Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors’ sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved.Methods: We measured peripheral chemoreceptors’ sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors’ sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478.Results: Ticagrelor significantly increased both HVR  and HCVR . The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR  and HCVR . Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation.Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated. Ticagrelor is one of the first-line antiplatelet agents prescribed following acute coronary syndrome (ACS) . The effDyspnea, the most common side effect of ticagrelor, was present in up to 38.6% of individuals enrolled in several clinical studies . While tIt is well-established that ticagrelor-induced dyspnea 1) is not the consequence of pulmonary dysfunction , 2) is dTwo hypothetical mechanisms have been proposed as the explanation of ticagrelor-related dyspnea. Cattaneo et al. suggested that the local adenosine accumulation and/or cumulation of intracellular cAMP may lead to afferent pulmonary parasympathetic C-fiber activation and, as a result, to dyspnea sensation . Another2 and increase in H+ or CO2 arterial blood concentrations. Otherwise, CCh are responsive to an increase in H+ or CO2 within cerebrospinal fluid  in the bifurcation of common carotid arteries (carotid bodies) and along the aorta and its main branches (aortic bodies)—these are known as arterial or peripheral chemoreceptors (PCh) ; 2) in tal fluid . Stimulaal fluid . Moreoveal fluid .12 receptors are present in mammalian chemosensory cells (glomus cells) and that activation of these receptors inhibits hypoxia-induced response  in humans . It has response . Thus, bs’ level , leading12 adenosine receptor inhibitors on PCh or CCh has not been studied so far. We hypothesize that these pharmacological agents, particularly ticagrelor, may increase the sensitivity of chemoreceptors. PCh would be primarily affected since ticagrelor does not cross the blood–brain barrier  and was performed in accordance with the latest review of the Helsinki Declaration. All subjects gave informed written consent. The study is registered at 12 inhibitor-naïve patients who were planned to be administered clopidogrel in the peri-PCI period. Eleven patients from the first group constituted the ticagrelor group. These subjects were age-, BMI-, and gender-matched with 11 individuals from the second group (clopidogrel group).Patients suffering from chronic coronary artery disease referred to the Cardiology Department of University Hospital in Wroclaw for elective percutaneous coronary intervention (PCI) were prospectively screened to find two clinical scenarios: 1) patients taking clopidogrel in the peri-PCI period and planned to be switched to ticagrelor following the PCI, due to the complexity of the procedure ; 2) P2Y12 inhibitors, were altered during the study timeframe  clinical assessment (laboratory testing and transthoracic echocardiography), 2) dyspnea assessment (questionnaire), 3) evaluation of baseline hemodynamic and ventilatory parameters, 4) measurement of the sensitivity of PCh, and 5) measurement of the sensitivity of CCh. The clinical assessment took place during the hospitalization scheduled for PCI. Procedures 2–5 were performed during a 2-hour-long session, with an approximately 30-min break between PCh and CCh sensitivity testing. The procedures were performed twice: 1) prior to the switch from clopidogrel to ticagrelor and 4 ± 1 weeks later in the ticagrelor group and 2) before clopidogrel loading dose and 4 ± 1 weeks later in the clopidogrel group. Study participants were asked to avoid caffeine intake or nicotine on the day of testing and to take the P2Y12 inhibitor approximately 4 h prior to the second session. The latter was based on the pharmacokinetics of ticagrelor, clopidogrel, and their active metabolites . Further−1 flowhead  to a differential pressure transducer  was used for the measurement of minute ventilation (VI). Hemodynamic parameters were monitored non-invasively, in a beat-by-beat manner, using a Nexfin device  and included heart rate (HR), systolic arterial blood pressure (SBP), and diastolic blood pressure (DBP). Blood oxygen saturation (SpO2) was evaluated using a pulse oximeter  with an ear clip, and the recording was shifted backward by 15 s to compensate for the circulatory delay. All data were collected using PowerLab 16/30  and recorded on a laptop .Subjects were examined in a quiet room with a stable temperature of 22 °C in the supine position. After being attached to the study equipment via a silicone mask covering the mouth and nose , patients were allowed to rest for 5 to 10 min to get familiarized with the research environment. After this period, baseline values were averaged from the 5 min of the recording preceding PCh sensitivity testing. A one-way open breathing circuit  with an inspiratory arm connected to a high-pressure electric valve, which allowed silent switching between 100% nitrogen and room air, and the expiratory arm connected via a 1000 L min−1 %−1] , as a measure of PCh sensitivity [L min−1 %−1] . Subject2. The slope of the linear regression, including the baseline data, was calculated similarly to the HVR calculation for HR–heart rate response to hypoxia (HRR [bpm %−1]) and SBP–systolic blood pressure response to hypoxia (SBPR [mmHg %−1])  . In two −1 mmHg−1]  was monitored with a CO2 analyzer attached to the silicone mask . The test started with a 5-minute-long resting phase when subjects were breathing in room air for familiarization with the study equipment, followed by a rebreathing phase. During the test, VI and ETCO2 were measured breath-by-breath until the patient signaled breathlessness or ETCO2 exceeded 70 mmHg. Mean EtCO2 levels at the beginning of rebreathing phase were as follows: 38.3 ± 4 vs. 37.7 ± 3.5 mmHg and 39.1 ± 4.3 vs. 37.3 ± 4.4 mmHg for ticagrelor vs. clopidogrel and before/after drug initiation, respectively; all p = NS. Due to the hyperoxic nature of HCVR testing, mean SpO2 during the rebreathing phase was 100% for all groups and time points. An inflection point was identified by visual inspection of the chart relating VI to ETCO2, and the HCVR was calculated as a slope of the data past this point (Read’s rebreathing technique—hypercapnic hyperoxic ventilatory response (HCVR)—was employed to calculate CCh sensitivity [L min mmHg−1] . Subjectis point . Data we12 inhibitor initiation, independence of exertion, lack of any clinical signs, and symptoms suggestive of other known pathology causing new onset dyspnea. This definition was in line with that of previous studies on the subject  visual–analog scales assessing the presence and the severity of rest and exertional dyspnea; 2) six multiple choice questions allowing for the characterization of the dyspnea sensation: the frequency, duration, timing, onset, course, and accompanying symptoms of the episodes  in HRR; all other variables were non-normally distributed. The unpaired Student’s t-test or Mann–Whitney U test was used where appropriate to assess the differences between studied groups. The significance of changes in measured parameters following P2Y12 inhibitor initiation within studied populations was evaluated using the paired Student’s t-test and the Wilcoxon paired data test. The differences in categorical data were assessed using Fisher’s exact test. The correlations between variables were assessed with Pearson correlation coefficient, followed by visual graph evaluation for potential non-linear relationships. Data are presented as mean and standard deviation (SD). A p-value < 0.05 was considered statistically significant.Statistica 13 (StatSoft Inc.), LabChart 8 (ADInstruments), and MATLAB (MathWorks) were employed to analyze the data. The distribution of the variables was tested using Shapiro–Wilk’s W test. Normal distribution was found for HCVR, age, BMI, glomerular filtration rate (GFR), HR, SBP, DBP, VI, SpOp = NS). Furthermore, baseline HVR, SBPR, HRR, and HCVR before switch from clopidogrel to ticagrelor in the ticagrelor group and before initiation of clopidogrel in P2Y12 naïve individuals in the clopidogrel group, , SBPR , HRR , and HCVR . The mean absolute change from the baseline (delta) in chemosensitivities and the comparison of post-drug changes between study groups are presented in Clopidogrel administration did not significantly influence any of the measured parameters, including HVR , SBPR , and HCVR , but did not influence HRR . The mean absolute change from the baseline (delta) in chemosensitivities and the comparison of post-drug changes between study groups are presented in Ticagrelor significantly increased HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L minp < 0.01)—p = NS). There were no relationships between the values of baseline HVR or baseline HCVR and the change in HVR or HCVR .The absolute change in the HVR correlated with the absolute change in the HCVR in the ticagrelor group  reported dyspnea prior to the study intervention. In seven of eight patients (four in the clopidogrel group and three in the ticagrelor group), the sensation was moderate to severe (5.7 ± 3.2/10) and was provoked mainly by physical exertion. During the follow-up visit, after the PCI, those subjects declared alleviation of dyspnea. In those patients, the initial dyspnea was interpreted as a symptom of coronary artery disease. One of eight subjects (from the clopidogrel group) reported resting and exercise-related dyspneic episodes of moderate severity (6/10), occurring several times a day, lasting several hours, alleviating spontaneously or following tranquilizer administration. The symptoms were also present following the clopidogrel initiation and the PCI, and hence were judged to be of psychogenic origin.12 inhibitor initiation was reported by three subjects in the ticagrelor group (27% of ticagrelor-treated subjects) and by none in the clopidogrel group. None of those subjects reported shortness of breath prior to PCI. Dyspnea was described as mild by two patients (3/10 and 4/10) and as severe by one subject (8/10). Dyspneic episodes occurred suddenly and spontaneously on a daily basis, most frequently in the evenings, and alleviated gradually. In two patients with mild dyspnea, the events terminated in the 2nd and the 3rd week of ticagrelor treatment. In those subjects, the therapy remained uninterrupted. In the remaining severely dyspneic subject, who had high baseline HVR and HCVR, the sensation persisted for more than 6 weeks, and the switch to clopidogrel was made at the patient’s request. Detailed characteristics of the dyspneic subjects compared to non-dyspneic individuals can be found in New onset dyspnea following P2YIn this pilot study, we followed unique clinical scenarios to investigate the influence of clopidogrel and ticagrelor treatment on HVR and HCVR. There are several novel findings of the study: 1) ticagrelor and clopidogrel exert divergent influence over the HVR and HCVR; 2) ticagrelor significantly increases ventilatory (HVR) and blood pressure (SBPR) responses to selective PCh stimulation with transient hypoxia, when the effects of clopidogrel are negligible; 3) ticagrelor (but not clopidogrel) significantly increases ventilatory response to selective CCh stimulation (HCVR) with