The braConsider the organs with weak autonomic regulation of blood flow. Circulation to the skin and sublingual mucosa, which have weak autonomic regulation and abundant α-adrenergic receptors, is often sacrificed early in shock. Thus, assessing perfusion of these areas is important; however, due to the weak autonomic regulation of blood flow, it is difficult to extrapolate perfusion changes in these locations to those of other organs. Because the LLA value is unclear, it is rarely used as guidance for pressure management.(KI)BCDE’ protocol proposed by the Chinese Critical UltraSound Study Group [Studies on renal perfusion assessment have been relatively mature and have mainly focused on non-invasive methods such as ultrasonography, dynamic contrast-enhanced magnetic resonance imaging (MRI), isotopic renography, and computed tomography (CT) perfusion imaging. Because of the lack of a linear relationship between MRI signal intensity and contrast agent concentration , the raddy Group  adopts tFirst, through renal blood flow distribution, information regarding the amount of blood flow and the perfusion area can be acquired directly. The renal arterial and venous spectral waveforms and corresponding RRI and VII can reflect the perfusion resistance and return resistance of the kidney, respectively, to a certain extent. Several factors influence the correlation between RRI and vascular resistance, such as vascular compliance, distal vascular bed cross-sectional area, and heart rate . Vascula4.The necessity and priority of renal perfusion assessment proposed in this study do not imply that the kidney is more important than other important organs. The kidney has good ability to autoregulate blood flow; however, it also has the characteristics of the more vulnerable organs with weaker autoregulation. Therefore, during shock, the kidneys can reflect macrocirculatory changes earlier than the other important organs, such as the heart, brain, and spinal cord, and assist in titration of perfusion pressure. If renal perfusion is improved, the perfusion of the heart, brain, and spinal cord should also be improved. When patients have cardio-cerebrovascular disease—that is, when the autonomous regulation of cardio-cerebral blood flow is dysfunctional—the evaluation for cardio-cerebral perfusion should not only be emphasised but also prioritised. When conflicts exist with cardio-cerebral perfusion, perfusion of the heart and brain should be guaranteed and optimised as the first priority .In conclusion, optimal autoregulation of renal blood flow and adequate perfusion are important to guarantee that the kidney can regulate water, electrolytes, acid-base balance, and neuroendocrine function. This serves as the essential basis for evaluation of renal perfusion in shock. The kidneys have weaker autonomous regulatory capacity and are more sensitive and dependent on pressures, such as MAP and CVP, than the heart, brain, and spinal cord. Hence, the LLA value tends to be higher, contributing to its vulnerability to damage, and this vulnerability further justifies the necessity and priority of renal evaluation. The LLA of the kidneys, which is relatively clear and higher than that of the heart and brain, is the goal of MAP optimisation after initial shock resuscitation. Bedsides, ultrasonography can comprehensively evaluate renal blood perfusion and guide LLA titration, which is essential in the evaluation of organ perfusion in shock. This blood pressure level is not the final goal of shock resuscitation and must be further titrated to ensure perfusion of the other organs with weaker autonomic blood flow regulatory capacity, such as the gastrointestinal tract and skin. Therefore, further assessment of cardio-cerebral perfusion is needed in cases of cardiovascular and cerebrovascular diseases; however, these still must be based on renal perfusion assessment.


Anticoagulant-related nephropathy (ARN) is a relatively novel recognized entity characterized by hematuria-associated acute kidney injury (AKI) in the context of overanticoagulation. Preexisting or underlying kidney disease seems to be a predisposing factor; however, few studies have described histologic findings in patients with ARN. We aimed to evaluate underlying kidney pathology in patients on oral anticoagulation who presented an episode of AKI with hematuria in whom a kidney biopsy was performed.Retrospective observational multicenter case study in patients treated with oral anticoagulants who developed macroscopic or intense hematuria followed by AKI. Only patients with available kidney biopsy specimens were included. Histologic findings and clinical data throughout follow-up were analyzed.A total of 26 patients were included with a median age of 75 years (62–80) and a follow-up period of 10.1 months. Of the patients, 80% were male, and most cases (92%) were on anticoagulation with vitamin K antagonists (VKAs). At admission, median serum creatinine (SCr) level was 4.2 mg/dl (2.8–8.2), median international normalized ratio (INR) 2.4 (1.5–3.4), and 11 patients (42%) required acute dialysis during hospitalization. Kidney biopsy results revealed that all patients except 1 had an underlying nephropathy: IgA nephropathy (IgAN) in 19, probable IgAN in 1, diabetic nephropathy in 3, nephrosclerosis in 1, and idiopathic nodular glomerulosclerosis in 1. At 12 weeks after discharge, only 6 subjects (24%) attained complete kidney recovery whereas 7 (28%) remained on chronic dialysis.IgAN was the most common underlying kidney disease in our biopsy-proven series of ARN, in which a significant percentage of patients did not achieve kidney function recovery.  We included adult patients on chronic oral anticoagulant therapy with VKAs or DOACs who presented an episode of gross hematuria or intense microhematuria on urinary sediment followed by AKI  in which a kidney biopsy was performed. Patients without histologic assessment were excluded. All patients were admitted to the hospital during the anticoagulation-related AKI episode and were discharged according to the criteria of the treating physician.This study was performed in accordance with the Declaration of Helsinki. Given the retrospective nature of the study, a waiver of informed consent from individual patients was granted.Baseline and follow-up data were compiled from medical records of all participating centers, following a uniform protocol that included demographics, clinical presentation, therapeutic management, pathologic features of kidney biopsy specimens, and laboratory parameters that were deemed of interest.,In order to assess reproducibility of biopsy evaluations by pathologists, 22 of the 26 (84.6%) kidney biopsy specimens were centrally assessed at Hospital Universitario 12 de Octubre by an expert pathologist (OT) who was blinded to clinical data. The following pathologic features were recorded by light microscopy: number of glomeruli per biopsy, percentage of glomerulosclerosis, mesangial expansion (graded as none to diffuse), endocapillary proliferation, extracapillary proliferation, focal segmental glomerulosclerosis lesions, interstitial fibrosis and tubular atrophy (graded as none to severe), arterio- and arteriolosclerosis , RBC casts in tubules, and acute tubular necrosis. Except for 1 case, all samples were further evaluated with direct immunofluorescence staining with IgA, IgM, IgG, C3, C4, C1q, Igκ, and Igλ (when available) (graded as 0–3+). In cases where sufficient material was available, an electron