Novel smartwatch-based cuffless blood pressure (BP) measuring devices are coming to market and receive FDA and CE labels. These devices are often insufficiently validated for clinical use. This study aims to investigate a recently CE-cleared smartwatch using cuffless BP measurement in a population with normotensive and hypertensive individuals scheduled for 24-h BP measurement.Patients that were scheduled for 24-h ambulatory blood pressure monitoring (ABPM) were recruited and received an additional Samsung Galaxy Watch Active 2 smartwatch for simultaneous BP measurement on their opposite arm. After calibration, patients were asked to measure as much as possible in a 24-h period. Manual activation of the smartwatch is necessary to measure the BP. Accuracy was calculated using sensitivity, specificity, positive and negative predictive values and ROC curves. Bland-Altman method and Taffé methods were used for bias and precision assessment. BP variability was calculated using average real variability, standard deviation and coefficient of variation.Forty patients were included. Bland-Altman and Taffé methods demonstrated a proportional bias, in which low systolic BPs are overestimated, and high BPs are underestimated. Diastolic BPs were all overestimated, with increasing bias toward lower BPs. Sensitivity and specificity for detecting systolic and/or diastolic hypertension were 83 and 41%, respectively. ROC curves demonstrate an area under the curve (AUC) of 0.78 for systolic hypertension and of 0.93 for diastolic hypertension. BP variability was systematically higher in the ABPM measurements compared to the smartwatch measurements.This study demonstrates that the BP measurements by the Samsung Galaxy Watch Active 2 show a systematic bias toward a calibration point, overestimating low BPs and underestimating high BPs, when investigated in both normotensive and hypertensive patients. Standards for traditional non-invasive sphygmomanometers are not met, but these standards are not fully applicable to cuffless devices, emphasizing the urgent need for new standards for cuffless devices. The smartwatch-based BP measurement is not yet ready for clinical usage. Future studies are needed to further validate wearable devices, and also to demonstrate new possibilities of non-invasive, high-frequency BP monitoring. Hypertension is a leading risk factor for heart disease . CurrentNovel methods replace the oscillometric measurements of BP by cuffless measurements often using photoplethysmography (PPG), ballistocardiography (BCG) and/or electrocardiography (ECG) to estimate BP. This is performed by either analysing the pulse wave of the PPG signal  , as is tWhile guidelines recommend only upper-arm inflatable cuff measurements of BP, commercial devices such as smartwatches capable of measuring BP using cuffless methods are already coming to market. In recent years, smartwatch devices first fulfilled the requirements for a medical device in the International Organization for Standardization (ISO) 81,060–2:2018 Non-invasive sphygmomanometers . HoweverIn clinical practice immediate problems are now to be faced. One problem with unvalidated devices is that they cannot be actively used and prescribed before proper validation. A second and more pressing problem is that, once on the market, patients will use these devices for monitoring their health, and proper advice and interpretation by clinicians will be necessary. In a recent review, Elgendi et al. therefore emphasize that to increase reliability and validity of medical use of smartwatch-based BP measurements, more research is required in both normotensive and hypertensive subjects .This study aims to investigate a recently CE-cleared smartwatch using cuffless BP measurement in a population with normotensive and hypertensive individuals scheduled for 24-h BP measurement. In doing so, this study aims to contribute to the evidence base for validating new technologies, already available on the consumer market, for medical use.The study is a prospective, single-arm, cross-sectional study.Consecutive patients that were scheduled for 24-h ambulatory blood pressure monitoring (ABPM) were recruited from the cardiology outpatient clinic. The inclusion criteria were as follows: scheduled for ABPM, age ≥ 18 years and able to understand the informed consent. The exclusion criteria were as follows: history of paroxysmal or permanent atrial fibrillation, difference in BP between both arms exceeding 20 mmHg as measured by a sphygmomanometer, inability to measure BP on one of both arms and inability to work with the smartwatch despite explanation by the research team. Demographic and medical information of the participants was collected from the hospital medical records and included age, gender, height, weight, cardiac risk factors, cardiac and non-cardiac comorbidities, and medication schedules. This study was approved by the ethics committee of Jessa Hospital and Hasselt University (file number 2021/050) and all subjects provided written informed consent.Reference method measurements were performed using a validated automatic cuff-based upper-arm sphygmomanometer ; ABPM was performed by a cuff-based, upper-arm automatic device , measuring BP every 15 min throughout the day (8AM-11:59PM), and every 30 min throughout the night (00:00AM-7:59AM). A Samsung Galaxy Watch Active 2  was used for cuffless BP measurement at the wrist (strap circumference range 50–70 mm) in combination with a Samsung Galaxy A21s smartphone . The smartwatch requires calibration to allow for BP measurement. The manufacturer recommends calibration at least every 28 days. Calibration was performed in all patients at inclusion. Algorithms that are used by the Samsung Galaxy Watch are not openly disclosed, but due to studies conducted by Samsung research and development institute it is likely that PWA using the PPG signal and derivatives in combination with a machine learning model are used .Patients were first screened by measuring the BP consecutively at their left and right arms using the reference method. Smartwatches were then connected to the arm of the patient. ABPM devices are by standard protocol attached to the left arm; smartwatches were thus attached to the right arm in all patients. A calibration of the smartwatch was then performed according to the manufacturer’s instructions: three consecutive measurements were performed by the conventional BP monitor together with three measurements of the smartwatch.Patients were instructed to manually start a measurement on the smartwatch each time the ABPM device had finished its measurement. This technique was chosen to avoid interference with the ABPM measurement. Patients were asked to perform as many measurements as possible in the 24-h interval, with a minimum of five measurements. The patients were instructed that during their sleep, measuring with the smartwatch would not be possible since a manual activation was necessary. They were instructed to resume measurements if they were awake at night or as soon as they woke up in the morning, after the first measurement of the ABPM. After 24 h, both the ABPM and the smartwatch were detached and read out.Data analysis was performed using R  aBland-Altman plots were constructed and bias and limits of agreement were calculated. In the Bland-Altman plots difference is calculated as ABPM minus smartwatch measurements. However, as recently described by Taffé et al., the Bland-Altman method has certain limitations when comparing a new measurement method with a reference method . Also, tSensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both systolic and diastolic BP during daytime. For these analyses the average systolic and diastolic BPs measured by the smartwatch during daytime was compared with the average ABPM daytime measurements as reference value. A cut-off for hypertension was based on the European Society of Cardiology (ESC) guidelines for measurement of daytime mean BP (≥135/85 mmHg) (w) was calculated as described by Parati et al.  night-time smartwatch measurements were available in each patient. A p-value of <0.05 was considered statistically significant. A comparison of daytime ARV per patient between smartwatch and ABPM was plotted.BP variability was calculated using three widely used indices: the standard deviation (SD), the average real variability (ARV) and the coefficient of variation (CV) –21 whichPulse pressure (difference of systolic minus diastolic BP) was calculated for each measurement of both devices; mean pulse pressure was calculated for the total population and means per patient were plotted.The primary outcome is the differential and proportional bias as defined by the Taffé method. It should be noted that due to lack in validation standards no cut-off can be pre-specified and a descriptive method will be used. Secondary outcomes include the Bland-Altman-based bias and precision as compared to ISO standards, AUC as defined by ROC analysis, and BPV as defined by ARV and SD.A total of 40 patients participated in the study. A total of 101 patients was screened for participation. Seventeen patients were excluded based on the exclusion criteria . Sixteen patients were not interested. Seven patients indicated that they were not able to work with the technology sufficiently. In 10 patients technical problems occurred: in 3 patients the watch was too large for making skin contact, in 5 patients the smartwatch was unable to perform a measurement due to reasons not specified by the smartwatch output, and two patients had a BP that was too high for calibration by the smartwatch resulting in an error message (191/94 mmHg and 216/120 mmHg). Eleven patients did not participate due to other reasons.Baseline characteristics and the mean number of measurements per device are depicted in Bias and precision plots according to the Taffé method are depicted in For systolic BP, the smartwatch overestimates the BP up to a BP value of approximately 140 mmHg. After this point it underestimates the systolic BP, illustrating the presence of proportional  [0.60–0.70]) and differential  bias. To further illustrate the implications of this proportional bias, it is clear from For diastolic BP, differential  and proportional bias  are present, resulting in an overestimation of the diastolic BP at all observed values, with a higher overestimation at lower values. Precision for the gold standard method was higher at lower BP values, while precision for smartwatch measurements was higher at higher BP values (from approximately 70 mmHg and upward).Analysis according to the Bland-Altman method demonstrated an association between the true value and the measurement error, as also demonstrated by the Taffé method. As proposed by Bland and Altman , the appScatterplots and Bland-Altman plots that were obtained through the method described above are depicted in In Receiver operating characteristic curves are depicted in Positive predictive value and NPV optimization curves were constructed. To obtain these curves, PPV and NPV were calculated for each cut-off ranging from 125 to 146 mmHg systolic and 75 to 96 mmHg diastolic. The optimal point was calculated as the point on which the sum of PPV and NPV was highest. For systolic BP, the optimal point was at 145 mmHg with a PPV and NPV of 100 and 72%, respectively. The highest NPV was obtained at 128 mmHg with a PPV and NPV of 46 and 92%, respectively. For diastolic BP, the optimal point was at 93 mmHg with a PPV and NPV of 100 and 87%, respectively. The highest NPV was reached at 84 mmHg with a PPV and NPV of 50 and 100%, respectively. The highest PPV was reached at 93 mmHg with a PPV and NPV of 100 and 87%, respectively.day), SDw and daytime ARV (ARVday) in t-tests for SDday and ARVday demonstrate a significant difference between BP variability of the ABPM versus the smartwatch