Patients with chronic kidney disease (CKD) require a personalised strategy for cardiovascular risk management (CVRM) to reduce their high risk of cardiovascular morbidity and mortality. Despite their high risk, patients with CKD appear to be underrepresented in randomised controlled trials (RCTs) for pharmacological CVRM interventions to reduce cardiovascular risk . As a result, it remains unclear whether the efficacy of these interventions found in patients without CKD is similarly applicable to patients with CKD. This evidence map aims to provide an overview of the availability of the evidence from pharmacological CVRM trials for patients with CKD by assessing how often patients with reduced kidney function are specifically excluded or included from RCTs on pharmacological CVRM interventions and whether studies report efficacy estimates of interventions specifically for kidney patients.We will perform a systematic literature search in ClinicalTrials.gov to identify relevant planned, ongoing, and completed RCTs on a broad range of CVRM medications after which we will retrieve the published protocols and papers via ClinicalTrials.gov itself, Embase, MEDLINE, or Google Scholar. We will include RCTs that investigate the efficacy of platelet inhibitors, anticoagulants, antihypertensives, glucose-lowering medication, and lipid-lowering medication on all-cause mortality, cardiovascular mortality, cardiovascular morbidity, and end-stage kidney disease in patients with a cardiovascular history or a major risk factor for cardiovascular disease. Two reviewers will independently screen trial records and their corresponding full-text publications to determine eligibility and extract data. Outcomes of interest are the exclusion of patients with reduced kidney function from RCTs and whether the study population was restricted to kidney patients or subgroup analyses were performed on kidney function. Results will be visualised in an evidence map.The availability of evidence on the efficacy and safety of pharmacological CVRM interventions in patients with CKD might be limited. Hence, we will identify knowledge gaps for future research. At the same time, the availability of evidence, or lack thereof, might warrant caution from healthcare decision-makers in making strong recommendations based on the extrapolation of results from studies to patients who were explicitly excluded from participation.PROSPERO CRD42022296746.The online version contains supplementary material available at 10.1186/s13643-022-02108-x. Results will be presented narratively and in tables and figures. We will report the proportion of studies that exclude patients with reduced kidney function, smoking, diabetes, and hypertension, and the proportion of studies that perform subgroup analyses on kidney function. We will provide an overview of kidney-related exclusion criteria of studies that exclude patients with CKD. Characteristics of studies that include or exclude patients with reduced kidney function, perform subgroup analyses, and report kidney function at baseline will be compared using chi-square tests, independent For our methodological substudy, we will match the search results from ClinicalTrials.gov with the search results from a bibliographic database search and report the proportion of matches identified. We will estimate publication bias by the number of studies that have a published protocol  but which have never published results. Studies that were expected to be finished after 1 January 2019 will not be classified under reporting bias because they might still publish results. Vice versa, as an indication of good research practice, we will look at the proportion of publications of RCTs that do not have a registration in ClinicalTrials.gov. Additionally, for studies that have both a ClinicalTrials.gov registration and a publication of the trial results, we will compare the outcomes that were stated in the registration to the outcomes that were reported in the publication.This study does not fall under the Dutch Medical Research Involving Human Subjects Act as it does not involve patients or individual patient data. Therefore, no ethical approval was sought from a medical ethics committee. We intend to disseminate the results of our study through peer-reviewed scientific journals, conferences, and meetings with patient organisations. Since CVRM for CKD patients does not only concern nephrologists but also other medical disciplines like general practitioners, cardiologists, endocrinologists, and vascular medicine specialists, we will target journals that have a broader audience.Although CVRM is of paramount importance for CKD patients, uncertainty remains about the availability of evidence on pharmacological CVRM interventions specifically for this patient population. This study will provide an overview of how often patients with CKD are excluded from cardiovascular RCTs. Looking at subgroup analyses on kidney function and studies restricted to patients with CKD will allow us to create an overview of what evidence exists for different interventions for specific groups of CKD patients. Hence, we will identify whether an evidence gap exists for certain interventions for this patient population. We will not determine the efficacy of specific interventions due to the large number of expected RCTs, the expected heterogeneity in study designs, and the fact that the efficacy of interventions lies outside the scope of our research objective.We have taken several steps to increase the relevance of our results for clinical practice. We have limited ourselves to RCTs as these are generally considered to provide the highest level of evidence to determine the effectiveness of such interventions , 46 ContOur substudy will have both methodological and clinical implications. A trial registry search may be more efficient means to identify relevant RCTs for a literature search than a search in traditional bibliographic databases. RCTs frequently publish more than one article. Instead of having to screen all the individual articles, one might be able to limit the screening process to the information provided in the trial registry. Validating our search in ClinicalTrials.gov with a bibliographic database search will provide insight into the comprehensiveness of our search results and the viability of performing a literature search in a trial registry. Our substudy will also give an indication of the extensiveness of publication bias in RCTs on CVRM interventions and accuracy of reporting of study protocols in trial registries.This study will likely have some limitations. We might miss some RCTs when the publications are not linked to the trial record or not registered in the trial registry that we searched. We expect this will include most RCTs conducted before February 2000, when ClinicalTrials.gov became available . We alsoAdditional file 1: Appendix 1. search strategy in ClinicalTrials.gov. Appendix 2. search strategy for validation study.


To quantify the retinal vessel density in thyroid-associated ophthalmology (TAO) patients with visual field (VF) defect and examine its associations with mechanical and system vascular risk factors for underlying pathogenesis of VF defect in TAO.The cohort was composed of 62 TAO eyes (39 with VF defect and 23 without VF defect). The pulse pressure (PP), intraocular pressure (IOP), ophthalmic rectus muscular index (MI), superficial retinal capillary plexus (SRCP), radial peripapillary capillary (RPC) density, and other related parameters were measured. The associations among these factors and VF mean deviation (MD) were analyzed.In TAO patients with VF defect, reduced RPC density, higher PP, and larger horizontal and vertical MI were found  when compared to TAO patients without VF defect. The RPC density was correlated with VF MD value , while SRCP density was not (P = 0.419). In univariable general estimating equation (GEE) analysis with RPC density as the outcome, PP and its fluctuation showed a significant association (both P < 0.04). In the final RPC model with multivariable GEE analysis, only PP  showed significance while PP fluctuation (P = 0.080) did not.The elevated PP was correlated with reduced retinal peripapillary perfusion in TAO resulting in VF defect. These data suggested that the system vascular factor may be important in the pathogenesis of reduced retinal perfusion resulting in visual impairment in TAO. Visual field (VF) defect is one of the most frequent and almost the first clue of vision threats during the progression of thyroid-associated ophthalmology (TAO) . The patThe health of the retinal perfusion might be of great importance in maintaining normal visual function. The impaired ophthalmic drainage and related retinal perfusion in TAO with visual impairment had been reported , 5. HoweIn the current study, we explore the retinal perfusion alteration, as an alternative important mechanism in TAO patients with visual defect, and examine the relative important risks in the pathogenesis of retinal perfusion alteration. It might help us understand