progressive hyperoxic hypercapnia; 4) there is a strong relationship between the changes in HVR and HCVR following ticagrelor initiation.12 inhibitors) potentially influencing the chemoreflex arc, including B-blockers and renin–angiotensin–aldosterone axis inhibitors (12 inhibitor introduction). Such a clinical course allowed for the assessment of chemosensitivities before and during clopidogrel or ticagrelor de novo administration.As mentioned before, the influence of ticagrelor on chemoreflex has been previously proposed by Giannoni et al., who observed elevated HCVR in post-ACS patients taking ticagrelor compared to those on prasugrel . Howeverhibitors . To over12 receptors on chemosensory (glomus) cells  inhibition of adenosine P2Ys) cells  and 2) is) cells .12 adenosine receptors are present on mammalian glomus cells in PCh, and stimulation of these purinergic receptors leads to inhibition of hypoxia-induced response  patients included in the study, which is concomitant with the reports from previous trials . No drugTreatment with ticagrelor increased the ventilatory response (HVR) and also augmented the blood pressure response (hypertension) to the hypoxic stimulus (SBPR) but did not influence HRR. This finding is concomitant with those of our previous observations and further suggests that PCh (at least carotid bodies) are not responsible for hypoxia-mediated tachycardia. As we previously reported, selective activation of the carotid body in conscious humans leads to bradycardia instead of tachycardia , and bilIt is worth noticing that hyperreflexia of chemoreceptors is known to play a role in the pathogenesis of sleep-disordered breathing and sympathetically mediated diseases, such as hypertension, and is an ominous sign in patients with systolic heart failure . GiannonFinally, the chronic coronary artery disease clinical model was used in our study to assess the effects of P2Y12 inhibitor initiation on chemoreceptors. It is rather unlikely, as our results are concomitant with those made by 12 inhibitor therapy by choosing drugs with lower potential for chemosensitization with unbeneficial consequences.Ticagrelor administration is associated with a significant increase in peripheral and central chemoreceptor sensitivities, while clopidogrel does not exert such effects. Analysis of the individual, numerical data of subjects suffering from ticagrelor-related dyspnea suggests that two mechanisms may be involved in the pathogenesis of the phenomenon–one is an excessive increase in PCh sensitivity or PCh and CCh sensitivities and the other one is the high baseline (before the drug administration) PCh and CCh sensitivities. The second pattern was observed in a participant with severe ticagrelor-induced dyspnea. Further studies are necessary to shed more light on the pathomechanism of ticagrelor-related dyspnea. This will allow for 1) development of treatment strategies to alleviate this common side effect; 2) inventing screening tests, to identify patients at risk for ticagrelor-induced dyspnea; and 3) tailoring P2Y


We aimed to provide data on the normal blood pressure of haemodynamically stable neonates. Our study uses retrospective, real-life oscillometric blood pressure measurement values to determine the expected blood pressure in different gestational age, chronological age and birth weight groups. We also investigated the effect of antenatal steroid on neonatal blood pressure.Our retrospective study (2019–2021) was carried out in the Neonatal Intensive Care Unit of the University of Szeged, Hungary. We involved 629 haemodynamically stable patients and analysed 134,938 blood pressure values. Data were collected from electronic hospital records of IntelliSpace Critical Care Anesthesia by Phillips. We used the PDAnalyser program for data handling and the IBM SPSS program for statistical analysis.We found a significant difference between the blood pressure of each gestational age group in the first 14 days of life. The systolic, diastolic and mean blood pressure rise are steeper in the preterm group than in the term group in the first 3 days of life. No significant blood pressure differences were found between the group with a complete antenatal steroid course and those who received incomplete steroid prophylaxis or did not receive antenatal steroids.We determined the average blood pressure of stable neonates and obtained normative data by percentiles. Our study provides additional data on how blood pressure varies with gestational age and birth weight.The online version contains supplementary material available at 10.1007/s00467-023-05979-x. Blood pressure measurements are essential to evaluate the cardiovascular stability of preterm and term infants. Patients who have received neonatal intensive care unit (NICU) treatments have a well-recognised risk of developing hypertension, affecting their long-term cardiovascular and kidney health , 2. DiagGestational age and birth weight are known factors affecting the blood pressure of newborn infants. Several studies investigated neonatal blood pressure and its influencing factors related to maternal and infant health and therapy, but the results are still controversial , 12, 22.The intra-arterial blood pressure measurement method is still considered the gold standard in the evaluation of neonatal blood pressure. However, arterial lines are associated with several side effects, making them less frequently used in non-critically ill neonatal patients.Our study provides and evaluates a large amount of data on oscillometric blood pressure values in hemodynamically stable NICU patients intending to determine the normal average blood pressure in patients with different gestational ages and birth weights.Our retrospective single-centre study was performed at the NICU of the University of Szeged, Hungary. Over a 3-year period (from 01 January 2019 to 31 December 2021), all the blood pressure readings were collected from the entire patient group admitted to the unit.In order to select haemodynamically stable neonates, we excluded all infants with a substantial risk of hypotension or hypertension from the study. The exclusion criteria –6, 18 weThe blood pressure values and patient and maternal demographic and medical data were retrieved from the IntelliSpace Critical Care Anesthesia (ICCA) electronic medical records by Phillips and the hospital information system, Medsol. The collected data included all the blood pressure records, antenatal steroids, Apgar scores at 1 and 5 min of life, birth weight, ventilated days (either invasive or non-invasive), neonatal medication , maternal medical history  and neonatal diagnosis .The gestational age was determined with the use of the last menstrual period and early ultrasound scans by the obstetrics team. The obstetrics team applied a complete steroid course, which means four times 6 mg doses of dexamethasone administered intramuscularly every 12 h . The steWe calculated the weight percentiles with the use of Fenton growth charts. Blood pressures were measured according to the unit’s existing blood pressure measurement and hypertension guidelines. Generally, a single blood pressure measurement was taken. On a daily average, the number of measures by patient varied between one and twelve in the study group’s first two weeks of life. The medical team decided the frequency of the measurements based on the patient’s condition. The aim was to avoid repeating measurements to ensure comfort and keep the settled states of the neonates under the measure. In case of invalid values or suspected hypo- or hypertension, the blood pressure was remeasured based on the medical team’s decision. The unit used the blood pressure percentile table created by Dionne et al.  for the Blood pressure was measured using an oscillometric device with an appropriate-sized cuff (cuff width to the arm circumference ratio closest to 0.50) , 15. We Data on the infants’ wakefulness state were unavailable in the medical records. According to our protocol, the measurements were done during sleep or in a quiet awake state. In case of an unsuccessful measurement (e.g. the newborn woke up during measurement and cried), the protocol was to remeasure the blood pressure in a settled state.The unit used the GE Dash 3000 multiparameter monitor system with the GE DINAMAP blood pressure algorithm for blood pressure measurements . The ICCp < 0.05. Linear regression analyses were used to determine trend lines to approximate the arithmetic means calculated from the raw blood pressure values. The graphs were created by Microsoft Excel version 2209.Statistical analysis, as required, was carried out using the IBM SPSS Statistics program (version 29) and Microsoft Excel Data Analysis module. One-sample Kolmogorov–Smirnov test was performed to prove the normal distribution of the data. For the verification, the significance level was set by The Local Human Research Ethics committee approved the study.We admitted 839 patients in our neonatal intensive care unit over 3 years 2019–2021). From the total 839 patients, we excluded 136 patients who required inotropic support and mechanical ventilation longer than 24 h, 27 patients who died and 28 patients for other reasons . Another 19 patients were excluded due to technical reasons (e.g. insufficient data). After applying the exclusion criteria, we included data from 629 infants in the study, of whom 378 (60%) were preterm and 251 (40%) were full-term patients  had one of the abovementioned medical conditions, but only 3.9% (n = 23) had two or three investigated medical problems together. The maternal medical information was not processed with enough details to let us draw a statistically valid conclusion on their effects on the newborn’s blood pressure.We also collected data on the medical conditions  of 594 affected mothers. Among them, 35% . After applying the exclusion criteria, the remaining 629 patients had 44,990 systolic, 44,977 diastolic and 44,971 mean blood pressure values . In this patient group, the average daily measurement count for one patient was 4.44, and the daily measurement numbers varied between 1 and 12. One-sample Kolmogorov–Smirnov test has confirmed that the blood pressure data sample follows normal distribution.n = 170, 55%) to the patient group who had an incomplete antenatal steroid course  or did not receive steroid prophylaxis . A possibly significant difference between the groups above was refused because the applied paired sample T-test calculated significance as p = 0.191.We compared the average blood pressure values of the preterm patients  who received a complete course of antenatal steroids  were processed. The patient and measurement numbers in the different gestational age groups are presented in Supplementary Table All the blood pressure curves representative of a certain gestational age were created. We calculated the daily arithmetical average blood pressure and the standard deviation for each gestational age from the daily blood pressure measurements. Due to the low patient number in the very preterm group and the low measurement number in the term group, we investigated gestational weeks between 25–28 and 40–42 together, respectively. As a representative example, we present the daily average systolic and mean blood pressure curves as the function of time for different gestational age groups in the first two