measurements. Scatterplots of daytime ARV-values per patient are depicted in p < 0.01; for DBP the CV was 4.2% ± 1.1% for the smartwatch as compared to 13.1% ± 3.8% for the ABPM device, p < 0.01, again confirming a significantly lower BP variability in the smartwatch measurements.Blood pressure variability is depicted as daytime SD . A scatterplot for mean pulse pressures per person is depicted in Pulse pressure (systolic BP minus diastolic BP) was compared for the total population and per patient. Mean pulse pressures over the total population were 49.2 mmHg and 45.6 mmHg for the ABPM and smartwatch measurements, respectively. The difference over the total population was thus 3.5 mmHg  and that the device was tested on, 20% (10 patients) were not able to participate due to limitations of the technology . The fact that a high BP at calibration impedes the calibration process already limits the usage of the device in a hypertensive population. Also, 7 patients of the total screened population indicating not being able to work with the technology limits the usage in populations with low digital literacy.It is known that validation standards for cuffless BP estimating devices are lacking, and the World Health Organization (WHO) and independent research groups have emphasized the urgent need for developing such validation standards , 24. WitThe results of the Taffé method indicate that, based on the bias plots, BP measurements are reliable in normal BP ranges. The farther BP deviates from a normal range, the larger the bias on the measurements becomes. Precision of both measurements is comparable in normal ranges. As already indicated by the developers of this method, Taffé et al., current validation methods suffer from the same limitations as the Bland-Altman analysis when comparing a new measurement method with a gold standard reference method and new international validation protocols using this new method are urgently needed . ExistinThe ROC curves demonstrate acceptable AUCs . For systolic BP maximal sensitivity and specificity were 71.4 and 76.9%, respectively at a BP of 136.1 mmHg and for diastolic BP maximal sensitivity and specificity were 84.6 and 88.9%, respectively at a BP of 89.9 mmHg. The PPV and NPV optimization curves demonstrate that high PPVs and NPVs can be achieved when using different cut-off points for the smartwatch compared to the reference standards. At first glance these results seem to be acceptable for a diagnostic test, but with validation standards lacking, one should keep questioning if these results are good enough to replace or complement gold standard BP measurements.BP variability is systematically lower in the smartwatch compared to the ABPM measurement, with a systematic difference clearly being demonstrated in SD, SDw, ARV values, CV and in the ARV scatterplot.Pulse pressure measurements are significantly different, but with a difference of 3.5 mmHg and no systematic error in the scatterplot, this latter result seems clinically acceptable.Taking all these results together, namely the proportional bias in the Taffé method, the association needing correction in the Bland-Altman plots and the systematically lower BP variability, it seems that the smartwatch currently suffers from an anchoring point that is set when calibrating the device. After calibration, it tends to keep its BP measurements closer to the calibration point than the BPs are in reality, resulting in an overestimation of lower BPs, an underestimation of higher BPs, and thus a low BP variability. The results of our study thus indicate that a one-to-one translation of a conventional BP monitor to the smartwatch does not seem appropriate yet.The Korean Society of Hypertension has stated that the future of cuffless devices might lie in detecting hypertension in the general population, but that they are currently not suited for monitoring treatment response in hypertensive patients . An addiOther studies dare to broaden the scope of usage of these devices. Recent studies predict possibilities for integrating continuously measured BP measurements with other biological and environmental signals , 27. DatAt this moment, wearable cuffless BP monitors are not capable of replacing cuff-based BP monitors. If the technology is improved, it is possible that in the future there could be a role for complementary use next to cuff-based BP monitors, for example in different environments and settings, at home and away from home. Devices allowing automatic measurements can allow for continuous and nocturnal measurements, capabilities that conventional BP monitors do not offer.To take the field forward several things are needed. First, there is an urgent need for validation standards for cuffless devices to allow for standardized research. Second, open disclosure of commercial validation studies could allow for better resource usage as studies will not have to be repeated unnecessarily. Third, further development of the cuffless devices will allow for new possibilities in the field of BP monitoring, especially unobtrusive, continuous and nocturnal monitoring. Finally, research should continue to focus on validation of these devices compared to conventional standards, but also on broadening its use and demonstrate new possibilities of continuous BP monitoring.Patients will start using these devices today. It is thus up to researchers and clinicians to start understanding the vast range of possibilities that cuffless BP measuring has to offer.This study has several limitations. First, this study uses a 24-h interval to conduct a validation study. As a smartwatch will be used in patients in a long-term setting a long-term validation study could be the scope of future research.Second, while the algorithms that are used by the Samsung watch are not known, it is known that some algorithms use patient demographics  to improve BP prediction based on PPG signals. As a single account was used on the Samsung watch, demographics were not adjusted in each patient .Third, due to the nature of the intervention, patients had to manually activate the smartwatch after the measurement by the ABPM. This could result in bias by order effect which is a limitation of the study.This study demonstrates that the BP measurements by the Samsung Galaxy Watch Active 2 show a systematic bias toward a calibration point, overestimating low BPs and underestimating high BPs, when investigated in both normotensive and hypertensive patients. Standards for traditional non-invasive sphygmomanometers are not met, but these standards are not fully applicable to cuffless devices, emphasizing the urgent need for new standards for cuffless devices.The smartwatch-based BP measurement is not yet ready for clinical usage. However, when used complementary to a cuff-based BP monitor, BP measurements might be of value. Future studies are needed to further validate wearable devices, and also to demonstrate new possibilities of non-invasive, high-frequency BP monitoring.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethische Toetsingscommissie Jessa Ziekenhuis. The patients/participants provided their written informed consent to participate in this study.MF: conceptualization, experiment conduction, data analysis, and manuscript writing and editing. MS: conceptualization and manuscript writing and editing. KD: experiment conduction and data handling. ZP: data analysis. TK: conceptualization and writing – review and editing. LX: writing – review and editing. EC, PC, and AF: data analysis and writing – review and editing. GP: writing – review and editing and supervision. PD: conceptualization, writing – review and editing, resources, and supervision. All authors contributed to the article and approved the submitted version.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.


Both English and Chinese articles about original investigations in humans were searched. Two independent authors extracted the data, and disagreements were resolved by discussion. ReviewManager 5.3 software provided by Cochrane did a meta-analysis of selected randomized controlled trials (RCTs). Quality of experimentation and risk bias were analyzed by the Cochrane Handbook tool. A total of thirteen randomized controlled clinical articles along with 1237 patients were included in the study. Findings of meta-analysis showed that compared with nonacupoint application treatment, the total effective rate of acupoint application treatment is more effective , Z = 6.70, P < 0.00001). Besides, acupoint application can improve patients' lung function, the lung function index FVC , Z = 8.40, P < 0.00001), FEV1 , Z = 5.86, P < 0.00001), FEV1/FVC (%) , Z = 2.97, P = 0.003), FEV1 (%) , Z = 27.44, P < 0.00001), and PEF (day) , Z = 12.40, P < 0.00001) of patients treated by acupoint application therapy were increased. Moreover, acupoint application might lower the level of immunoglobulin E , Z = 11.93, P < 0.00001) and EOS , Z = 2.77, P = 0.006). The LCQ (Leicester cough questionnaire) total score of CVA patients was also increased , Z = 5.98, P < 0.00001). Acupoint application therapy is effective in controlling symptoms of CVA. It also has a positive effect in improving lung function and life quality of patients. It can reduce the eosinophil levels and peripheral blood IgE levels of patients as well.Acupoint application has been used in China to treat various illnesses for ages. In cough variant asthma (CVA), the main clinical sign is episodic night cough. Acupoint application therapy of traditional Chinese medicine is an effective procedure to treat cough variant asthma. The current study is designed to systematically assess the effectiveness of acupoint application therapy in traditional medicine for patients with cough variant asthma. The comprehensive computer retrieval related to comparison between acupoint application and nonacupoint application therapy for cough variant asthma was carried out in various databases ( Cough variant asthma (CVA) is a particular form with typical common cold symptoms and dry, nonproductive cough. Other manifestations, like dyspnea or gasping, are not generally observed; however, there could be episodic night cough which can be alleviated by a bronchodilator . The symIn addition, the prevalence of cough variant asthma is still prominent due to air pollution , smokingCurrent treatments for CVA are generally the same as ordinary respiratory illness, along with bronchodilators, glucocorticoid drugs, antihistamines, and leukotriene receptor antagonists . AlthougAcupoint application (AP) is a traditional Chinese medicine (TCM) method with a long history. The main steps of this treatment are grinding the herbs into powder and turning them into herbal patches, directly sticking to acupoints or affected areas to treat chronic cough. Studies have shown that acupoint application can affect the level of immunoglobulin and eosinophils in patients with CVA, regulate the proportion of lymphocytes, and influence the proportion of some cytokines, such as TGF, TNF, and IF, to control the symptoms of CVA and achieve long-term relief –8.Recently, there have been many studies demonstrating AP's positive results for curing CVA . Howeverhttps://pubmed.ncbi.nlm.nih.gov/), EMBASE (https://www.embase.com/landing?status=grey), Web of Science (https://mjl.clarivate.com/search-results), the Cochrane Library (https://www.cochranelibrary.com/), Chinese Journal Full-Text Database (CNKI) (http://kns55.en.eastview.com/kns55/brief/result.aspx?dbPrefix=CJFD), Database of Chinese Sci-Tech Periodicals (VIP) , “Wanfang” Database (http://www.wanfangdata.com/), and China Biology Medicine Disc (CBM). The following keywords were used: “stimulating acupoints,” “acupoint sticking,” “traditional Chinese medicine,” “TCM,” “acupoint,” “CVA,” “cough variant asthma,” “cough type asthma,” “cough-variant asthma,” “randomized controlled trial,” “random,” “control and trial,” and “RCT.”We systematically searched the literature for the formation of every database to July 4, 2021. Databases include PubMed  OR Traditional Chinese Medicine[MeSH Terms]) OR Chinese Traditional Medicine[MeSH Terms]) OR acupuncture[Abstract]) OR moxibustion[Abstract]) OR “auricular points plaster therapy”[Abstract]) OR “acupoint sticking”[Abstract])) AND “Cough Type Asthma”[Abstract]) OR “Cough variant asthma”[Abstract]) OR “Cough-Type Asthma”[Abstract]) OR “Cough-variant asthma”[Abstract]).