the high risks of altered retinal perfusion and the underlying mechanism of VF defect in TAO.All TAO patients were recruited from the Eye Hospital of Wenzhou Medical University, Wenzhou, China. The TAO diagnosis was decided by one professor, based on the criteria of Bartley . The patAll TAO patients were given a comprehensive ophthalmic examination, including spherical equivalents with best-corrected visual acuity (BCVA) and slit-lamp examination. The VF test was done by a Humphrey field analyzer . All included VF results were with the reliable scans as false-positive error <15%, false-negative error <15%, and fixation loss <20%. The VF test with mean deviation (MD) ≤-2 dB was considered as a VF defect. We divided the TAO patients into two groups depending on their VF test result: (1) VF defect and (2) no VF defect. If one TAO patient has one eye with VF defect and the other without VF defect, it would be excluded. For both eyes with VF defect in the same TAO patients, only the severer eye would be included for analysis. For both eyes without VF defect in the same TAO patients, only the milder eye would be included for analysis. The orbital computed tomography (CT) scans were done to evaluate the ophthalmic rectus muscular index (MI) . Among aDiurnal measurements of blood pressure  and intraocular pressure  were collected at 05:00, 07:00, 10:00, 14:00, 18:00, and 22:00 in a single day. The six time points chosen for measurement provided sufficient time to observe diurnal rhythms of blood pressure and IOP. All patients were forbidden to do any physical activities (like swimming) or have any alcohol (or caffeine), which could affect blood pressure and IOP. Both blood pressure and IOP were measured after patients had sat and rested for at least 5 min. The pulse pressure (PP) was defined as the difference value between systolic and diastolic blood pressure. The mean PP and IOP were calculated by the average value among six measurement points, and the fluctuation of PP and IOP was defined as its standard deviation (SD) value among six measurement points.The optical coherence tomography angiography (OCTA) system , with a scanning speed of 70,000 A-scans per second, was used to image the retinal capillary distribution. The radial peripapillary capillary (RPC) imaging was centered on the optic nerve head with a scan size of 4.5 × 4.5 mm, and the superficial retinal capillary plexus (SRCP) imaging was centered on the fovea with the scan size of 3.0 × 3.0 mm  were used to calculate relationships among retinal capillary density, age, IOP, MI, and other related parameters. The GEE was also used to adjust the IOP influence on the RPC density, SRCP density, and pRNFL thickness between the two groups. The P-value less than 0.05 was considered to be statistically significant.All continuous data were shown in the form of means ± SD and analyzed by SPSS 22.0 . The spherical equivalent (SE) was calculated as the spherical power plus one-half of the cylindrical power, and BCVA was converted into the form of the logarithm of minimal angle resolution (LogMAR). The independent t-test was used to compare the parameters between two groups, and χ Sixty-two TAO patients (39 with VF defect and 23 without VF defect) were included. The MD was -7.39 ± 6.36 dB in TAO with VF defect and -0.54 ± 0.79 dB in TAO without VF defect (P < 0.001). There was no significant difference in age, sex, and SE , while no correlation was found between SRCP density and pRNFL thickness .When we further did Pearson’s correlation of RPC and SRCP with VF MD value, we only included their density in the whole analyzed area. There was a significant correlation between RPC density and VF MD value , while no correlation was found between SRCP density and VF MD value .In the univariable GEE analysis with the RPC density as the outcome factor, the mean PP and its fluctuation  were statistically significant, while age, gender, SE, vertical MI, horizontal MI, mean IOP, and its fluctuation were not significant  and no-DON .The reduced peripapillary vessel density was correlated with the degree of VF defect in TAO patients. The VF defect, as the result of several optic neuropathies, had been reported to be with peripapillary degeneration . The perHow and why some TAO eyes had reduced retinal perfusion and resulted in VF defect, while others did not, were still unclear and likely involved multiple factors. In the current study, we considered MI and PP as biomarkers for the “mechanical” and “system vascular” factors, respectively. The reduced retinal perfusion in TAO patients might be associated with both two factors. For the “mechanical” factor with orbital apex compression, the increased orbital volume resulted in the elevated retrobulbar space pressure with sustained stretching of the optic nerve and altered venous drainage , 4. HoweFrom our multivariable GEE analysis results, the abnormal PP was more associated with the peripapillary perfusion compared to the “mechanical” factor of the enlarged muscle in TAO patients. The abnormal blood pressure would play a more important role in the retinal vessel changes even previous to the mechanical compression . In TAO There were still some limitations in our current study. The sample size we included was small, which still should be enlarged to further confirm our findings. We only measured the diurnal rhythms of the blood pressure and IOP but not the OCTA parameters in the current study. With the data of diurnal rhythms for OCTA parameters, the current conclusion of our study would be stronger, although it had been reported that these OCTA parameters would not be variable . We woulIn conclusion, we demonstrated that PP but not MI was more associated with reduced RPC in TAO, which further led to visual field defect. The elevated PP was a high risk of reduced retinal peripapillary perfusion and visual field defect, although the interrelationships among the blood pressure, retinal perfusion, and visual function in TAO patients still warrant further study.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was reviewed and approved by the Ethics Committee Board, the Eye Hospital of Wenzhou Medical University, Wenzhou, China. The patients/participants provided their written informed consent to participate in this study.JY, WW and YT contributed to the conception and design of the study. JY, WL and XH determined the experimental methods. JY, HXJ, MX and HCJ performed the experiments. JY, MW, ZL and QC analyzed and interpreted the data. JY and YT wrote and modified the manuscript. All authors contributed to the article and approved the submitted version.This study is supported by research grants from the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (Grant No. 2020KY192).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.


P < 0.05), rather than ankle-brachial index. Compared to those with uncontrolled hypertension, the prevalence of asymptomatic HMOD was lower in patients with controlled hypertension. In summary, the prevalence of HMOD in Chinese people aged 35 or older was very common, indicating a substantial future burden of both morbidity and mortality from hypertension in China. Clinical trial registration number: ChiCTR-ECS-14004641.Hypertension is a major health burden worldwide. However, there is limited data on the status of hypertension-mediated organ damage (HMOD) and established cardiovascular (CV) disease in Chinese hypertensive patients. The aim of this study is to determine the prevalence of HMOD and established CV disease in a nationally representative population in China. A stratified multistage random sampling method was used in the China Hypertension Survey and 21,243 participants aged 35 or older were eligible for analysis in this study. For each participant, the demographic information and a self-reported medical history were acquired. Blood pressure was measured with the electronic device 3 times on the right arm, supported at heart level, after the participant was sitting at rest for 5 min. Samples of blood and urine were tested. 