weeks of life see Fig. . The diaT-test .The standard deviation was also calculated for the different gestational age groups. The average standard deviation for the systolic, diastolic and mean blood pressures are 9.7 mmHg, 7.9 mmHg and 8.5 mmHg, respectively. We found a statistically significant difference among the average blood pressure values of the different gestational age groups using the SPSS program paired-samples We found that blood pressure increases with an increasing number of postnatal days and gestational age see Fig. .According to our findings, the systolic blood pressure rise over the first 3 days of life is steeper in preterm infants (25–36-week gestation) than in the term infant group. The systolic blood pressure increased by 3.75 mmHg/day in preterm infants and 1.60 mmHg/day in the term infants in the first 3 days. After the first 5 days, the increasing average systolic blood pressure values might show a mild decrease  with the daily average blood pressure data. The calculated p < 0.001 value shows a significant correlation between them.Figure As shown in Fig. The average blood pressure of the different gestational age groups increased rapidly over the first 3 days of life . The following 2 days, there was a less pronounced increase in the systolic blood pressure (1.28 mmHg/day) and the mean and the diastolic blood pressures had not increased further .Supplementary Table T-test: significance p < 0.001). The systolic blood pressure increased by 8.44 mmHg in the first 5 days. The daily average increment was 2.85 mmHg in the first 3 days and 1.36 mmHg over the following 2 days. The mean blood pressure showed a similar pattern in the first 3 days of life; the calculated average daily increment was 2.86 mmHg, and the blood pressure was almost static over the following 2 days.We investigated the change in neonatal blood pressure by increasing birth weight and generated eight patient groups; every patient group had a 500 g difference in birth weight. The blood pressure data of 613 patients were included in the analysis. The data of 16 patients with a weight higher than 4500 g was not used for calculation due to the low number of measurements and short hospital stay. We used 18,370 systolic, 18,363 diastolic and 18,439 mean blood pressure data points in the analysis. The systolic and mean blood pressure values and linear regression lines are shown in Fig. The following table Table  containsOur single-centre retrospective study provides data on the systolic, diastolic and mean blood pressure of clinically stable neonates. We collected data from a haemodynamically stable term and preterm patient group without substantial hypotension or hypertension risks. The exclusion criteria described above were applied after collecting all the diagnoses and treatment data of the patients.The study has some limitations, coming from its retrospective nature. The infants’ wakefulness state and the place of measurement are not documented in our electronic records. However, data are collected in natural life circumstances, where the schedule and the quality of the measurements are ensured by following the NICU’s corresponding protocols.Some therapeutic interventions have uncertain effects on blood pressure , but they are part of the routine neonatal treatment; therefore, patients receiving them could not have been excluded from the study. We also could not further divide the patient groups based on non-invasive ventilation data because it would result in several groups with insufficient patients and blood pressure data for a statistical valuation.Both our patient number and the volume of our measured data are comparable to the largest previous investigations done in this field of research. Most of the other clinical studies investigated healthy patient populations by excluding cardiovascularly compromised patients, but infants with a risk of hypertension were just partly excluded , 6. The We compared our results to previous studies by using oscillometric blood pressure measurement methods. Kent and colleagues investigated a homogenous preterm patient group without ventilated patients or patients needing inotropic support . Their pIn clinical practice, average blood pressure values and percentile are helpful. A corresponding table with our results is presented in this paper Supplementary file 1 Information on the gestational age groups, the measurement numbers (see Supplement Table 1) and figures on diastolic blood pressure are presented in Supplementary Table 1 and Supplementary Figures 1, 2, and 3. We also present the average blood pressure and percentile table in the first five days of life (Supplementary Table 2) (PDF 154 KB)Below is the link to the electronic supplementary material.


Kidney blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) has shown great promise in evaluating relative oxygen availability. This method is quite efficacious in evaluating acute responses to physiological and pharmacologic maneuvers. Its outcome parameter, R2∗ is defined as the apparent spin-spin relaxation rate measured in the presence of magnetic susceptibility differences and it is measured using gradient echo MRI. Although associations between R2∗ and renal function decline have been described, it remains uncertain to what extent R2∗ is a true reflection of tissue oxygenation. This is primarily because of not taking into account the confounding factors, especially fractional blood volume (fBV) in tissue.This case-control study included 7 healthy controls and 6 patients with diabetes and chronic kidney disease (CKD). Using data before and after administration of ferumoxytol, a blood pool MRI contrast media, the fBVs in kidney cortex and medulla were measured.n = 7) versus CKD (n = 6). These were then combined with BOLD MRI measurements to estimate oxygen saturation of hemoglobin (StO2)  and partial pressure of oxygen in blood (bloodPO2)  in control versus CKD. The results for the first time demonstrate that cortex is normoxemic in controls and moderately hypoxemic in CKD. In the medulla, it is mildly hypoxemic in controls and moderately hypoxemic in CKD. Whereas fBV, StO2, and bloodPO2 were strongly associated with estimated glomerular filtration rate (eGFR), R2∗ was not.This pilot study independently measured fBV in kidney cortex (0.23 ± 0.03 vs. 0.17 ± 0.03) and medulla (0.36 ± 0.08 vs. 0.25 ± 0.03) in a small number of healthy controls (Our results support the feasibility of quantitatively assessing oxygen availability using noninvasive quantitative BOLD MRI that could be translated to the clinic.  When studying acute responses such as following the administration of loop diuretics, it is assumed that there is minimal effect on fBV and Hct, and therefore any observed response was ascribed to changes in oxygen availability, StO2. Loop diuretics acutely increase tissue oxygenation by reducing oxygen-consuming tubular reabsorption of sodium.,,BOLD MRI uses hemoglobin as a reporter of oxygen status and has been shown to be useful in the noninvasive evaluation of relative oxygenation status of the kidneys over 2 decades ago.2 but also depends on fBV and Hct.,2, that is, whereas reduced fBV and Hct would decrease R2∗, reduction in StO2 will increase R2∗. Considering that all 3 could be reduced in CKD, the net effect on R2∗ may be compromised leading to minimal change in R2∗ observed with disease severity. This was articulated in the editorial commentAround the same time as kidney BOLD MRI was gaining initial interest, chronic hypoxia hypothesis2 in brain tissue in animal models,,S5,,,2 estimates with those from Near Infrared Spectroscopy.2.2 or bloodPO2 can be used to infer the regional oxygen availability. In this pilot case-control study, we have adapted the method previously used in rat brains,2 and bloodPO2 in the kidney cortex and medulla in a small number of healthy volunteers and individuals with CKD. We used ferumoxytol to measure fBV and used a measure of Hct in peripheral blood to estimate cortical and medullary Hct based on prior literature.Quantitative BOLD (qBOLD) MRI methods have been applied to the brain.All procedures were performed with approval from the institutional review board (EH20-117) and written consent from each of the participants. Fifteen subjects participated in this pilot case-control study, with 9 healthy controls and 6 individuals with CKD and diabetes. CKD patients were from our institutional Nephrology Clinics. The healthy participants were recruited from an established database consisting of participants in prior imaging studies at our center. Among the controls, 1 participant did not complete imaging acquisitions and another 1 had inadequate image quality and therefore were not included in the analysis. All patients with CKD were either stage 3 or 4. One subject was taking ferrous sulfate to treat anemia. One subject had a prior administration of ferumoxytol (at least 2 months before the study).2 calculated by CKD-Epidemiology Collaboration formula. CKD patients should have, a diagnosis of type 1 or type 2 diabetes and 15 ml/min per 1.73 m2 < GFR < 60 ml/min per 1.73 m2 calculated by CKD-Epidemiology Collaboration formula.Inclusion criteria for all participants included, age ≥18 years; ability to give informed consent; ability and willingness to follow study protocol; and absence of contraindication for magnetic resonance study including claustrophobia, presence of a pacemaker, intracranial clips, or intraocular debris. Healthy participants for control group should have no history of diabetes, hypertension, or heart disease; be normotensive, that is, <130 mm Hg systolic blood pressure and <90 mm Hg diastolic blood pressure; normal kidney function for age as evidence by GFR >60 ml/min per 1.73 mExclusion criteria for all participants included the following: pregnant or nursing females; history of decompensated heart failure (acute or chronic diastolic or congestive heart failure); history of unilateral kidney disease such as renal artery stenosis or ureteral obstruction; and chronic use of nonsteroidal anti-inflammatory agents; iron overload, defined as serum ferritin >800 ng/ml. CKD patients should not have CKD because of primary glomerular disease, primary interstitial disease, or polycystic kidney diseaseBlood specimens were collected for each participant at the screening visit for kidney function before scheduling of MRI scan. Urine samples for protein-to-creatinine ratio were taken immediately before the MRI scan. Participants’ demographic information, including eGFR estimates based on both creatinine and cystatin C using CKD-Epidemiology Collaboration equations are summarized in Participants were instructed to fast overnight before coming for the MRI scans performed in the morning. They were also asked to refrain from using nonsteroidal anti-inflammatory drugs for 3 days before the scheduled MRI scans. If they are using insulin, participants were instructed to use half their dose the previous evening and hold the morning dose until after the scan. Similarly, if they were taking blood pressure medications such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, they were asked to not take the dose on the previous day and hold the scan day’s dose until after the scan. Participants on furosemide were asked to not take the day’s dose.Fit, Siemens Healthcare, Erlangen, Germany). Because R2∗ comprises of 2 