#1 “auricular points plaster therapy”[Abstract/Title].#2 “acupoint sticking”[Abstract/Title]).#3 Traditional Chinese Medicine[MeSH Terms].#4 “ #1 OR #2 OR #3 ”.#5 “Cough Type Asthma”[Abstract/Title].#6 “Cough variant asthma”[Abstract/Title].#7 “Cough-variant asthma”[Abstract/Title].#8 “CVA” [Abstract/Title].#9 “ #5 OR #6 OR #7 OR #8”.#10 “Randomized controlled trial”[Abstract/Title].#11 “Random”[Abstract/Title].#12 “Control”[Abstract/Title].#13 “Trial”[Abstract/Title].#14 “ #10 OR #11 OR #12 OR #13”.#15 “ #4 AND #9 AND 14”.http://www.who.int/ictrp/en/) were also explored.Moreover, to include all the possible information, incomplete and finished experiments on the Chinese Scientific Experiments Register (update to July 2021) and World Health Organization ICTRP . These parameters were studied and included in the analysis.From the studied sections, participants of those studied articles were also screened. The following features of the study participants, age limit, gender, disease identification, other signs, and treatment count, as well as control samples, key features of treatment and control groups, and total completed experiments as well as incomplete or withdrawn, were taken for further analysis.In interventions, site for acupoint application, time of interference, and noninterference were focused.From the results section of the literature, total effective rate, forced expiratory volume (FVC), forced expiratory volume in one second, FEV1/FVC (%), FEV1/predication (FEV1/pre), peak expiratory flow (PEF), EOS count per milliliter in peripheral blood, IgE level per milliliter in the peripheral blood, and LCQ total score were taken for further study and analysis.Evaluation of standard of research was done by ReviewManager 5.3 software risk bias assessment tool equipped from Cochrane Collaboration: (a) to generate the randomized data, (b) concealing the allocation, (c) blinding of research individuals, (d) blinding of the evaluation of results, (e) no proper information retrieved, (f) prediction of specific results, and (g) different partialities. Each group was regarded as “high risk of bias” and “low risk of bias”/“unclear risk of bias.”We used the Cochrane ReviewManager 5.3 software for meta-analysis and assessment of reviewed data. Dichotomous data were displayed as odds ratio/risk ratio having 95% confidence intervals that predict the chance of risk or relative risk. Continuous variable dataset assessment was done by MD odds ratio and 95% confidence intervals (CIs). Key point of evaluation is the research volunteers.P value: if P value was less than 0.10, this showed statistically significant results. I2 statistic was applied as guided by the Cochrane Handbook for Systematic Reviews of Interventions. IfI-square (I2) was used as a statistical method to assess data heterogeneity, the value of I2 < 40% was indicative of less heterogeneity, whereas more than 75% indicated significant heterogeneity in experimentation. The funnel plot visually analyzed the “risk of reporting” bias.Assessment of the experiments was done for clinical heterogeneity , diversity in methodology , and statistical diversity. The chi-square test was applied with a I2 > 50%, the random-effect model (REM) was applied for assessment.Sensitivity analysis was done as described below: assessment of outcomes of two statistical models, i.e., random-effect model (REM) and fixed model, were applied and compared. If A total of 534 records were analyzed after excluding the duplicated data. This data was further meta-analyzed, and all the information related to the search for knowledge and protocol selection for research is presented in Out of the screened articles, thirteen articles were disclosed in 2014-2020 from nine provinces in China about AP in CVA. A total of 1237 volunteers participated in these researches, aged of 4-65 years. In previously published articles, the test groups consisted of patients who had undergone AP along with different treatments. In the control group, no AP was applied, and only Western or traditional Chinese medicines were used for the treatment of CVA.The acupoint application test and control samples had 621 and 616 cases, respectively. Key features of all elected research are mentioned in Assessment of “risk of bias” is presented in 2 = 11.37, P = 0.33, and I2 = 12%, and the fixed-effect model was applied for evaluation . The funnel plot revealed a uniform plot on both sides (left and right) and stacked on the upper side, showing a certain risk of bias, as shown in The sum of eleven types of research , 12–21 ialuation . Total eZ = 8.40, P < 0.00001)  Z = 5.86, P < 0.00001). These findings suggested that AP has more ability to improve the pulmonary function index FEV1 compared to the control group , and a subgroup analysis was performed. In the subgroup of patients younger than 7, the subgroup evaluation of four researchers reported a statistically small difference , Z = 8.00, P < 0.00001). In the subgroup of patients older than 7, the subgroup analysis showed a statistically significant difference , Z = 6.93, P < 0.00001).Five articles , 18, 22 ol group . A test Z = 2.97, P = 0.003). This suggests that acupoint application improves pulmonary function index FEV1/FVC (%) better than the control group. Heterogeneity among researchers  and subgroup analysis were performed. For the subgroup of patients whose intervention period is less than 30 days, subgroup evaluation in the 180 patients resulted in a statistically significant difference , Z = 5.65, P < 0.00001). Statistically significant results were found in those patients (n = 120) whose intervention period was more than 30 days and less than 6 months , Z = 12.00, P < 0.00001), whereas 120 patients were found with statistically significant results whose intervention period was more than 6 months , Z = 13.72, P < 0.00001)  .Z = 27.44, P < 0.00001). The difference between the three subgroups was significantly small (I2 = 0%)  , I2 = 0%) .Z = 12.40, P < 0.00001) which demonstrated that AP treatment is more effective in improving the pulmonary function index PEF compared to the control group , which reported that acupoint application treatment could better decrease the peripheral blood IgE level of CVA patients as compared to control samples , the cough variant asthma measure for acupoint application therapy (I2 = 66%). The random-effect analysis algorithm was applied to analyze two groups of samples , Z = 2.77, P = 0.006), indicating that acupoint application treatment could better decrease the peripheral blood EOS count of CVA patients as compared to control samples  , evaluating acupoint application treatment which might lead to better increase of the LCQ score of CVA patients compared with the control group  . The fixol group .It is widely believed that CVA is regarded as a particular form of respiratory illness with a histopathological process, just like common asthma. These include hyperresponsiveness (BHR), eosinophilic airway inflammation, and airway remodeling . Variousβ2 receptor agonists, inhaled anticholinergic drugs, and short-acting theophylline. These drugs are very effective in alleviating symptoms, reducing airway inflammation, and improving quality of life. However, adverse reactions of these drugs have also been observed. Glucocorticoids may cause hoarseness of voice and oral candida infection. The use of β receptor agonists may lead to sympathetic nerve excitation and accelerated heart rate, resulting in palpitations, chest pain, and other symptoms. So, it is advised to use these drugs only in emergencies and for the shorter period of time. Acupoint application is a nice alternative to these drugs [Asthma can be treated by inhaled glucocorticoids and leukotriene modulator drugs, etc. These drugs are categorized into a control group and need to be taken for a long period for the therapy to be effective, whereas other drugs include palliative drugs which include short-acting 13se drugs .Acupoint sticking therapy has a long history in traditional Chinese medicine. The main steps of this treatment are as follows. First, a variety of herbs were ground into a powder. Second, adhesive materials such as ginger water were prepared. Next, mix the powder with the adhesive to make a pulp salve that may look like “caking agent” and put it on certain acupuncture points of the body. For treating cough variant asthma, we often choose the “TianTu” (RN22), “DaZhui”(DU14), “FeiShu”(BL13), and “ShanZhong” RN17) acupoints. Acupoint application allows drugs to be absorbed directly through the skin into capillaries without the need for liver metabolism, which preserves the biological activity of some drugs  acupoint.Acupoint application has an advantage over other treatment therapies in treating asthma as acupoint stimulation promotes flow of blood to dispel pathogenic factors. This can stimulate the body's immunity and reduce allergic states . But stiFindings of this meta-analysis revealed that the rate of effectiveness, lung function index , FEV1 (%), PEF (day)) of the CVA sample showed more significant values as compared to the control group, whereas IgE and peripheral blood EOS count showed lower values when compared with control samples. This suggested that AP for cure of CVA has better efficacy than the other drug treatments.The main advantage of this study is that we conducted a meta-analysis of 13 RCTs involving 1237 participants. Compared to previous systematic reviews of acupoint application for CVA , this stHowever, this study still has some limitations. The foremost limitation is that, although the treatment of CVA by acupoint application is frequently used, random clinical controlled studies are usually single-center studies with a small sample size. There are problems such as having no recognized standard for efficacy evaluation and clinical heterogeneity. These problems suggest the need for high-quality clinical research methods in treating CVA by acupoint application, including correct randomization, double-blind, and allocation concealment methods, as well as large-scale multicenter studies. Second, since the acupoint application requires the application operating on the patient, and the herbs have a special smell, it is impossible to blind the patients during the operation in all employed research. Therefore, based on risk-of-bias assessment software provided by the Cochrane Organization, the “blinding of participants and personnel” in whole reports was evaluated as “high risk.” Third, the language of retrieval in the present research was in Chinese and English, and the literature was only from 8 databases. Besides, all the reports used in the meta-analysis were in Chinese, and all the experiments were conducted in China, limiting the present results' specifications because of sample features. Fourth, due to the complexity of acupoint application, this study mainly focused on the treating method of acupoint application but did not explore the influence of different acupoint selections and the type of herbal medicine on treating effectiveness.The current study concluded that acupoint application is better for the CVA treatment than the control group, which was treated with other traditional medicines. Moreover, it was observed that AP improved respiration and chronic airway inflammation by reducing eosinophil levels and peripheral blood IgE levels.


