Methods: In this monocentric, retrospective data analysis, the reliability of continuous non-invasive blood pressure measuring using ClearSight® (Edwards Lifesciences Corporation) is validated in 31 women undergoing central neuraxial anaesthesia for caesarean section. In addition, patients and professionals evaluated ClearSight® through questioning. Results: 139 measurements from 11 patients were included in the final analysis. Employing Bland–Altman analyses, we identified a bias of −10.8 mmHg for systolic, of −0.45 mmHg for diastolic and of +0.68 mmHg for mean arterial blood pressure measurements. Pooling all paired measurements resulted in a Pearson correlation coefficient of 0.7 for systolic, of 0.67 for diastolic and of 0.75 for mean arterial blood pressure. Compensating the interindividual differences in linear regressions of the paired measurements provided improved correlation coefficients of 0.73 for systolic, of 0.9 for diastolic and of 0.89 for mean arterial blood pressure measurements. Discussion: Diastolic and mean arterial blood pressure are within an acceptable range of deviation from the reference method, according to the Association for the Advancement of Medical Instrumentation (AAMI) in the patient collective under study. Both patients and professionals prefer ClearSight® to oscillometric blood pressure measurement in regard of comfort and handling. The close monitoring of blood pressure during a caesarean section performed under central neuraxial anaesthesia should be the standard of safe anaesthesia. As classical oscillometric and invasive blood pressure measuring have intrinsic disadvantages, we investigated a novel, non-invasive technique for continuous blood pressure measuring.  The incidence of hypotension during the induction of central neuraxial anaesthesia for caesarean section is up to 74% , resultiIn the perioperative setting, blood pressure usually is measured oscillometrically by pneumatic transmission between the brachial artery and an upper arm cuff. The mean arterial pressure (MAP) is measured directly, whereas the systolic and the diastolic arterial pressures are derived using corresponding algorithms . MAP is The gold standard for measuring blood pressure in an operating room or intensive care unit (ICU) still relies on invasive measurements through the catheterisation of an arterial vessel. The key advantage is the direct beat-to-beat measurement of the blood pressure. Maheshwari et al. demonstrated that during non-cardiac surgery the continuous monitoring of haemodynamic parameter is able to significantly lower the rate of hypotension compared to non-continuous monitoring . However® , has been conceived to complement the advantages of both invasive and non-invasive blood pressure measuring. This device non-invasively outputs a continuous blood pressure curve. To investigate the accuracy of ClearSight® for blood pressure monitoring during labour, we compared ClearSight® against the established oscillometric method during an extended evaluation-phase and asked the patients and attending physicians regarding their preferences for distinct methods to measure the blood pressure. These data were obtained during clinical routine and were retrospectively analysed and described in this manuscript.ClearSight® (Edwards Lifesciences Corp.). Measurements were obtained between January 2021 and March 2021 at the Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine at the University Hospital Würzburg. The data were analysed retrospectively in accordance with Article §27 of Bavarian hospital law as they were obtained during routine procedures. In addition, we declared all analyses performed on these data to the local ethics committee of Würzburg (ref. nr. 20210903/01). For our benchmark of ClearSight® against oscillometric blood pressure measurements, we only included patients undergoing primary or secondary, non-emergency caesarean sections. Epidurals, spinal or combined spinal epidural anaesthesia (CSE), were required for inclusion. Exclusively patients with sinus rhythms and more than five data points for comparison between the two measuring methods were considered in our analysis. The primary endpoint was defined as the difference between oscillometric blood pressure measurement and ClearSight® according to the Association for the Advancement of Medical Instrumentation (AAMI). Secondary endpoints were defined as patient comfort and physician’s preferences for blood pressure measuring methods.Within the context of quality management of an extended non-invasive haemodynamic monitoring system in obstetric anaesthesia, vital parameters were recorded simultaneously according to both established clinical protocols (Philips MX750 and Philips IntelliVue X3) and ClearSight®, single-shot spinal anaesthesia (SSA) was performed in a sitting position under sterile conditions according to established clinical protocols. Parallel to co-loading with 1000 mL of balanced crystalloid infusion solution (Sterofundin©), lumbar spinal anaesthesia (level: L3/4 or L4/5) was performed with an atraumatic Sprotte needle . After the positive aspiration of cerebrospinal fluid (CSF), 9–10 mL of a mixture containing local anaesthetic and opioid (4 ml bupivacaine 0.25% isobaric plus sufentanil 5 µg plus 5 mL Sodium chloride 0.9%) were carefully injected intrathecally [®) and, respectively, a special CSE needle . A loss-of-resistance to the saline method was used to identify epidural space, and subsequently a catheter  was inserted epidurally. In case of insufficient analgesia, ropivacaine 0.75% (up to 10 mL) was administered. If an epidural catheter was already in place, a top-up with 15–20 mL of ropivacaine 0.75% was administered for secondary caesarean section. Adequate analgesia was confirmed when a TH5 level was achieved. Hypotension was treated according to established clinical protocols, at the discretion of the attending anaesthesiologist. Hypotension was defined by clinical standards as MAP < 65 mmHg or a systolic blood pressure < 90 mmHg. After implementing clinical monitoring and ClearSightthecally . Epidura® finger sensor was attached to the left index finger. Concurrently, vital and haemodynamic parameters were displayed in parallel on a monitor (Philips MX750). These finger sensors were available in three different sizes that could be further adapted individually. Data were stored in the anaesthesia database of the hospital’s patient data management system (PDMS), Copra . As part of the standard electronic documentation system in the operating room, body-mass-index (BMI), physical status according to ASA (American society of Anesthesiologists) classification, type of intervention, the medication administered and the measurement location of ClearSight® were routinely documented. Both the anaesthesiologists and the patients were surveyed on a voluntary basis regarding their preferences for either of the employed measuring devices. Corresponding results served as internal quality management and provided practical experiences when deciding on acquiring the ClearSight®. In addition to standard monitoring by cuff-based, non-invasive blood pressure measurements (NIBP) on the right upper arm, a ClearSight® blood pressure measurements from the corresponding values obtained by the reference method [n = 11.All statistical analyses of the primary data were performed employing the R platform (V.4.1.0). Following reports from the literature and recommendations by AAMI, we considered a difference of 5 mmHg with a SD of ±8 mmHg between the compared measurement methods as acceptable . To invee method ,15. We fe method . In orde® was used in 31 subsequent childbearing patients undergoing caesarean section. Twenty-seven patients underwent primary and four patients underwent secondary caesarean section. From the beginning, we excluded in our analysis two patients who underwent caesarean sections under general anaesthesia. Spinal anaesthesia was established in twenty patients, eight patients received CSE and in one patient epidural anaesthesia was topped up for a secondary section. A patient with atrial fibrillation was further excluded from the analysis. Seventeen patients could not be included in the analysis due to insufficient data quantity with less than five paired measurements, because non-invasive blood pressure measuring was deactivated by the attending anaesthesiologist after establishing ClearSight®. The period during which measurements were observed thereby extended over the entire intervention period with a measurement interval of the non-invasive blood pressure of >5 min. Eventually, eleven patients  with, in total, 139 paired measurements, were included in our further analysis . Almost all patients developed hypotension, requiring vasopressor therapy during the placement of neuraxial anaesthesia, including the subsequent caesarean section. Of the patients, 96.7% received cafedrine/theodrenaline (Akrinor®) to treat hypotension. A satisfaction survey showed that 93.4% of the patients and 96.7% of the anaesthesiologists preferred ClearSight® to conventional oscillometric measurement. 2 and ASA category II.ClearSight® achieved PCC values of 0.67  for diastolic blood pressure, a PCC of 0.7  for systolic blood pressure and a PCC of 0.75  for mean blood pressure  and first assessed collinearity by linear regression and calculating the corresponding PCC. Compared to the oscillometric measurement, ClearSightpressure . Subsequently, we also assessed the presence of systematic biases between the two investigated measuring methods employing Bland–Altman plots. Our analyses pinpoint a bias value of −0.45 mmHg for diastolic blood pressure, a bias of −10.8 mmHg for systolic blood pressure and a bias of +0.68 mmHg for mean blood pressure .® can be employed for continuous, non-invasive blood pressure monitoring during caesarean sections under neuraxial anaesthesia. Based on our small cohort, an acceptable agreement, according to the AAMI, between the established oscillometric blood pressure measurement with ClearSight® for diastolic and mean arterial pressure was shown. However, systolic blood pressure measurements are beyond these limits of acceptance. Based on a survey of professionals and patients, ClearSight® is superior to the conventional oscillometric blood pressure measuring both concerning early warnings for hypotensive episodes and also with respect to better patient comfort.The results of our pilot study demonstrates that ClearSight® are based on two distinct methods, namely the volume clamp method and the so-called “PhysioCal”. Based on the volume clamp method, the diameter of the artery is kept constant by applying external pneumatic pressure by a finger cuff [Blood pressure measurements by ClearSightger cuff . This diger cuff . Adjustmger cuff . ® in different cohorts. Our observations that the deviation of systolic blood pressure measurements by ClearSight® are outside the AAMI limits confirm the results of the study by Tani et al., Rogge et al. and Schumann et al. [n = 90) and Rogge et al., with the most data points of almost 100,000 [® compared to the oscillometric control group [® offers the ability to predict hypotension based on a machine-learning index—the so-called “Hypotension Prediction Index” (HPI). Frassanito et al. determined a sensitivity and also a specificity of 0.85 for ClearSight® by correctly predicting hypotension 15 min before the event under general anaesthesia in major surgical procedures [n et al. ,20,21. T 100,000 ,21. Furtol group . In addiocedures . Focusinocedures . ® and the established standard (transthoracic echocardiography) in 44 pregnant women [®-guided goal-directed fluid therapy [® is a valid alternative, especially for surgical procedures with limited access to the patient’s upper arms [® can be placed easily [Haemodynamic parameters, such as stroke volume, stroke volume variation, systemic vascular resistance, and cardiac output, play an important role, particularly in pregnant women due to their physiological changes. Duclos et al. therefore compared the accuracy of stroke volume and cardiac output measurements between ClearSightnt women . The aut therapy . Also acper arms . Highligd easily .Besides the investigated volume-clamp method, other alternative methods for blood pressure measurements are pulse wave velocity/pulse transit time or through applanation tonometry ,34. Furt® and the reference method. Importantly, we demonstrate that in our dataset the linear models, which regressed for the paired measurements of each patient individually, differ in slope and shift. Hence, a straightforward analysis on measurements obtained from different patients underestimates the true correlation, but biases can successfully be alleviated when combining individual PCC estimates through transformed Z-scores. These observations are likely to have an even higher impact on larger studies with more patients. Furthermore, we exclusively analysed immobilized patients. In this light, no conclusion can be drawn about the possible use of ClearSight® in mobile patients or in outpatients. Our study provides by design no insights on whether certain risk groups of pregnant women benefit from the use of continuous blood pressure monitoring. Additionally, concerning the positive judgment regarding the early detection of hypotensive episodes, observer biases can be intrinsic to the approach taken in this study. Regarding the interpretation of our results, some constraints may arise due to the retrospective and single-centre design of our study, allowing us to investigate only a limited number of cases. Due to the limited sample size, we cannot confidently exclude the possibility of under powering some of the single patient analyses. However, the number of paired measurements allowed the conclusion of a significant correlation between ClearSight® are within the acceptable range, according to AAMI, in our limited cohort. Both patients and medical professionals prefer ClearSight® to conventional oscillometric measurement in terms of comfort and handling. In conclusion, ClearSight® has the potential to become the new standard for close blood pressure monitoring and early detection of supine hypotension syndrome during caesarean section with neuraxial anaesthesia. The measurements of mean arterial blood pressure and diastolic blood pressure using ClearSight