primary components, namely, inherent spin-spin relaxation rate R2 and a component related to the susceptibility effect,All MRI data were acquired on a 3.0 T whole body scanner (Magnetom SkyraAfter baseline R2∗ images were acquired using the multiple gradient echo sequence (R2∗ Map_pre in firevoxel.org), a noncommercial research-only software freely distributed by the developers at New York University. Manual definition of regions of interest in kidney cortex and medulla were drawn for each slice on each kidney ,P < 0.05 was considered as statistically significant. In case of missing data, the specific participants were excluded from the analysis.Given the small sample size, for comparing control versus CKD, nonparametric Mann-Whitney U test was performed. Associations of MRI estimates with kidney function were performed using Spearman correlation. Pair-wise comparisons were performed using nonparametric Wilcoxon test for evaluating response to furosemide. All statistical analysis were performed using SPSS 22.0 software . The demographic data for the participants (7 controls and 6 with CKD) in the study whose MRI data are reported are summarized in 2 and bloodPO2 were obtained, using equation S3 and S4, respectively. These measurements are summarized in 2 and bloodPO2 were significantly lower in CKD in both kidney cortex and medulla, even though the corresponding R2∗ values were not significantly different. Consistent with our prior reports, the median medullary R2∗ in CKD was slightly lower than that in healthy controls.R2∗ maps at baseline and post 5 mg/kg of ferumoxytol in a representative control participant and an individual with CKD are shown in 2, and bloodPO2 with eGFR_creatinine and eGFR_cystatin-C, as well as urine albumin-to-creatinine ratio are summarized in 2 and bloodPO2 in the cortex and medulla were strongly associated with eGFR_creatinine and eGFR_cystatin, even though R2∗ was not. Only cortical fBV, StO2, and bloodPO2 were associated with urine albumin-to-creatinine ratio.The Spearman correlation coefficients for regional fBV, StOThe administration of furosemide does not appreciably change the mean post-ferumoxytol R2∗ but demonstrates variable response in the medulla in terms of directionality , although the magnitude of change was relatively minimal .Figure 42 and bloodPO2 indicate that kidney cortex is normoxemic in healthy controls but moderately hypoxemic in CKD. Similarly, kidney medulla is mildly hypoxemic in controls but moderately hypoxemic in CKD. These estimates are quite consistent with the chronic hypoxia hypothesis, a fact that has remained elusive. To-date, the only data supporting a possible existence of hypoxia in human kidneys are based on histologic assessments of hypoxia inducible factor activation.2 in the medulla in CKD. A prior report showed that the reduced medullary R2∗ was associated with annual loss of kidney function.The data presented here reports for the first time fBV in human kidneys, which is significantly decreased in individuals with CKD. Most interestingly, taking fBV into account, the estimated StOThe main conclusion to be drawn from 2 compare with literature values?How do our estimates of fBV and bloodPO,There is very limited literature on kidney fBV. Our data suggest substantially higher fBV in the medulla compared to the cortex. Even though this is apparently counterintuitive, there are prior data to support this observation. A recent report using an enhanced microfill techniqueMeasurements by labeled blood cells and labeled albumin in young healthy volunteers reported cortical vascular volumes in the range of 37 to 57 ml/100 g.2.2 in both compartments simultaneously. Our estimates of bloodPO2  show values in the range of 88 to 100 mm Hg in the cortex, 38 to 68 mm Hg in the medulla and 18 to 26 mm Hg in inner medulla. Our estimated values in the medulla are consistent with the range in the outer medulla.Although a number of reports demonstrated the measurement of tissue oxygenation using microelectrodes or probes in preclinical modelsbloodPO2  in healtA recent report based on preclinical application of the method used here indicated a potential for overestimation of fBV in the medulla because of contributions of large vessels outside the slice in the vicinity of medulla.2 within the human kidney. Availability of StO2 or bloodPO2 can facilitate classification of relative regional hypoxemia. In this regard, this is the first demonstration of kidney hypoxemia in human kidneys using a noninvasive measure that can be translated to the clinic. Even though, the method necessitates the off-label use of an approved agent, ferumoxytol is compatible and may be preferred for use in individuals with CKD.,Overall, our data demonstrate the feasibility of noninvasive quantitative estimation of bloodPO2 related to reduction in oxygen consumption consistent with prior microelectrode data in rat kidneys.Considering that furosemide did not demonstrate consistent changes in post-ferumoxytol R2∗ in both the cortex and medulla, there is no indication that fBV is reduced post-furosemide. The variable response observed in the medulla is most probably related to partial volume effects. Prior preclinical reports have indicated a transient decrease in R2∗ in the inner medulla following furosemide after administration of ultrasmall superparamagnetic iron oxide with minimal changes in the cortex and outer medulla.All clinical applications pursued with BOLD MRI should be feasible with qBOLD MRI. Apart from CKD, we believe another clinical application of qBOLD MRI is in the evaluation of renal artery stenosis. Given that fBV may be reduced because of the stenosis, the measured kidney R2∗ values do no indicate the true levels of hypoxemia. Although measurements using an intravascular agent may be preferred for fBV measurements, alternate methods such as using conventional gadolinium agents,2. In this preliminary report, we only showed regions of interest measurements, but in the future it should be feasible to create StO2 and bloodPO2 maps. However, it will require registration of data from different breath-holds.Our study is not without limitations. Ferumoxytol is approved for human use in the US and is being used both as a therapeutic and/or diagnostic agent, but is not being used in other countries. This preliminary feasibility study included only a small number of participants and the groups were not age matched. However, it should be mentioned that even with such small sample size, the data demonstrated statistically significant differences between controls and CKD. Multiple Spearman’s rank analysis increase the risk of multiple tests, without Bonferroni correction. Given the preliminary nature of this report with a limited sample size, we did not perform the correction. Our analysis did not include pH and other variables that could potentially affect the hemoglobin oxygen desaturation curve. We used the measure of Hct in peripheral blood to estimate Hct in the cortex and outer medulla  based on prior preclinical data.2 and bloodPO2, the values of which are consistent with the limited literature to-date. StO2 and bloodPO2 were significantly lower in individuals with CKD, both in kidney cortex and medulla, consistent with chronic hypoxia hypothesis. The data in the medulla is significant because currently, based on reduced R2∗ in CKD compared to controls leads to a wrong interpretation that medullary oxygen availability is improved in CKD. Overall, qBOLD MRI allows for direct evaluation of kidney oxygen status and therefore facilitates mechanistic evaluation of interventions targeting kidney hypoxia such as sodium glucose cotransporter inhibitors.In conclusion, we present preliminary experience using ferumoxytol to measure fBV in kidney cortex and medulla and show for the first time that it is reduced in individuals with CKD. These measurements in combination with kidney BOLD MRI measurements allowed us to estimate cortical and medullary StOAll the authors declared no competing interests.


However, sirolimus use was significantly associated with a higher risk of estimated glomerular filtration rate decline > 30% than MMF . Our results demonstrate that sirolimus use may have worsened long-term kidney outcomes compared to MMF. Close monitoring of kidney function, dose adjustment, and timely transition to MMF is necessary for LT patients receiving sirolimus.Impaired kidney function is associated with increased morbidity and mortality in patients undergoing liver transplantation. Although immunosuppressants are essential in these patients, they impair kidney function. This study aimed to compare adverse kidney outcomes between patients treated with a reduced dose of tacrolimus  plus sirolimus or mycophenolate mofetil (MMF) in the liver transplant center at Kaohsiung Chang Gung Memorial Hospital between April 2011 and December 2017. Propensity score matching was used to identify 232 patients. The risk of adverse kidney outcomes was estimated using Cox proportional hazards regression, and changes in kidney function over time were analyzed using linear mixed modeling. Acute kidney disease risks in this study cohort were not significantly different for the two immunosuppressants (aHR 1.04; 95% CI: 0.70–1.55,  Liver transplantation (LT) is an effective treatment for end-stage liver disease . The disKidney function plays an important role in the long-term outcomes of patients undergoing LT. Both acute kidney injury (AKI) and CKD, which are associated with short- and long-term risks, develop after LT. AKI is a condition defined by a sudden loss of kidney function on the basis of increased serum creatinine levels or reduced urinary output within a duration of 7 days . CKD is Post-LT immunosuppressive agents, particularly CNIs, play important roles in the development of post-LT AKI and CKD. Possible mechanisms of CNI nephrotoxicity involve afferent and efferent glomerular arteriole vasoconstriction, increased platelet aggregation, and the subsequent development of thrombotic microangiopathy within the glomerular arterioles . To miniSirolimus, introduced in the 1990s, was the first mTORi and has been widely used in many liver transplant centers, including ours. It inhibits the mTOR pathway, which is involved in the activation and proliferation of immune cells. Earlier studies have demonstrated that either sirolimus monotherapy or sirolimus plus a reduced dose of a CNI could offer renal protection from CNI-induced nephrotoxicity ,21. HencMycophenolate mofetil (MMF), a semi-synthetic 2-morpholinoethyl ester of MPA, is a selective and reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, a crucial enzyme in DNA formation . MMF is Previous studies have demonstrated that CNI dose reduction combined with sirolimus or MMF contributes to the preservation of kidney function and is a useful strategy for reducing the risk of nephrotoxicity in LT recipients. However, kidney function deterioration still occurs in these patients; therefore, a head-to-head comparison between sirolimus and MMF combined with a CNI is warranted. Consequently, this study aimed to examine the effects of sirolimus and MMF on kidney outcomes in patients undergoing LT.p = 0.02). The majority of indications for LT in our cohort are hepatitis B, hepatitis C-virus-related end-stage liver disease, and hepatocellular carcinoma (HCC). The proportion of