Introduction: The cardioprotective effect of halogenated drugs in cardiac surgery has been the subject of several studies. However, there is scarcity of data on their potential nephroprotective effects. Aortic valve replacement and coronary revascularization are the most frequent cardiac surgery procedures. The objective of this explorative study was to examine the effect of desflurane vs. propofol on renal function, when administered in aortic valve replacement surgery, including the extracorporeal circulation period. Method: A quasi-experimental prospective study was performed in 60 patients, who were allocated to receive either desflurane or propofol intraoperatively during aortic valve replacement surgery. As a hypnotic, group 1 received propofol, whereas group 2 received desflurane. Markers of renal function and level of cardiac preservation were determined based on biochemical parameters . Results: In the propofol group, there were significant variations between postoperative values of urinary NGAL and creatinine and baseline values. In contrast, no variations were found in the desflurane group in terms of hemodynamic parameters and myocardial damage. Conclusions: The use of propofol vs. desflurane during aortic valve replacement surgery is associated with a decrease in renal function. The intraoperative use of halogenated agents in cardiac surgery provides multiple benefits, primarily on cardiac function ,2,3. CarThe use of halogenated agents in the perioperative period of cardiac surgery is associated with a reduction of low cardiac output syndrome (LCOS) and lower levels of myocardial damage markers ,10.The perioperative role of halogenated agents in organ protection has been the subject of study in the recent years. Thus, numerous studies have focused on their effects on the kidneys, due to their relationship with mortality during the postoperative period of cardiac surgery. Hence, different investigations correlate the use of halogenated agents with improved renal function due to their two-fold role. Firstly, they induce myocardial conditioning, thereby improving cardiac output and ultimately preserving cardiac function. Secondly, they provide nephroprotection through a similar mechanism ,10,11.Of the range of drugs used in cardiac surgery, studies most frequently focus on the beneficial effects of sevoflurane. However, the role of this agent during cardiopulmonary bypass has only been evaluated in a few studies, of which primary objective was to assess its cardioprotective effects .Our primary objective was to examine the association between variations in kidney function in patients who received propofol vs. desflurane for anesthesia. Thus, variations were determined on the basis of associated biochemical and clinical parameters . Our secondary objective was to compare the level of cardiac preservation in the two study groups to understand the biochemical  and clinical impact of the intraoperative use of desflurane, as compared to propofol.Malaga Norte Ethics Committee (EPA SP-DESF 1/14). Informed consent was obtained from all the patients included in the study. The study was carried out in accordance with the tenets of the Declaration of Helsinki. The recruited patients were candidates for aortic valve replacement surgery and met the inclusion/exclusion criteria, as follows . 2. EUROSCORE  of less than 8 . 3. Degree of anesthetic risk according to the American Society of Anesthesia (ASA) below or equal to 4 (patient with moderate-high anesthetic risk).Exclusion criteria: 1. Clinical history of adverse reaction to different anesthetic drugs. 2. A severely diseased organ  diagnosed preoperatively, determined through a review of the clinical judgments recorded on the medical history of the patient. 3. Combined surgery . 4. Patients with hemodynamic instability, heart failure or needing inotropic or vasoactive drugs prior to the intervention. 5. Treatment with oral antidiabetics not suspended at least 48 h before the procedure. 6. Treatment with euphylline/theophylline prior to the intervention.The drug administered was determined by the anesthesiologist in charge before the beginning of the study.Group 1: Intraoperative propofol.Group 2: Intraoperative desflurane.The hemodynamic management of LCOS was performed according to the consensus and recommendation document of the Spanish Society of Intensive Care , as foll®  monitor. Pulse oximetry, capnography and blood pressure (BP) monitoring were also performed through bispectral index (BIS) hypnosis , provided that the patient remained sedated and connected to mechanical ventilation at an adequate concentration to maintain the level of hypnosis within the sedation ranges described (60–70). In the two groups, anesthesia was induced with etomidate 0.3 mg/kg, fentanyl 4 mcg/kg and succinylcholine 0.6 mg/kg. The different hypnotic groups were adjusted to maintain BIS within the 45–60 range. Neuromuscular relaxation was induced through intravenous administration of a bolus of cisatracurium  0.15 mg/kg, followed by a perfusion of 1–2 mcg/kg/min in the two groups. Likewise, in all patients, the opiate of choice post-intubation was intravenous remifentanyl at an infusion rate of 0.1–0.2 mcg/kg/min .All patients were monitored with a 5-lead electrocardiogram. In all of them, a continuous record was kept of lead II and V, of invasive (BP) through the radial artery and of cardiac output through the MostcareEpidemiological data were collected, including age, sex and EUROSCORE . Intraoperative data included: ECC time, ischemia time.Biochemical analysis included troponin I, CK, CKMMB, creatinine, lactate, and NT-ProBNP. Determinations were performed at diagnosis, immediately before the intervention, and during the following 48 h, at 24 h intervals. Urine NGAL (uNGAL) was collected at baseline and at 2 h from arrival to the Resuscitation Unit.2 ; or SatVO2 < 65% after hemodynamic optimization or need for inotropic drugs. These parameters were calculated at 12-h intervals after the patient entered the operating room and for the following 48 h.Hemodynamic parameters: heart rate; mean arterial pressure; right ventricular end-diastolic pressure; SatVO2, diagnosis of LCOS CI < 2 L/min/mRenal function parameters: dieresis, creatinine, need for furosemide or renal replacement therapy (RRT), stage according to AKI scale  , every 6The urine NGAL ELISA was performed using a commercially available assay  that specifically detects human NGAL .Urinary NGAL excretion is presented as the volume of urinary NGAL in ng per ml urine, as well as in ng per mg of urine creatinine to correct for differences in NGAL due to urine dilution. All measurements were made in triplicate. Several studies show that urine neutrophil gelatinase-associated lipocalin (NGAL) measured by ELISA is an early predictive biomarker of acute kidney injury (AKI) after cardiopulmonary bypass (CPB).Interferences of these biomarkers occur in settings of hyperbilirubinemia, hypertriglyceridemia and intense hemolysis with elevated hemoglobinuria.According to Prabhu et al. , uNGAL dn = 30 per group were analyzed using the t-test for normal distributions and homogeneous variances. Non-normal distributions were analyzed using the Mann–Whitney–Wilcoxon test. Binary variables were analyzed with the two-proportions z-test.Normal distribution was studied using the Shapiro–Wilk normality test and sample variance distribution using the Levenne test. Results with normal or non-normal distribution but with There were no statistical differences between groups in hemodynamic or biochemical parameters related to myocardial damage and heart insufficiency either at baseline, at 24 h or at 48 h. In relation to kidney function, no significant differences were observed at baseline levels of NGAL and creatinine between groups. NGAL was determined at baseline and at two hours after the procedure, without any significant differences between groups in terms of baseline and postoperative values. Determination of creatinine and diuresis was performed at baseline and at 24 and 48 h, without any significant differences. Intragroup analysis revealed significant differences in the propofol group, as compared to desflurane, where differences were not observed. There were no significant differences in the administration of crystalloid solutions during the first 24 h and 48 h between groups.There were no significant differences between groups in the epidemiological and intraoperative variables collected. .No differences were found in the hemodynamic parameters monitored during the study . There were no significant differences between groups in renal function in terms of biochemical parameters and stage of kidney function. .In relation to variation in kidney function, there were significant variations in the increase in creatinine and NGAL in the propofol group at baseline, at 24 h and at 48 h, compared to the desflurane group .The intraoperative use of desflurane in aortic valve replacement surgery in patients without pre-existing kidney disease has been shown to exert nephroprotective effects.The use of halogenated drugs has been consistently associated with a cardioprotective role based on the molecular effects of pharmacological pre- and postconditioning. Its final effects are modulated by different mediator enzymes involved in the SAFE and RISK pathways ,15. ClinSeveral studies have assessed the effects of halogenated hypnotics on kidney function in cardiac surgery patients. Initially, it seemed that the effects of sevoflurane on the kidneys mediated by compound A could cause toxicity and kidney injury; as a result, flow rates < 2 L/min were not recommended for anesthesia induction. Subsequent studies showed that the use of sevoflurane could be beneficial in cardiac surgery patients, since it preserves renal function during the perioperative period ,17. The The mechanism by which halogenated drugs exert nephroprotective effects could be multifactorial. Firstly, decreased LCOS and preserved perfusion would result in nephropreservation ,2,3,4. SThe purpose of this observational study was to investigate whether halogenated agents exert protective effects against kidney injury in aortic valve replacement surgery. Another objective was to assess the association between the use of halogenated agents and the incidence of low cardiac output syndrome or perioperative myocardial injury. We expect that these results open an avenue for future randomized trials testing the hypothesis that halogenated agents have a protective effect against kidney injury that is independent from their action at the myocardial level.In our study, the propofol group showed significant intra-group variations in the levels of creatinine at baseline, at 24 and 48 h, a phenomenon that was not observed in the desflurane group. In the statistical analysis, the difference between groups at baseline, 24 and 48 h was 0.05. Despite not reaching statistical significance, an important difference was observed between the two groups in the behavior of creatinine. In fact, intra-group variations reflect a different tendency in renal function in the two groups.In our search for a more sensitive and specific marker of renal dysfunction, we determined baseline and postoperative values of urinary NGAL in the 30 patients of each group. However, five samples of each group could not be analysed, since they were out of the limit of detection of ELISA due to hemolysis occurring during ECC . Even soOur results show that the use of desflurane compared to propofol during a low-risk perioperative intervention in cardiac surgery generates a benefit at the kidney level, which is an independent factor of mortality in this group of patients. This potential