The aim of the study was to study the effects of the ultrasound-guided stellate ganglion block on hemodynamics, stressful response, and postoperative gastrointestinal functions in patients with colorectal cancer.  A total of 100 patients with colorectal cancer hospitalized from January 2021 to December 2021 were selected. After anesthesia induction, the right stellate ganglion block was performed under ultrasound guidance in the research group and the general anesthesia was performed in the control group. The heart rate (HR), mean arterial pressure (MAP), epinephrine, cortisol, self-rating anxiety scale (SAS), Ramsay sedation score (RSS), postoperative bowel sound recovery time, anal exhaust time, and the incidence of gastrointestinal adverse reactions 24 hours after operation were studied pre-and post-24-hour anesthesia induction. p < 0.05). Following 24-hour operation, epinephrine and cortisol became obviously higher (p < 0.05). After 24-hour operation, the levels of epinephrine and cortisol in the research group were greatly lower. The score of the SAS in the study cohort was less than that of the controls (p < 0.05). The RSS of the research group was obviously increased (p < 0.05). The recovery time of intestinal sound and the anal exhaust time of the study cohort became remarkably shorter (p < 0.05). The incidence of gastrointestinal adverse reactions 24 hours after operation of the study cohort was much less common (p < 0.05).  Following 24-hour operation, the HR and MAP values were largely reduced ( The ultrasound-guided stellate ganglion block can reduce the fluctuation of blood circulation during radical resection of colorectal cancer, reduce postoperative gastrointestinal dysfunction and stress reaction, relieve patients' anxiety, and contribute to the recovery of gastrointestinal function. Colorectal cancer is a malignant disease with a high incidence. Most of the patients had no obvious symptoms in the early stage, and most of the patients are found in the middle and the late stage. Common clinical manifestations are usually changes in defecation habits, such as abdominal pain and diarrhea . Among tSo far, the most important and effective treatment for colorectal cancer is surgical treatment , 8. In aPrevious studies have shown that the stellate ganglion block (SGB) can inhibit surgical stress and inflammation and adjust the level of gastrointestinal hormones in rats undergoing gastrointestinal surgery , so that2, with an average BMI of (21.48 ± 2.33) kg/m2. In the control group, there were 24 males and 26 females, aged from 47 to 69 years, with an average age of (58.42 ± 4.17) years. The body mass index was 18.6∼24.0 kg/m2, with an average BMI of (21.51 ± 2.29) kg/m2.A total of 100 patients with colorectal cancer hospitalized from January 2021 to December 2021 were selected. A total of 100 patients with colorectal cancer were randomly divided into the study cohort and the control cohort, including 50 cases, respectively. In the research group, there were 25 males and 25 females, aged from 48 to 69 years old, with an average age of (58.36 ± 4.22) years. The body mass index was 18.5∼24.0 kg/mInclusion criteria were as follows: (1) patients who underwent colorectal cancer surgery within a limited period of time; (2) patients aged between 45 and 65 years old; (3) ASA grade I∼II; (4) cardiopulmonary function was basically normal, no obvious heart, liver, kidney, endocrine diseases, preoperative laboratory, and related imaging examination results were not significantly abnormal.Exclusion criteria were as follows: (1) patients with a history of upper respiratory tract infection within 2 weeks; (2) those with an obvious abnormality of heart, liver, and renal function; (3) those with a history of drug and alcohol abuse; (4) those with a history of allergy to narcotic drugs; (5) long-term use of anticoagulant drugs; (6) those with skin injury or infection at the puncture point of the neck; (7) those with an abnormal immune system; (8) those who refused to participate in this study; (9) the clinical data were incomplete.As shown in The patients visited the day before the operation and were asked about their relevant medical history. The patient and his family were informed about the anesthesia-related procedures and possible complications.μg·kg−1, propofol 1.5∼2.0 mg·kg−1, and cis atracurium 0.2 mg·kg−1. The patient's BIS was in the range of 45 to 55, the muscle was completely relaxed, and endotracheal intubation was performed using a visual laryngoscope. After successful intubation, mechanical ventilation was performed, and the tidal volume was 6∼8 ml·kg−1. The partial pressure of end-expiratory carbon dioxide was maintained at 35∼45 mmHg, and the respiratory rate was adjusted according to the partial pressure of end-expiratory carbon dioxide. Continuous intravenous infusion of propofol and remifentanil was used for sedation and analgesia during anesthesia maintenance. The maintenance dose was adjusted according to the BIS value, which should be maintained in the range of 50–60. For the fluctuation of hemodynamics during operation, under the condition of ensuring the appropriate depth of anesthesia, the blood pressure was maintained in the range of ±20% of the basic value. Above or below this range, urapidil or ephedrine can be administered to regulate blood pressure. When the blood pressure was reduced, fluid replacement treatment can be carried out according to the specific conditions. The heart rate would be maintained at 50∼100 beats/min. If it was higher or lower than this range, after excluding the causes of blood loss, arrhythmia, and improper depth of anesthesia, intravenous injection of esmolol or atropine can adjust the heart rate.The control group received routine general anesthesia. After entering the room, the peripheral venous pathway was established. The electrocardiogram, heart rate, blood oxygen saturation, noninvasive arterial blood pressure, and EEG bispectral index were monitored by using the Drager Infinity C500 anesthesia monitor. All patients were given general anesthesia by endotracheal intubation. Anesthesia induction consisted of midazolam 0.03 mg/kg, fentanyl 3∼5 In the research group, the right stellate ganglion block was performed under ultrasound guidance after anesthesia induction. After induction of general anesthesia, the planetary ganglion was blocked at the level of the seventh cervical vertebra on the right under the guidance of ultrasound. The medical staff arranges the patient to lie down, turns the patient's head to the left, disinfects the puncture point, and spreads a surgical towel. After determining the structures of the thyroid, carotid artery, vertebral artery, inferior thyroid artery, trachea, and esophagus, the puncture needle was inserted from the lateral transverse plane of the probe, and the carotid sheath was pushed to the outside as far as possible. To avoid vascular damage, when the tip of the needle entered the deep side of the prevertebral fascia on the surface of the cervical longus muscle, 0.2% ropivacaine hydrochloride 4 ml is slowly injected after pumping no blood, gas, or cerebrospinal fluid.μg·kg−1+tropisetron 4 mg + dexmedetomidine 0.1 μg·kg−1·h−1 diluted to 100 ml to relieve postoperative pain. After the patient entered the anesthesia recovery room, a suitable position for the patient was arranged. In addition to psychological support measures by using words such as comfort and encouragement, nurses needed to make use of nonverbal skills, such as guiding patients to communicate with patients by blinking, nodding, and shaking their heads. Mental health education was given after the patients were fully conscious. According to the patient's own tolerance, the nurse carried out massage nursing to the patient according to the standard of gentle operation.Tropisetron was administered intravenously 30 minutes preoperation ending. The intravenous analgesia pump was routinely used in all patients after operation. The formula was fentanyl 10 To study the heart rate (HR) and mean arterial pressure (MAP) before anesthesia induction and 24 hours after operation.To study the levels of epinephrine and cortisol before and 24 hours after anesthesia induction, peripheral blood 5 ml was collected and centrifuged at 3000 for 5 minutes. The supernatant (plasma) was stored in a refrigerator at −80°C. The levels of adrenaline and cortisol were detected by using the ELISA kit. All ELISA kits are purchased from the CUSABIO company.α coefficient was 0.94. The score range of the scale was 1–6.To study the scores of the self-rating anxiety scale (SAS) and the Ramsay sedation score (RSS) during anesthesia recovery, the score of the SAS was divided into 4 grades, including 20 items , of whicTo study the recovery time of intestinal sound and the time of anal exhaust after operation.To study the incidence of gastrointestinal adverse reactions 24 hours after operation.s). The paired samples t-test was employed for intragroup comparisons, and the independent sample t-test was used for inter-group comparisons. p < 0.05 was considered statistically significant.The statistical analyses of the results were carried out by SPSS 24.0. Statistical figures were plotted by Graphpad Prism 8.0. Data conforming to a normality distribution were represented as the mean ± standard deviation (±p < 0.05). See Tables Twenty-four hours after operation, the HR and MAP values in both groups were significantly lower than those before anesthesia induction (p < 0.05). Twenty-four hours after operation, the levels of epinephrine and cortisol in the research group were considerably lower than those in the control group (p < 0.05) . The RSS score of the research group was greatly higher (p < 0.05) ( see The score of the SAS in the study cohort was considerably less than that in the control group (05)  see .p < 0.05)  see .p < 0.05)  see .Colorectal cancer is a malignant tumor of the digestive system, which is caused by genetic, environmental, and other factors. The global mortality rate of colorectal cancer is about 50%, with the fourth fatality rate . The incThe sympathetic nervous system is widely distributed in the palace of primary and secondary lymphoid organs. The adrenergic receptors are also widely distributed in immune cells such as macrophages and neutrophils. When sympathetic excitation occurs, sympathetic postganglionic fibers release catecholamines to activate adrenergic receptors of immune cells in lymphoid organs , 30. In The stellate ganglion is a kind of a sympathetic ganglion. Its fibers can widely dominate the skin of the heart, brain, throat, shoulder and neck, trachea and bronchus, lung, and chest wall . The steThe results have proved that the ultrasound-guided stellate ganglion block can reduce the fluctuation of blood circulation, reduce the concentration of epinephrine and cortisol in peripheral blood, and reduce gastrointestinal dysfunction and stress reaction after operation. The anxiety can be relieved during the perianesthetic period so that the patients pass the anesthetic recovery period safely. This was mainly because all patients in this study underwent the ultrasound-guided stellate ganglion block by the same anesthesiologist. Some studies pointed out that the left stellate ganglion block can increase left ventricular diastolic pressure and myocardial oxygen consumption, weaken myocardial contractility, reduce the left ventricular ejection fraction, and increase the cardiac QT interval, while the right stellate ganglion block can effectively reduce sympathetic nerve activity, reduce cardiac oxygen consumption, and has little effect on circulatory fluctuation , 35. In In conclusion, the ultrasound-guided stellate ganglion block can reduce the fluctuation of blood circulation during radical resection of colorectal cancer, the concentration of epinephrine and cortisol in peripheral blood, and gastrointestinal dysfunction and stress reaction after operation. The anxiety can be relieved during the perianesthetic period to promote the recovery of gastrointestinal function after operation.