2-D and Doppler echocardiography were used to assess the heart’s function and structures. Sampling weights were calculated based on the 2010 China population census data. Overall, the weighted prevalence of asymptomatic HMOD was 22.1%, 28.9%, 23.1%, 6.4%, and 6.2% for wide pulse pressure, left ventricular hypertrophy, microalbuminuria, chronic kidney disease, and abnormal ankle-brachial index, respectively. For the established CV disease, the weighted prevalence was 1.8%, 1.3%, 2.0%, and 1.1% for stroke, coronary artery disease, heart failure, and atrial fibrillation, respectively. The prevalence of asymptomatic HMOD and established CV disease was greater with higher blood pressure level ( The global prevalence of hypertension was estimated to be 1.13 billion in 2015, with an alarming number of 235 million in east Asia [Hypertension is the leading cause of cardiovascular (CV) disease globally . It is wIdentifying HMOD could help to estimate the burden of high-CV-risk populations in the hypertensive population. Furthermore, earlier screening and intervention in HMOD may lead to more effective therapeutic strategies and reduce future CV events –7. SinceThe China Hypertension Survey was conducted between October 2012 and December 2015, and the design was published previously , 11. BriWritten informed consent was obtained from each participant before data collection. The ethics committee of Fuwai Hospital approved the study.2) for each participant. BP was measured 3 times on the right arm supported at heart level with the OMRON HBP-1300 professional portable BP monitor  after the participant was sitting at rest for 5 min, with 30 s between each measurement. The accuracy of the Omron HBP-1300 for BP measurement had been verified in our prior study [A standardized questionnaire developed by the coordinating center, Fuwai Hospital , was administered by trained staff to obtain information on demographic characteristics and socioeconomic factors. Height was measured without shoes using a standard right-angle device and a fixed measurement tape (to the nearest 0.5 cm), and weight was measured without heavy clothing using an OMRON body fat and weight measurement device . BMI was calculated as the weight divided by height squared  between 24.0 kg/m or more . BP was  or more . Awarene or more .2 in men and >47 g/m2 in women), microalbuminuria , chronic kidney disease (CKD), or an abnormal ankle-brachial index (ABI) < 0.9. CKD was defined as either decreased estimated glomerular filtration rate  or albuminuria  according to KDIGO guidelines [2 and severe CKD was defined as as GFR < 30 mL/min/1.73 m2.Asymptomatic HMOD was defined by wide pulse pressure ≥60 mmHg in older adults (aged ≥ 65 years), LVH , were defined based on self-reported history, which was verified with medical or hospital records. The stroke included subarachnoid hemorrhage, or a hemorrhagic or ischemic lesion in the brain. CAD was defined as previous having a myocardial infarction, or surgery for coronary revascularization. Heart failure was diagnosed according to the recommendations of the European Society of Cardiology , 19, witt tests and ANOVA were used to compare continuous variables and chi-square tests were used to compare categorical variables. All 95% confidence intervals (CI) for the parameters were estimated. A two-sided P < 0.05 was considered significant. Two multiple logistic regression analyses were performed to identify factors associated with HMOD and CVD. In each analysis, the following independent variables were included: age group , sex, education, urban/rural, BMI, diabetes, dyslipidemia, and the control status of hypertension. Only the characters with β ≥ 0.5 were shown in the forest plot. Statistical analyses were conducted with SAS version 9.4  and Stata 14 .Variables were summarized using means for continuous data, and with frequencies, percentages, and proportions for categorical data. Two-tailed Student’s To represent the national population, sampling weights were calculated based on the 2010 China population census data, and the sampling scheme included an oversampling for specific age or geographic subgroups, nonresponse, and other demographic or geographic differences between the sample and the total population . AdjustmA total of 21,243 participants aged 35 years or older  were included in the analysis. The hypertensive patients on antihypertensive medications tended to be older, women, overweight/obesity, with higher education levels, and with more complications . Furthermore, among the patients who were aware of having hypertension, the prevalence of established CVD was higher in those with antihypertensive medicines than those without antihypertensive medicines . The details of the prevalence of asymptomatic HMOD and established CV disease were presented in Table Overall, the prevalence of asymptomatic HMOD, as well as established CVD, was significantly higher in participants with hypertension. The patients who were aware of having hypertension had a higher prevalence of established CVD compared to those who were not aware of having hypertension , except for ABI . The difference of CKD  and abnormal ABI  did not reach the statistically significant between controlled and uncontrolled hypertension groups. For those with established CVD, we found that only the prevalence of HF was lower in patients with controlled hypertension compared to those with uncontrolled hypertension (2.0% vs. 1.9%; P = 0.936, Fig. The prevalence of asymptomatic HMOD, as well as established CVD, was greater for them with higher BP level (ABI Fig. . CompareThe characteristics significantly associated with HMOD and CVD were different, as shown in Fig. This study reported the nationally representative estimates of HMOD and established CVD in hypertensive patients. Our study showed that the presence of HMOD in Chinese adults aged 35 or older was common, especially LVH and microalbuminuria. HF was the most common disease complicated with hypertension. Overall, the prevalence of asymptomatic HMOD was lower in patients with controlled hypertension than those with uncontrolled hypertension.LVH is the most frequent end-organ damage associated with high BP, and it increases the risk of congestive heart failure, sudden cardiac arrest, angina pectoris, myocardial infarction, and cerebrovascular disease , 23. In Microalbuminuria has been recognized as an early sign of renal damage, and increased microalbuminuria indicates endothelial dysfunction or developing atherosclerosis, and predicts end-organ damage, major CV events, and death –29. The The pulsatile component is pulse pressure, which depends on ventricular ejection, arterial stiffness, and timing of wave reflections. Pulse pressure has been shown as an independent risk factor for mortality or CV events in several studies in screening populations or hypertensive patients , 37.Epidemiologic studies have established a strong linear relation between BP and CVD, and randomized trials have documented that BP reductions by antihypertensive drugs against HMOD and established CV disease , 39. AltWe found no significant difference between residents living in urban and rural areas for asymptomatic HMOD and established CV disease in this study. However, the prevalence of wide pulse pressure, CKD, and abnormal ABI were significantly higher in women, while the prevalence of established CVD was higher in men. This finding is in line with majority of previous studies , 24, 43.The current results revealed that the prevalence of HMOD and CVD was higher in the patients on medication. Probably, the medicine use is related to more severe disease, possibly indicating a lack of early screening or late medical intervention in these hypertensive patients. It also may explain the higher prevalence of CVD in patients with controlled hypertension. However, it was not too late that BP control could not play a role in secondary prevention. On the contrary, HMOD was inversely related with BP controlled. It meant early intervention, even without medicine, could delay the progress of damage on the great vessels and the kidney.This study provided significant contemporary data on the epidemiology of HMOD and established CVD in hypertensive patients in China based on a representative population. One major limitation was that the explanation of the difference between hypertensive patients taking antihypertensive medicines and those not taking antihypertensive medicines should be cautious because we were unable to identify the course of hypertension and severity of hypertension. Another limitation was that the CV events were obtained based on the self-reported history and verified with medical or hospital records, which might lead to underestimation. In addition, the cross-sectional design could not prove a causal relationship. However, as a large survey on HMOD and established CV disease in hypertensive patients, this study still provided significant epidemiological knowledge gaps for middle-income countries.In summary, our study showed that the presence of HMOD in Chinese people aged 35 or older was very common. The findings suggest a substantial future burden of both morbidity and mortality from hypertension in China. National strategies should aim at reducing HMOD and established CVD in the population through improving the detection, treatment, and control of hypertension, and through population-based public health interventions to address upstream determinants of health.Identifying HMOD could help to estimate the burden of high-CV-risk populations in the hypertensive population.Earlier screening and intervention in HMOD may lead to more effective therapeutic strategies and reduce future CV events.Determine the prevalence of HMOD and established CVD in a nationally representative population in China.Supplemental