benefit may be modulated by sustained exposure to desflurane throughout the intraoperative period of aortic valve replacement surgery, including the extracorporeal circulation period. In previous studies, the cardioprotective effects of desflurane have been associated with drug concentration and duration of exposure. The desflurane concentrations used were established for clinical purposes guided by hypnosis monitoring. Therefore, results are related to the usual use of the drug in this group of patients.The explanation of this nephroprotective effect may be related to the cardioprotective mechanisms of desflurane. However, the treatment for LCOS was similar in the two groups, without significant variations in central venous saturation; therefore, we assume that oxygen transport was adequate in terms of oxygen consumption, and there were no differences in mean arterial pressures that would justify these differences. In addition, no differences were found either between groups in values of central venous pressure or its possible correlation with retrograde pressure. To the best of our knowledge, this is the first study to assess variations in NGAL associated with the use of anesthetics in patients undergoing aortic valve replacement surgery. Julier evaluated kidney function in patients undergoing off-pump myocardial revascularization surgery who received anesthesia with sevoflurane vs. propofol. Differences between our study and those of Julier  and GuerThere is little evidence on the effects of the different anesthetics on renal function in cardiac surgery patients. Indeed, assessing this association was not the primary objective in any of the studies available. Of note, Julier  carried The reasons that raised our interest in assessing the role of desflurane in renal function in the setting of aortic valve replacement surgery were two-fold: (i) there were no studies available in which the primary objective was to examine the association between the anesthetic used during cardiac surgery and renal function; and (ii) there was a scarcity of studies examining desflurane , which has been suggested to have similar cardioprotective effects as sevoflurane in cardiac surgery patients. Considering that the association between the beneficial effects of inhalatory agents is dependent on the time of exposure to and concentration of the drugs administered, desflurane at 6% could play a relevant role in organ protection during cardiac surgery. This study reveals that the nephroprotective effect of desflurane in short low-risk cardiac surgery is more intense than the one reported in previous studies. To achieve this effect, it is necessary to maintain expired gas concentrations more than twice the ones required for sevoflurane, according to the pharmacodynamics of each of these gases and their action on the brain, to achieve adequate hypnosis.The potential clinical benefits of desflurane in aortic valve replacement surgery are two-fold, i.e., myocardial conditioning and nephropreservation. The latter would reduce the risk of infection. This would have a direct impact on mortality in this population with kidney failure through a nephroprotective effect that is independent from its cardioprotective effect on patients, as, in cardiac surgery, mortality increases with the occurrence of acute kidney failure.One of the biases of our study was the non-randomization of patients due to the quasi-experimental design of the study; however, the anesthesiologists were permitted to select the type of hypnotic according to their usual practice. In addition, the statistical analysis showed no baseline differences between study groups. On the other hand, the same algorithm was used for the treatment of low cardiac output syndrome and for blood volume optimization in the two groups, thereby ensuring homogeneity. Another limitation of this study is that the mechanism by which halogenated anesthetics exerts nephroprotective effects, independent from its cardioprotective effects, is not identified.Therefore, the potential association between the intraoperative use of desflurane and a lower elevation of biochemical parameters of renal dysfunction (NGAL and creatinine) needs further study with randomized studies that confirm our hypothesis.The use of desflurane vs. propofol in aortic valve replacement surgery, including the extracorporeal circulation period, is associated with a decrease in creatinine and NGAL values. Further larger randomized studies are needed to confirm the potential causal relationship between anesthetics and renal function in aortic valve replacement surgery.


Delayed graft function (DGF) commonly occurs after kidney transplantation, but no clinical predictors for guiding post-transplant management are available.Data including demographics, surgery, anesthesia, postoperative day 1 serum cystatin C (S-CysC) level, kidney functions, and postoperative complications in 603 kidney transplant recipients who met the enrollment criteria from January 2017 to December 2018 were collected and analyzed to form the Intention-To-Treat (ITT) set. All perioperative data were screened using the least absolute shrinkage and selection operator. The discrimination, calibration, and clinical effectiveness of the predictor were verified with area under curve (AUC), calibration plot, clinical decision curve, and impact curve. The predictor was trained in Per-Protocol set, validated in the ITT set, and its stability was further tested in the bootstrap resample data.P < 0.001), serum creatinine level  and dialysis postoperative  compared with patients without DGF. Among 41 potential predictors, S-CysC was the most effective in the parsimonious model, and its diagnostic cut-off value was 3.80 mg/L with the risk score . Its specificity and sensitivity indicated by AUC was 0.832  with well fit calibration. S-CysC yielded up to 50% of clinical benefit rate with 1:4 of cost/benefit ratio.Patients with DGF had significantly higher postoperative day 1 S-CysC level (4.2 ± 1.2 vs. 2.8 ± 0.9 mg/L; The postoperative day 1 S-CysC level predicts DGF and may be used as a predictor of DGF but warrants further study. Delayed graft function (DGF) is common after kidney transplantation. Once DGF occurs, 3.2 years graft survival decreases by 40%, 3 years death increases by 53%, and 3.5 years acute rejection increases by 38% –3. CurreScr, as the most used renal function biomarker, is used in the diagnosis of DGF, but it has low sensitivity when predicting DGF . Indeed,P = 0.01) (Previous studies reported Serum cystatin C (S-CysC) increased 24 h earlier than Scr after unilateral nephrectomy in kidney organ donors . S-CysC  = 0.01) . S-CysC  = 0.01) . Given t = 0.01) –19. In p = 0.01) . The fir = 0.01) , 21. TheThis study was approved by the ethics committee of the First Affiliated Hospital of Xi’an Jiaotong University (XJTUIAF2019LSL–008). This study was in accordance with the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis. Written informed consent was waived because de-identified retrospective data were used. All the medical procedures adhered to the principles of the Declaration of Helsinki and the Istanbul Declaration, and all renal grafts were voluntarily donated. All organs (except kinship donor kidneys) were obtained by the Organ Procurement Organization of the First Affiliated Hospital of Xi’an Jiaotong University, supervised by the Red Cross Society of Shaanxi Province, and were allocated by China Organ Transplant Response System. Receptors were included in this cohort when they met the following criteria: (1) older than 18, (2) underwent kidney transplantation for end-stage kidney disease under general anesthesia, and (3) admitted to the First Affiliated Hospital of Xi’an Jiaotong University from January 1, 2017 to December 31, 2018. Donors who met any of the following criteria were excluded from the study: (1) combined kidney and other organ transplantation, (2) re-transplantation, and (3) missing clinical records of the S-CysC (24 h) or creatinine (72 h). All perioperative data  in kidney transplant patients from January 1, 2017 to December 31, 2018 were collected, cross-checked, and de-identified by a team of experienced clinicians. DGF was defined as post-transplant graft kidney dysfunction with no spontaneous 10% decline in serum creatinine in 72 h, and dialysis is required 72 h after transplantation . The datThe data of preoperative donors and recipients were obtained from the registry system of organ donation database and then evaluated and recorded in electronic medical record system by surgeons and anesthesiologists. Anesthesia management, surgery, and perioperative care followed standard institutional protocols. A triple immunosuppressive regimen with calcineurin inhibitors (CNIs), entericcoated mycophenolate sodium  and prednisone were treated all recipients. Cyclosporine A  and tacrolimus  composed the CNIs. The initial dosages of CsA, TAC, EC-MPS and prednisone were 4.0–4.5 and 0.06–0.08 mg/kg/day, 1,080–1,440 and 10–20 mg/day, respectively. Rabbit anti-thymocyte globulin  at a dosage of 1.25–1.50 mg/kg/day as induction therapy during the surgery were given to all recipients in a total of 4–6 days after kidney transplantation.The collective data of all the recipients and donors were obtained and presented. For each patient, the baseline characters were screened: age, gender, body mass index, nationality, smoke, dialysis , dialysis duration, comorbidities , pathogenesis of end-stage kidney disease . The donor characteristics were as follows: donor , right or left kidney, and duration of ischemia (warm ischemia and cold ischemia). Operation factors, such as American Society of Anesthesiologist classification, iliac fossa, operation location, vascular anastomosis , and time of operation. Intraoperative medication  and intake and output volumes  were collected. Postoperative kidney function indexes, including S-CysC, Scr, glomerular filtration rate (GFR), urea nitrogen (BUN), and uric acid (UA) on the first day after surgery were compared.t-tests, Mann–Whitney U test, Chi-square test, and Fisher’s exact test. All perioperative variables in the PP set were entered in the Least Absolute Shrinkage and Selection Operator (LASSO) selection process for the generation of a single predictive model of DGF. Missing predictor values in the ITT set (N = 517) were imputed through multiple imputation with chained equations. We used L1-penalized LASSO for multivariable analyses, augmented with 10-fold cross validation for internal validation. This logistic regression model penalizes the absolute size of the coefficients of a regression model to minimize the potential collinearity of variables measured from the same patient and model overfitting. The optimal diagnostic model and the most parsimonious model of LASSO regression were identified with minimum criteria and one standard error of the minimum criteria (the 1-SE criterion) in the 5 times multiple interpolation ITT sets. To compare the predictive effect of optimal model and the most parsimonious model in ITT set without multiple interpolation, the same items among the 5 optimal diagnostic models were collected by univariate analysis with P < 0.1, calculated their relative risk by multivariate analysis, and compared with the most parsimonious model by using the area under the receiver operating characteristic curve (AUC) and the DeLong method.Between the DGF and non-DGF groups in the ITT set, the normally distributed continuous variables were presented as means ± standard deviations (SDs); otherwise, they were presented as medians (interquartile ranges). The categorical variables were reported as numbers (percentages). They were analyzed with