microscopy study was also conducted. Furthermore, we applied a chronicity score that has been validated for C3 glomerulopathy.The definition and staging of AKI were described according to the Kidney Disease: Improving Global Outcomes guidelines.The main outcome was to describe pathologic findings in kidney biopsy specimens of patients with clinical suspicion of ARN. Secondary outcomes were to evaluate renal prognosis during follow-up and to analyze histopathologic findings in patients with ARN previously reported by means of a thorough literature review.,,,Given the scarcity of published data regarding biopsy-proven ARN, a thorough review of the literature was conducted to perform a comparative analysis of our data. We searched PubMed, the Cochrane Library, MEDLINE, and reference lists from relevant articles up to and including August 1, 2021. We used the search terms “anticoagulant-related nephropathy,” “warfarin-related nephropathy,” “hematuria and anticoagulant treatment,” “IgA nephropathy and anticoagulation,” OR “acute kidney injury” in combination with the terms “anticoagulation,” OR “anticoagulant therapy,” OR “anticoagulant treatment,” OR “warfarin,” OR “vitamin K antagonists,” OR “novel oral anticoagulants,” OR “hematuria,” OR “gross hematuria,” OR “macrohematuria.” Only English language papers were reviewed. This search revealed 3 case seriesU test was used for comparing medians. P < 0.05 were established as criteria for statistical significance. All statistical tests were 2 sided and performed with Stata software for Windows, version 12.0 .Results are expressed as frequencies and percentages for categorical variables and medians and interquartile ranges (IQRs) for continuous variables. Proportions were compared with the use of the Fisher exact probability test. Mann-Whitney 2 (IQR 49–75) and 1.1 mg/dl (IQR 0.9–1.4), respectively. Of 11 cases with urine sediment available in the previous 6 months before the AKI episode, 8 (72%) already had microhematuria, of whom 6 (54%) presented >20 RBCs per high-power field. VKAs represented the most frequently used anticoagulant agent (92% of the cases) with a median length of anticoagulation therapy of 48 months (IQR 12–89) and a median INR at the time of hospital admission of 2.4 (IQR 1.5–3.4). Clinical presentation was characterized by gross hematuria in 84% of the cases, intense microhematuria in the rest, and all exhibited AKI with a median peak SCr of 6.3 mg/dl (IQR 3.8–9.5). Most patients presented with AKI stage 3 (84.6%), 11.5% with AKI stage 2, 3.8% with AKI stage 1, and 42% required acute dialysis. Additional management included anticoagulation withdrawal in 61% and immunosuppression based on corticosteroids in 73% and mycophenolic acid in 19%. The main clinical and laboratory features of the population are detailed in The study comprised a total of 26 patients with a median age of 75 years (IQR 62–80), 80% male. Most patients (92%) had hypertension, 38% diabetes, and 42% chronic kidney disease (CKD). Baseline median eGFR and SCr were 62 ml/min per 1.73 mAll patients underwent a kidney biopsy as a consequence of the AKI episode, with a median time to kidney biopsy from admission of 14 days (IQR 5–30). Except for 1 case, an underlying nephropathy was found in every sample . IgAN wan = 7) and 19% (n = 5) of the cases, respectively, without detecting light-chain restriction in any case. Only 16 samples were included for electron microscopy, with the most relevant finding being the presence of mesangial deposits in 35% of the specimens.Direct immunofluorescence study was available in 25 of the 26 cases. Positive  IgA staining was observed in 19 samples (73%), most of them 1+ (19%) or 2+ (38%), and C3 staining was positive in 16 specimens (61.5%), predominantly 1+ (46%). Igκ and Igλ were performed in 26.9% (2 (IQR 14–39). At 12 months, 12 (46%) patients had available follow-up data, with a mean SCr of 1.7 mg/dl (IQR 1.3–2.1), mean eGFR of 38 ml/min per 1.73 m2 (IQR 31–49), and 7 remained on dialysis.At 12 weeks after hospital discharge, 6 patients (24%) achieved complete kidney function recovery whereas 19 (76%) did not have recovery, of whom 7 (28%) remained dialysis dependent (missing data in 1 case). New CKD developed in 10 cases, whereas CKD worsened in 9 (of 11) cases with previous CKD . Overall2 (IQR 14–39) and those with non-IgA diseases of 20 ml/min per 1.73 m2 (IQR 4–39). Despite that most patients with previous CKD did not recover, no significant differences were found between the groups based on histologic signs of chronicity, such as glomerulosclerosis, interstitial fibrosis/tubular atrophy, or arterio-arteriolosclerosis ,,,We found 3 case series ,,,To the best of our knowledge, at the present time, only 3 case series  had deterioration in kidney function that could be related to anticoagulation.Traditionally, the diagnosis of ARN can be based on a SCr level increase of ≥0.3 mg/dl in patients with an INR >3 in the previous week, with no other evident cause, even in the absence of a kidney biopsy.,,The pathophysiology of AKI-associated ARN is not completely understood. The absence of retrodiffusion of Tamm-Horsfall protein into the glomeruli does not support a pure obstructive hypothesis secondary to intratubular RBC or hemoglobin casts.,Management of ARN at the present time remains largely supportive. In the aforementioned study in 5/6 nephrectomy rats, treatment with vitamin K prevented AKI and histologic changes associated with warfarin.Considering most cases of ARN have an underlying glomerular disease (mostly IgAN), the use of immunosuppressive drugs may seem appealing. Since most patients in our series were diagnosed with ARN retrospectively, the use of immunosuppressants can be explained by the fact that local practice in some centers includes immunosuppressive therapy for hematuria-related AKI in the context of IgAN;54et al.,,Kidney outcomes of patients with ARN are poor. In the original study of Brodsky ,Data on factors associated to kidney recovery in patients with ARN are scarce. In our case, we did not find significant differences between patients with complete kidney function recovery and those with no recovery. Some studies have described that the presence of atrial fibrillation and higher albumin levels were protective against the development of ARN.The main limitation of our study is its observational and retrospective nature. Nevertheless, the present work represents one of the largest series with detailed histologic description of patients with ARN and a relatively long follow-up period.In summary, ARN is an uncommon clinical entity that should be suspected in patients on anticoagulant therapy or with acute coagulopathy who present with AKI and hematuria. Our findings confirm that subjects with mild or very mild forms of IgAN are at increased risk for the development of ARN and that IgAN represents the most common underlying kidney disease associated to ARN. Nonetheless, it is important to consider that IgAN is the most common primary glomerulonephritis and is typically manifested by hematuria. Hence, ARN may be easier to detect in these cases. Considering the poor renal prognosis, new therapeutic approaches are urgently needed, including preventive strategies in patients with risk factors for developing ARN. Larger observational or prospective studies that include histologic descriptions should be performed to get a better understanding of the true epidemiology of ARN.All the authors declared no competing interests.