Treatment-resistant hypertension (TRH) is defined as blood pressure levels that remain above the therapeutic goal despite concurrent use of three or more antihypertensive medications taken at maximally tolerated doses, one of which should be a diuretic. Additionally, individuals on four or more antihypertensive agents regardless of blood pressure are also considered to have TRH. Amongst people diagnosed with TRH, African American adults face a huge management gap, resulting in increased cardiovascular disease risk. The primary objective of this review was to identify the commonly encountered etiologies and extensively discuss the current management strategies of TRH with a particular focus on African Americans. Relevant studies were identified by analyzing scientific databases and journals such as PubMed, Cochrane, MEDLINE, Cureus, and American Heart Association (AHA). The studies identified and examined common causes of TRH, describing their pathophysiology and highlighting different treatment options for the respective etiologies. The most prevalent etiologies of TRH amongst African Americans were chronic kidney disease (CKD), renal artery stenosis (RAS), fibromuscular dysplasia, obstructive sleep apnea (OSA), endocrine causes , sympathetic nervous system overactivity, lifestyle factors, inaccurate blood pressure measurement, and inappropriate treatment. Of the etiologies reviewed, OSA, lifestyle factors, and CKD exhibited a striking prevalence among the subpopulation studied. Unfortunately, there was a paucity of articles addressing this topic amongst African Americans, and therefore there was not a substantial appreciation of the prevalence of some of the identified etiologies in the population of interest. Thorough diagnostic testing for associated or underlying conditions provides a basis for successful management. This review brought to the fore the need for doctors and patients to collaborate in order to improve TRH management and help patients lead healthier lives. Treatment-resistant hypertension (TRH) is a frequently encountered clinical challenge that primary care clinicians, specialists, and patients face . AccordiMany risk factors are associated with TRH, but older age, African American race, diabetes mellitus, obesity, and chronic kidney disease (CKD) are amongst the most common. Additionally, specific underlying causes play a pivotal role in TRH pathophysiology. Examples include obstructive sleep apnea (OSA), Conn syndrome, and renovascular diseases .To be effective, treatment strategies for TRH must address three fundamental principles: availability, affordability, and the ability to be adapted to different healthcare settings. Practically, treatment modalities may not always fulfill the aforementioned factors within a given clinical scenario . This reChronic kidney diseaseTo better understand the correlation between TRH and CKD, it is essential to illustrate prior situations leading to CKD. As per the guidelines outlined by the Kidney Disease Outcome Quality Initiative of the National Kidney Foundation (NKF), CKD refers to kidney damage or an estimated glomerular filtration rate (eGFR) lower than <60 mL/min/1.73 m² for at least three months -9. NotabManagementThe goal of managing patients with TRH caused by the progression of CKD is to monitor blood pressure and albuminuria. TRH is managed and achieved through multiple therapies, including ACE inhibitors, ARBs, CCBs, mineralocorticoid receptor blockers, and thiazide diuretics. The longer half-life of chlorthalidone and indapamide results in increased and potent natriuresis, which prevents blood pressure elevation. Furthermore, the restriction of dietary sodium intake by 1 g has shown a decrease in blood pressure by 2.1 mmHg, which would be beneficial in addition to the recommended therapy . It is aRenal artery stenosis and fibromuscular dysplasiaRenal artery stenosis (RAS) is known to be caused by fibromuscular dysplasia or atherosclerotic lesions . FibromuManagementMaintaining target blood pressure <130/80 mmHg) with minor medication adverse effects and minimal drug combinations is the main goal 0/80 mmHg. ACE inhObstructive sleep apneaOSA is defined as recurrent obstructive breathing events generated by complete upper airway obstruction during sleep and is accompanied by daytime symptoms and sleep hypoventilation syndrome . UsuallyOSA, a cause of high blood pressure, has also been associated with changes in day-to-night blood pressure, severe hypertension, and TRH . Male seSleep disturbances are prevalent among middle-aged and older adults and vary by race/ethnicity, sex, and obesity status . The SleMany pathophysiological mechanisms exist between hypertension and OSA despite several studies showing that the cause of OSA is mainly unknown. Negative intrathoracic pressure, which places stress on the heart, inflammatory and cytokine-mediated effects of hypoxia, impaired sleep quality, nocturnal fluid shift, increased sympathetic autonomic system, and decreased parasympathetic autonomic system lead to activation of the RAAS. These mechanisms potentiate TRH . StudiesManagementAll patients with OSA should be assessed for treatment, including the exploration of possible behavioral modifications and weight loss. Appropriate diagnosis and management are required to prevent its harmful effects and death. Although not indicated for all patients with TRH, polysomnography is required when OSA poses a possibility of causing TRH. This requires the simultaneous monitoring of several cardiovascular and respiratory variables during nocturnal sleep  . DependiFor patients who are unable to tolerate CPAP or those with mild to moderate OSA, oral appliances (OA) are available as an alternative . OA are Samuelson et al. described a surgical technique in OSA management called uvulopalatopharyngoplasty (UPPP) . UPPP isA list of other surgical procedures that have significant positive outcomes in the management of OSA includes hypoglossal nerve stimulation, hypopharyngeal procedure, soft palate implant, tracheostomy, maxillomandibular advancement (MMA), uvulopalatine flap, and tonsillectomy in adults with tonsillar hypertrophy .Endocrine causes of TRHPrimary Hyperaldosteronism (Conn's Syndrome)The use of diagnostic thresholds coupled with specific laboratory biochemical cutoffs  often aids in diagnosing primary hyperaldosteronism. It is defined as an aberration from normal physiology in which aldosterone is produced independently of its dominant regulators, resulting in a shift from normovolemia. The initial insult often involves the formation of one or more aldosterone-secreting tumors in either a unilateral or bilateral manner. This secretion is independent of the RAAS and also results in a hypokalemic state, which physiologically should suppress aldosterone secretion. The net effect of this pathophysiologic process is to increase sodium and water reabsorption. Subsequently, an isotonic volume expansion occurs, which enhances glomerular hyperfiltration and sets in motion a vicious cycle of distal sodium delivery. The net effect is increased sodium reabsorption and hypervolemia . ApproxiManagement: Surgical adrenalectomy is the best option for long-term blood pressure management in patients with unilateral adrenal lesions as it has curative intent. Several indicators that predict a favorable outcome of surgical adrenalectomy have recently been established. These include: a duration of hypertension of fewer than five years; treatment with two or fewer antihypertensive agents, preoperative response to spironolactone, and the underlying lesion being an adenoma rather than adrenal hyperplasia. The primary aldosteronism surgery outcomes (PASO) study demonstrates that most patients with unilateral Conn syndrome have persistent hypertension, although in a significantly milder form. However, curative unilateral adrenalectomy has proven to be instrumental in preventing incidental atrial fibrillation compared to medical therapy with spironolactone. Recently, venous sampling approaches that pinpoint the exact location of aldosterone production within the adrenal gland have heralded promising supplementary surgical options. Partial adrenalectomy has been employed in both unilateral and bilateral primary hyperaldosteronism and yielded results pointing towards future success. Nevertheless, the technique has not had extensive clinical implementation ,31.Spironolactone is a practical, affordable, and readily available treatment for primary hyperaldosteronism in most individuals. However, there are concerns over long-term outcomes with mineralocorticoid antagonists, such as hyperkalemia, bleeding after menopause, and diarrhea. Thus, surgery remains the ideal option for eligible candidates. Medical therapy with spironolactone or eplerenone coupled with restriction of dietary sodium is recommended if the patient is not a surgical candidate or has bilateral disease. Patients with Conn syndrome usually receive 200 mg of spironolactone daily, resulting in significant reductions in cardiovascular events. Optimal response to mineralocorticoids may be achieved with additional medications such as patiromer and amiloride -32.PheochromocytomaThis clinical entity involves chromaffin cell tumors of the adrenal medulla that result in a supranormal secretion of catecholamines. Pheochromocytomas occur