N = 28), the community setting (N = 4), both laboratory and community settings (N = 3), and during blood donation (N = 10). CPM improved standing systolic blood pressure  and heart rate , however, responses of total peripheral resistance, stroke volume, or cerebral blood flow were not widely documented. Most patients experienced symptom improvement following CPM use . The most prominent barrier to employing CPM in daily living was the inability to recognize an impending faint. Patterns of postural sway may also recruit the skeletal muscle pump to enhance cardiovascular control, and its potential as a discrete, proactive CPM needs further evaluation. Physical CPM were successful in improving syncopal symptoms and producing cardiovascular responses that may bolster against syncope; however, practical limitations may restrict applicability for use in daily living.Physical counter pressure maneuvers (CPM) are movements that are recommended to delay or prevent syncope (fainting) by recruiting the skeletal muscle pump to augment cardiovascular control. However, these recommendations are largely based on theoretical benefit, with limited data evaluating the efficacy of CPM to prevent syncope in the real-world setting. We conducted a semi-systematic literature review and meta-analysis to assess CPM efficacy, identify literature gaps, and highlight future research needs. Articles were identified through a literature search  of peer-reviewed publications evaluating the use of counter pressure or other lower body maneuvers to prevent syncope. Two team members independently screened records for inclusion and extracted data. From 476 unique records identified by the search, 45 met inclusion criteria. Articles considered various syncopal conditions . Maneuvers assessed included hand gripping, leg fidgeting, stepping, tiptoeing, marching, calf raises, postural sway, tensing , leg crossing, squatting, “crash” position, and bending foreword. CPM were assessed in laboratory-based studies ( Syncope   is commoUp to 30% of those who have fainted will experience recurrent and severe episodes . Living The final common pathway for syncope is a reduction in cerebral blood flow, which is exacerbated by orthostatic or gravitational stress, and as such syncope is typically associated with prolonged standing. When upright, gravitational fluid shifts redistribute blood into the lower limbs (venous pooling), which promotes capillary filtration and subsequent edema  20–23).–23.20–23The skeletal muscle pump  also helPhysical counter pressure maneuvers (CPM) are movements that promote cardiovascular stability and boost blood pressure through exploitation of the skeletal muscle pump, often accompanied by increases in sympathetic drive , 35–37. While CPM are often recommended to patients, these are based largely on clinical experience with a paucity of direct evidence for their benefit. Systematic reviews performed by Dockx et al. , and JenIn the present review, we take a semi-systematic approach to exploring the utility of CPM in syncope prevention. First, we provide an overview of the cardiovascular responses to these movements and explore plausible mechanisms for their utility. We also review the evidence for the efficacy and practical applicability of CPM that are currently recommended. Finally, we explore the role of postural sway in the maintenance of cardiovascular homeostasis, as this movement may provide a discrete, versatile, and accessible adjunct to currently recommended CPM.A semi-systematic approach was used to retrieve and review the current literature, as this is recommended for topics that have been conceptualized differently by various groups of researchers within diverse disciplines . This meN = 34), while articles that did not evaluate these common outcomes were discussed in narrative form (N = 45).In our literature search, we identified works evaluating the role of CPM and other lower body maneuvers in preventing syncope . The iniCardiovascular responses to CPM have been studied most widely, with 21 articles considering responses in the laboratory setting , 54–73. N = 628, p < 0.0001), demonstrating evidence of benefit of CPM for syncope prevention.Most studies reported that CPM were successful in improving both systolic (SAP) and diastolic (DAP) arterial pressure, as expected during sustained CPM. Isometric muscle contraction leads to concurrent increases in SAP and DAP, driven by a net increase in total peripheral resistance (TPR) which occurs largely due to the mechanical compression of the vasculature by working muscle , 76, 77.N = 539, p = 0.006)   and this= 0.006) . However= 0.006) , 78, 79.In almost all studies that reported CO responses, CO was increased following CPM. Given the small HR response to CPM identified in our combined analysis, this suggests that improvements in CO are likely driven by the well documented increase in SV (observed in every study that examined SV responses), reflecting improved venous return, and ultimately, effective skeletal muscle pumping , 35, 36.TPR responses during sustained (isometric) CPM were variable, with some studies reporting increases and some reporting decreases in TPR. This likely also reflects contradictory regulatory mechanisms with different CPM approaches. As with SV data, a combined analysis on TPR was not possible due to a lack of uniformity in reporting measures. During exercise, muscle mechanoreflexes and chemoreflexes promote increased TPR through increased sympathetic nerve activity. Of note, chemoreflex responses may not contribute to all findings reported, as they only become prominent after approximately 1 min of sustained muscular contraction , 63, 79.The final common pathway for syncope is a reduction in cerebral perfusion , 81, theaCO2 and PETCO2 . This mtriction , or perhCPM are considered a low-cost, first-line management strategy for syncope prevention , 73, 85.Our combined analysis revealed that CPM diminished symptoms of presyncope and syncope for 62 ± 4% of patients in the laboratory, and 72 ± 9% of patients when used in combination with usual care during activities of daily living . AlizadeThere was also a lack of standardized methodology to document patient symptoms, with those used often relying on patient reports or extended recall of events , 58, 65.Following the release of CPM, symptoms may return , 71, 73;Thus far, much of the documented benefit of CPM comes from laboratory studies, and few studies have included follow-up assessments considering their use in daily living , 90, 96.N = 121) and those treated with usual care (N = 141), we found no significant differences in time to first syncopal recurrence with the adoption of CPM (p = 0.004), which was associated with a number needed to treat of 5.75 patients (p = 0.004), and an odds ratio of 0.49 . Of note, in our combined analyses, we did not include studies that did not incorporate a control group (p = 0.005). The reasons for this discrepancy are unclear; all four studies recruited a similar patient population with a similar frequency of syncopal events prior to enrollment in the study. In summary, as noted previously, there was a clear benefit of CPM on cardiovascular responses during laboratory testing. However, the efficacy of CPM in the community setting is less clear, and this may reflect challenges with adopting CPM in the real-world.We conducted a combined survival analysis  for the available data reporting efficacy of CPM in the community setting . When con of CPM . Howeverol group , 96  of papers were retrieved providing preliminary evidence for a potential role of postural sway as a CPM . . N = 6) as a CPM .The fine movements initiated by postural sway, while small, recruit lower body musculature and may be sufficient to bolster against syncope through skeletal muscle pumping. The oscillatory nature of postural sway would yield benefits in comparison to classically recommended counter maneuvers, as postural sway is dynamic; thus, it may better promote pumping in the lower limbs, and could be performed proactively. Further, it can be performed in resting upright posture without a change in body position , and could therefore be more accessible to mobility limited patients. Indeed, postural movements correspond with blood fluid volume shifts, indicating that sway may reduce orthostatic pooling associated with capillary filtration , 42. AddEnhanced postural sway during quiet standing has been observed in populations with poor cardiovascular control . OtherwiWhile a relationship between postural behavior and cardiovascular control exists in this cohort, any underlying cause is still unclear. It may be that enhanced postural sway is a subconscious adaptation, or other compensatory mechanism to combat reduced cardiovascular control. Habitual leg restlessness, another discrete leg movement, has been noted in patients with orthostatic hypotension secondary to autonomic failure, and was also thought to reduce symptomatic drops in blood pressure . Trends While the contribution of locally  and neurally-mediated  responses to orthostatic stress are well understood, the regulation of skeletal muscle pumping in upright standing is less clear. Decreased blood pressure  and cereIntegration between blood pressure and cardiovascular control has also been evaluated mathematically through identifying the coherence , 133 andCPM are a mainstay component of syncope management recommendations, and offer a cheap and relatively risk-free means to abort or delay an episode of syncope that can be adopted in addition to other commonly used preventative management strategies . Physiological evidence suggests that CPM hold promise in syncope prevention, with demonstrable improvements in blood pressure, SV and CBFv; however, the effects of CPM on HR, CO and TPR are more complex, and require further investigation to assess their mechanistic underpinnings, as well as to ascertain whether the significant improvements reported hold practical significance. The real-world efficacy of CPM to prevent syncope is less clear and few studies have directly assessed CPM benefit in daily living. Community-based investigations are often limited by a lack of comparator group, and inconsistent quantification of treatment success.Ultimately, there is a need for rigorous clinical trials that include a placebo or control group in order to properly evaluate CPM efficacy. While it is recommended that patients learn multiple maneuvers so they can combine them in daily living, or select based on their social setting, abilities, or preference, comparisons between different CPM  would best inform clinical practice. Future trials should also include more diverse patient populations including those without a prodrome, pediatric patients, patients with POTS, and patients with cardioinhibitory VVS. These should evaluate improvement with consideration of each patient’s baseline episode frequency, presyncopal episodes that would have resolved without intervention, and improvements in patient quality of life after CPM introduction.There is emerging evidence that postural sway may contribute to the maintenance of cardiovascular homeostasis through activation of the skeletal muscle pump. Relationships between postural movements and cardiovascular responses have been identified that are suggestive of either a learned response of enhanced sway to combat orthostatic intolerance, or a more complex regulatory mechanism. While the oscillatory nature of postural sway has potential to serve as a dynamic CPM, more work is needed to identify the potential of this movement to enhance cardiovascular stability and prevent syncope.VC and EW conceived the manuscript. EW and FK conducted the search, screened articles for inclusion, and extracted data from included studies. All authors performed data analysis and visualization, interpreted the data, contributed to writing the manuscript and approved the final version for submission.