Little is known about adult asthma patients' perspective of their disease burden. This study aimed to obtain a comprehensive picture of patient needs, evaluate their knowledge, source of information, and perception of the severity of their asthma, and compare these variables between severe (SA) and non‐severe (NSA) asthma patients.We conducted an online cross‐sectional survey in Spain among asthma patients aged ≥18 years. A bespoke questionnaire was used to collect sociodemographic data, asthma characteristics, treatments, disease burden, patient's perception of disease severity, and asthma information sources. Patients were classified as SA and NSA according to GINA 2020 treatment steps recommendations. To compare populations, 600 participants (200 SA and 400 NSA) were randomly selected to complete the survey.p < 0.001). Fewer asthma exacerbations (SA) and improved quality of life (QoL) (NSA) were the most frequently expected therapy outcomes. NSA patients believe that asthma impacts their daily life (37%) and worsens QoL (34%) to a lesser degree than SA . Patient‐preferred sources of information were specialists  and primary care physicians .Participants were mostly women, mean age >38 years. SA patients underestimated the severity of their asthma; 52% judged it as mild, and only 2% considered their asthma severe. Overall, 50% of NSA and 96% of SA patients had experienced ≥1 exacerbation the previous year (Despite the effective therapies currently available, the results of this study still show a significant emotional burden and QoL impairment in patients with severe asthma. International and national guidelines stipulate goals for optimizing asthma management, such as preventing chronic symptoms, minimizing exacerbations and emergency care, minimizing the use of rescue short‐acting β2‐agonists (SABA), and maintaining regular physical activity.To the best of our knowledge, no survey has previously been conducted in a large sample of persons with asthma in Spain to understand patients' perceptions of the burden of disease according to severity. The aim of this survey was to draw a comprehensive picture of the needs of adult asthma patients in order to identify the factors that patients consider essential for the management of their condition, evaluate their level of knowledge, source of information and perceptions of the severity of their asthma, and compare these variables between severe and non‐severe asthma populations. We also aimed to identify unmet needs to optimize communication between patients and healthcare professionals.22.1A cross‐sectional survey of patients ≥18 years with asthma was conducted between March 4 and March 17, 2020. In order to stratify the target population (patients with severe and non‐severe asthma), 84 976 individuals from the general population of the Ipsos Spain database were randomly invited by email to respond to an initial online questionnaire related to the diagnosis of asthma and treatment. The participants were asked about their diseases in an initial online questionnaire that included asthma as an option. Respondents who self‐reported having asthma were included in the subsequent analyses. Participants were asked to specify which of the following treatments they were receiving at the time of completing the questionnaire: injectables , oral therapies , and inhaled therapies . According to their responses, participants were classified as having SA when they met one of the following criteria: (i) receiving biologics, (ii) receiving high‐dose ICS plus LABA plus LAMA, or (iii) receiving high‐dose ICS plus LABA, with or without a leukotriene receptor antagonist. All other patients were classified as NSA. After targeting populations, the main interview was conducted online using a semi‐structured self‐administered website questionnaire that required an average of 15 min to complete. Adult patients were eligible for the study if they were at least 18 years of age, self‐reported a previous diagnosis of asthma by a doctor, and had the ability to give informed consent. Patients in the Ipsos Spain database represent ~0.18% of the Spanish population, and geographical distribution of participants was representative of the Autonomous Communities.2.2A bespoke questionnaire was developed for the study, which, while not formally validated, was created specifically to address the study objectives. All participants completed the questionnaire in Spanish. This tool consisted of 24 multiple‐choice questions that provided information on the following aspects: patient demographics, their relationship to other prevalent diseases , medical intervention for asthma in the preceding year, incidence of exacerbations , perception of the burden of symptoms and disease severity, social and emotional impact of asthma on everyday life, disease knowledge, preferred medication attributes, satisfaction with current therapies, and preferred source of information.2.3We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting the study's findings.Completed questionnaires were analyzed for the total population and by asthma severity. A sample size of 600 participants was required to obtain a margin of error of 4% and a 95% confidence interval. In order to increase statistical power for the comparative analyses, the participants were randomly chosen from each group to adjust the 1:2 ratio between SA and NSA .t tests were used to compare the means of continuous variables, and chi‐square tests were used to test differences in proportions of categorical variables between groups. All analyses were performed in SPSS v. 25.0.32. A p value <0.05 was considered significant.Descriptive statistics appropriate for the measurement level  were used. Independent Student 2.4This study was conducted in accordance with the confidentiality guidelines set down in the International Chamber of Commerce/European Society for Opinion and Marketing Research (ICC/ESOMAR) and European Pharmaceutical Market Research Association (EphMRA) codes of conduct and conformed to the requirements of Spanish legislation in terms of confidentiality and data protection.2.5The data that support the findings of this study are available from the corresponding author on reasonable request.3p = 0.042). According to the comorbidities that participants were asked if they had at the time of the study, diabetes  and mental disorders  were the most common. All comorbidities were significantly more prevalent in participants with SA (p < 0.05), except stroke and degenerative diseases, for which no significant differences were found. A diagnosis of asthma and chronic obstructive pulmonary disease (COPD) was reported by 1.2% of NSA and 8.0% of SA patients (p < 0.001). Asthma medications taken at the time of the survey are summarized in Table p = 0.003). Significantly more SABA was prescribed in the NSA group . In contrast, 18.8% of NSA and 80.0% of SA patients were prescribed ICS/LABA (p < 0.001).A total of 10 000 respondents completed the initial questionnaire. Of these, 862 (8.6%) were subjects with self‐reported, physician‐diagnosed asthma; 350 (3.1%) were categorized as SA (GINA Steps 4–5), while 512 (5.1%) were categorized as NSA (GINA Steps 1–3). Six hundred participants (200 with SA and 400 with NSA) randomly selected completed the full interview. Baseline demographic and clinical characteristics of participants according to asthma severity are presented in Table 3.1p < 0.001), and the percentage of patients who reported ≥4 exacerbations in the last year was significantly higher for SA patients compared to those with NSA . Hospitalizations were also significantly more frequent in the SA group , and these patients also received systemic steroids during hospitalization more frequently than NSA patients   Figure .3.2p = 0.008). When participants were asked about what improvements they expected from their current treatment, the most frequently mentioned options were to improve QoL (32%) for the NSA group and to reduce asthma exacerbations (37%) for the SA group. Notably, 21% of NSA and 12% of SA patients responded that all expectations had been met   and worsened their QoL (58.5%) significantly more frequently than NSA patients  Figure . There w) Figure  and S2.p < 0.001) .Absenteeism due to asthma was more pronounced in SA patients, who reported having more frequently missed >5 workdays in the last year than NSA patients  Figure . NotablyFigure 3.4Perception and knowledge of other diseases are represented in Figure 3.5p = 0.003); online patient forums of asthma ; Wikipedia ; and social networks  . Notably, 22.5% of NSA and 16.0% of SA patients said that they did not seek additional information on their condition and treatments beyond that received during consultations .Primary care physicians and specialists were the main sources of information about asthma for NSA (82.8%) and SA (71%) patients Figure , and the4This study explores perceptions surrounding asthma and its impact on QoL in a Spanish cohort of asthma patients with severe and non‐severe disease. According to this study, the perception of asthma severity was underestimated by 95% of the SA patients, a result consistent with previous reports.We found that SA patients received more OCS prescriptions and had more exacerbations than NSA patients. This was to be expected considering the GINA 2020 recommendation for prescribing OCS in patients with severe, uncontrolled asthma.Although both groups had a positive attitude to and extensive knowledge of asthma, significantly more patients with SA were concerned about their disease and recognized that asthma has a detrimental effect on their daily life, social integration, and overall QoL. In both groups, patient