independent-sample student’s P < 0.05 considered to be statistically significant.The internal validation of the single predictor was tested in the PP and ITT sets: (1) The predictive accuracy estimates and mean absolute error were calculated by 200 bootstrap resamples, (2) The calibration curves of the predictor on DGF were plotted and tested by Hosmer–Lemeshow test. (3) The optimal cut-off value of the single predictor was calculated by Youden’s index, and the relative risk was calculated by univariate logistic regression. (4) The clinical value of the predictor for DGF diagnosis was finalized through decision curve analysis (DCA). (5) A clinical impact plot was used in depicting the estimated number of high-risk patients and the true positive cases. All data were analyzed using R software (version 4.0.2) and Empower . Packages in R that were used in this study were “rms,” “rmda” and “glmnet.” The reported statistical significance levels were two-side, with a n = 90) and non-DGF (n = 427) groups except for pneumonia , and the diagnostic cutoff value of the model was 3.80 mg/L  of AUC and well-fit calibration curves, yielding approximately 50% of clinical benefit rate and predicting positives cases with 1:4 cost/benefit ratio in the PP set on the basis of 19.35% DGF incidence , and the 200 repetitions of bootstrapping validation further confirmed this value. The calibration curve of S-CysC for the probability of DGF indicated the consistency between prediction and observation in the ITT dataset (P = 0.142), suggesting that the predictive model fitted well with the ideal model The decision curve analysis demonstrated that using this model to predict the diagnosis of DGF would have more benefits than those in all dialysis or non-dialysis patient when the threshold probability of a patient was 3–78% . S-CysC had 50% of the net benefit of the 1:4 cost/benefit ratio based on 19.35% of the DGF incidence (P < 0.001), and the 200 repetitions of bootstrapping validation further confirmed that the AUC was 0.828. The calibration plot diagram showed a good consistency between the actual and predicted diagnoses. The Hosmer–Lemeshow test further illustrated the predicted diagnoses, and the ideal dotted line had no significant difference , but Scr level was not selected as the single predictor by the LASSO regression. The cohort study with 91 patients reported that Scr on postoperative first day is not predictive for AUC 0.53   . Scr is 35–0.71) . Several35–0.71) . S-CysC,35–0.71) . The ret35–0.71) .The strength of our study were the logical and strict predictor selection, verification, and manifestation in a large sample size of 517 patients. S-CysC was screened from all perioperative data by the most parsimonious diagnostic LASSO regression of DGF. Meanwhile, AUC, the clinical utility of the model, DCA, and clinical impact curve analysis were all implemented. Finally, the predictive effect was validated with the ITT set, bootstrap resample data, and multiple interpolation data. The postoperative first clinical routine S-CysC as a single predictor of DGF facilitates the postoperative individual patient management and hospital resources allocation in the high-risk patients with DGF. The DGF high-risk patients will be performed ultrasound examination to exclude surgery-related complications; adjusted the immunosuppressors; provided critical care or dialysis whenever need. In the future, however, the limitation of our study is a single center and retrospective study and hence its value to predict DGF warrants further prospective study. Meanwhile, it would have been more appropriate to combine S-CysC with the biomarkers of renal tubular injury, such as KIM-1, IL-18, and NGAL. Multi-biomarkers study would have helped to characterize better the complexity of DGF.In conclusion, the postoperative first day S-CysC level may be a single predictor of DGF with good discrimination, calibration, and clinical benefit and may be used in routine clinical use, although validation studies are still needed.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.YL and WG: study conception. YL, BW, LW, KS, WZ, SG, JC, CD, and JD: acquisition or interpretation of data. WG and YL: statistical analyses. YL, BW, and WG: drafted the manuscript. YL, BW, WG, CD, and JD: critically revised the manuscript for important intelectual content. WG: obtained funding. WG, YL, BW, LW, KS, WZ, SG, CD, and JD: provided administrative, technical, or material support. All authors contributed to the article and approved the submitted version.


Posterior urethral valves are urethral leaflets that cause Lower Urinary Tract Obstruction (LUTO) in boys and are associated with congenital renal dysplasia and abnormal bladder function. They affect 1:4,000 to 1:25,000 births and can be responsible for End-Stage Renal Failure in childhood. There have been several studies on the effect of pop-off mechanisms in boys with posterior urethral valves, but results are contradictory. We aimed to assess and discuss the effect of pop-off mechanisms on renal function in a large cohort of patients.Boys with PUV with and without pop-off mechanisms  were divided into three severity groups for renal function according to their nadir creatinine . We compared children with and children without pop-off mechanisms for mean renal function as well as patient distribution within each severity group.We included 137 boys of which 39 had a pop-off mechanism. Patients had complete data for at least 5 years follow-up. Though there was no significant statistical difference in mean renal function between the pop-off and non-pop-off group, patient distribution within each severity group varied according to whether patients had a pop-off mechanism or not.Though there was no significant difference in mean renal function between boys with and without pop-off mechanisms, it is possible that these are two different patient populations and direct comparison is not possible. Posterior urethral valves cause both bladder and renal damage because of increased intravesical pressure during fetal kidney development. Some cases of posterior urethral valves are associated with pressure “pop-offs” that, in theory, could buffer elevated intravesical pressures thus preserving the urinary tract . SeveralIn this retrospective study, we included all boys with prenatally diagnosed lower urinary tract obstruction born between 2000 and 2013 in two University Hospitals. Information came from two prospectively gathered databases. We excluded patients who presented a LUTO other than PUV, children who presented multiple birth defects and neonatal deaths. We did not exclude some patients who were subsequently lost to follow-up if sufficient relevant data was available, but those with insufficient data were excluded. We included data on gestational age at birth, age at surgery, presence or absence of a pop-off mechanism, nadir creatinine (NC), i.e., lowest creatinine during the first year of life, long-term renal function (defined by the Chronic Kidney Disease classification based on latest serum creatinine), presence of febrile urinary tract infections. Patients had complete data for at least 5 years follow-up.Boys with PUV with and without pop-off mechanisms were divided into three severity groups for renal function according to their NC using the classification proposed by the team from Birmingham . This clWe defined pop-off mechanism as presence of either: VURD  syndrome as defined by voiding cystogram and DMSA scan; urinoma or urinary ascites, confirmed by ultrasound, or a large bladder diverticula, defined as a diverticula measuring more than a third of the bladder volume.t-test or Mann–Whitney test for quantitative data, as appropriate. All tests were performed at a 2-tailed type I error of 5%.Characteristics of patients were described as frequencies and proportions for categorical variables and mean with standard deviation or median and quartiles for quantitative variables. Bivariate analyses were performed using Pearson Chi-Square or Fisher exact test for qualitative data, and Student's All analyses were performed using SAS 9.4 .The original series included 172 patients. We excluded 4 other LUTOs, 2 neonatal deaths and 29 lost to follow-up or insufficient data. We therefore included 137 boys who had complete renal function evaluation, of which 39  had a pop-off mechanism. Median follow-up was 8.3 years [IQR: 6.9–12.6].Characteristics of patients are summarized in p = 0.31). However, patient distribution within each severity group (based on nadir creatinine) varied according to whether patients had a pop-off mechanism or not (There was a non-significant difference in mean renal function, as determined by latest creatinine, between both the pop-off and non-pop-off group: respectively 35.7 +/−12.2 µmol/l and 44.5 +/−29.9 µmol/l (m or not . Whilst Pressure pop-off mechanisms, and their putative protective effect on renal function in boys with posterior urethral valves, were initially described by Rittenberg et al. . These pThere are several possible explanations for these discrepancies. As in many cases, there is quite a large disparity in patients and methods between published articles rendering direct comparison and analysis difficult and meta-analysis impossible. There are for instance large variations in the proportion of children with pop-off mechanisms in the study groups, ranging from 6 to 71%, which indicates significant differences in patient population. The accepted incidence for pop-off mechanisms is 30% . And theFor this study we decided to evaluate a large homogeneous series of patients with posterior urethral valves. We selected only children with prenatal diagnosis of PUV and immediate postnatal management, in order to exclude late diagnosis PUV patients who, as mentioned previously, are different patients.We performed multiple analyses, of mean results but also of patient distribution using nadir creatinine and CKD classification because a single analysis gives only a limited view. We decided to classify renal function in three categories as again a binary classification between normal and abnormal is too restrictive for this population for whom the range of impairment goes from normal to early-onset end-stage renal disease.Nevertheless, direct comparison of means between patients with a pop-off mechanism and those without shows no statistical difference. Does this mean pop-off mechanisms have no protective effect? This is obviously one of the possible explanations but pop-off mechanisms occur by definition in boys with high-pressure. Urinomas, giant diverticula or high-grade reflux appear because of high-pressure in a closed circuit. In the recent study by d'Oro et al., patients with pop-offs had worse bladder dynamics initially, which to them suggests that pop-offs are a manifestation of more excessive pressure build-up prior to valve ablation . High prWe have a fairly large series with significant follow-up, however we cannot certify that a difference in renal function would appear later. Indeed, in the series by Okutesh et al. , the meaAlso, all pop-off phenomena do not necessarily have similar effect on kidney function. It can be postulated that at least affected kidney has suffered in VURD syndrome and perhaps in urinoma but both kidneys may be preserved in patients with bladder diverticula. We do not however have sufficient patients to allow for a full subgroup analysis. In our series different types of pop-off mechanisms seemed to have similar effects.We have the impression that boys with pop-off mechanisms will not by definition fare better than boys without pop-off mechanisms, but that they will do better than they would themselves have done without pop-off.