patients with hepatocellular carcinoma (HCC)  and baseline proteinuria  were higher among sirolimus users than among MMF users. Patients in the sirolimus group had a lower baseline estimated glomerular filtration rate (eGFR) than those in the MMF group . The proportion of patients with a baseline eGFR < 60 mL/min/1.73 m2 was higher in the sirolimus group than in the MMF group (16.7% vs. 1.9%)  at Kaohsiung Chang Gung Memorial Hospital (KCGMH). We identified 472 patients who met the inclusion criteria (318 in the sirolimus group and 154 in the MMF group). Notably, 69 patients were excluded due to a follow-up period of less than 3 years, of which 41 were foreign nationals and could not be consistently monitored at our center. Furthermore, 74 patients were excluded because they did not use sirolimus or MMF as their immunosuppressant. An additional 52 patients were excluded as they were treated with counterpart therapy during the follow-up period. Finally, five patients were excluded as they used the target agents for less than a year . Prior ts. 1.9%) .p = 0.36)). Neither nonalcoholic steatohepatitis (NASH) nor primary sclerosing cholangitis (PSC) were observed in our study cohorts.The baseline characteristics of the study cohort are presented in p = 0.71), warm ischemia time , and cold ischemia time  during surgery.Certain intra- and post-operative factors, such as blood loss, cold and warm ischemic time, and post-op acute rejection rate, may influence renal outcomes after liver transplantation ,27. Therp = 0.58), alanine transaminase (ALT) , total bilirubin , and albumin  between the two groups. The number of biopsy-proven acute rejection occurring in two months after LT were 15 in the sirolimus group (12.9%) and 11 (9.4%) in the MMF group (p = 0.40).Liver function one month after LT was also compared between the two groups. There was no significant statistical difference in aspartate aminotransferase (AST) .The initiation of sirolimus treatment in the sirolimus group varied based on postoperative conditions, with a mean value of 10.7 ± 3.1 days after LT. The mean sirolimus dose was 1.60 ± 0.70 mg/day. In the MMF group, the initiation of MMF treatment occurred 2.4 ± 0.5 days after LT, and the mean dose of MMF was 944 ± 167 mg/day. For both the sirolimus and MMF groups, tacrolimus treatment was initiated according to the protocol described in p < 0.001). The trough levels of tacrolimus were also higher in the MMF group than in the sirolimus group , both of which were within the CNI low dose range , baseline biochemical data , and other medications with ≥28 days of use . Trough levels of tacrolimus at the index date and 6 months after (considered a relatively stable dosage period) were considered potential confounders for kidney function change from baseline .To level the baseline demographic and clinical discrepancies between the sirolimus and MMF groups, PS matching was used. The individual propensity scores of patients treated with either sirolimus or MMF were approximated via logistic regression. We matched new users of sirolimus and MMF on a 1:1 basis using the greedy technique in the PS-matching method. Before and after PS matching, we evaluated baseline traits and comorbidities between the two treatment groups. The standardized mean difference (SMD) was used to gauge comparability in baseline traits between groups, with an SMD < 0.1 considered as no meaningful difference.2), HBV, HCV, HCC, DM, and AKD in eGFR decline. A two-tailed test result of p < 0.05 was considered statistically significant. All statistical analyses were performed using SAS 9.4 .We utilized the chi-squared test to calculate adverse kidney outcomes (AKD and eGFR decline). The time-to-adverse kidney outcome endpoint was probed using the Kaplan–Meier approach with log-rank tests. We employed the Cox proportional hazard regression model to scrutinize the independent correlation between the selection of MMF (or sirolimus) and the occurrence of individual adverse kidney diseases. A linear mixed-effects model was employed to estimate the discrepancy in the average eGFR changes over time between sirolimus and MMF users. To evaluate the heterogeneous impacts of sirolimus and MMF by varying baseline characteristics, we conducted stratified analyses in the matched cohorts considering sex, age (<55 years vs. >55 years), and baseline eGFR groups (<90, and ≥90 mL/min/1.73 mIn conclusion, our study showed that among LT patients, the use of sirolimus plus tacrolimus may carry a higher risk of long-term kidney function deterioration than the use of MMF plus tacrolimus. These findings highlight the need for periodical monitoring of kidney function and early detection of kidney injury at least every 1–3 months and other reno-protective strategies, such as dose optimization of immunosuppression and early transition to MMF in LT patients using sirolimus.


This study aims to verify the new-onset diabetes after kidney transplant (NODAT) incidence in recipients within 1 year after kidney transplantation from a single center in Southern Brazil and to assess the associated conditions.A retrospective study of 258 post-renal transplant patients was performed. Demographic  and clinical  at transplant time and 6 and 12 months after, causes of renal failure, and comorbidities) data were analyzed. All patients were on tacrolimus, mycophenolate mofetil, and prednisone treatment. Patients with and without NODAT were compared.A NODAT incidence of 31.2% was noted 1 year post transplantation. In the univariate analysis, patients with NODAT were older (p = 0.001), mostly had African–American ethnic background (p = 0.02), and had renal failure secondary to high blood pressure (HBP) (p = 0.001). The group of patients with NODAT also had more incidence of post-transplant HBP (p = 0.01), heart failure (p = 0.02), and dyslipidemia (p = 0.001). Logistic regression showed that African–American ethnic background, post-transplant HBP, and dyslipidemia were independently associated with NODAT.This study shows a NODAT incidence that is greater in patients with African–American ethnic background and that is associated with HBP and dyslipidemia. New-onset diabetes after transplant, or NODAT, is one of the major complications after solid organ transplantation ,2. ThereThe pathophysiology of NODAT closely mimics type 2 DM: insulin resistance and insulin hyposecretion develop in both situations. Nevertheless, in NODAT, insulin hyposecretion seems to be a crucial determining factor in glucose tolerance deterioration .Several risk factors were known to be associated with NODAT, such as ethnic background, family history of diabetes, sedentary lifestyle, high body mass index (BMI), and cytomegalovirus and hepatitis C virus (HCV) infection. A high dose of glucocorticoids and the use of immunosuppressive regimen with calcineurin inhibitors may also be associated with this condition -8. NumakGenetic background may influence the prevalence of NODAT in different populations . The incThis retrospective study was approved by the local Committee of Ethics in Research (56934016.4.0000.0103). Charts of kidney transplant patients from a single center, a university evangelical hospital, located in the city of Curitiba, Paraná, Brazil, registered from July to December 2015, were reviewed for epidemiological, clinical, and treatment profile.Patients under 18 years of age, those with DM prior to transplantation, those who had first-degree relatives with DM, and those who had used immunobiological drugs or had graft rejection were excluded.The study sample included 258 patients . All patients were on standard treatment, with prednisone, mycophenolate mofetil, and tacrolimus, which is determined by the Brazilian Health Ministry, Ordinance 1.168, in 2004.The following data of all patients were reviewed retrospectively for 12 months: BMI prior to transplantation and six and twelve months post transplantation, causes of renal failure prior to transplantation, graft origin (either from deceased or living donor), and occurrence of hepatitis C and CMV infections. The diagnosis of DM was made according to the American Diabetes Association, through the analysis of three altered values of blood glucose, which was done by the transplant doctor and was registered in the patient medical record 12 months after transplantation .The obtained data was collected in frequency and contingency tables. The epidemiological and clinical profiles between patients with and without NODAT were compared using the Fisher exact test and chi-square tests for nominal data and unpaired t-test and Mann–Whitney test for numeric data. To assess variables independently, logistic regression was used. The significance level adopted was 5%.The description of clinical, epidemiological, and treatment data of kidney transplant patients being studied are shown in Only three patients had HCV infection. In this sample, the NODAT incidence was 31.2%.When all variables with p < 0.1 were studied through logistic regression, it was found that African–American ethnic background , dyslipidemia , and hypertension  were independently associated with NODAT.In the present study, which included 258 renal post transplanted recipients, all in the same therapeutic regimen, there was a NODAT incidence of 31.2% in the first year after the transplant procedure. It is noteworthy that individuals with DM in the first-degree relatives in the sample were excluded, so the possible occurrence of a common type 2 DM was minimized. In addition, it was observed that NODAT was independently associated with factors such as African–American background, arterial hypertension, and dyslipidemia.2 which is close to the accepted normal range. Therefore, obesity, which is widely linked to DM, was underrepresented in the sample. This may explain the diversity of the results found. Additionally, CMV infection could not be associated with NODAT in this study, considering the very low incidence of infection in patients. The same occurs with HCV infection. However, literature concerning HCV infection and NODAT is ambiguous, with some authors supporting higher prevalence of these findings  and hepatitis C infection . BMI alofindings  and othefindings ,21. In tNODAT's association with African–American background was also described by other authors . This asTacrolimus is considered one of the main NODAT causes,  and all The mechanism involved in tacrolimus-induced NODAT includes diminished insulin secretion, as calcineurin is expressed in pancreas β cells. This medication disrupts mitochondrial permeability, causes inhibition of NFAT transcription factor, and targets cAMP-responsive element-binding protein transcriptional coactivator . In addiNODAT is associated with lower survival of transplanted recipients, and it is an independent risk factor linked to graft failure . FurtherThis is a retrospective study, which is also considered one of the limitations. It is also possible that the occurrence of NODAT would be higher in longer periods of observation.In conclusion, this study shows a higher NODAT incidence in kidney transplant recipients with African–American ethnic background. Moreover, NODAT is associated with higher blood pressure levels and dyslipidemia in all transplant recipients, regardless of the ethnic background. Prospective and multicentric studies may be useful to better understand and prevent NODAT.