expectations of asthma management were modest; few participants believed that asthma could be controlled and did not affect their day‐to‐day lives. In addition, SA patients were more worried about the long‐term effects of asthma exacerbations, and they expected that medication would improve this aspect. These attitudes can have a negative impact on patient care and QoL since asthma management practices and the knowledge, attitudes, and behavior of adult asthma patients in the general population are associated with their degree of asthma control.Most participants indicated that they preferred the information that came from healthcare professionals, emphasizing the need for both patients and professionals to have the same perception of asthma severity and control. It has been well documented that both patients and physicians overestimate control, whereas overestimation by patients is greater, particularly in uncontrolled asthma.The strengths of this study include a large sample size and a study design that enables the evaluation of a large sample of patients stratified by asthma severity that were representative of asthma patients in Spain, and similar to a population reported in another comparable study.This study has some limitations. First, survey data were generated by patient self‐assessment and, as such, must be viewed in the context of representing the perceptions of patients, and the outcomes have not been clinically verified. In addition, The GINA 2020 step was used as a proxy to assess asthma severity without considering symptoms and clinical implications, as these may residual confounding elements that can lead to classification bias. As a result, the severity level of some patients may not be adequately defined. The GINA 2020 step was used as a proxy to assess asthma severity without considering symptoms and clinical implications may have resulted in classification bias, therefore constituting residual confounding. An implication of this strategy may be that some patients' severity level was not adequately defined.Another limitation is that it was a cross‐sectional survey and therefore, cause and effect relationships cannot be established. Furthermore, we used a non‐validated questionnaire to assess the impact of the disease and satisfaction with the treatment, while we could have used a validated questionnaire to evaluate disease control. However, none of the validated questionnaire could fully meet all the study objectives.In summary, despite the effective therapies currently available, our results show that asthma still has a significant emotional burden and impairs the QoL of patients with this disease. This is especially true of patients with severe asthma. The impact on daily life, workdays lost, and a considerable number of exacerbations and hospitalizations are indicators that there is still room for a massive improvement in the management of asthma. The survey also gathered a large amount of novel information on patients' attitudes toward asthma. This could be used to analyze patients' behavior and attitudes to improve various sources of information about asthma, such as websites and patient support organizations, that could effectively complement and increase knowledge and skills to help patients collaborate effectively with healthcare professionals in the management of their disease.Eunice Fitas is an employee of AstraZeneca Farmacéutica Spain S.A.All authors contributed equally to this manuscript and were responsible for data analysis and interpretation. All authors drafted the manuscript, provided critical revisions, and approved the final version of the manuscript for submission.The inclusion of cases was carried out in accordance with the requirements expressed in the Declaration of Helsinki  and the Spanish Organic Law on Data Protection 15/1999. The study was approved at San Juan de Alicante University Hospital Ethics Committee.Table S1. Treatment experience and expectationTable S2. Attitude towards asthma, quality of life, and work productivity impactTable S3. Degree of agreement: definitions, uses and attitudes towards asthmaTable S4. Source of information consulted and ranking of preferred source of informationClick here for additional data file.


The pathogenesis of diabetic kidney disease (DKD) is complex and involves both glomerular and tubular dysfunction. A global assessment of kidney function is necessary to stage DKD, a progressive kidney disease that is likely to begin in childhood. The present study evaluated whether kidney injury biomarkers identified as early DKD biomarkers in adults have any prognostic value in the very early stages of childhood diabetes.We measured urine free Retinol-binding protein 4 (UfRBP4), albumin (UAlb), Kidney injury molecule-1 (KIM-1) and the microRNAs miR-155, miR-126 and miR-29b in two cohorts of paediatric T1DM patients without evidence of DKD, but with diabetes of short-duration, ≤ 2.5 years  or of long-duration, ≥ 10 years ; non-diabetic siblings  were recruited as controls. A p value < 0.05 was considered significant for all results.UfRBP4 and UAlb were not significantly different across the three groups. No differences were found in KIM-1 excretion between any of the three groups. UfRBP4 was correlated with UAlb in all three groups , whereas KIM-1 showed no correlation with albumin excretion. Among microRNAs, miR-29b was higher in all diabetic children compared with the H control group (p = 0.03), whereas miR-155 and miR-126 were not significantly different. No differences were found between the SD and LD groups for all three microRNAs. No associations were identified between these biomarkers with sex, age, BMI, eGFR, T1DM duration or glycaemic control.UfRBP4, KIM-1, miR-155, and miR-126 were unaffected by the presence and duration of diabetes, whereas miR-29b showed a modest elevation in diabetics, regardless of duration. These data support the specificity of a panel of urine biomarkers as DKD biomarkers, rather than any relationship to diabetes per se or its duration, and not as early DKD biomarkers in a paediatric setting.The online version contains supplementary material available at 10.1186/s13098-022-00839-4. Although complications such as diabetickKidney disease (DKD) in early onset Type1 diabetes mellitus (T1DM) in children are usually not detected clinically until reaching adulthood, the underlying pathology is likely to begin in childhood. Indeed, structural changes in the kidney have been reported in humans and animal models early in the course of diabetes mellitus (DM) . MoreoveThe need for early and reliable biomarkers of DKD, other than microalbuminuria alone, is increasingly important, not only in screening for DKD and its earlier detection, but also as potential clinical trial endpoints following an intervention. Currently, patients with non-albuminuric DKD are largely excluded from early (Phase 2) clinical trials typically of 6–12 months duration, because albuminuria reduction is still the most widely used surrogate endpoint for new drug treatment in DKD clinical trials .The free form of Retinol-Binding Protein 4 (fRBP4) is a 21 kDa low molecular weight protein (LMWP) recognized as a functional biomarker of the proximal tubule (PT) in the setting of acute and chronic tubular dysfunction . There iKidney injury molecule (KIM)-1 is an immunoglobulin superfamily protein that is markedly upregulated in the proximal tubule of the injured or diseased kidney, and its urinary levels have been reported to be higher earlier in patients with T1DM and progressive DKD , 13. It Urinary microRNAs are another recently explored means of studying the kidney, reflecting structural, functional and pathophysiological pathways along the nephron. Using a profiling approach of 754 microRNAs in pooled urine samples of DKD patients, miR-155, miR-126 and miR-29b were significantly increased and this has been confirmed in an independent cohort of patients with DKD, with DM without DKD, and in controls [In view of the glomerular-tubular interplay in protein handling, the concept of DKD as a glomerulo-tubular disorder, and existing data supporting increased excretion of UfRBP4, KIM-1 and microRNAs in patients with longstanding DM, we designed the present study to explore several potential kidney injury biomarkers in children and young adults with different durations of T1DM.Our principal aim was to determine whether a panel of biomarkers that includes UfRBP4 (glomerular and tubular disfunction), KIM-1 (an early and widely recognized marker of tubular injury and DKD progression) and the three microRNAs, miR-155, miR-126 and miR-29b, might prove useful early renal biomarkers in a normoalbuminuric cohort of young diabetic patients, and if there is any correlate with diabetic control and disease duration.All subjects were recruited from the T1DM Outpatient Clinic at the Paediatric Service of Azienda Socio-Sanitaria Territoriale (ASST) Spedali Civili di Brescia. Healthy controls were siblings of the diabetic patients in the clinic. Recruitment began in July 2017 and was completed in June 2018. Specimens preserved on dry ice were sent to the Core Biochemical Assay Laboratory (CBAL) of Cambridge University Hospitals NHS Foundation Trust, UK to measure UfRBP4, Ualb and KIM-1 and to the Wales Kidney Research Unit  to measure microRNAs., albuminuria  [, congenital anomalies of the kidney and urinary tract (CAKUT), chronic hypertension, inflammatory or neoplastic diseases, liver disease, recurrent urinary tract infection, presence of Type 2 DM, age < 6 months and > 19 years. Autoimmune thyroiditis or celiac disease were not exclusion criteria.Inclusion criteria for Short Duration (SD) T1DM patients