Background: Intermittent hypoxic-hyperoxic exposure (IHHE) and aerobic training have been proposed as non-pharmacological interventions to reduce age-related risk factors. However, no study has yet examined the effects of IHHE before aerobic exercise on cardiovascular risk factors in the elderly. Therefore, the aim of this study was to investigate the acute and chronic effects of IHHE prior to aerobic cycling exercise on blood lipid and lipoprotein concentrations as well as blood pressure in geriatric patients.Methods: In a randomized, controlled, and single-blinded trial, thirty geriatric patients (72–94 years) were assigned to two groups: intervention  and sham control group . Both groups completed 6 weeks of aerobic cycling training, 3 times a week for 20 min per day. The IG and CG were additionally exposed to IHHE or sham IHHE  for 30 min prior to aerobic cycling. Blood samples were taken on three occasions: immediately before the first, ∼10 min after the first, and immediately before the last session. Blood samples were analyzed for total (tCh), high-density (HDL-C), and low-density lipoprotein cholesterol (LDL-C), and triglyceride (Tgl) serum concentration. Resting systolic (SBP) and diastolic blood pressure (DBP) was assessed within 1 week before, during , and after the interventions.Results: The baseline-adjusted ANCOVA revealed a higher LDL-C concentration in the IG compared to the CG after the first intervention session (ηp2 = 0.12). For tCh, HDL-C, Tgl, and tCh/HDL-C ratio there were no differences in acute changes between the IG and the CG (ηp2 ≤ 0.01). With regard to the chronic effects on lipids and lipoproteins, data analysis indicated no differences between groups (ηp2 ≤ 0.03). The repeated measures ANOVA revealed an interaction effect for SBP (ηp2 = 0.06) but not for DBP (ηp2 ≤ 0.01). Within-group post-hoc analysis for the IG indicated a reduction in SBP at post-test (d = 0.05).Conclusion: Applying IHHE prior to aerobic cycling seems to be effective to reduce SBP in geriatric patients after 6 weeks of training. The present study suggests that IHHE prior to aerobic cycling can influence the acute exercise-related responses in LDL-C concentration but did not induce chronic changes in basal lipid or lipoprotein concentrations. Aging impairs the state and function of almost all major organ systems including the nervous , cardiovHigh blood pressure is the leading risk factor for cardiovascular disease mortality and disease burden . AlthougDyslipidemia is commonly characterized by changed lipid and lipoprotein levels, more particularly by reduced high-density lipoprotein cholesterol (HDL-C) and/or increased total cholesterol (tCh), low-density lipoprotein cholesterol (LDL-C) and/or triglyceride (Tgl) levels. Studies have shown that HDL-C levels decrease during the aging process, whereas tCh, LDL-C, and Tgl levels increase . In addiGenerally described as polypill , physicaiO2] = 0.30–0.40, termed intermittent hypoxic-hyperoxic exposure [IHHE])  . Previou [IHHE]) , ischemi [IHHE]) , mild co [IHHE]) , prediab [IHHE]) , comorbi [IHHE]) , and in  [IHHE]) . Hence,  [IHHE]) . However [IHHE]) .To date, no study has investigated the influence of IHHE conducted prior to aerobic exercise on major cardiovascular risk factors in geriatric patients. Therefore, the aim of the present study was to examine the acute effect of IHHE prior to aerobic cycling exercise on blood lipid and lipoprotein concentrations  in geriatric patients. To obtain further insight into the chronic effects of IHHE in combination with aerobic cycling training on age-related cardiovascular risk factors, training induced changes  in lipid and lipoprotein concentrations as well as blood pressure  were also investigated in the present study.iO2 = 0.12) through a face mask. The hypoxic air mixture was automatically provided by an altitude breathing therapy device , while the patients’ peripheral oxygen saturation (SpO2) as well as pulse rate were steadily monitored and stored by the device. Furthermore, the patients were supervised by a physician and monitored using a 12-channel electrocardiogram  during the entire duration of the hypoxic test. Based on the temporal parameters recorded during the hypoxic test , an individually tailored IHHE program  was suggested by the hypoxic device for each patient. The maximum duration of a single hypoxic period in the IHHE program was limited to 8 min . For the readjustment of the hypoxic dose during the IHHE training, the hypoxic test was repeated after 3 weeks of the intervention .This study was a randomized, two-armed, placebo-controlled intervention trial conducted in two inpatient care facilities for geriatric patients in Magdeburg  from April 12 to 17 August 2022. Due to a limited number of training devices and the different locations of the facilities, the study was divided into two blocks of 8 weeks each. The 8-week block in each facility included a 6-week intervention period as well as 1-week pre-diagnostic and 1-week post-diagnostic. Prior to the start of the study, all participants and, if acquired, their legal guardians were informed about the aims and the procedure of the study. Every patient or their legal guardian signed a written consent form. After agreeing to participate in the study, patients were screened regarding the inclusion and exclusion criteria see . AfterwaOnce the pre-diagnostic period was completed, patients were randomly  assigned to either the intervention group (IG) or a sham control group (CG). The patients were unaware of their group assignment (single blinded). During the intervention period, blood samples were collected immediately before and ∼10 min after the 1st training session as well as immediately before the last training session see . FurtherThe experimental protocol was approved by the local Ethics Committee of the Otto-von-Guericke University Magdeburg (No. 202/20) confirming to the principles of the Declaration of Helsinki on human experimentation. The study was retrospectively registered at drks. de (DRKS-ID: DRKS00025130).n = 16, CG: n = 17, pO2 below 93%, and the simultaneous participation in other interventions.A total number of 33 geriatric patients were recruited to participate in the present study . This aThe training was conducted on 3 days per week  for 6 weeks resulting in 18 training sessions for each patient. The patients in each facility were divided into multiple encounter groups consisting of a maximum of four patients. It was ensured that each encounter group consisted of patients from the IG and CG (ratio 1:1). The training sessions took place in the morning and in the afternoon. Every training session was accompanied by at least one supervisor.iO2 of approximately 0.21 . Afterwards, the face masks were removed and the patients performed 20 min of aerobic cycling exercise using a motorized cycle ergometer  under normoxic conditions.Each training session lasted approximately 60 min and consisted of two parts. In the first part, patients of both groups were connected to an altitude breathing therapy device  through a facemask and inhaled a gas mixture for 30 min while sitting on an armchair. While the IG intermittently inhaled a hypoxic and hyperoxic gas mixture, the CG received a sham mixture with a constant FpO2 and pulse rate was continuously monitored via a fingertip pulse oximeter  and stored by the device. When the individual minimum SpO2 value determined during the hypoxic tests was reached in the course of a hypoxic period, the device automatically switched to hyperoxia until the pre-hypoxia SpO2 level was achieved. Subsequently, the next hypoxic-hyperoxic cycle started. Depending on the individual tolerance to hypoxia and patients’ acute responses , the IG inhaled hypoxia (FiO2 = 0.10–0.14) for 1–5 min, interspersed by the exposure to hyperoxia (FiO2 = 0.30–0.40) for 1–3 min. Each program lasted 30 min and consisted of 4–8 hypoxic-hyperoxic cycles. In the course of the IHHE program, the patients from the IG reached an average minimum and maximum SpO2 of 84 ± 3.4% and 97 ± 1.9%, respectively , 2) ∼10 min after the 1st training session (t2), and 3) immediately before the last (18th) training session (t3). This approach was utilized to investigate the acute (changes from t1 to t2) and chronic (changes from t1 to t3) effects of IHHE or sham-IHHE prior to aerobic cycling exercise on lipid and lipoprotein blood concentrations. In order to keep the conditions as similar as possible for the first (t1) and last (t3) blood collection , the third blood sample was taken immediately before the last (18th) training session.Blood sample collection was performed at three time points: 1) immediately before the 1st training session (t® II Advance) to determine lipid and lipoprotein serum levels. Immediately after the blood samples were collected, the vacutainer were swirled head down for ten times. Subsequently, the samples were stored for 30 min at room temperature before the serum was separated by centrifugation at 2000 G for 15 min. For each blood collection, 600 μL of