sporadically or are usually associated with other familial endocrinopathies or syndromes , in which case the disease usually has a bilateral presentation. The high levels of circulating hormones result in an increased adrenergic response of the cardiovascular system, thereby leading to hypertension. Hypertension in pheochromocytoma often manifests in an episodic pattern accompanied by headaches and sweating. In between episodes, patients are often normotensive. The disease poses a more significant challenge to individuals with a pre-existing diagnosis of hypertension, as this may result in TRH . The preManagement: Imaging using an abdominal MRI or CT scan confirms the diagnosis, which usually warrants surgical treatment with unilateral adrenalectomy. To minimize intraoperative blood pressure instability and counter volume contraction from pressure natriuresis, alpha-adrenergic blockade using agents like phenoxybenzamine, increased fluid intake, and a high sodium diet are recommended for at least a week before surgery. Post-surgical follow-up is of the essence in patients with a familial form of the disease .In metastatic disease, combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) is associated with clinically beneficial outcomes. This is echoed by the results of a multivariate study that demonstrated a significant median overall prolonged survival among those who received CVD  compared to other combinations . RadiophHypercortisolism (Cushing Syndrome)Cushing syndrome is an endocrinopathy involving chronic excessive exposure to high levels of endogenous or exogenous glucocorticoids, with the latter accounting for most cases. Endogenous causes are further classified into adrenocorticotropic hormone (ACTH) dependent (ACTH-secreting pituitary adenomas and ectopic ACTH-secreting neoplasms) and ACTH-independent .There is high variability in the prevalence of Cushing syndrome amongst different ethnic groups. According to studies, up to 80% of cases of hypercortisolism are due to iatrogenic causes . BesidesManagement: Tapering exogenous corticosteroids provides the basis of treatment for iatrogenic causes of Cushing syndrome. If done appropriately, outcomes are often favorable with a return to physiologic hormone levels. Individuals diagnosed with adrenal tumors, pituitary adenomas, or ACTH-secreting neoplasms usually benefit from surgical resection. Importantly, post-surgical follow-up with measurement of free urine or serum cortisol to monitor recurrence should be performed. In patients with pituitary adenomas that fail to respond to transsphenoidal resection, radiotherapy yielded desirable outcomes. Poor surgical candidates or those that preferred conservative treatment options benefited from oral medications like cabergoline, pasireotide, and mifepristone .Other rare endocrine causes of TRHThe literature describes other uncommon endocrine diseases that account for a negligibly small part of TRH prevalence. Table Sympathetic nervous system overactivityHuman SNS dysfunction is linked to the onset and progression of hypertension, heart failure, and chronic kidney disease and is a major player in sustaining TRH. SNS overactivity as a cause of TRH is characterized by overstimulation of the RAAS with subsequent sodium retention . This leManagementSNS overstimulation is managed by device-based treatment, which includes renal sympathetic denervation and baroreflex activation therapy. Renal sympathetic denervation is a non-pharmacological method of TRH treatment. In this regard, catheter-based devices can be employed to ablate the renal artery's sympathetic afferent and efferent nerves by radiofrequency or ultrasound energy or by transarterial injection of acidic substances . An alteLifestyle factorsEvidence-based studies have proven a relationship between lifestyle factors and hypertension. These lifestyle factors include but are not limited to obesity, physical inactivity, dietary habits, sleep deprivation, alcoholism, and drugs, which in the long term can lead to TRH. Of note, behavioral factors tend to be more prevalent in African Americans than in Asians or whites .ObesitySome cases of uncontrolled blood pressure and TRH in African American adults have been linked to obesity. Obesity continues to rank as one of the most critical public health problems in the USA, with nearly two-thirds of US adults (66.3%) considered to be overweight  or obese  . While lDietary HabitsAccording to several studies, there is evidence to suggest that African Americans are more salt-sensitive than Caucasians, which is due to a tendency to retain sodium in the kidneys . Salt seSleep DeprivationGrowing evidence has implicated sleep deprivation or poor sleep hygiene as one of several risk factors that are thought to contribute to high blood pressure or TRH in the African American population. The Center for Disease Control and Prevention (CDC) has recommended a seven-hour sleep duration for adults per night for good health and well-being. Short sleep duration is defined as less than seven hours of sleep per 24-hour period. Adults who were short sleepers (less than seven hours per 24-hour period) were more likely to report 10 chronic health conditions than those who got enough sleep (seven or more hours per 24-hour period). Short (<6 hours) and very long (≥9 hours) sleep duration has been associated with poorer cardiovascular health compared with sleep lasting seven to eight hours .Physical InactivityIn the USA, older African Americans report high levels of physical inactivity, especially those with chronic conditions such as hypertension, diabetes mellitus, arthritis, and chronic obstructive pulmonary disease (COPD) . PhysicaTobacco Smoking and AlcoholismSmoking, a modifiable risk factor for hypertension, can contribute to the development of atheromatous RAS, a leading cause of TRH . NotablyDrugsSeveral studies have described various drugs that increase blood pressure significantly. However, some effects may be reversible with body adjustments or discontinuation. A few others may have contributed to the development of TRH. The implicated pharmacological agents include non-steroidal anti-inflammatory drugs (NSAIDS), erythropoietin, vascular endothelial growth factor (VEGF) inhibitors, sympathomimetics, oral contraceptives, alcohol, amphetamines, antidepressants, cocaine, glucocorticoids, mineralocorticoids, and immunosuppressive agents .Suboptimal treatmentA clinician-centered factor contributing to poorly controlled blood pressure levels is that patients are not receiving the proper treatment regimen. An article published by AHA reports that black adults with TRH are either inappropriately treated or lack appropriate counseling about healthy lifestyles and behavioral practices to lower blood pressure. Carey et al. documented a low use of antihypertensive medications and poor lifestyle factors among African Americans with apparent TRH. Previous studies show that regulating blood pressure according to the 2017 American College of Cardiology/AHA blood pressure guideline could prevent about 400,000 CVD events per annum in African Americans and that the population-attributable risk of hypertension is higher in black compared to white adults. Of note, blood pressure control is more challenging in black adults than in white adults . NonetheMedication adherence is another crucial factor in hypertension management. Unfortunately, one-quarter of patients who start antihypertensive treatment do not complete their initial prescription, and 50% to 80% do not adhere to their medications properly. The significant pill burden, dosing complexity, expense, high frequency of adverse reactions, poor patient-clinician relationship, and clinician inertia with reduced insistence on adherence are all factors that contribute to this relatively high proportion of nonadherence that may mimic TRH ,51. A stInaccurate measurementThe misinterpretation of TRH may be due to blood pressure measurement errors. This arises when blood pressure measurement is not done according to recommended guidelines and can result in apparent TRH. The accuracy rate of blood pressure measurements was found to be 33% in a study of patients referred for TRH . PatientThe treatment success of TRH depends on an extensive workup of probable underlying causes that requires an individualized management approach with prompt interventions resulting in better outcomes. Remarkably, the true prevalence of TRH in African Americans can be limited by intensifying emphasis on addressing modifiable risk factors such as lifestyle behaviors, administration of appropriate antihypertensive medications, and treatment compliance and adherence. Constant communication and follow-up amongst multidisciplinary team members are equally essential to facilitate maximal healthcare delivery, minimize the prevalence of TRH and other cardiovascular implications, improve quality of life, and reduce mortality risk. Research gaps in the African American subpopulation indicate the need for more extensive study of this clinical entity in the respective category.