were onset of T1DM ≤ 2.5 years; for the Long Duration (LD) T1DM group onset of T1DM ≥ 10 years. The SD group was selected to detect any very early change in urine biomarkers excretion as according to current guidelines, the screening for DKD in T1DM begins only after 5 years from diagnosis . The cutmg/mmol) , persistUrine for routine analysis was collected as a midstream second void in the morning and sent immediately to the local clinical biochemistry laboratory. Urine for measurement of Urine free Retinol-Binding Protein 4 (UfRBP4), urinary albumin , KIM-1 and microRNAs was put on wet ice immediately and frozen at −80 °C within one hour. Diabetic patients were also tested for asymptomatic urinary tract infection by urine routine culture. Pre-analytical procedures were carried out with standardized protocols for all patients. This is crucial, especially considering the sensitivity of proteins to degradation and the unfavourable milieu of urine as a source of biological material. RBP in urine samples is unaffected by freezing at −70 °C for short-term storage  and KIM-For diabetic patients, after an overnight fast, measurements included glycated haemoglobin, blood glucose, triglycerides, total cholesterol, high density lipoprotein, antithyroid antibodies, anti-transglutaminase antibodies, thyroid-stimulating hormone, serum creatinine, urate, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase.Except for three patients, urine and blood tests were collected on the same day. Any potential confounders, such as fever, severe exercise and vaccinations were avoided during the three days before collection.Serum creatinine was not measured in healthy controls because of ethical restrictions for venepuncture in healthy children.2). We used an online calculator that provides BMI, percentile and z-score [BMI was calculated as weight (Kg) divided by height squared (m z-score  BMI was  z-score . Blood pGuidelines from the American Diabetes Association (ADA) and the International Society for Paediatric and Adolescent Diabetes (ISPAD) specify a patient target of HbA1c < 59 mmol/mol and such patients are considered to have good glycaemic control .T1DM-related complications were defined as any acute complications requiring admission to hospital.The threshold for defining hyperfiltration is challenging and a generally accepted definition is lacking. Some authors report thresholds corresponding to a GFR that exceeds two standard deviations above the mean GFR in healthy individuals. Notably, the use of any GFR cut off does not consider differences between genders, ethnicity, nephron endowment at birth and age . The Sch® RxL enzymatic creatinine assay. Two minor modifications were made to the original UfRBP4 assay to improve assay performance at low analyte concentrations: sample pre-dilution was one in two instead of one in five and an additional low standard was added to the standard curve. The lower limit of detection (corrected for dilution) of UfRBP4 in the original urine was 1.0 µg/L. KIM-1 was measured by Quantikine™ Elisa . MicroRNA analysis proceeded according to our previously developed protocol [Caenorhabditis elegans miR-39  was spiked into each sample to act as an internal control. Reverse transcription (RT) was carried out using the High-Capacity cDNA RT Kit  before quantification of specific microRNAs using TaqMan microRNA assays (Life Technologies).Urine creatinine was measured by the Siemens Dimensionprotocol  RNA was . Statistical analyses were conducted with GraphPad Prism® 8 and STATA®. For microRNAs, analysis was carried out in GraphPad Prism® six by unpaired t-test with Welch’s correction. Data were normalized to endogenous control miR-191 and are presented as mean ± SEM. A two-tailed p-value < 0.05 was considered significant for all studies. The present study represents a pilot study and as the expected small effect size, the aim of the study was to recruit at least 25 subjects each group [Continuous variables with a normal distribution were expressed as mean ± standard deviation (SD); variables with a non-normal distribution as median and interquartile range (quartile 1 and quartile 3). To test for normality, we used the D'Agostino-Pearson Test. ANOVA, Unpaired Student t test, Wilcoxon rank-sum and Mann–Whitney tests were used as appropriate for comparison of continuous variables, and the Chi-squared test was used for comparison of categorical variables. Pearson and Spearman’s correlation analysis was used to detect correlation. Multivariable logistic regression analyses were performed to test the independent strengths of associationsch group .Over one year, 93 subjects were screened for the study, of whom 80 were recruited and included in the final analysis. Thirteen patients were excluded as they met one or more exclusion criteria. The distribution of the patients across the three groups and the exclusion criteria for each patient are shown in Fig. Baseline demographic and clinical features of the subjects are shown in Table The first aim of the study was to establish whether a functional tubular biomarker such as UfRBP4 and a tubular injury biomarker such as KIM-1 were significantly different between patients with a short duration of T1DM and healthy participants without DM, and between short and long duration T1DM patients. We found that both biomarkers were not significantly different across all paediatric groups Table ; Fig. 2.On average, all three groups had normal and not significantly different Ualb. Among microRNAs, miR-29b was higher in diabetic children overall compared with healthy controls p = 0.03), whereas miR-155 and miR-126 were not significantly different  cohort, UfRBP4 was not different from age-matched healthy controls (H) or from children with longer duration (LD) diabetes. The process underlying increased urinary excretion of fRBP4 appears relatively late in the course of T1DM, with studies of URBP4 indicating that increases in this protein are relatively common in late stage T1 and T2DM in adults , 21, 25.eability . The cliKIM-1 is a non-invasive kidney biomarker that has shown reliable performance in identifying children with chronic kidney disease at risk of progression . In T1DMmilieu in which many proteins undergo degradation. MicroRNAs in body fluids may be evaluated in total or following subfractionation, for example of exosomes and other microvesicles. Our previous work has demonstrated that in urine, microRNAs are stabilised by presence in microvesicles and also by association with RNA binding proteins, including Ago proteins, while non-protected microRNAs are rapidly degraded [We also explored the expression of three different microRNAs reported previously to show a microRNA signature associated with DKD . One of degraded . Future degraded . miR-155degraded , 35.A surprising finding was the lack of any increase in biomarkers in the LD group. The absence of any difference between LD and healthy controls suggests that our negative findings indicate the absence of nephropathy in this group of young T1DM patients, regardless of the duration of diabetes. The susceptibility to DKD reflects genetically and epigenetically determined differences in the kidney response to metabolic and autoimmune disease  that areOur study has two main limitations. We could not evaluate routine blood chemistry in healthy children because of ethical restrictions. Moreover, the controls were all siblings of patients with T1DM and their lifetime risk of developing DM is known to be increased relative to the general population . HoweverThe current literature describes very few studies evaluating a panel of urinary biomarkers in diabetic children and adolescents, and none has recruited patients with T1DM of short duration to compare with those of longer duration. Study of T1DM does make interpretation of our results easier, because of the known time of onset of diabetes and the absence of any potentially confounding co-morbidities in otherwise healthy children, in contrast with T2DM.Taken together, UfRBP4, KIM-1, miR-155 and miR-126 were not increased in young T1DM patients with normal renal function and no urinary albumin excretion. These biomarkers have been reported to be elevated in cohorts with established DKD, mainly in adults, in other studies; however, we have not found them to be increased in carefully phenotyped children, adolescents and young adults with T1DM, and they are unlikely to be of added value in screening for early DKD in the absence of albuminuria.A panel of biomarkers, including functional and structural biomarkers such as UfRBP4 and KIM-1, and three tested microRNAs linked previously to DKD in an adult setting showed no differences in children, adolescents, and young adults with different durations of T1DM and without other evidence of nephropathy. These findings support the specificity of the biomarkers tested for those diabetics with nephropathy. Further studies are required to determine whether very early nephropathy is discernible using these biomarkers. Our findings also suggest that children with T1DM today have a more favourable renal outlook, probably the result of improvements in early diagnosis and routine clinical care.Additional file 1: TableS1 Baseline features of continuous variables of the study population. Table S2 Baseline biochemical and metabolic parameters of the diabetic population. Table S3 Bivariate correlations of several variables in the study population. Fig.S1 Relationship between KIM-1 with UfRBP4 and Ualb across all study groups. KIM-1: Kidney injury molecule 1 (ng/mL); UfRBP4: urine free retinol-binding protein 4 (ug/mmol); Ualb: urinary albumin expressed as albumin to creatinine ratio (mg/mmol).