Background: The long-term benefits of conversion from calcineurin inhibitors (CNIs) to belatacept in kidney transplant recipients (KTr) are poorly documented.Methods: A single-center retrospective work to study first-time CNI to belatacept conversion as a rescue therapy . Patient and kidney allograft survivals, eGFR, severe adverse events, donor-specific antibodies (DSA), and histological data were recorded over 36 months after conversion.Results: We included N = 115 KTr. The leading cause for switching was chronic histological lesions with non-optimal eGFR (56.5%). Three years after conversion, patient, and death-censored kidney allograft survivals were 88% and 92%, respectively, eGFR increased significantly from 31.5 ± 17.5 to 36.7 ± 15.7 ml/min/1.73 m2 (p < 0.01), the rejection rate was 10.4%, OI incidence was 5.2 (2.9–7.6) per 100 person-years. Older age was associated with death, eGFR was not associated with death nor allograft loss. No patient developed dnDSA at M36 after conversion. CNI-induced TMA disappeared in all cases without eculizumab use. Microvascular inflammation and chronic lesions remained stable.Conclusion: Post-KT conversion from CNIs to belatacept, as rescue therapy, is safe and beneficial irrespective of the switch timing and could represent a good compromise facing organ shortage. Age and eGFR at conversion should be considered in the decision whether to switch.  Despite the improvement of kidney allograft short-term survival with conventional immunosuppressive agents, allograft long-term survival has not increased as expected . One of de novo belatacept treatment coupled with the improvement of estimated glomerular filtration rate (eGFR), and similar patient or kidney allograft survival in comparison with cyclosporine  reported long-term safety and efficacy of osporine .Since, growing evidence has suggested shifting KTr from CNIs-based regimen to belatacept, especially in those with low graft function or chronic histological lesions where belatacept is used as a rescue therapy –15. AddiIn this study, we assessed the safety and tolerability of belatacept treatment as a rescue therapy up to 3 years after switching from CNIs. Additionally, we analyzed kidney allograft function, patient and kidney allograft survival, and major outcomes after switching to belatacept and its effects on both DSA and kidney allograft histology changes.In this retrospective monocentric study, we included all adults KTr converted for the first time from CNI-based immunosuppressive regimen to belatacept from January 2012 to January 2019. Patients who tested negative for EBV before transplantation, pregnant women, or women not on any contraceptive methods were not included since they were not eligible to receive belatacept treatment.The KTr Cohort Was Approved by IRB #00003835.Early and late conversion groups were defined according to the time of conversion from KT to first belatacept infusion: < 3 months or >3 months, respectively. In early-stage conversion, CNIs were stopped at day 1, and KTr were given 10 mg/kg belatacept infusions at days 1, 5, 14, and 28, and weeks 8 and 12, and then 5 mg/kg from week 16 onwards, every 4 weeks. In late-stage conversion, CNIs were stepped down to 50% at day 14 and stopped at day 28 after conversion, and belatacept infusions were given at 5 mg/kg at day 1, 14, 28, and then every 4 weeks thereafter  included community-acquired infections requiring hospitalization, OIs, acute rejections, and neoplasia.dnDSA evolution, and 6) histological lesions evolution.Secondary endpoints were: 1) eGFR and urine protein/creatinine ratio (UPCR) evolution up to 3 years after conversion, 2) identification of different clusters of eGFR trajectory after conversion, 3) metabolic parameters  and blood pressure profile evolution, 4) CMV or BK viremia, 5) pre-existing and Mycobacterium sp., Listeria monocytogenes, and Nocardia sp.- Bacteria: - Viruses: Cytomegalovirus (CMV), Varicella-Zoster virus (VZV), Human Herpes Virus-8 (HHV8), Norovirus, BK virus nephropathy, and JC virus.- Fungi: Candida spp., Cryptococcus spp., invasive molds, and Pneumocystis jirovecii.- Parasites: Toxoplasma gondii, Microsporidium sp., Cryptosporidium sp., Leishmania sp.Community-acquired infections were considered only in case of hospitalization. Opportunistic Infection (OIs) were defined according to the current literature and international guidelines . OIs cau+/R− and 3 months in intermediate-risk patients CMV D+/R+ or CMV D−/R+ .2 and histological lesions associating ci + ct ≥ 3 and/or cv + ah ≥ 2.GFR was estimated using the Modification of diet in renal disease (MDRD) formula . IndicatDelayed graft function (DGF) was defined as the need for dialysis within 7 days after transplantation . Allograde novo DSA (dnDSA) on all HLA loci  at the time of KT, at conversion, at 3, 12, 24, 36, 48, and 60 months using high-resolution Luminex SAB assay technology  on Luminex platform. All beads with MFI >1,000 were considered positive  at the time of KT. All serum samples were assessed for the presence of circulating preformed DSA and positive . DnDSA wNaturally existing DSA antibodies , as well as IgM DSA, were not considered in our study .Patients underwent for-cause or protocol kidney allograft biopsies. Acute and chronic histological lesions were described according to the updated Banff classification .t-test or Wilcoxon test for continuous variables, and Chi-2 or Fisher exact tests for categorical variables. Paired t-test was used to compare quantitative variables at two different time points. In patients who had at least two kidney biopsies (before and after conversion), paired comparisons of histological lesions were performed using Mc Nemar test or binomial test.Continuous variables were presented in mean  or median  as appropriate, and categorical variables in number and percentage. We used Time to death and to allograft loss, and survival without rejection after conversion  were displayed with Kaplan Meier curves. Hazard ratios were estimated by the Cox regression model. Incident rates of SAEs were estimated per 100 person-years (PY) with their confidence interval and the inter-group ratio of such incidence rate.2) alone then death and allograft loss together. However, data missed because of belatacept treatment interruption over the 3-year period were not imputed since the causes of interruption were multiple.Sensitivity analyses of eGFR and proteinuria evolution after conversion to belatacept were performed with imputations of missing data regarding allograft loss  had an early-stage switch, and 76 patients (66.1%) were men.+/R−).At the time of transplantation , the mea).At the time of conversion , 10 2–2).N = 58/115 (51%) completed 36 months of follow-up. Of the remaining 57 patients who did not reach the third year time point, N = 26/57 discontinued belatacept , N = 13/57 died, N = 9/57 lost their KT, N = 8/57 did not complete 36 months, and N = 1/57 was lost to follow-up. Three of the study patients  aged more than 70 years old were treated for less than 3 months. The first developed BK virus nephropathy a month after conversion (blood BK virus replication >6 log at the time of switch), hence the interruption of belatacept. The other two patients were switched to belatacept for arterial thrombosis and primary non-function. Both developed rapid kidney allograft failure requiring renal replacement therapy and interruption of belatacept.The last follow-up checking was on August 30, 2021. Recipients were followed over 40.2 ± 30.1 months after conversion and 2 (p < 0.01). This significant increase was confirmed in the sensitivity analysis   .At the end of follow-up, 18/115 (16%) patients died, 12/115 (14%) had allograft failure, and 31/115 (26.9%) discontinued their treatment. The main causes of death were infection , including three cases of COVID-19, followed by cardiovascular diseases , and neoplasia . Allograft loss was mainly due to chronic allograft dysfunction ; other causes implied primary non-function , chronic antibody-mediated rejection (ABMR) , and BK virus nephritis .n = 10/31, 32.3%), albeit no patient discontinued because of allograft loss or death. None of the 31 patients who had their treatment interrupted died and N = 6/31 (19.3%) lost their kidney allograft within 1 year after belatacept interruption. Reasons for kidney allograft loss in those were as follows: N = 4/6 chronic dysfunction, N = 1/6 acute ABMR, and N = 1/6 severe focal and segmental glomerulosclerosis (FSGS).The leading cause of belatacept discontinuation was OIs episodes (p = 0.14) . Two patients developed another rejection episode. The most common rejection mechanism was acute T-cell mediated (TCMR) , occurring within the first 3 months after conversion. Incidence was similar in early and late switch groups  . Evolutip = 0.012). Among the N = 19 OI patients, the infection caused the death of N = 4/19 (21%), but no allograft loss was reported.Incidences rates of OI and community-acquired infections were 5.2 (2.9–7.6) and 15.6 (11.1–20) per 100 PY, respectively. The 19 OIs happened 10  months aMalignancies were reported in 14/115 (12.2%) recipients, the incidence rate was 3.9 (1.9–6.0) per 100 PY. Most of them had solid malignancy  and non-melanoma skin cancers . We documented one case of post-transplant lymphoproliferative disorder. Of the 14 cancer patients, none stopped belatacept treatment, one died of esophagus neoplasia within 6 months of diagnosis, and two lost their kidney allograft after chronic progressive kidney allograft dysfunction.The incidence rate ratio between late and early switch groups was similar for all of the studied SAE  .p < 0.01), previous KT (p = 0.01), eGFR <30 ml/min/1.73 m2 at the time of conversion (<0.01) (Two distinct eGFR trajectories were identified in the N = 114 recipients after conversion : traject (<0.01) . Other cdnDSA at the end of the follow-up.Before the switch, DSA was detected in N = 18/115 (15.7%) patients whose number remained stable over time after conversion , though p < 0.001). Microvascular inflammation (MVI) remained stable. As for the chronic lesions, all remained stable over time apart from the significant increase in tubular atrophy (p = 0.04).Among the 48 patients who underwent paired kidney allograft biopsies , the secWe herein report a large monocentric cohort in a real-life situation where KT recipients were switched from CNI-based regimen to belatacept and followed for 3 years. In this cohort, belatacept safety was confirmed. At year 3, the recipient and death-censored kidney allograft survivals reached almost 90%. Estimated GFR improved significantly over the 36-month period after conversion, regardless of the switch early or late timing. To our knowledge, our study is the second-largest cohort studying CNIs-to-belatacept conversion as a rescue therapy with at least 3-years outcomes assessment, the longest follow-up currently available in this indication.de novo belatacept and no CNIs are well known (2)  . We alsonown (2) , 28 and nown (2) . The cli2)  . Here weRecipient and kidney allograft survivals were up to 90% at year 3 after conversion and belatacept safety remained acceptable. Early and late switch groups had similar survivals, suggesting that belatacept could increase kidney allograft survival at any time after transplantation as in KTr with severe vascular lesions . Surviva3)  . Infecti3) .p = 0.031), which is consistent with eGFR improvement after belatacept conversion in our cohort   , 41. Theer study . DSA deter study , 42. Theated KTr .Despite some limitations including the monocentric, retrospective design and lack of control cohort, our study has several strengths: 1) 3-years post-switch follow-up in a real-life study design, 2) including recipients with impaired kidney allograft function who were potentially not eligible for randomized studies, 3) extensive data collection for each patient, from clinical characteristics to histological and DSA evolution. Data collection was exhaustive over a long follow-up interval.In conclusion, we showed that in real-life conditions, conversion from CNIs to belatacept, as rescue therapy, is safe and beneficial in terms of long-term kidney allograft preserved function. Patient and kidney allograft survivals were excellent 36 months after conversion with a low incidence of SAE (acute rejection or infections). The immunological risk remained stable after conversion. CNI-to-belatacept switch should also be considered in CNI-treated recipients who develop TMA without ABMR, and could stabilize chronic histological lesions. Prospective studies are warranted to confirm those results.