A 56‐hole porous tip radiofrequency catheter was developed to provide more uniform cooling with less fluid delivery than a prior 6‐hole irrigated design. This study aimed to evaluate the impact of contact force (CF) ablation with the porous tip on complications (congestive heart failure [CHF] and non‐CHF related), healthcare resource utilization, and procedural efficiency in patients undergoing de novo paroxysmal atrial fibrillation (PAF) ablations in a real‐world setting.Consecutive de novo PAF ablations were performed between February 2014 and March 2019 by six operators at a single US academic center. The 6‐hole design was used through December 2016 with the 56‐hole porous tip adopted in October 2016. The outcomes of interest included symptomatic CHF presentation and CHF‐related complications.p < .0001). CHF‐related complications within 7 days, particularly fluid overload, were substantially reduced with the porous tip  and the proportion of patients with symptomatic CHF presentation within 30 days postablation was significantly lower .Of 174 patients who were included, mean age was 61.1 ± 10.8 years, 67.8% were male, and 25.3% had a history of CHF. Ablation with the porous tip catheter significantly decreased fluid delivery  for atrial fibrillation patients that during oral anticoagulant therapy suffer from ischemic events is still a matter of debate. In the absence of a high bleeding risk, a hybrid approach of LAAO + lifelong anticoagulant therapy could be an effective novel strategy Compared with nonirrigated catheters, irrigated tips allow for longer and deeper lesions by preserving a low electrode temperature during RF application.The safety and acute effectiveness of the porous tip design for paroxysmal atrial fibrillation (PAF) ablations have been established for contact force (CF)‐sensing catheters in the SMART‐SF trial.The objective of the current study was to evaluate the impact of CF ablation with the porous tip versus the conventionally irrigated tip on complications (CHF and non‐CHF related), healthcare resource utilization, and procedural efficiency among patients undergoing de novo PAF ablations in a real‐world clinical setting.22.1This retrospective study analyzed data on de novo PAF ablations performed by six operators at a single US academic center between February 2014 and March 2019. Data were extracted from the patients' electronic medical records into standardized data collection forms.This study was determined to meet the criteria for exemption from review by the University of Cincinnati Institutional Review Board on May 30, 2019.2.2® SF Catheter , which incorporates the new porous tip, or THERMOCOOL SMARTTOUCH® Catheter , with the prior 6‐hole design. Patients with a history of persistent AF and/or belonging to a vulnerable population were excluded.The study population consisted of consecutive adult patients aged 21 years or older who underwent a de novo PAF catheter ablation at the study site with one of the two study catheters—THERMOCOOL SMARTTOUCH2.3RF ablations were performed using the ST between February 2014 and December 2016 or the STSF from October 2016 onwards, both in conjunction with the CARTO VISITAG™ Module (Biosense Webster Inc.).Pulmonary veins (PVs) were isolated by wide‐area circumferential ablation using the dragging technique. Respiratory gating was utilized. Contact force between 5 and 20 g was sought while maintaining 35 Watts through the left atrium. Pacing of the PVs was performed to verify lack of capture. Entrance block at each PV was then verified by remapping.2.4Patients were followed up for a year after ablation for safety, symptoms, and treatments. Routine follow‐up visits were scheduled at 7–10 days, 4–6 weeks, and yearly thereafter.2.5The primary outcome was symptomatic CHF presentation, defined as a new diuretic prescription, an increase in dosage of a diuretic to alleviate exacerbation, and/or a CHF‐related hospital, emergency room, or clinic visit within 30 days postprocedure. Secondary outcomes included complications (CHF and non‐CHF related) within 7 days and documented fluid overload within 30 days. Procedural efficiency and ablation details were also of interest.2.6All available baseline patient characteristics, procedural details, and safety outcomes were summarized by descriptive statistics and compared across catheter cohorts using chi‐square tests for categorical measures and t‐tests for continuous measures.Logistic regression modeling was utilized to compare the likelihood of a symptomatic CHF presentation within 30 days postablation between the catheter cohorts, while simultaneously adjusting for baseline CHF and any additional patient characteristics that were associated with the outcome at a significance level of 0.15.Statistical analysis was performed using SAS software, version 9.4 (SAS Institute Inc.).33.1A total of 174 patients who underwent a de novo PAF catheter ablation at the study site between February 2014 and March 2019 were included in the study. Of these, 79 patients (45.4%) underwent ablation with ST and 95 patients (54.6%) with STSF. Patients were followed for an average of 309 ± 134 days postablation.Patients' mean age was 61.1 ± 10.8 years and 67.8% were male. The mean preablation AF duration was 31.8 ± 42.9 months. Hypertension was the most prevalent comorbidity (78.7%) and 25.3% of the patients had a history of CHF at baseline.Most patient characteristics were similar across catheter cohorts Table . However3.2p < .0001)    (Table p = .0254).CHF‐related complications within 7 days were significantly reduced after introduction of the porous tip, from 15.2% of patients in the ST cohort to 5.3% in the STSF cohort (1) Table . The greThe two catheter cohorts were comparable with respect to non‐CHF complications within 7 days (STSF 17.9% vs. ST 16.5%). Groin hematoma and pericardial effusion were the most common non‐CHF complications across both cohorts.3.5The majority of patients were free from all‐cause hospitalizations within 30 days (76.4%), all‐cause hospitalizations after 30 days through 12 months (64.9%), and cardiovascular‐related hospitalizations within 12 months postablation (70.1%), with rates similar between STSF and ST cohorts (Figure 4Previous studies have evaluated and compared the safety of ST and STSF ablation catheters.In line with published literature,The marked decrease in the incidence of fluid overload following STSF ablations—more than 400% within 7 days, and approximately 200% within 30 days—suggests that the porous tip catheter may play an important role in easing the associated impacts on both the patient and payers, particularly considering that a considerable proportion of AF patients have comorbidities that place them at a higher risk of fluid overload.Low and similar complication rates for STSF and ST ablations have been reported by prior studies. Major complications are uncommon with either catheter, with rates varying between 0% and 2.7% in the available literature.4.1The primary limitations of this study are associated with the nonrandomized retrospective design. ST ablations generally predated those performed with the STSF. Therefore, factors other than the catheter used may have influenced our results. These could have included changes in ablation workflow, increased operator experience over time and/or inclusion of new operators will less experience in the later portion of the study. Confounding by unmeasured variables may have also occurred. Procedure times were not captured in the case records, so could not be summarized for comparison with fluid volumes. Lastly, the single‐site design may limit the generalizability of our findings because of site‐specific contextual factors, namely procedural workflow and levels of operator experience and skill.5In a real‐world setting, a porous catheter tip led to significantly reduced CHF‐related complications and healthcare utilization in PAF patients undergoing CF catheter ablation compared to a traditional 6‐hole irrigated ablation catheter. This reduction likely resulted from the significant decrease in fluid that was delivered via the ablation catheter during the procedure. This finding has the potential to evoke a substantial positive economic impact in addition to the positive impact on patient safety.This study was funded by Biosense Webster, Inc.Alexandru Costea is a speaker for Biosense Webster, Inc. and Biotronik. LM Boo is an employee of Biosense Webster, Inc., the study sponsor. TD Hunter is an employee of CTI Clinical Trial & Consulting, which is a consultant to Biosense Webster, Inc., the study sponsor. The other authors have no conflicts of interest relating to this manuscript.This study was determined to meet the criteria for exemption from review by the University of Cincinnati Institutional Review Board on May 30, 2019.


Low pulse pressure (PP) in venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is a marker of cardiac dysfunction and has been associated with acute brain injury (ABI) as continuous-flow centrifugal pump may lead to endothelial dysregulation.2, PaCO2), and on-ECMO complications .We retrospectively analyzed adults (≥18 years) on “peripheral” VA-ECMO support for cardiogenic shock in the Extracorporeal Life Support Organization Registry (1/2018–7/2023). Cubic splines were used to establish a threshold (PP≤10 mmHg at 24 hours of ECMO support) for “early low” PP. ABI included central nervous system (CNS) ischemia, intracranial hemorrhage, brain death, and seizures. Multivariable logistic regressions were performed to examine whether PP≤10 mmHg was associated with ABI. Covariates included age, sex, body mass index, pre-ECMO variables , on-ECMO variables , 8,294 (85%) had PP>10 mmHg vs. 1,513 (15%) had PP≤10 mmHg. Patients with PP≤10 mmHg experienced ABI more frequently vs. PP>10 mmHg . After adjustment, PP≤10 mmHg was independently associated with ABI . CNS ischemia and brain death were more common in patients with PP≤10 mmHg vs. PP>10 mmHg . PP≤10 mmHg was associated with CNS ischemia  but not intracranial hemorrhage .Early low PP (≤10 mmHg) at 24 hours of ECMO support was associated with ABI, particularly CNS ischemia, in peripheral VA-ECMO patients. Therefore, PP may be a good surrogate marker for predicting neurological outcomes in ECMO patients. A recent study demonstrated PP < 20 mmHg within 12 hours of ECMO cannulation was associated with ABI in 123 VA-ECMO patients.11 Still, this study was limited by small sample size, from single center, and including central VA-ECMO and post-cardiotomy shock patients who are at higher predisposition of ABI.12 Furthermore, peripheral VA-ECMO patients have hemodynamics states that are associated with vascular and perfusion abnormalities13 and are thus an important population to investigate the association between PP and ABI.VA-ECMO operates with a continuous-flow centrifugal pump, which is associated with endothelial dysregulation/dysfunctionUsing the largest registry of ECMO patients globally, the Extracorporeal Life Support Organization (ELSO) Registry, we sought to investigate the association between early PP and ABI in peripheral VA-ECMO patients. We hypothesized that low PP in the first 24 hours of ECMO support was independently associated with higher occurrence of ABI.14 The Registry collects demographics, pre-ECMO comorbidities, pre-ECMO and on-ECMO hemodynamic and arterial blood gas (ABG) information, on-ECMO neurological and other systemic complications, and outcomes such as mortality.15 Comorbidity information was recorded using the International Classification of Diseases, 10th Revision (ICD-10) codes.This study was approved by the Johns Hopkins Hospital Institutional Review Board with a waiver of informed consent since this was a retrospective observational study (IRB00216321). The ELSO Registry is an international multicenter registry from over 500 ECMO centers.We included patients who were 1) 18 years of age or older; and 2) supported with “peripheral” VA-ECMO and diagnosed with CS from 2018–2023. We excluded repeat ECMO runs within the same patient to avoid complexity and bias. We also excluded patients with missing blood pressure (systolic and diastolic at 24 hours of ECMO support) and cannulation information, central cannulation, on-ECMO percutaneous ventricular assist device or central venous access device support, coronary artery bypass graft or percutaneous coronary intervention, and post-cardiotomy shock. Patients with these conditions were excluded as they could impact the interpretation of PP readings and their association with ABI.The ELSO Registry collects ABG and hemodynamic information before and after ECMO cannulation . Pre-ECMO ABGs were drawn at maximum 6 hours before ECMO cannulation, and pre-ECMO ventilator settings were recorded within 6 hours of ECMO cannulation. If multiple ABGs existed within a specific duration, the pre-ECMO ABG that was closest to the beginning of ECMO cannulation was selected. On-ECMO ABGs were drawn after ECMO cannulation started, no longer than 30 hours post-cannulation. If multiple