This pilot study was conducted to investigate changes in the pulse rate and blood pressure in healthy volunteers after applying auricular acupressure at the “heart acupoint.”  A total of 120 healthy volunteers with hemodynamic indexes within normal limits were randomly allocated into 4 groups to receive auricular acupressure treatment either at the heart acupoint of the left or the right, or in both ears, and one control group without applying auricular acupressure. p < 0.05); however, pulse rate increments during the two cold pressor tests (with and without auricular acupressure) were similar (p > 0.05).  Before the application of auricular acupressure, there were no statistical differences in pulse rate and blood pressure increments among the four groups during the first cold pressor test. In groups in which auricular pressure was applied, the pulse rate was significantly reduced after the application of auricular acupressure in three groups; however, no statistically significant difference was detected among the groups. Changes in blood pressure were not statistically significant in or among the different groups after applying auricular acupressure. The average recorded pulse rate values during the second cold pressor test (after auricular acupressure) were significantly lower compared to the corresponding values taken during the first cold pressor test (before auricular acupressure) ( These findings suggest that auricular acupressure could be used as an adjunctive nonpharmacological method for reducing the pulse rate. The preart rate . More reart rate .Several reports have described the role of auricular acupuncture, which uses needles to stimulate acupuncture points (acupoints) in specific zones of the ear, in inducing vagal tone as a counteractive measure to ameliorate patients' physical, emotional, and neurological symptoms and signs –9. It waAuricular acupressure (AA) is a noninvasive form of auricular acupuncture, which uses physical pressure applied to acupoints by Vaccaria seeds . There iThe cold pressor test (CPT) was developed as a safe method to induce experimental sinus tachycardia and blood pressure acceleration by increasing the sympathetic tone .By using CPT, we aimed to make the volunteer's heart rate  and blood pressure increased to examine the AA's effectiveness. This study was designed to investigate changes in pulse rate and blood pressure in healthy volunteers after applying AA either at the “heart acupoint” of the left or the right, or in both ears while using CPT. Furthermore, we aimed to compare the resulting changes in pulse rate and blood pressure across three groups as well as investigating possible side effects of both CPT and AA.The study time was from December, 2017, to June, 2018.This study was designed as a pilot study in which 120 healthy volunteers were recruited by the research team at the Faculty of Traditional Medicine, University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam. The study protocol and Institutional Review Board (IRB) documents were submitted to the ethical committees in the designated medical center for approval.n=2xCx(1 − r)/ES2.The sample size was calculated according to the formula n is the number of sample sizes needed for the study; r is the correlation coefficient between the two measurements. ES is the influence coefficient estimated by the formula: ES = d/s. d and s are the average and standard deviation of pulse rate when conducting CPT, respectively. According to Saab et al., the mean standard deviation of heart rate when doing CPT in the feet is 13.2 beats/minute [n = 29.30. So, the sample size for each group is 30 and the total sample of the study is 120.s/minute . With thFollowing the signing of written informed consent, participants were randomly allocated into 4 groups (30 people in each group) using GraphPad software to receive AA treatment either at the heart acupoint of the left (1), the right (2), both ears (3), and one control group without AA application (0). They were then monitored to determine the efficacy of the given treatment.2, pulse rate ranging between 60 and 99 beats per minute (bpm), supine arterial pressures of less than 140/90 mmHg, not suffering from any medical conditions and willing to consent to the study terms and protocol. They were also committed to come on the study day devoid of drugs, smoking, and caffeine as well as stress . Exclusion criteria included volunteers who were outside of the age range, suffered from acute diseases, using stimulants  within 24 hours before the study, exercising immediately before the study, or taking medications affecting pulse rate and blood pressure within the previous month. Also, pregnant or menstruating females were excluded.Participants were individuals aged between 18 and 30 years, with a body mass index (BMI) of 18 to 23 kg/mWe selected heart acupoints (CO15), located in the middle of the ear cavity, as suggested in the nomenclature and location of auricular points . IrrespeParticipants had to immerse their feet in cold water (7°C) for 3 minutes under supervision . The watThe study was carried out in a quiet room with an air temperature of 26°C. The volunteers lied comfortably in a semi-recumbent position. After a 10-minute rest, baseline values of the pulse rate (PR) and blood pressure (BP) (systolic and diastolic) were taken (T10). At T25, the first CPT (CPT1) was started. PR was recorded continuously over 6 minutes from T25 to T31 (3 minutes during CPT and 3 minutes after CPT has ended) using an oximeter  in the right hand. Simultaneously, BP was measured twice at the beginning and at the end of CPT (T25 and T28), using a digital blood pressure monitor  in the left hand. After the second period of rest (between T31 and T43), AA was started at T43 and lasted for 17 minutes (till T60). The practitioner stimulated the heart acupoint every 5 minutes . PR was measured before and after each stimulation, and BP was measured before the beginning of AA (at T42) and at its end (at T59). Then, the second CPT (CPT2) started, and the PR was continuously recorded over 6 minutes from T60 to T66 (3 minutes during the CPT and 3 minutes after its end). BP was measured twice; at the beginning and at the end . The study protocol is shown in t-test or ANOVA test was used to compare changes in age, PR, and systolic and diastolic BPs within and among four designated groups at certain time points , and a chi-squared test was used to check the compare the gender variables among the four groups. Additionally, a mixed-effects