Obstructive airway disease is a major health problem and has a great impact on global socioeconomic burden. Despite therapeutic advances in recent decades, there is still a need for effective and safe therapeutic agents for patients with asthma or chronic obstructive pulmonary disease (COPD).  This prospective observational study explored the effects of herbal medicines in patients with asthma and COPD. All participants visited the hospital at least every 4 weeks for 12 weeks to receive their herbal medicines based on their pattern identification and to evaluate safety and efficacy endpoints. We followed the diagnostic criteria used by Korean medicine doctors to prescribe herbal medicines, explored variations in prescribed herbal medicines, and explored a number of clinical features in patients with asthma or COPD.  A total of 24 patients were enrolled: 14 were diagnosed with asthma and 10 with COPD and 19 completed the study. After 12 weeks of herbal medicine treatment, herbal medicines significantly improved the modified Clinical Asthma Measurement Scale in Oriental Medicine-V in asthma patients and the modified Medical Research Council Dyspnoea Scale and St. George's Respiratory Questionnaire in COPD patients. For all patients, modified Medical Research Council Dyspnoea Scale score and interleukin-13 were found to be significantly different after treatment. Additionally, the majority of patients were satisfied with our herbal medicine treatments, and no severe adverse events were reported during the study.  Our study provides preliminary clinical data on the safety and efficacy of herbal medicines in patients with asthma and COPD. Asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent obstructive airway diseases associated with chronic inflammation and airway obstruction . DespiteAsthma is defined by a history of respiratory symptoms such as wheezing, shortness of breath, chest tightness, cough, and variable airflow limitation. For the current treatment for asthma, bronchodilators and anti-inflammatory medications are primarily used to control symptoms and to reduce the risk of asthma . HoweverOver the past decades, complementary or alternative medicine (CAM), including herbal medicines, has been widely used for the treatment of asthma and COPD, with little risk and few complications. A previous study reported that 52% of patients with asthma and 33% with COPD had used CAM before . AnotherTherefore, in this study, we investigated the effects of various herbal medicines on asthma and COPD in real-world clinical practice at the Korean Medicine Hospital to identify candidates for novel therapeutic agents. We observed the diagnostic criteria used by Korean medicine doctors to prescribe herbal medicines, variations in prescribed herbal medicines, and diverse clinical features, including respiratory symptoms, lung function, quality of life, and physical activities in patients with asthma or COPD. We expect that our findings will be used as a basis to find an effective herbal medicine and to develop a well-designed clinical trial to confirm the safety and efficacy of herbal medicines in obstructive airway diseases.This prospective observational study explored the effects of herbal medicines in patients with asthma and COPD. The study was conducted at the Daejeon Korean Medicine Hospital of Daejeon University between 26 February 2019 and 4 December 2020. A total of 24 patients diagnosed with asthma or COPD were enrolled, and 19 completed the study. After participants were determined to be eligible based on the inclusion and exclusion criteria and voluntarily signed a written consent form, they were prescribed appropriate herbal medicines based on pattern identification diagnosis by a professional clinician of Korean medicine. All participants were asked to visit the hospital at least every 4 weeks  for 12 weeks to receive their herbal medicines, as well as to evaluate safety and efficacy endpoints. During the study period, participants were allowed to visit the hospital as often as they needed and receive other Korean medicine treatment options, such as acupuncture, pharmacoacupuncture, moxibustion, cupping, and physical therapies or Western medications. All of these concomitant treatments were recorded, and all data were coded confidentially.The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. This study was approved by the Institutional Review Board of the Daejeon Korean Medicine Hospital of Daejeon University (DJDSKH-18-BM-14) and registered at the Clinical Research Information Service (KCT0004919).Participants aged 19 years who were diagnosed with asthma according to the Global Initiative for Asthma (GINA) standard  or COPD Herbal medicines for each participant were prescribed according to the pattern identification, a diagnostic criterion to determine the treatment methods based on the patients' clinical data by a professional clinician in Korean medicine. At baseline, the professional clinician determined the pattern identification of each participant by their disease based on the clinical symptoms and signs, among the pattern types previously developed for asthma and COPD. The pattern identification for asthma consists of lung deficiency, wind-cold, heart-kidney deficiency, upper excess and lower deficiency, phlegm-dampness stagnation, phlegm-heat, and cold-phlegm , and theAccording to the determined pattern identification, participants were prescribed personalized herbal medicines for the next 4 weeks. For each pattern identification type in asthma and COPD, specific herbal medicines that responded to each pattern were prescribed. All participants were then reevaluated for pattern identification at every visit, and the herbal medicines being prescribed were maintained or changed by their newly determined pattern types for the next 4 weeks. The number of doses of each herbal medicine was also determined by the disease status of each participant, two to three times daily. All herbal medicines prescribed in this study were manufactured by a pharmaceutical company that obtained authorization from the Korea Good Manufacturing Practice.For the efficacy outcome measures in this study, lung function, respiratory symptom scales, health-related quality of life questionnaire, biomarkers, and patient satisfaction scale were evaluated in all patients with obstructive airway diseases throughout the study.The pulmonary function test (PFT) and peak expiratory flow rate (PEFR) were assessed to evaluate the changes in airway obstruction after herbal medicine treatments compared to the baseline. The PFT, including forced volume capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC, was measured at baseline and week 12 using a spirometer , according to the PFT guidelines established by the Korean Academy of Tuberculosis and Respiratory Diseases . AdditioFor the assessment of respiratory symptoms, the modified Clinical Asthma Measurement Scale in Oriental Medicine-V (mCAMSOM-V), COPD assessment test , asthma control test , modified Borg Scale, and modified Medical Research Council (mMRC) Dyspnoea Scale were used. The mCAMSOM-V is a modified version of the CAMSOM-V which was suggested as the primary outcome measure in the Traditional Korean Medicine Clinical Practice Guidelines for antiasthmatic agents . We addeHealth-related quality of life was measured by the St. George's Respiratory Questionnaire (SGRQ) before and after treatment with herbal medicines. The SGRQ is a validated and widely used dyspnoea-specific quality of life questionnaire for chronic respiratory diseases such as asthma and COPD , consistα (TNF-α), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 13 (IL-13), immunoglobulin E (IgE), and eosinophils, which are specific to the inflammatory process of asthma or COPD, were measured at baseline and endpoint to determine if there were any changes in these markers after the administration of herbal medicines. For other additional outcomes, the Integrative Medicine Patient Satisfaction Scale (IMPSS) was measured for all participants at week 12 to assess patient satisfaction after herbal medicine treatments [Biomarkers including C-reactive protein (CRP), fibrinogen, neutrophil, tumor necrosis factor-eatments .For safety outcomes, vital signs , adverse events, and laboratory examinations  were assessed throughout the study. Vital signs and adverse events were observed at every visit, and laboratory examinations were performed before and after treatment.® . Continuous variables are presented as mean , and categorical variables are reported as frequencies (percentages). Statistical significance was accepted with a two-sided test and an α level of 0.05. The missing values were handled using a multiple imputation method. For efficacy outcome measures, Student's paired t-test was used.All statistical analyses were performed by an independent statistician using SASA total of 29 patients with obstructive airway disease were screened, and 24 eligible patients were enrolled in this study. During the study period, 5 patients dropped out due to the withdrawal of informed consent and loss of follow-up. All 24 enrolled participants were included in the full analysis and safety datasets.The baseline characteristics of the 24 patients are shown in The herbal medicine treatments were prescribed by the pattern identification of each participant at every visit, and the initial herbal medicines were prescribed by the pattern types diagnosed at baseline, as shown in The distribution and flow chart of the prescribed herbal medicines throughout the trial for all participants are shown in During the trial period, participants were also treated with Western medications  and otheAt baseline, the study participants with asthma and COPD obtained results of 67.29% and 54.90%, respectively, in FEV1/FVC, and 65.50% and 79.93%, respectively, in predicted FEV1 value, indicating that the average included participant with asthma and COPD had a moderate degree of disease. After the herbal medicine treatments for 12 weeks, FEV1, FEV1/FVC, and PEFR did not show significant changes in the asthma and COPD groups .V score significantly decreased from 22.86 at baseline to 20.06 at week 12 in the asthma group (p=0.0401), indicating that the overall symptoms of cough, wheezing, sputum, dyspnoea, daily activities, and night-time