ABGs were taken, the on-ECMO ABG nearest to 24 hours after the start of cannulation was chosen. On-ECMO hemodynamics were gathered closest to 24 hours after ECMO cannulation, though they could be collected at 18–30 hours after cannulation. Each variable was abstracted by a trained ELSO data manager/abstracter and was collected simultaneously.2) was calculated as “On-ECMO PaCO2 at 24 hours” - “Pre-ECMO PaCO2”. Pre-ECMO ventilator settings included conventional ventilation, high-frequency oscillatory ventilation, other high frequency ventilation (high frequency jet ventilation or percussive ventilation), other non-specified ventilations, and absence of ventilation. Pre-ECMO additional temporary mechanical circulatory support (tMCS) included intra-aortic balloon pump (IABP), Impella®, and left and right ventricular assist devices . Pre-ECMO vasopressor infusions included dopamine, epinephrine, norepinephrine, phenylephrine, and vasopressin. Infusions were treated as a binary variable, meaning we treated them as the presence or absence of the infusions. Pre-ECMO vasopressor infusions were utilized for at least 6 hours within 24 hours of the start of ECMO cannulation. Pre-ECMO cardiac arrest was defined as an event that required the use of cardiopulmonary resuscitation in conjunction with the administration of external cardiac massage within 24 hours of ECMO cannulation. Central cannulation was defined as placement of the reinfusion cannula directly into the aorta. Peripheral cannulation was defined as placement of cannula in a site other than the aorta .On-ECMO PP was calculated as “SBP at 24 hours” - “DBP at 24 hours”. Delta partial pressure of arterial carbon dioxide  infarction (ischemic stroke), diffuse ischemia , intra/extra parenchymal hemorrhage, intraventricular hemorrhage, seizures determined by electroencephalograph or clinically, and neurosurgical intervention  and brain death during ECMO support. CNS ischemia was defined as ischemic stroke  and HIBI (determined by CT or MRI). ICH included intra/extra parenchymal hemorrhage and intraventricular hemorrhage (both determined by CT or MRI).The primary outcome was ABI during ECMO support between patients with PP ≤ 10 vs. PP > 10 mm Hg. The secondary outcomes were subtypes of ABI, CNS ischemia and ICH.16 to augment statistical power. Continuous, unordered categorical, and dichotomous missing variables were imputed using regression with predictive mean matching, polytomous logistic regression, and logistic regression. All missing variables are shown in Supplemental Table 1.Continuous variables were represented as median with interquartile range (IQR). Categorical variables were presented as frequency with percentages. The Wilcoxon rank-sum and Pearson’s chi-square tests were utilized to compare continuous and categorical variables, respectively. Differences in PP between those with ABI vs. those without ABI were compared with Wilcoxon rank-sum. Statistical significance was set at a p-value < 0.05. Data missingness was handled with multiple imputation with five separately imputed datasets (Rubin’s Rules)a priori based on clinical judgement and prior data for each model.17 Adjusted covariates in the ABI model included age, sex, body mass index, pre-ECMO variables , on-ECMO variables , delta PaCO2, and on-ECMO complications . In the CNS ischemia (ischemic stroke or HIBI) model, age, sex, pre-ECMO variables , delta PaCO2, and on-ECMO complications  were included in the adjustment. In the ICH model, age, sex, pre-ECMO variables , on-ECMO variables , delta PaCO2, and on-ECMO complications  were included in the adjustment. In an exploratory analysis, we performed a multivariable logistic regression model for central VA-ECMO patients to determine if PP was associated with ABI. Adjusted odds ratios (aOR) were presented with 95% confidence intervals (CIs). All statistical analyses were performed using R Studio .Cubic spline analysis was utilized to non-linearly model the impact of PP on ABI. Based on inflection points (“spline knots”) in this model, combined with prior data and clinical knowledge, we determined an appropriate PP threshold (≤ 10 mmHg) for logistic regression analysis. Boxplots were used to descriptively portray the association between PP vs. ABI. We performed univariable and multivariable logistic regression for ABI, CNS ischemia, and ICH in peripherally cannulated patients to determine if PP ≤ 10 mmHg was a significant risk factor for each of these outcomes even after adjustment for clinically relevant covariates. We chose covariates selected Of 18,701 VA-ECMO patients with CS, we included 9,807 patients in our study after the inclusion and exclusion criteria . Cubic sSupplemental Table 2). Overall, 608 (6.2%) patients experienced CNS ischemia (ischemic stroke or HIBI) and 311 (3.2%) patients experienced ICH. CNS ischemia and brain death were more common in patients with PP ≤ 10 mmHg vs. those with PP > 10 mmHg . Patients with PP ≤ 10 mmHg were more likely to die vs. those with PP > 10 mmHg .A total of 1,096 (11.1%) patients experienced ABI. Patients with PP ≤ 10 mmHg experienced ABI more frequently than those with PP > 10 mmHg . Patients with ABI had a lower on-ECMO PP vs. those without ABI  , pre-ECMO cardiac arrest , hemolysis , arrhythmia , and renal replacement therapy . Higher on-ECMO PaO2  was protective against ABI.In a multivariable logistic regression after adjusting for pre-selected clinically relevant covariates, on-ECMO PP ≤ 10 mmHg was independently associated with ABI , arrhythmia , and pre-ECMO cardiac arrest . Pre-ECMO vasopressor infusions  were protective against CNS ischemia.In a multivariable logistic regression, on-ECMO PP ≤ 10 mmHg was independently associated with CNS ischemia .In a univariable logistic regression analysis for ABI, on-ECMO PP ≤ 10 mmHg was also significantly associated with ABI in central VA-ECMO patients  and for ischemia . In a multivariable logistic regression, on-ECMO PP ≤ 10 mmHg was not associated with ABI , CNS ischemia , or ICH , in central VA-ECMO patients  measured at 24-hours of ECMO support was independently associated with greater occurrence of ABI in peripheral VA-ECMO patients after adjusting for pre-selected clinically relevant covariates. Additionally, low PP was associated with CNS ischemia but not ICH. We also identified other risk factors for ABI in peripheral VA-ECMO patients: higher delta PaCO20 as nonpulsatile flow is associated with elevated vascular resistance, increased muscular sympathetic nervous system activity, coronary artery disease, limited oxygen consumption, and interruption of cerebral autoregulation.23 These factors have been associated with increased incidence of ABI29 in non-ECMO patients. Additionally, patients undergoing coronary artery bypass graft with IABP and cardiopulmonary bypass  have been shown to have less endothelial activation33 and to observe a reduction in nitric oxide35 due to systemic inflammatory response syndrome.37 Patients on the ECMO circuit frequently experience extreme changes in hemodynamic parameters such as PaO217 and PaCO2,40 which were previously shown to be associated with ABI. These blood gas derangements, combined with already compromised endothelium function and nonpulsatile cerebral blood flow,41 may lead to ABI. Additionally, as left ventricular (LV) venting may lower PP and further predispose VA-ECMO patients to ABI, future research is warranted to investigate the effects of tMCS such as IABP and Impella® on the association between PP and ABI.There may be multiple mechanisms at play that can lead to PP influencing ABI in this cohort. One potential mechanism relates to the loss of pulsatility that occurs inherently with VA-ECMO and is enhanced by adjustment of pump speeds,2 consumption and impaired cerebral autoregulation, potentially contributing to CNS ischemia.21 Furthermore, low PP can indicate inadequate cardiac contractility, and thus systemic hypoperfusion, which may increase the risk of CNS ischemia. Interestingly, in contrast to previous literature describing that a larger delta PaCO2 was associated with ICH,42 our study demonstrated that delta PaCO2 was associated with CNS ischemia rather than ICH. These results did not persist in central VA-ECMO which may be due to different hemodynamic states between both cohorts.13 Other additional key factors such as the use of systemic anticoagulation, duration of ECMO support, hemolysis, and platelet imbalance may also be involved in the pathophysiology of ICH.43 Overall, these findings suggest that additional research is necessary to clarify how certain risk factors lead to either CNS ischemia or ICH in peripheral VA-ECMO patients.Our results demonstrated that low PP was associated with CNS ischemia but not ICH in peripheral VA-ECMO. Induced by ECMO circuit, the absence of pulsatility is associated with reduced O17 an increase in PaO2 was a protective factor for ABI in our analysis. One explanation is that aggressive oxygen therapy helps mitigate the effects of potential hypoxemia during ECMO support as hypoxemia in ECMO patients is well documented.45 Furthermore, a higher PaO2 may help increase regional brain oxygen tension46 and accordingly improve the cerebral metabolic rate of oxygen. We also note we did not “bin” PaO2 values (continuous variable) by groups as this previous study did which may increase their risk of bias.47 Overall, these results suggest that additional research with methodically rigorous study design is necessary to elucidate the mechanisms regarding how these physiological variables lead to ABI in continuous blood flow under the ECMO circuit.Interestingly, unlike a previous study suggesting severe hyperoxia is associated with ABI,48 LV venting,49 or pulsatile ECMO flow50 to improve hemodynamics. Notably, our analysis showed that the use of vasopressors before ECMO support was protective of ABI, supporting our speculation. Additionally, upon recognizing low PP, clinicians can consider more vigilant and standardized neuromonitoring strategies to ensure adequate cerebral perfusion and prevent occurrence/worsening of ABI, which is especially important in peripheral VA-ECMO due to the potential for differential oxygenation.51Early assessment and recognition of myocardial function using low PP during the first 24 hours of ECMO support has important clinical implications. Recognizing low PP may allow providers to promptly develop appropriate management techniques, including fine-tuning ECMO settings and using inotropes/vasopressors,52 Furthermore, it is unclear how such variance would systematically bias our results as any variation should be at random and thus favor the null hypothesis. Additionally, low PP may represent a population with higher severity of illness which may explain the higher occurrence of ABI despite attempting to account for this with statistical modeling. The ELSO Registry also does not contain specific anticoagulation data, which is a known risk factor for ABI. Nevertheless, we adjusted for many ECMO-specific and clinically relevant covariates in our analysis, and low PP was still independently associated with ABI. Additionally, our study represents the largest and most comprehensive analysis to-date investigating the association between PP and ABI in VA-ECMO patients. We also used methodically rigorous methods in our analysis including multiple imputation to handle missing data, thus minimizing bias and invigorating the validity of our analysis53 and cubic spline analysis when identifying a PP threshold to abate the loss of information and poor predictions when using continuous variables.54 We also excluded ECMO patients simultaneously on LV venting devices as LV venting can directly modulate the PP in ECMO and thus could potentially confounding our findings.3 Finally, the optimum ECMO pump flow rate based on body surface area for each patient was not able to be determined in the ELSO Registry and should be noted.Our analysis was retrospective and observational, thus limiting our ability to determine causation effects. Additionally, the ELSO Registry lacks granular ABG data, only allowing us to extract one pre-ECMO and one on-ECMO data point for each patient in our analysis. Similarly, for PP we are limited to a single value at 24 hours, however, it is unclear if there is significant variance over the first 24 hours that would influence interpretation. This methodology has also been previously validated in an ELSO Registry analysis of PP and mortality in 2,400 VA-ECMO patients.In the largest analysis to-date of peripheral VA-ECMO patients with CS, a PP reading of 10 mmHg or less at the 24-hour time point of ECMO support was associated with increased occurrence of ABI. Low early PP was also uniquely associated with CNS ischemia but not ICH. Accordingly, PP during ECMO support may serve as a distinct marker for ABI in this high-risk population. Given these findings, prospective observational studies investigating the association between PP and ABI with granular data and standardized neurological diagnoses is warranted.