The endothelial function increased too, even if not significantly (p = 0.688), after 1 year of melatonin administration. Moreover, the supplemented group showed a significative reduction in TAC levels (p = 0.041) correlated with the improvement of arterial stiffness. These data suggest that melatonin may play an important role in reducing the serum levels of TAC and, consequently, in improving arterial stiffness. Among cardiovascular diseases, hypertension is one of the main risk factors predisposing to fatal complications. Oxidative stress and chronic inflammation have been identified as potentially responsible for the development of endothelial damage and vascular stiffness, two of the primum movens of hypertension and cardiovascular diseases. Based on these data, we conducted an open-label randomized study, first, to evaluate the endothelial damage and vascular stiffness in hypertense patients; second, to test the effect of supplementation with a physiological antioxidant (melatonin 1 mg/day for 1 year) in patients with essential hypertension vs. hypertensive controls. Twenty-three patients of either gender were enrolled and randomized 1:1 in two groups (control and supplemented group). The plasmatic total antioxidant capacity (as a marker of oxidative stress), blood pressure, arterial stiffness, and peripheral endothelial function were evaluated at the beginning of the study and after 1 year in both groups. Our results showed that arterial stiffness improved significantly ( Arterial hypertension is one of the most frequent cardiovascular disorders, more predominant in the older generation . The GloAccording to the WHO’s ratings, overall, cardiovascular diseases (CVDs) accounted for 17.9 million deaths in 2019. At present, although the mortality rate has reduced, the prevalence of CVDs remains high, and it is important to note that hypertension is—among possible causes and risk factors for CVDs—one of the most easily preventable and controllable diseases ,7. MoreoAmong all the cases of hypertension, approximately 95% of them are identified as essential hypertension (EH), a complex multifactorial haemodynamic and structural disorder characterized by an overall increased systolic blood pressure (SBP) of ≥140 mmHg and/or diastolic blood pressure (DBP) of ≥90 mmHg ,13, resuPhysiologically, blood pressure (BP) values remain within a physiological range thanks to a fine balance maintained between factors that could increase BP and those that normalize it, working as compensatory mechanisms. It is when this slender and fragile dynamic stability fails that EH “appears” ,16. EH pNext to the endothelial dysfunction, arterial stiffening must also be considered in EH etiopathogenesis: it is one of the main responses to chronical stress exerted by dyslipidaemia, ageing, and high BP itself. The arterial modulation to external stress limits the buffering capacity of the elastic arteries, exposes the microvasculature to increased pulsatile stress, and contributes to targeted organ damage via capillary rarefaction and microvascular ischemia ,20, defiAnother important background mechanism in EH development  is repreMelatonin, N-acetyl-5-methoxytryptamine, is a ubiquitous and widely distributed indoleamine that can be found in almost all living organisms . MelatonIncreasingly, clinical trials have been designed to evaluate the activity of exogenous melatonin; however, the precise mechanism(s) by which it acts in hypertense patients is not completely clear, and its link with the pathogenesis of EH development remains controversial ,32.Moreover, most of the studies conducted up to now have been carried out for a limited period (90 days) and with a standard dosage of about 5–6 mg/die of melatonin ,34. We decided to carry out this randomized clinical trial in order to (1) better evaluate the connection between plasmatic oxidative status and vascular conditions in essential hypertense patients; (2) understand if the continued administration of a lower dosage of melatonin  for a longer period of time (1 year) could be beneficial not only clinically, but also to the structural changes involving the micro- and macro-vasculature of hypertensive patients. No adverse effects that might be related to the additional melatonin were reported after 1 year of supplementation. Nine patients (five within the melatonin group and four in the control one) were unable to return for the 1-year evaluation due to COVID-19 pandemic restrictions, leaving 14 patients in the final groups (11 within the melatonin group and three in the control one). The demographic and clinical characteristics of the study population are reported in Of the 23 patients initially enrolled, 16 were randomly supplemented with melatonin, 10 were females (63%) and 6 were males (37%). The other seven patients only maintained their antihypertensive therapy; of these, three were females (42%) and four were males (57%). 2 for the melatonin group and 25 ± 3 Kg/m2 for the control group.The patients' ages were between 40 years and 60 years (mean ± SD age: 53 ± 9 years for the melatonin group and 48 ± 6 years for the control group) and the mean body mass index (BMI) was 26 ± 4 Kg/mp = 0.089 and p = 0.452, respectively).During the first visit (T0), three sequential BP measurements were carried out in all patients. From these measurements, the average values obtained in the melatonin group were 133 ± 10 mmHg for the systolic blood pressure (SBP) and 83 ± 7 mmHg for the diastolic blood pressure (DBP), with a mean heart rate (HR) of 67 ± 12 bpm. For the control group, the data showed 128 ± 5 mmHg for the SBP and 84 ± 8 mmHg for the DBP with a mean HR of 71 ± 7 bpm. The groups did not significatively differ regarding the mean age and BMI , comparing the starting values (T0) and the final ones (T1), it is possible to underline a different trend of these values in the melatonin group if compared to the control group. p = 0.041) in the TAC levels.At T1, in the supplemented patients, there is a significant reduction  in patients who have taken melatonin, remaining almost unchanged, or worsening in the controls  and second (T1) assessments is showed, respectively, in controls .p = 0.688). This point is strictly related to the mean age of the enrolled patients: considerations obtained by EndoPAT , it is interesting to note that there is a worsening of the mean values of both SBP and DBP in the control group.Ultimately, considering the SBP and the DBP over time, it is possible to see an improvement, especially in patients supplemented with melatonin. Even if, in this case, it is a non-significant improvement  and endothelial alteration associated with EH. The evaluations performed in this study allowed us to assume that (1) it is possible to define a direct relationship between plasmatic TAC levels and vascular alterations; in particular, arterial stiffness, (2) acting by improving plasma oxidative balance—administering an additional amount of melatonin—could lead to an enhancement in vascular functionality; and (3) considering the lack of adverse events related to the melatonin’s administration, it is possible to consider it for a future perspective, in order to include it as a part of combined treatment plans to achieve a clinical and prognostic improvement in hypertensive patients. In particular, our results allowed us to understand that supplementation with melatonin is beneficial, even if delivered at lower dosages than are normally used (1 mg vs. 5–6 mg). However, it must be considered that the administration time in our case was longer (1 year vs. 90 days maximum).Despite all the precautions taken by the operators, our study has limitations that must be considered. The validity and reproducibility of estimating aortic BP, Aix@75, and PWV under ambulatory conditions by the ambulatory BP monitoring device (Mobil-O-Graph) applied in this study were confirmed in previous studies . The cliAnother limitation of this clinical investigation is represented by the small number of patients involved. However, we only included consecutive newly diagnosed cases without cardiovascular risk factors to avoid selection biases, and so, in the beginning, it was difficult to reach a large number of patients who were appropriate to be studied.Ultimately, the main limitation of the study is perhaps represented by the lack of a complete follow-up evaluation by the whole population, a bias upon which we could not act due to the tight constraints and concerns of the patients themselves associated with the COVID-19 pandemic.This study was born from a collaboration between the Cardiology Unit, ASST-Spedali Civili, Brescia, Italy and the Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Italy. The study was conducted in accordance with the 1975 Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the ASST-Spedali Civili, Brescia, Italy . The investigation was designed as a randomized, prospective, and monocentric control trial with nutritional supplement, as described in The recruitment of patients was performed in the Cardiology Unit, ASST-Spedali Civili of Brescia, Italy, from March 2018 to April 2019 and comprised patients aged 40–60 years at the time of enrolment who were affected by EH and followed by the Cardiology Unit.-Any kind of heart disease ;-Autoimmune, rheumatological, or vascular diseases other than EH;-Antihypertensive therapies with nitrates, statins, or β-blockers;-Pregnancy and lactation;-Obesity;-Diabetes;-Irregular sleep/wake rhythm, such as workers with night shifts (for a period of less than 3 months before recruitment).For the enrolment, the following were considered as exclusion criteria:-A diagnosis of essential hypertension dating back at least 1 year before the start of the study;-Treatment with antihypertensive drugs already in progress and not modifiable during the course of the study;-No other cardiological  and metabolic  comorbidities;-No pregnancy in progress;-Regular sleep/wake rhythm (no worker with night shifts for a period of less than 3 months before recruitment);-Fasting blood sugar < 100 mg/dL;-Total cholesterol < 200 mg/dL and triglycerides < 150 mg/dL;On the contrary, the following were considered as inclusion criteria:Moreover, the patients were not allowed to change their BP medication during the trial. Considering the above-mentioned criteria, 23 patients of either gender were enrolled  after signing their informed consent. The sample size  needed to capture 0.25 of the RH-PAT index 17, 0.5 m/s in cfPWV, was 12. The calculation was performed online using the input values of a power of 80% and a two-sided level of significance of 5% ,50,51.