sleep disturbance had improved after herbal medicine treatments with significant differences. However, the score in the COPD group did not show significant differences, although it showed a decrease from 13.70 to 13.52 after 12 weeks of herbal medicine treatment . The mMRC score in COPD patients gradually decreased from 1.60 at baseline to 1.50 at week 4 and 8, and to 0.89 at week 12 (p=0.0033), indicating that palmijihwang-tang is effective in relieving the symptoms of dyspnoea in airway obstructive diseases , and the impact subscale score also significantly decreased from 24.67 to 16.51 after the administration of herbal medicine (p=0.0147). The other scores of symptom and activity subscales also showed improvements from 51.95 to 51.99 at baseline to 46.30 and 42.95 at week 12, respectively; however, neither of the changes was statistically significant. The difference in total SGRQ scores was also found to be more than the minimal clinically important difference of 4 in COPD and all participants, being 7.62 points in the COPD patients and 4.12 points in all participants , fatigue (1 case), anorexia (1 case), chest discomfort (1 case), palpitations (1 case), and cellulitis (1 case). Among the seven adverse events, six were determined as mild and one as moderate, with the latter being a case of cellulitis that required prolonged hospitalization. The majority were also considered to be unrelated to the intervention, and two cases of general weakness and palpitations were recorded as probably related to herbal medicine use and were instructed to discontinue the administration of herbal medicine. In the vital signs and laboratory tests, there were no significant differences or clinically significant values during the study period.Obstructive airway disease is a major health problem and has a great impact on global socioeconomic burden. Diseases classified as obstructive airway diseases, asthma and COPD, have overlapping clinical features and frequently coexist. Both diseases exhibit similar respiratory symptoms, such as cough, wheezing, sputum, and chest discomfort, and both are mostly managed by bronchodilators and inhaled corticosteroids . The herIn previous studies, several herbal medicines have been reported for their efficacy in asthma and COPD, such as maekmoondong-tang (Mai-Men-Dong-Tang), yukmijihwang-tang (Liu-Wei-Di-Huang-Wan), samryungbaekchul-san (Shen-Ling-Bai-Zhu-San), gami-sagunja-tang (Jai-Wei-Si-Jun-Zi-Tang), jeongcheon-tang (Ding Chuan Tang), and sibak-tang (saiboku-to) for asthma and geumsuyukgunjeon (Jinshui Liujun decoction), gami-okbyungpoongsan (Jiawei Yupingfeng), bojungikki-tang (hochuekkito), and ginseng (Panax ginseng extract capsule) for COPD. However, the efficacy of herbal medicines still lacks evidence due to the low quality of studies, and we found no prior clinical trials using herbal medicines for asthma or COPD performed in South Korea. Thus, we investigated the use of various herbal medicines for patients with obstructive airway diseases in Korean medicine clinical practice. Notably, in our study, we focused on herbal medicines which are manufactured by the pharmaceutical company as a formula, since our study aimed to find a candidate for a novel therapeutic remedy which can be used worldwide in obstructive airway diseases.In our study, a total of 24 patients were enrolled, with 14 being diagnosed with asthma and 10 with COPD, and 19 completed the study. For 12 weeks, participants were administered herbal medicines, which were prescribed based on their pattern identification as diagnosed by professional clinicians. Professionals of Korean medicine diagnose the patterns of patients according to their symptoms and signs related to the disease. Moreover, pattern identification tools have been developed for each disease in an attempt to achieve objectivity. Both the pattern identification questionnaires for asthma and COPD were also developed previously, although they have not yet been validated. In our study, patients were diagnosed using their patterns both by professional and pattern identification questionnaires, although herbal medicines were actually prescribed by the professional as questionnaires were not validated yet and are still not widely used in clinical practice. When we compared the diagnosed pattern identifications between professionals and questionnaires after the study, we found inconsistent patterns. In asthma, patients were categorized as follows: 1 as wind-cold, 5 as phlegm-dampness stagnation, 3 as heart-kidney deficiency, 4 as upper excess and lower deficiency, and 1 as lung deficiency on pattern identification questionnaire. This was in contrast to the results from the professionals, where 3 were classified as phlegm-heat, 1 as phlegm-dampness stagnation, 9 as heart-kidney deficiency, and 1 as upper excess and lower deficiency. Similarly, in COPD, patients were classified as follows: 2 as wind-cold, 3 as kidney-yang deficiency, 2 as kidney-yin deficiency, 2 as phlegm-dampness stagnation, and 2 as lung deficiency on questionnaires; this is in contrast to the distribution of 2 as wind-cold, 7 as kidney-yang deficiency, and 1 as kidney-yin deficiency determined by the professional. These inconsistent results indicate that further studies are needed to develop reliable and useful pattern identification tools for asthma or COPD that are highly correlated with clinical practice.Moreover, we obtained information on the types of frequently used herbal medicines in patients with asthma and COPD. Palmijihwang-tang was the most prescribed herbal medicine for both asthma and COPD patients, accounting for 13 cases among a total of 24 cases. Then, yukmijihwang-tang and mahaenggamsuk-tang were followed by asthma patients and samsoeum and yukmijihwang-tang by COPD patients. We believe that these reported medicines can be considered candidates for our next confirmatory trial to evaluate the safety and efficacy of herbal medicine in obstructive airway diseases.For the assessment of herbal medicines in the treatment of obstructive airway diseases, various outcomes including PFTs, respiratory symptom scales, QoL, and inflammatory biomarkers were observed throughout the study period. Based on the clinical outcomes at baseline, both asthma and COPD patients enrolled in our study were revealed to have a moderate degree of airway obstruction, poor health status, and quality of life, while the symptoms of dyspnoea were not symptomatic. In the pulmonary function tests, airway obstruction was found to be more severe in COPD patients than in asthma patients, as 65.50% was recorded for the predicted FEV1 value in COPD patients and 79.93% in asthma patients. Additionally, asthma patients showed uncontrolled levels of their disease by scoring 14.57 in the ACT, and COPD patients also showed poor health status by scoring 17.70 CAT, with the cut-off value being 10 in the CAT . For botAfter 12 weeks of herbal medicine treatments, we found significant improvements in respiratory symptoms in asthma patients, assessed by mCAMSOM-V, and symptoms of dyspnoea and quality of life in COPD patients, as measured by mMRC and SGRQ. For all participants with asthma and COPD, mMRC and IL-13 were found to have significant differences after treatment. Analysis by each herbal medicine prescribed for participants showed that palmijihwang-tang had significant efficacy in relieving dyspnoea by improving the mMRC score for patients with obstructive airway disease. Additionally, it was found that the majority of patients were satisfied with our treatment with herbal medicines, and no severe adverse events were reported during the study.In asthma patients, herbal medicines have shown significant efficacy in mCAMSOM-V, which evaluates patients' overall symptoms of cough, wheezing, sputum, dyspnoea, daily activities, and night-time sleep disturbance. These results demonstrate that herbal medicines have beneficial effects in the treatment of asthma by controlling respiratory symptoms, which is the major goal in the management of asthma. Moreover, as mCAMSOM-V was originally developed for the evaluation of asthma and is suggested as the primary outcome measure in the Traditional Korean Medicine Clinical Practice Guidelines for antiasthmatic agents, our finding that herbal medicines have shown significant efficacy in mCAMSOM-V is worthwhile. On the other asthma control outcome measure, ACT, a significant improvement was not found after the herbal medicine treatments. However, we found that the number of patients included in the control level of asthma increased from 2 at baseline to 5 at week 12. Overall, the severity of asthma was also found to be improved in four patients, by stepping up from persistent mild to intermittent mild in 3 and from persistent moderate to persistent mild in 1, while 6 had no change in their severity and 4 had dropped out.For COPD patients, significant efficacy of herbal medicines was found when assessed using the mMRC and SGRQ. Dyspnoea is the most common and debilitating symptom experienced by patients with COPD, which also reduces the quality of life and physical activities . The levMoreover, we found a significant decrease in the level of IL-13 in both asthma and COPD patients, which was measured as a biomarker of obstructive airway diseases in our study. Over the past few years, compelling evidence of IL-13 as a key mediator and critical effector molecule in the inflammatory processes of asthma and COPD has been established . InhibitOverall, we revealed the potential of herbal medicines for obstructive airway diseases as an effective and safe remedy. We could also see the possibility of a therapeutic effect on palmijihwang-tang, which had shown efficacy in relieving dyspnoea and was found to be the most prescribed formula in our study. Despite these beneficial effects of herbal medicines in patients with asthma and COPD, our findings need to be interpreted in light of a few limitations. First, our study was conducted with a small sample size. Although the aim of our study was not to firmly conclude the effectiveness of herbal medicines, it was difficult to find significant differences and estimate the effects of our treatment precisely with a relatively small number of patients. We could not confirm a significant efficacy of typical herbal medicines except for the mMRC results, and we believe that a larger number of patients will be needed to address this. As a small study, there are limitations in concluding reliable and precise results, due to the problems with a large standard error, false-positive errors, and statistical analyses , and thuOur study provides preliminary clinical data on the safety and efficacy of herbal medicines in patients with asthma and COPD. We obtained information on the distribution of pattern identification and herbal medicine prescription for obstructive airway disease, which will be used for deciding the herbal medicine candidate for a subsequent confirmatory clinical trial. We also found the potential effects of herbal medicines in relieving overall respiratory symptoms in asthma and improving the symptoms of dyspnoea and quality of life in COPD patients, as well as inhibiting IL-13 levels in both asthma and COPD patients, with a high level of patient satisfaction. We expect that our findings will be used as a basis to establish a well-designed, large-scale, confirmatory clinical trial to evaluate the safety and efficacy of herbal medicines in obstructive airway diseases.