Early diagnosis of spinal tuberculosis (STB) remains challenging. The aim of this study was to develop a predictive model for the early diagnosis of STB based on conventional laboratory indicators.The clinical data of patients with suspected STB in four hospitals were included, and variables were screened by Lasso regression. Eighty-five percent of the cases in the dataset were randomly selected as the training set, and the other 15% were selected as the validation set. The diagnostic prediction model was established by logistic regression in the training set, and the nomogram was drawn. The diagnostic performance of the model was verified in the validation set.A total of 206 patients were included in the study, including 105 patients with STB and 101 patients with NSTB. Twelve variables were screened by Lasso regression and modeled by logistic regression, and seven variables  were finally included in the model. AUC of 0.9468 and 0.9188 in the training and validation cohort, respectively.In this study, we developed a prediction model for the early diagnosis of STB which consisted of seven routine laboratory indicators. AccordiSpinal tuberculosis (STB) is an extrapulmonary manifestation of tuberculosis that occurs as a secondary infection caused by Mycobacterium tuberculosis in the spinal vertebrae and adnexal tissues. STB accounts for approximately 2% of all tuberculosis cases and 50% of all osteoarticular tuberculosis cases. Worldwide, the annual incidence of spinal tuberculosis exceeds 100,000 . STB canHowever, early diagnosis in patients with spinal tuberculosis has been difficult, and cases are frequently missed or misdiagnosed . PatientIn our present study, we collected routine laboratory serology upon admission of patients with spinal tuberculosis, screened variables by lasso regression, built a model by logistic regression, and drew a nomogram for the early diagnosis of spinal tuberculosis based on a model used for patients in a multicenter retrospective study.22.1This study included 206 patients with suspected spinal tuberculosis who were admitted to the Xiangya Hospital of Central South University, Xiangya Boai Hospital, Changsha First Hospital, and Hunan Chest Hospital from January 2016 to October 2022. The data of the included patients were taken from the first routine serological examination at the time of patient admission for treatment. The inclusion criteria were as follows: 1. CT and MRI reports of patients included in the study showed that patients had suspected spinal tuberculosis, including irregular lytic lesions or bone destruction that affect the vertebral body, endplate, or adjacent margin of the intervertebral disc, featuring fragmentary destruction, osteolytic destruction, and local destruction with sclerotic margins. Intervertebral disc destruction or decreased disc height, calcification or bone fragment formation accompanied by abscesses, vertebral collapse or posterior convex deformity, as well as soft tissue involvement and large paravertebral abscesses ; 2. PatiPatients included in this study were diagnosed with spinal tuberculosis if they met one of the following criteria : 1. posiPatients were classified into the NSTB group based on the following criteria: 1. microbiological evidence that the infection was caused by other bacteria, fungi or viruses; 2. pathological histological diagnosis of other lesions of the spine (including septicemia and tumors).Ethical Approval: Institutional Review Board approval was obtained (IRB#: 201303232). This study was approved by the Ethics Committee of Xiangya Hospital Central South University, and written informed consent was obtained from all patients.2.2We collected the following routine laboratory test data at the time of admission for the study population: tubercle bacillus antibody (TB.antibody), interferon-γ release assays (IGRAs), white blood cell (WBC), red blood cell (RBC), hemoglobin (HGB), platelet (PLT), neutrophil (Neut), lymphocyte (lymph), eosinophil (EO), basophil (BASO), monocyte (Mono), neutrophil % (Neut%), lymphocyte % (Lymph%), basophil % (BASO%), eosinophil% (Eo%), monocyte % (Mono%), red blood cell distribution width (RDW), platelet volume (PCT), mean platelet volume (MPV), total protein (TP), albumin (A), globulin (G), albumin/globulin (AG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), triglyceride (TG), cholesterol (Chol), high-density lipoprotein (HDL), low-density lipoprotein (LDL), glucose (BS), prothrombin time (PT), activated partial thromboplatin time (APTT), international normalized ratio (INR), D dimer (DD), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP).2.3All statistical analyses and graphing were based on R version 4.2.2. The “CBCgrps”  package 33.1A total of 206 patients with suspected spinal tuberculosis were enrolled according to the inclusion and exclusion criteria established for the study. We diagnosed 105 cases as spinal tuberculosis and 101 cases as non-STB according to the diagnostic criteria. The characteristics of the patients, routine laboratory data, and the results of statistical comparisons of these indicators between the STB and NSTB groups are presented in 3.2The results of the univariate analyses for STB patients and NSTB patients are presented in 3.3We observed a strong correlation between some of the variables in our dataset  screened by Lasso regression, and we excluded variables that were not significant in the logistic regression model. We finally included seven variables, including TB.antibody, IGRAs, RBC, Mono%, RDW, AST, and BUN. We rebuilt the logistic regression model with these seven variables and drew a nomogram based on the logistic regression model that could be used in clinical practice Figure 33.5We first plotted the calibration curve of the model in the training set . Nevertheless, by plotting the ROC curves and calculating the AUC, we found that, except for IGRAs, which had good performance in the diagnosis of STB (AUC = 0.8326), other variables did not play a significant role in the diagnosis of STB (AUC < 0.7). An increasing number of studies have shown that one indicator alone is often unable to lead to a valid and accurate diagnosis, and the use of multiple indicators is more widely applicable. To meet practical clinical needs and minimize test costs, combining multiple routine laboratory tests to improve the early diagnostic efficacy of spinal tuberculosis can be applied for patients with spinal tuberculosis in underserved and remote areas.Thirty-eight routine laboratory test variables and 2 other variables, including the age and sex of the patients, were included in this study. The variables selected are generally available at most hospitals to ensure practical application of the predictive model. Correlation analysis identified a high correlation between many of the variables, and this could be observed on the correlation heatmap. The problem of multicollinearity among the characteristics could not be resolved in the stepwise regression local optimum estimation of logistic regression . TherefoLogistic regression was used to construct a predictive model for spinal tuberculosis. Twelve variables identified by Lasso regression were included in the logistic regression equation, and variables that were not significant in the logistic regression model were eliminated. Finally, seven variables were retained, including TB.antibody, IGRAs, RBC, Mono%, RDW, AST, and BUN were retained, and the model was refitted with these variables. Column line plots were drawn for better applicability to clinical practice. To evaluate the predictive model, we plotted calibration curves and ROC curves in a validation cohort different from the training cohort. The calibration curves showed a good fit, and the prediction model achieved an AUC value of 0.9188 in the validation cohort. The final model had good diagnostic validity. Based on our findings, increased levels of RBC, RDW, and mono% in patients could indicate a greater likelihood of STB diagnosis, whereas elevated BUN and AST levels may suggest a higher probability of NSTB diagnosis. In previously published studies, elevated RDW and mono% were commonly observed in patients with TB . PatientIn published studies, we noted that Liyi ®).TB, both of which share a similar underlying principle. Moreover, previous studies have highlighted the potential utility of the TBAg/PHA ratio as a means of improving diagnostic accuracy in tuberculosis (®).TB for spinal tuberculosis in a larger cohort of patients.To enhance the generalizability of our model, we incorporated two distinct methods for IGRAs, namely QuantiFERON-TB Gold In-Tube and T-SPOT(rculosis , with parculosis . AlthougThis study was a retrospective study, and due to missing data, we excluded some cases and other factors, such as calcitoninogen and body mass index, that might have been meaningful. We intend to conduct further prospective studies informed by our present results which will include complete clinical data and patient imaging data to further improve the early diagnosis of spinal tuberculosis.5In this study, we developed a nomogram to predict the occurrence of spinal tuberculosis for early diagnosis. Our model contained seven conventional laboratory indicators, including TB.antibody, IGRAs, RBC, Mono%, RDW, AST, and BUN. We hope to use this model to improve the early diagnosis of STB, especially in hospitals in poor and remote areas where testing is limited.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Xiangya Hospital Central South University. The patients/participants provided their written informed consent to participate in this study.XH and QG designed research, performed research, analyzed data, and wrote the paper. HZ, MT and SL developed the idea for the study. GZ, BT and DX collected the data. All authors contributed to the article and approved the submitted version.