®”, 1 mg, 120 microtablets, linea Notte Relax, ESI srl, Albisola Superiore, SV, Italy), which was approved by the Ministry of Health of the Republic of Italy (Number: 64598) [The patients were randomized 1:1 in two groups (control and supplemented group) by random number generation that minimized selection bias. The participants belonging to the supplemented group were given a dietary integration of 1 mg/die of melatonin for 1 year , while DBP was noted when it ceased (Phase V of the Korotkoff sound). The cuff was deflated at a rate not greater than 2 mmHg/s . Peripheral venous blood samples were carried out between 2 and 4 p.m. when melatonin is not physiologically secreted, according to Cagnacci and colleagues' indications . The bloThe plasmatic antioxidant capacity was assayed using a colorimetric assay kit  that measures Cupper (Cu)++ reduction to Cu+ by the antioxidant factors in the sample, by coupling with a colorimetric probe. After processing as described by the manufacturer’s instructions, the microplate was read at 490 nm , and the plasmatic TAC was expressed as μM Copper Reducing Equivalents (CRE) . Currently, the value of total antioxidant capacity appears to be a valid indicator in the context of alimentary supplementation ,56. In aPeripheral arterial tonometry (PAT) was obtained using EndoPAT-2000 , which was previously validated in numerous populations ,51. The The examination in this study involved the use of specially designed finger probes placed on the middle finger of each subject’s hands. As showed in The ratio of the PAT signal after cuff release compared with baseline was calculated through a computer algorithm, automatically normalizing for baseline signal and indexed to the contralateral arm. The calculated ratio is called the RH-PAT index or RHI. Its normal value is >2.00 (pure number), while a clear endothelial dysfunction is shown by a value ≤ 1.67. The software calculated the peripheral augmentation index (AIx), which is a measure of arterial stiffness. In particular, since this parameter is influenced by HR, it was standardized automatically per 75 bpm (AIx@75). According to EndoPAT software, peripheral AIx@75 is normal when <17%.The central aortic haemodynamic parameters, the augmentation index at a heart rate of 75 beats per minute (AI@75), the augmentation pressure (AP), and the pulse pressure (PP) were measured using the applanation tonometry method and the SphygmoCor system  . All meaThe tip of the tonometer was pressed gently against the radial artery at the site of maximum pulsation at the wrist. This micromanometer precisely records pressure within the artery, recording the pulse wave for 10–12 s  . ao), and left ventricular end-systolic pressure (LVESP) were determined with the integrated software. AIx is a measure of the stiffness of the arterial walls. As there is a linear relationship between this and the heart rate (HR), AIx was standardized to an HR of 75 bpm (AIx@75).A generalized transfer function  was applThe AP is defined as the height of the late systolic peak above the inflection point; in healthy patients of cohort sizes between 25 and 88, the within-observer difference varied from 0.5 ± 5.4 to 1.4 ± 1.2%. In the same way, carotid and femoral waveforms were recorded and the distance between the two points measured. By means of electrocardiogram (ECG) gating, the ratio between this distance to the travelling time of the pulse wave (using the foot–foot convention) is called the carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness . At the one-year follow up, all participants were invited for a second medical examination, in which all the evaluations were performed .p < 0.05 was considered significant. Each statistical test was a two-way test.The statistical analysis of the various parameters examined was carried out after possible transformation of the non-normal distribution variables, by means of a two-way (time-treatment) variance analysis. Bivariate correlations between the variation of blood parameters and cardiovascular parameters were carried out, and a value of As regards the number of patients, reference is made to recent studies carried out in the Cardiology Unit of ASST-Spedali Civili, Brescia, Italy . The samEH is a wide and complex pathology, and it is impossible to consider that it might be solved with the administration of a single drug. Moreover, the drugs that are currently used have a pool of side effects that must be taken into account, and that often require the introduction of blended therapies. Moreover, not all patients are able to tolerate the drug combinations that are often proposed to reduce these side effects. In this sense, identifying a supplementation that can be added to the current main therapy’s schemes without affecting the patient’s balance would be a considerable step forward, particularly considering the data confirming the presence of a very small number of side effects attributable to melatonin.Despite all the limitations to bear in mind, we believe that these results may represent a good pathophysiological basis for future studies that aim to better analyse a correlation between hypertensive patients of different ages and sex, being able to involve a larger number of patients that could be studied prospectively for several years in order to highlight an effective clinical outcome, and giving more importance to the new non-invasive methods that could represent a real breakthrough in the prevention of major cardiovascular events.


Tacrolimus has unpredictable pharmacokinetic (PK) characteristics, which are partially attributed to CYP3A5 polymorphism. The potential effects of clinical factors in the postoperative period of transplantation on tacrolimus PK and those of early tacrolimus PK variability on clinical outcomes are yet to be clarified. Findings. The CYP3A5 genotype were strongly associated with tacrolimus concentration/dose ratio (C0/D). Additionally, ABCB1 (rs1045642 and rs2032582) and ABCC2 (rs3740066) were found to have potential independent effects on early tacrolimus C0/D in multivariate analysis. Red blood counts and albumin level were the most significant clinical factors associated with tacrolimus C0/D. Wuzhi capsule also exerted an effect on tacrolimus PK. A model combined with pharmacogenetic and clinical factors explained 43.4% tacrolimus PK variability compared with 16.3% on the basis of CYP3A5 genotype only. Notably, increasing tacrolimus concentrations in the early postoperative stage were associated with AR, but not DGF.  We examined the genetic and clinical factors affecting early tacrolimus PK variability in 256 kidney transplant recipients. The relationships among tacrolimus exposure, graft function delay (DGF), and acute rejection (AR) were further explored.  Combined analysis of genotype and specific clinical factors is important for the formulation of precise tacrolimus dose regimens in the early stage after kidney transplantation. Tacrolimus is an important component of immunosuppression therapy after solid organ transplantation . HoweverGenetic polymorphisms play a critical role in tacrolimus pharmacokinetic (PK) variability . TacroliTacrolimus PK variability within the early posttransplant period is associated with poor outcomes after kidney transplantation . DelayedThis study included 256 kidney transplantation patients from January 2015 to December 2019 in Union hospital, Tongji Medical College, Huazhong University of Science and Technology. The enrollment criteria were as follows: patients receiving conventional tacrolimus-based immunosuppressive regimen  and age over 18 years. The exclusion criteria were as follows: patients' age less than 18 years, combined other organ transplantation, receiving cyclosporine or intravenous tacrolimus, treatment with drugs affecting tacrolimus metabolism , or lack of relevant data. Our study was approved by the Institutional Ethics Board of Tongji Medical College, Huazhong University of Science and Technology  ([2018] S331). This was a retrospective analysis and did not interfere with patient diagnosis or the treatment process. The patients in our study received kidney transplant from donations after cardiac death (DCD). DCD procedures were performed by the Organ Procurement Organization of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, in accordance with the Declaration of Istanbul. Data on demographic, laboratory tests, basic diseases, and medication in the perioperation period were obtained through the electronic medical record system in our hospital.All patients were administered a tacrolimus-based triple immunosuppressive regimen. Tacrolimus was taken orally on the second day after transplantation, with an initial dose of 3.0-5.0 mg, twice a day. Mycophenolate mofetil was administered twice a day (0.5-1.0 g) on the day of transplantation. All patients were administered with methylprednisolone (500 mg daily) intravenously three days after kidney transplantation and 60 mg daily oral methylprednisolone from day 4, which was gradually reduced to a maintenance dose (20 mg daily). In cases of acute rejection, rabbit anti-human thymocyte immunoglobulin or anti-human T cell rabbit immunoglobulin was administered for 3-7 days, or methylprednisolone pulse therapy was performed.C0/D) ) and anemia (N = 117 [45.7%]) were the most common basic diseases in kidney transplant recipients. Overall, 224 (87.5%) patients received induction therapy with