The aim of this study is to develop multistage prediction models for pre-eclampsia (PE) covering almost the entire pregnancy period based on routine antenatal measurements and to propose a risk screening strategy.N = 15665), the testing set (N = 3917), and the validation set (N = 1000). Least Absolute Shrinkage And Selection Operator (LASSO) was used to do variable selection from demographic characteristics, blood pressure, blood routine examination and biochemical tests. Logistic regression was used to develop prediction models at eight periods: 5–10 weeks, 11–13 weeks, 14–18 weeks, 19–23 weeks, 24–27 weeks, 28–31 weeks, 32–35 weeks, and 36–39 weeks of gestation. We calculated the AUROC (Area Under the Receiver Operating Characteristic Curve) on the test set and validated the screening strategy on the validation set.This was a retrospective cohort study that included 20582 singleton pregnant women with the last menstruation between January 1, 2013 and December 31, 2019. Of the 20582 women, 717 (3.48%) developed pre-eclampsia, including 46 (0.22%) with early-onset pre-eclampsia and 119 (0.58%) preterm pre-eclampsia. We randomly divided the dataset into the training set (We found that uric acid tested from 5–10 weeks of gestation, platelets tested at 18–23 and 24–31 weeks of gestation, and alkaline phosphatase tested at 28–31, 32–35 and 36–39 weeks of gestation can further improve the prediction performance of models. The AUROC of the optimal prediction models on the test set gradually increased from 0.71 at 5–10 weeks to 0.80 at 24–27 weeks, and then gradually increased to 0.95 at 36–39 weeks of gestation. At sensitivity level of 0.98, our screening strategy can identify about 94.8% of women who will develop pre-eclampsia and reduce about 40% of the healthy women to be screened by 28–31 weeks of pregnancy.We developed multistage prediction models and a risk screening strategy, biomarkers of which were part of routine test items and did not need extra costs. The prediction window has been advanced to 5–10 weeks, which has allowed time for aspirin intervention and other means for PE high-risk groups. Pre-eclampsia is a pregnancy related syndrome defined as newly occurred hypertension at or after 20 weeks of gestation, accompanied by proteinuria or other organs damage . The incIn the first trimester, taking pharmacologic interventions  for high-risk pregnant women can reduce the risk of early-onset and preterm pre-eclampsia , 18. It However, pre-eclampsia related prediction models have been developed mainly in developed countries . In receIn this study, based on 20582 pregnant women in Beijing, we aimed to develop multistage prediction models covering almost the entire pregnancy period by selecting valuable predictors from routine antenatal measurements, and a risk screening strategy based on the optimal models.This was a Peking University Retrospective Birth Cohort in Tongzhou based on the hospital information system, including singleton pregnant women having prenatal care, delivery and outcome records, with last menstruation between 1 January 2013 and 31 December 2019 and with delivery gestational weeks no less than 28 weeks in Tongzhou Maternal and Child Health Care Hospital of Beijing. We further selected pregnant women with the latest record of deliveries, and with at least one, two and two antenatal examination records in the first, second, and third trimester, respectively. We excluded pregnant women using assisted reproductive technology, having systemic lupus erythematosus, or chronic hypertension, or gestational hypertension without pre-eclampsia. Also, we excluded pregnant women who lacked blood pressure measurements, blood routine examination and biochemical tests records at 5–10 weeks of gestation. Finally, we included 20,582 women in our study. The inclusion and exclusion criteria can be seen in We extracted maternal characteristics, medical history, blood pressure measurements, blood routine examination and biochemical tests from the electronic data system of Tongzhou Maternal and Child Health Hospital of Beijing. Maternal characteristics included maternal height (cm), pre-pregnancy weight (kg), pre-pregnancy BMI, pre-gestational diabetes mellitus, ethnicity, parity, gravidity, abortion history, family history of hypertension, family history of diabetes, maternal age, husband age. Blood pressure measurement records included systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurement records and we calculated mean arterial pressure (MAP) by MAP = (SBP+2 × DBP)/3. Blood routine examination and biochemical tests included 48 biomarkers,including hemoglobin, mean red blood cell volume, platelet, red blood cell, white blood cell, alanine aminotransferase, aspartate aminotransferase, urea nitrogen, and calcium, etc. Lists of all biomarkers were shown in Based on the Guidelines on Diagnoses and Treatments of Hypertensive Disorders in Pregnancy by Chinese Society of Obstetrics and Gynecology, pre-eclampsia is defined as hypertension first appeared after 20 weeks of pregnancy, systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg, with proteinuria or with any of the following organs or systems involved: heart, lung, liver, kidney and other important organs, or abnormal changes in blood system, digestive system and nervous system, placenta and fetus involved, etc . AccordiThe first trimester, the second trimester and the third trimester were defined as < = 13 weeks, 14–27 weeks and > = 28 weeks, respectively , 28. We The pregnant women's height, pre pregnancy weight, pre pregnancy BMI, pregnant women's age and husband's age were used as continuous variables. We divided pre-gestational diabetes mellitus, family history of hypertension, abortion history, family history of diabetes into yes or no and we divided ethnicity into Han nationality or other nationalities. Parity was divided into primiparous or multiparous, and gravidity was divided into the first pregnancy, the second pregnancy, the third and more pregnancies. We divided the pregnancy season into spring, summer, autumn and winter according to the date of the last menstruation after verification.We also kept blood pressure, routine blood and biochemical tests as continuous variables. If pregnant women had more than one measurement record during a certain period, we took the average value of these records. Therefore, regardless of missing values, each pregnant woman should have eight records of mean arterial pressure and biomarker measurements throughout pregnancy. There was one measurement record in each of the eight time periods. In particular, pregnant women rarely did biochemical tests in the second trimester of pregnancy. Therefore, there was no such test value in the 14–18 weeks, 19–23 weeks, and 24–27 weeks, so the variable was marked as missing.The missing rate of demographic characteristic variables was <2%. We used the median to impute the missing values of continuous variables and the mode to impute the missing values of categorical variables. For the mean arterial pressure measurements, blood routine examination and biochemical tests (except the second trimester of pregnancy), the missing values were imputed by the values in the previous period. For example, missing values at 32–35 weeks of gestation were imputed by the measurements at 28–31 weeks of gestation. A pregnant woman has a prenatal examination at 32–35 weeks of pregnancy, but for some reason, she lacked a blood routine examination. Then, this missing value can be replaced by the value tested during 28–31 weeks. In clinical application, this method is easy for health professionals to understand and use it. If a pregnant woman is unable to get biochemical indicators for some reasons, this method can be used to quickly impute the missing value. In addition, by using previous measurements, this method can avoid reverse causality. The missing data imputed by the last observation carried forward (LOCF) method was used in many clinical antidepressant trials and other high level clinical studies –31.N = 15665), a test set (N = 3917) and a validation set (N = 1000). The incidence rate of pre-eclampsia was almost the same in each data set (3.5%). We developed prediction models on the training set and verify the model on the test set. Based on the calculation results from the training set and test set, a screening strategy was formed and tested on the validation set. We did univariate analysis on demographic characteristics to compare the differences between each group and the control group (women without any types of pre-eclampsia), for example, comparison of women with early-onset pre-eclampsia and without any types of pre-eclampsia. We used Chi-test for categorical variables (Fisher exact test when the counts in some cells was fewer than five) and Kruskal-Wallis Rank Sum test for continuous variables.We sampled from women with and without pre-eclampsia to form a training set  on the test set to reflect the ability of prediction. We used LASSO technique to select the variables with the highest priority and the second priority to join in the model according to the order in which the coefficients enter into the model along the solution path.Least Absolute Shrinkage And Selection Operator (LASSO) is a shrinking technique used to do variable selection. It has been used to do variable selection and avoid overfitting for development of pre-eclampsia prediction models in previous studies , 32. LASThe objective of LASSO is to find the proper coefficients to minimize the loss function:Xi =  is the vector of observed variables of the subject i, yi is the outcome of the subject i, yiϵ{0, 1}, yi = 1 if the subject i developed pre-eclampsia and yi = 0 if the subject i did not develop pre-eclampsia. |βj| is the absolute value of the coefficient of the variable xij. λ is a tuning parameter: when it is big enough, all coefficients are zeros and the coefficients gradually turn to non-zero with the decrease of λ. l(yi|Xi) is the log-likelihood function of the logistic regression, given by the