model for time series was used to compare PR increments between two intervals of CPT. For all the above statistical tests, a p value of less than 0.05 was considered statistically significant. All data were transferred to the blinded analyst.The analysis of the data was performed by using STATA 13 software. A dependent There was no patient involved. Ethical approval for this study was obtained from the Board of Ethics in Biomedical Research of the University of Medicine and Pharmacy in Ho Chi Minh city.There were no participants who discontinued or were excluded from the trial. It took 68 consecutive minutes to finish the trial for one person. Data collection time was 50 days.p > 0.05, ANOVA test) and the DBP was significantly different across the four designated study groups . More specifically, the basal DBP in group 0 was significantly higher when compared to group 1 .p > 0.05, t-test), except for group 0 where PR at T25 was higher compared to basal PR. p < 0.05, t-test). Over the consecutive time intervals after the 210th second, changes in the recorded average PR from baseline values were not statistically significant . It was also noticed that from T25 to T31, differences in the average PR values recorded for each time interval relative to baseline were not statistically significant among the 4 participating study groups . Based on the results of the mixed-effects model, PR increments among the 4 groups were similar . After the end of the CPT1, the PR of groups 2 and 0 returned to normal at T28.5 (30 seconds later) , meanwhile PR of groups 1 and 3 became normal at T29 (60 seconds later).During CPT1, it was observed that the difference in PR at T10  and T25 (starting CPT1) was not statistically significant among groups . p < 0.05, t-test). In detail, in group 1, PR at T60  was lower than T43a  . Similarly, in group 2, PR at T60  was lower than T43a  , and in group 3, PR at T60  was lower than that at T43a  . Also, when comparing PR before each manipulation to the basal PR (T10), except for group 1, the PR was found to be significantly less than that before the second manipulation .p < 0.05, t-test), except for group 0 . As for the in-between group differences  in the recorded average PR values across every time point from T60 to T66, results showed that those differences were not statistically significant . Based on the results of the mixed-effects model, PR increments among the 4 groups were similar .p < 0.05, t-test), and then returned to normal at T42 before the AA stage beginning . However, when comparing changes in SBP and DBP among groups at corresponding time intervals, the results were not statistically significant .Tables p > 0.05, t-test, and ANOVA test).When comparing SBP and DBP measured at the time before (T42) and after (T59) the AA stage in each group as well as comparing differences among groups, the results were not statistically significant .When compared, the recorded average SBP and DBP between CPT1 (T25–T28) and CPT2 (T60–T63) within each group as well as among groups showed no statistically significant differences  = 86%; p = 0.005), systolic blood pressure , and diastolic blood pressure  = 61%; p = 0.04) using TENS of various frequencies [p < 0.001) with milder reductions occurring after using other areas and using the manual method of auricular stimulation as compared to the electroacupuncture [β fibers , myelinated Aδ fibers , and non-myelinated C fibers. The recruitment of different fiber types depends on the threshold stimulus that is determined by the total charge delivered to the nerve fiber [In comparing PR and BP changes before and after acupressure, it was noted that although SBP and DBP did not differ significantly before and after AA, every manipulation to the heart acupoint significantly reduced the post-manipulation PR in comparison to its pre-manipulation value. Moreover, the end-point PR was significantly lower than the starting PR at the beginning of the AA stage. Results pertinent to a decrease in PR were similar to those obtained by Gao et al. who investigated the effect of manual and vibratory ear stimulation on heart rate as well as other parameters in a cohort of 14 healthy volunteers of comparable anthropometric characteristics . In contquencies . Moreoveve fiber , 23. TheWith respect to comparing changes in PR and BP among the participating study groups , we found no significant differences in the abovementioned cardiovascular outcomes, implying that there was no difference in the desired outcomes no matter what the site of auricular stimulation was . Unfortunately, that was not the case in previous literature comparing the above outcomes according to the laterality of stimulation in the animal as well as human models , 24. StrAlthough the PR and BP increments of the two times CPT were similar, the PR values during the CPT2 (after auricular acupressure) were significantly lower as compared to the corresponding values taken during the CPT1 (before auricular acupressure), which has an important role in preventing excessive hemodynamic parameters when encountering acute stress. This phenomenon can be explained in terms of the fact that parasympathetic stimulation overrides the sympathetic one, a fact that has been proven to be extremely beneficial in cardiac failure patients due to their autonomic imbalance that would increase their risk of mortality , 27. SidThis is one of the first trials in comparing effects on hemodynamic indexes of auricular acupressure at heart acupoint of the left, right, and both ears. Our research has a number of limitations: we only recorded the PR every 30 seconds, so we could not find exactly when the PR returned to normal. SBP and DBP were only measured two times (at the beginning and end of the CPT). Future studies are suggested to continuously monitor these parameters.In conclusion, using the pilot study design, auricular acupressure did not affect PR increment in the CPT2, but it reduced PR values during the CPT2 (after auricular acupressure) when compared to the corresponding values taken during the CPT1 (before auricular acupressure). In groups in which AA was applied, every time the heart acupoint was manipulated, the PR was significantly reduced. Besides, auricular acupressure did not affect BP and there were no side effects were recorded when conducting auricular acupressure as well as CPT. Our study is among the pioneering research in comparing effects on hemodynamic indexes of auricular acupressure at the heart acupoint of the left, right, and both ears.