serum aliquoted in two tubes were extracted and stored at −80°C for later analysis. Blood serum concentrations of tCh, HDL-C, LDL-C, and Tgl were analyzed by commercial colorimetric kits  using Cobas 8000 chemistry analyzer .An 8.5 ml venous blood sample was taken from a superficial forearm vein under stasis conditions from a physician with the patients seated at quiet rest. The blood samples were collected in a vacutainer with separating gel and coagulation activator (BD Vacutainert-test was used to compare patients’ characteristics at baseline and training variables between the IG and the CG. To check for differences between groups regarding the acute (exercise-induced) and chronic (training-induced) changes in lipid and lipoprotein blood serum concentrations, univariate analyses of covariance (ANCOVA) with baseline values entered as a covariate (baseline-adjusted) were performed. Furthermore, regarding the analysis of acute exercise-induced changes, the average work performed during the aerobic cycling session was entered as a second covariate because studies indicated that the magnitude of acute exercise-induced effects on lipid and lipoprotein concentrations appears to increase with energy expenditure  and Cohen’s (d) were calculated. A ηp2 between 0.01–0.06, 0.06–0.14 and ≥ 0.14 was considered as a small, medium, and large effect size, respectively . Effect sizes are used to determine the practical relevance and generalizability of effects . Out of these remaining 33 patients that were randomized and assigned to the IG or CG, three had to be excluded from the final analysis due to a low attendance rate (< 80%). Thus, 30 patients  have finished the whole intervention period and had a sufficient training attendance rate . In addition to the eight patients who dropped out, there were irreversible data losses due to measurement errors during the post-test . All comp ≥ .298, d ≤ 0.35). The minimum SpO2 was lower  and the maximum SpO2 was higher  in the IG during IHHE than in the CG during sham IHHE. There were no differences between the IG and CG with respect to the average work (measured in kJ) generated during the 20 min aerobic cycling sessions and the average pulse rate prior as well immediately after these sessions . The participants’ characteristics , and cognitive ability  of the patients were similar between groups , while Tgl was higher in CG compared to IG . Data analysis revealed a higher LDL-C blood serum concentration with a medium effect size in the IG compared to the CG after an acute exercise session. For tCh, HDL-C, Tgl, and tCh/HDL-C ratio there were no differences in acute exercise-related changes between the IG and the CG. 1, pre-exercise) and the baseline-adjusted means and standard deviations after  a single exercise session together with the mean differences  between the IG and the CG as well as the results of the univariate ANCOVA .With regard to the acute effects, the univariate ANCOVA with baseline-adjustment showed differences between groups for acute exercise-related changes in LDL-C (3) as well as the adjusted mean differences  between the IG and the CG together with the results of the univariate ANCOVA .With regard to the chronic effects on lipid and lipoprotein blood serum concentrations, there were no differences between groups for tCh, HDL-C, LDL-C, Tgl, and tCh/HDL-C ratio, indicating that the IHHE had no effect on basal lipid or lipoprotein blood serum concentration. p ≥ .586, d ≤ 0.21) at baseline. With regard to SBP, the 4 × 2 ANOVA with repeated measures revealed an interaction effect  as well as a main effect of time  but no main effect of group . Within-group post-hoc analysis for the IG revealed a reduction in SBP by 7.67 mmHg  at post-test compared to 4-weeks mid-training. No interaction effect or main effect of group  but a main effect of time  was found for DBP. However, post-hoc analysis indicated no within-group differences . F-value, dfeffect, dferror, p-value, and effect size ηp2). Means and standard deviations of these variables as well as the mean differences  between pre- and post-training are also shown in F-value, dfeffect, dferror, p-value, and effect size ηp2).There were no differences between the IG and the CG in SBP and DBP  and chronic  effects of IHHE prior to aerobic cycling exercise on blood lipid and lipoprotein serum concentrations as well as the resting blood pressure in geriatric patients. The novel finding of this study was that IHHE increased LDL-C concentration in blood serum in response to aerobic cycling exercise. Furthermore, the results demonstrated that an additional IHHE prior to aerobic cycling exercise performed over 6 weeks had no influence on basal lipid and lipoprotein concentrations in blood serum but seemed to be effective to reduce resting SBP.iO2 = 0.10, average SpO2 = 80%) and the sham hypoxia  conditions in overweight/obese subjects. However, the participants did not perform any exercise after the intermittent hypoxia and sham interventions. Studies examining the acute effects of aerobic exercise only on lipid and lipoprotein concentrations showed inconsistent results, reporting both changed  was increased 5 min after acute prolonged hypoxic exposure  in sedentary overweight/obese males (iO2 = 0.12) has previously been shown to result in a 95% greater increase in circulating non-esterified fatty acids than under normoxia in fasting healthy males (iO2 = 0.15) led to an increased lipid oxidation rate in active healthy males 40 min post-exercise measured under normoxic conditions, whereas it remained unchanged during the exercise session under hypoxia (iO2 = 0.05) and high intra-session frequency (∼25 cycles∙h−1) reported reduced insulin sensitivity and increased blood glucose levels in healthy adults  have been reported to acutely reduce blood glucose concentration in overweight/obese subjects  stimulacles∙h−1 . On the subjects  and patisubjects . This wasubjects . Overallsubjects . Unfortu−1) in geriatric patients  in addition to a multimodal training and those who completed a multimodal training only. In contrast, studies in patients with metabolic syndrome (−1) of IHHE  compared to a control group (sham IHHE: FiO2 ∼ 0.21 for 40–45 min) in patients with metabolic syndrome (−1) of IHHE  in patients with prediabetes (−1) of IHHE  in patients with coronary artery disease  and found a decrease of 5.5% (∼9.0 mmHg) in SBP during submaximal exercise   in young males with stage I hypertension (−1) and/or the differences in patients’ characteristics .In addition, it should be considered that most of the patients participating in the present study have taken hypotensive drugs , which could have led to an interaction with the aerobic training and/or IHHE . However weight) . Furtherrtension . The gre−1) of IHHE , intermittent hypoxic exposure , and sham hypoxia on carbohydrate and lipid metabolism in prediabetic patients (Although, it has been hypothesized that replacing normoxia with hyperoxia can increase the adaptive response to the intermittent hypoxic stimulus by upregulating reactive oxygen species and hypoxia-inducible genes , there ipatients . The autpatients . Howeverpatients .The present study has a few limitations that need to be considered. First, the experimental design did not include a group that performed IHHE only to analyze its independent acute and chronic effects on blood lipid and lipoprotein concentration as well as resting blood pressure. Second, because nutrition intake may affect blood lipid and lipoprotein concentrations, it should be noted that patients’ diets were not monitored. Even though all patients received standardized meals within their facilities, some dietary habits may have changed during the duration of the intervention period. Third, blood samples were not analyzed regarding the potential changes in plasma volume. Acute exercise-induced changes in plasma volume are known to affect serum or plasma lipid and lipoprotein concentrations . TherefoThe present study provides first hints that IHHE prior to aerobic cycling can influence the acute exercise-related responses in LDL-C concentration in geriatric patients. Furthermore, the present results suggest that 17 training sessions of IHHE prior to aerobic cycling or sole aerobic cycling did not induce changes in basal lipid or lipoprotein concentrations. Further investigations are warranted to identify the long-term effects of IHHE on lipid and lipoprotein concentrations as well as its synergistic effect with exercise or training. Beside blood lipids and lipoproteins, the current study showed that an additional IHHE prior to aerobic cycling seems to be more effective to reduce SBP in geriatric patients in comparison to aerobic cycling alone after 6 weeks of training. Based on the results obtained, individually tailored IHHE prior to aerobic cycling is well tolerated by geriatric patients and effective in eliciting hypotensive effects. Therefore, IHHE might be a promising non-pharmacological intervention strategy to reduce cardiovascular risk factors in vulnerable populations.