following equation:where We determined a basic variable set, which was forced into models, and then selected the variables that can improve AUROC on the test set from the demographical variables, mean arterial pressure and biochemical markers in proper order in four stages. We developed predictions on each period . The four stages of developing models for each period were described as follows.As reported in previous studies, pre-pregnancy BMI, pre-gestational diabetes mellitus (PGDM), parity, family history of hypertension and maternal age were highly associated with pre-eclampsia, thus these five variables were forced into models and denoted as “basic variables” , 35, 36.Based on Stage1-Optimal Variables, we added MAPs measured at baseline (5–10 weeks) and the current period and then tested whether MAPs could improve the ability of prediction. For example, for women took prenatal examinations during 28–31 weeks, we added MAPs measured at 5–10 weeks and 28–31 weeks into the model. The optimal set of variables with the highest AUROC was denoted as Stage2-Optimal Variables.Based on Stage2-Optimal Variables, we added biomarkers measured at baseline (5–10 weeks) and the current period. By using LASSO, we selected the optimal set of variables with the highest AUROC denoted as Stage3-Optimal Variables. As mentioned before, we did not add biochemical tests measured in the second trimester, because it was rarely tested in the hospital.At the current period, we further added all MAPs measured in previous periods based on Stage2-Optimal Variables and added all biomarkers measured in previous periods based on Stage3-Optimal Variables to check whether adding other variables could improve the AUROC.We excluded women who had used aspirin during pregnancy and conducted sensitivity analysis by redeveloping optimal prediction models to test whether the valuable biomarkers we found could still improve the predictive ability of models .After developing the best prediction model at each stage, we selected the appropriate risk cutoff values to make the sensitivity of the prediction models reach 0.95, 0.96, 0.97, 0.98, and 0.99 in each period. Then, we screened the population in the validation set with different sensitivities to form the best screening strategy.We used R software  to do alFor early-onset and preterm pre-eclampsia, AUROC gradually increased from about 0.73 to 0.89 and 0.80 at 28–31 weeks of gestation, respectively. Generally, based on the Stage 1-Optimal Variables, the addition of MAPs increased AUROC for all pre-eclampsia and its subtypes, and the AUROC was higher for early-onset and preterm preeclampsia than that for late-onset and term pre-eclampsia. The Stage 2-Optimal Variables included Stage 1-Optimal Variables and MAPs measured at baseline (5–10 weeks) and at the current prenatal examination period.As can be seen in As can be seen in N = 3917), respectively. For the optimal prediction models in each stage, the results were very similar in the datasets with and without women who had used aspirin, which were shown in There were 104 and 28 women using aspirin in the training set (N = 15665) and test set , where odds = e*BMI) + (−0.920 if Multiparous) +  +  + (0.320* if Family history of hypertension) + (0.0551*).Y = (−13.40) + (0.102*BMI) + (−0.888 if Multiparous) +  +  + (0.319* if Family history of hypertension) + (0.0233* MAP measured at 5–10 weeks) + (0.0503* MAP measured at 11–13 weeks) + (0.00609* uric acid test at 11–13 weeks).Y = (−15.10) + (0.0890*BMI) + (−0.903 if Multiparous) +  +  + (0.347* if Family history of hypertension) + (0.0182* MAP measured at 5–10 weeks) + (0.0704* MAP measured at 14–18 weeks).Y = (−15.70) + (0.110*BMI) + (−0.917 if Multiparous) +  +  + (0.411* if Family history of hypertension) + (0.0253* MAP measured at 5–10 weeks) + (0.0648* MAP measured at 19–23 weeks) + (−0.0237* platelets test at 5–10 weeks) + (0.0231* platelets test at 19–23 weeks).Y = (−15.80) + (0.110*BMI) + (−0.929 if Multiparous) +  +  + (0.408* if Family history of hypertension) + (0.0274* MAP measured at 5–10 weeks) + (0.0664* MAP measured at 24–27 weeks) + (−0.0222* platelets test at 5–10 weeks) + (0.0217* platelets test at 24–27 weeks).Y = (−16.10) + (0.110*BMI) + (−0.941 if Multiparous) +  +  + (0.375* if Family history of hypertension) + (0.0262* MAP measured at 5–10 weeks) + (0.0778* MAP measured at 28–31 weeks) + (0.00974* uric acid test at 28–31 weeks) + .Y = (−15.60) + (0.0778*BMI) + (−0.968 if Multiparous) +  +  + (0.455* if Family history of hypertension) + (0.0203* MAP measured at 5–10 weeks) + (0.110* MAP measured at 32–35 weeks) + (0.00938* uric acid test at 32–35 weeks) + .Y = (−16.00) + (0.0586*BMI) + (−1.430 if Multiparous) +  +  + (0.332* if Family history of hypertension) + (−0.0144* MAP measured at 5–10 weeks) + (0.129* MAP measured at 36–39 weeks) + (0.0122* uric acid test at 36–39 weeks) + .Y = (−14.90) +  to achieve an AUROC of 0.975 for pregnant women with systemic lupus erythematosus . Chen etWallis et al. proposed a multi-stage screening strategy based on the British women: the first screening was conducted at < 18 weeks of gestation, and the second to fifth screening was conducted by using mean arterial pressure at 20, 25, 28, and 31 weeks of gestation. We and Wallis et al. tested the screening strategy based on the same number of pregnant women. Compared with the screening strategy proposed by Wallis et al., we advanced the prediction window as early as 5–10 weeks. After completing the screening at 28–31 weeks, we reduced the number of people to be screened by about 45%, while Wallis et al. reduced by about 35%. In particular, we extended the screening period to 36–39 weeks, which may effectively screen term pre-eclampsia and even later pre-eclampsia. Although the two strategies target different populations and it is necessary to compare the screening strategies of the two sides in the same population in the future, our screening strategy has the potential for improvement.We have several advantages in our study. First, our sample size and the number of outcomes were larger than that in previous prediction models based on Chinese population. Second, compared with the stepwise regression used in many studies, we used LASSO for variable selection, so it is less likely to over fitting, and we tested our model on the randomly divided test set and validation set. Third, we found that on the basis of demographic characteristics, medical history, and mean arterial pressure, the addition of uric acid can improve the prediction ability of the model from the first trimester; the addition of platelet and alkaline phosphatase can improve the prediction ability of the model in the second and third trimester, respectively. We did not test the predictive value of uric acid in the second trimester, because pregnant women rarely did biochemical tests in this period. We suggest that pregnant women in the second trimester do additional uric acid tests in the future. In particular, at 28–31 weeks, 32–35 weeks and 36–39 weeks of pregnancy, the AUROC of the prediction model for all pre-eclampsia reached 0.86, 0.89 and 0.95, respectively, which has the value in predicting late-onset and term pre-eclampsia. Fourth, to our knowledge, our study is the first study to develop multi-stage prediction models and propose a screening scheme based on the Chinese women. The screening time covers almost the entire pregnancy period: the earliest to 5–10 weeks of pregnancy and the latest to 36–39 weeks of pregnancy.Several clinical values can be seen in our study. First, we found that uric acid, platelets and alkaline phosphatase can improve the predictive ability of the model, which are part of the routine test items and it does not need extra costs. Second, a screening system has been developed for the Chinese population and policy environment, and the prediction window has been advanced to 5–10 weeks, which allows time for aspirin intervention and other means for high-risk groups. There were strong evidences supporting that aspirin is the only drug preventing pre-eclampsia . Some guHowever, the study has several limitations. First, the study had a large sample size and a large number of outcomes, but the incidence rate of early-onset pre-eclampsia was small, because the incidence rate of early-onset pre-eclampsia was particularly low. We used LASSO for variable selection, so it was less likely to cause over fitting. Second, there were missing values in biomarkers, but it was in line with the actual clinical situation. We used a simple imputation method, that is, using the previous tested values to impute the missing values. This method is easy for health professionals to use. Third, we did not conduct external validation. But we conducted internal validation on the test set and validation set by randomly dividing the data set. Moreover, we used LASSO to select variables, which reduced the possibility of over fitting. In the future, our model awaits validation on other data sets.whjun@pku.edu.cn.The data analyzed in this study is subject to the following licenses/restrictions the data that support the findings of this study are available from Tongzhou Maternal and Child Health Care Hospital of Beijing but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Tongzhou Maternal and Child Health Care Hospital of Beijing. Requests to access these datasets should be directed to Haijun Wang, The studies involving human participants were reviewed and approved by Institutional Review Board of Peking University Health Science Center (No. IRB00001052-21023). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.ZT, YJ, SZ, TS, ZY, and NH: data curation. ZT, YJ, JJ, and HW: methodology. ZT and JJ: software. ZT: writing—original draft. YJ, JJ, and HW: writing—review & editing. All authors contributed to the article and approved the submitted version.This study was funded by Beijing Natural Science Foundation (7212144) and National Natural Science Foundation of China (92046019).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.