Conclusions: In hospitalized chronic heart failure patients with implantable cardioverter-defibrillators, the hypertension status and higher systolic blood pressure measurements are independently associated with a lower risk of combined endpoints of ventricular arrhythmia and sudden cardiac death but not with all-cause mortality. Randomized controlled trials are needed to confirm the protective effect of hypertension on ventricular arrhythmia in chronic heart failure patients.Aims: Low blood pressure (BP) has been shown to be associated with increased mortality in patients with chronic heart failure. This study was designed to evaluate the relationships between diagnosed hypertension and the risk of ventricular arrhythmia (VA) and all-cause death in chronic heart failure (CHF) patients with implantable cardioverter-defibrillators (ICD), including those with preserved left ventricular ejection fraction (HFpEF) and indication for ICD secondary prevention. We hypothesized that a stable hypertension status, along with an increasing BP level, is associated with a reduction in the risk of VA in this population, thereby limiting ICD efficacy. Methods: We retrospectively enrolled 964 CHF patients, with hypertension diagnosis and hospitalized BP measurements obtained before ICD implantation. The primary outcome measure was defined as the composite of SCD, appropriate ICD therapy, and sustained VT. The secondary endpoint was time to death or heart transplantation (HTx). We performed multivariable Cox proportional hazard regression and entropy balancing to calculate weights to control for baseline imbalances with or without hypertension. The Fine–Gray subdistribution hazard model was used to confirm the results. The effect of random BP measurements on the primary outcome was illustrated in the Cox model with inverse probability weighting. Results: The 964 patients had a mean (SD) age of 58.9 (13.1) years; 762 (79.0%) were men. During the interrogation follow-up [median 2.81 years (interquartile range: 1.32–5.27 years)], 380 patients (39.4%) reached the primary outcome. A total of 244 (45.2%) VA events in non-hypertension patients and 136 (32.1%) in hypertension patients were observed. A total of 202 (21.0%) patients died, and 31 (3.2%) patients underwent heart transplantation  during a median survival follow-up of 4.5 (IQR 2.8–6.8) years. A lower cumulative incidence of VA events was observed in hypertension patients in the initial unadjusted Kaplan–Meier time-to-event analysis . The protective effect was robust after entropy balancing  and counting death as a competing risk . Hypertension diagnosis did not associate with all-cause mortality in this population. Random systolic blood pressure was negatively associated with VA outcomes ( Chronic heart failure (CHF) is a common final stage of heart disease and represents a major cause of death and disability worldwide  and addiHowever, contrary to the well-established linear association between elevated BP and cardiovascular events in the general population , the assAlthough death in patients with CHF is usually because of underlying cardiac disease, the cause-specific mechanisms could be split between sudden cardiac death (SCD) from arrhythmic events and non-sudden cardiac death (NSCD) because of pump failure . To prevTherefore, the present study aimed to comprehensively evaluate the association of hypertension and blood pressure measurements on ventricular arrhythmic events in a real-world cohort of CHF patients with different functional statuses. We raise the following hypothesis that diagnosed hypertension and easily accessible BP measurements could help identify SCD high-risk populations who are eligible for a primary-prevention ICD.n = 3), (2) without any interrogation follow-up beyond six months (n = 42), and (3) missing data on blood pressure and other significant variables (n = 13). Finally, 964 patients were included  (170–210 bpm) and ventricular fibrillation (>210 bpm). Supraventricular tachycardia discrimination algorithms were programmed for the VT zone. In all ICD patients, shock and anti-tachycardia pacing (ATP) during charging when possible were programmed in the ventricular fibrillation zone. The decision on programming ICD therapies in the fast VT zone was left to the discretion of the physician, which was primarily bursts of ATP followed by high-voltage shock(s) if ATP was unsuccessful.Clinical evaluation was performed before device implantation. The follow-up period started on day 1 after ICD implantation. Device interrogation including a review of the stored intracardiac electrograms was performed 3 months post-implantation and every 6–12 months thereafter. ATP and shocks were considered appropriate if the preceding rhythm was ventricular tachycardia or ventricular fibrillation (VT/VF). The primary outcome measure was defined as the composite of SCD, appropriate ICD therapy, and sustained VT. Sudden cardiac death was defined as unexpected death within 60 min of the onset of cardiac symptoms without prior cardiac deterioration, during sleep, or within ≤24 h of last being seen alive and clinically stable . Board-ct-test for normally distributed continuous variables, Kruskal–Wallis test for non-normally distributed continuous variables, and χ2 test for categorical variables.Continuous data are expressed as mean ± standard deviation or the median with the interquartile range (IQR) as appropriate; categorical data are presented as frequencies with percentages. Hypertension is defined as office SBP values ≥ 140 mmHg and/or DBP values ≥ 90 mmHg following repeated examination, and is classified as Grade 1 (SBP 140–159 mmHg and/or DBP 90–99 mmHg), Grade 2 (SBP 160–179 mmHg and/or DBP 100–109 mmHg), or Grade 3 (SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg) , 380 patients (39.4%) reached the primary outcome, 373 of whom had VT and ICD therapy and 7 (0.7%) of whom had SCD. A total of 244 (45.2%) VA events in non-hypertension patients and 136 (32.1%) in hypertension patients were observed. In the unadjusted Kaplan–Meier time-to-event curves, hypertension patients had a lower cumulative incidence of primary endpoints than non-hypertension patients  [hazard In the multivariable analysis with inverse probability weighting according to the propensity score, there was still a significant association between hypertension diagnosis and the composite primary endpoint  years, 202 (21.0%) patients died, and 31 (3.2%) patients underwent heart transplantation . The same set of analyses of the primary outcome was applied. No significant difference in all-cause mortality could be found in chronic heart failure patients with or without hypertension B.p > 0.10, p = 0.065). For DBP, a significant nonlinearity was found in the weighted cohort, with the highest risk of primary endpoint reached at around 70 mmHg , left atrial enlargement, diastolic dysfunction, functional mitral regurgitation, and neurohormonal changes, in which LVH has a well-established relationship with SCD ,29. LargIn addition, a higher proportion of pre-weighted patients with hypertension were receiving ACEI/ARB and CCB , which may have contributed to better-controlled reflex neurohormonal activation, and therefore better outcomes. Although entropy balancing achieved substantial between–group balance in all measured confounders, imbalances in their severity may remain and persist during follow-up. Furthermore, imbalances in unmeasured confounders may also, in part, explain the observed better outcomes in the hypertension group.p for interaction = 0.004), which is in accordance with the previous study [In the subgroup analysis, it is interesting to find that hypertension reduced the VA risk more evidently in ICM patients rather than in NICM  are adjusted for propensity scores, and those on the right panel (B) are inverse probability-weighted on 46 baseline characteristics.p for linear = 0.065). What surprised us is that DBP could demonstrate a possible converse U-shape association with VA (p for nonlinear = 0.004). We suspected that potential overfitting may exist when most single DBP measurements cluster around the median. Also, we can draw robust conclusions when dividing those diagnosed with hypertension into daily controlled or uncontrolled (random SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) groups  but not diastolic (DBP) was shown to directly correlate with the risk of cardiovascular disease. This phenomenon was also observed in our multiple sensitivity analysis, in which SBP showed a negative linear association with VA outcomes  groups . All theOverall, our analysis comprises a relatively long timeframe with a large number of patients in a real-world setting and reflects contemporary therapy. It is distinguished by the use of inverse probability weighting and entropy balancing to assemble a balanced cohort, the use of subgroup analyses to demonstrate homogeneity, and the use of multiple sensitivity analyses by diversified statistical models and grouping adjustments to assess bias. Thus, our findings may suggest that comorbid hypertension, along with elevated SBP, should be taken into account for improving risk stratification, as they are at a significantly lower risk for VA. Perhaps in those patients, the benefits of primary defibrillator implantation are more limited.However, several limitations are worth noting. First, to account for SCA events in subjects with an ICD, we included ICD discharges for ventricular fibrillation or fast ventricular tachycardia (>170 bpm). A more restrictive threshold would decrease the frequency of arrhythmic events  and could alter the results of this analysis. In addition, the lack of longitudinal measurements of blood pressure could underestimate its prognostic role in predicting outcomes. In other words, longitudinal measurements of blood pressure and electrophysiological properties are needed to investigate their relationship, both before the onset and during the worsening of heart failure.In hospitalized chronic heart failure patients with implantable cardioverter-defibrillators, hypertension status and higher systolic blood pressure measurements are independently associated with a lower risk of combined endpoints of ventricular arrhythmia and sudden cardiac death, but not of all-cause mortality. This may be useful for identifying lower-risk patients, in whom the benefits of primary defibrillator implantation are more limited.