antithymocyte globulin, and 32 (12.5%) received basiliximab therapy. An immunosuppressive regimen with mycophenolate mofetil as an antiproliferative agent was administered to 239 (93.4%) of the patients. All recipients underwent transplantation for the first time, using DCD as the source of kidneys.Among the 256 patients, 178 (69.5%) were male. Demographic and clinical data are shown in C0/D after kidney transplantation. Notably, CYP3A4∗1B mutations were absent, and only two among the 256 patients contained the CYP3A4∗22 mutation. Accordingly, these two genotypes were excluded from follow-up analysis.We examined the effects of CYP3A4∗1B (rs2740574), CYP3A5∗3 (rs776746), CYP3A4∗22 (rs35599367), ABCC2 , ABCB1 , PXR (rs6785049), and POR∗28 (rs1057868) polymorphisms on early tacrolimus C0/D in the CYP3A5 nonexpresser group were significantly higher than those in the CYP3A5 expresser group, indicating a strong association between CYP3A5 genotype and tacrolimus metabolism  and ABCC2 (rs3740066) were found to have potential independent effects on early tacrolimus C0/D. Compared with ABCB1 (rs1045642) TT genotype carriers, tacrolimus C0/D in patients with CC and CT genotypes was decreased by 15.03% and 14.59%, respectively. Patients with ABCB1 (rs2032582) AA genotype carriers increased tacrolimus C0/D by 16.52% compared with GG genotype carriers. In addition, tacrolimus C0/D increased by 14.42% in patients with ABCC2 (rs3740066) TT genotype carriers compared with CC carriers. Several clinical variables additionally showed significant associations with tacrolimus C0/D, including red blood counts (RBC), albumin (ALB), and Wuzhi capsule (WZC). RBC, ALB, and WZC were associated with 22.17%, 2.19%, and 27.2% increase in tacrolimus C0/D, respectively. A model incorporating combined genetic and clinical factors accounted for 43.4% (R2 = 0.434) of tacrolimus PK variability compared with 16.3% (R2 = 0.163) for CYP3A5 genotype status only.The results of univariate analysis are shown in Table DGF occurred in 29 (11.3%) of 256 patients during the first week after transplantation. The probability of DGF at different concentration ranges is shown in C0/D. Specific clinical variables  could also explain residual tacrolimus PK variability. Moreover, the tacrolimus concentration was not clearly associated with DGF but had significant correlation with AR. Our collective results seem to be relevant to a better individualization of tacrolimus regimen that ideally should combine TDM with clinical and pharmacogenetic information in the early postoperative kidney transplant.The standard method of tacrolimus dosing after kidney transplantation is mainly “one size fits all,” which is subsequently optimized and individualized based on therapeutic drug monitoring. However, tacrolimus shows unpredictable pharmacokinetic in early postoperative kidney transplantation patients, and the “one size fits all” regimen often fails to guarantee clinical efficacy and safety. Identification of the potential factors affecting tacrolimus PK may therefore aid in optimizing individualized regimens for kidney transplant patients. In this study, the CYP3A5 genotype showed a significant association with tacrolimus C0/D. Additionally, ABCB1 (rs1045642 and rs2032582) and ABCC2 (rs3740066) were found to have potential independent effects on early tacrolimus C0/D in multivariate analysis. Previous studies suggested that the CYP3A5 genotype accounts for 50% of tacrolimus PK variability [Tacrolimus metabolism is mainly mediated by the CYP3A5 enzyme, and many studies have confirmed that CYP3A5 genotype could predict tacrolimus metabolism . In a reiability , which hC0/D. Tacrolimus is mainly confined to RBCs [C0/D, respectively. The traditional Chinese medicine WZC is a prescription drug (registration number in China: Z20025766), widely used to increase the tacrolimus concentration in solid organ transplantation [C0/D. Results obtained using the multivariable mixed effects model result indicated that the CYP3A5 genotype only accounted for 16.3% of tacrolimus C0/D variation, while a model combining clinical factors and genotypes explained 43.4% C0/D variability, which was clinically significant increased. Therefore, these findings supported the development of effective tacrolimus dosing regimens for kidney transplant recipients in the perioperative period with combination of genotype and specific clinical variables.We additionally investigated the clinical factors affecting early tacrolimus  to RBCs  and high to RBCs , which aantation , 31. PatThe tacrolimus dosing adjustment regimen in the early period mainly depends on whether the concentration has a negative impact on clinical outcomes of patients. DGF is a significant problem for early allograft survival as it is compounded by acute rejection and allograft nephropathy in the early postoperative period . DGF is Our research has a number of limitations that should be taken into consideration. Firstly, this is a single-center retrospective design, and multicenter studies are required to validate our results, such as exclusion of the effects of immunosuppressive regimens at different research sites. Furthermore, the tacrolimus concentration is not measured every day in our hospital, especially at weekends, and therefore, some changes may have been overlooked. While the long-term tacrolimus concentration is significantly related to AR, we mainly focused on its association with early tacrolimus concentration in this study, without considering the long-term relationship. Thirdly, we mainly focus on DGF and AR in this study and did not involve de novo diabetes, trembling, or other toxicities, which require further evaluation. Finally, we did not investigate the effects of surgical and donor kidney factors, such as donor-specific antibody (DSA), human leukocyte antigen (HLA), and preoperative panel-reactive antibody (PRA).


Switching inhalation devices is a reasonable option if problems with control, adherence, or inhalation technique occur in patients with asthma treated with inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA). However, evidence to determine the extent to which the carefully monitored period persists after switching is insufficient. In this study, we aimed to investigate the duration of the carefully monitored period after switching to another ICS/LABA. This retrospective study used claims data from Japanese health insurance associations from May 2014 to April 2019. A total of 1,951 patients who switched to another ICS/LABA during the study period were selected for analysis. The relative risk of the first exacerbation after switching was calculated for each four-week interval after the switch compared with that before the switch in a self-controlled case series design. We further assessed patient background associated with exacerbations during the follow-up period. In the primary analysis, the risk of asthma exacerbation compared to the control period was derived from a conditional logistic regression model, which showed a significant decrease immediately after the switch . Subsequently, the risk increased again and was not significantly different from the control period until week 32 . In a sensitivity analysis among patients with a history of exacerbations, up to week 20 was the period of no continuous risk reduction . In the secondary analysis, chronic rhinosinusitis, sleep disorders, and a history of asthma exacerbation were significantly associated with asthma exacerbation. The incidence of exacerbation remained high for approximately 4 to 7 months after patients with asthma switched to another ICS/LABA. Therefore, these patients should be carefully monitored for at least 4 to 7 months and should be re-assessed at an earlier point in time, if necessary. Asthma is defined by Japanese guidelines as a disease characterized by clinical symptoms such as wheezing, dyspnea, chest tightness, and cough due to airway obstruction caused by chronic inflammation of the airways. The goal of asthma treatment is to control airway inflammation and achieve sufficient airway dilation by avoiding and removing the risk factors that cause airway inflammation and by providing appropriate treatment . InhaledAlthough ICS/LABA has been widely used as the gold standard therapy, inadequate adherence and inhalation technique have been reported in many patients in actual clinical practice –8; thus,While switching is a reasonable treatment option, good control may not possibly be achieved if it is not performed adequately . TherefoA better understanding of this information will enable a better post-switch follow-up. Therefore, the primary objective of this study was to evaluate the duration of the carefully monitored period for exacerbation occurrence after patients with asthma switched to another ICS/LABA, and the secondary objective was to investigate patient background associated with exacerbations.th revision (ICD-10) codes J45 (asthma) or J46 (asthma attack severity) between May 2014 and April 2019. The design of the study and time window are shown in This retrospective study used data from MediScope® , a Japanese claims database. The data consist of medical, dental, dispensing, and diagnosis procedure combinations collected from health insurance associations in Japan. The data also include age, sex, diagnosed disease, medication, and medical treatment of the patients, as well as the region of the patients and their families. A list of databases that can be used for research in Japan, including MediScope®, can be found on the website of the Japanese Society for Pharmacoepidemiology . In thisPatients who met all the criteria, shown in The outcomes of this study were asthma exacerbations, which were defined using the ICD-10 codes for diagnoses, Anatomical Therapeutic Chemical Classification System codes, generic names for prescriptions, and Japan-specific standardized procedures for medical treatment . Asthma Age and sex at the index date, asthma treatment within 3 months prior to the index date, and records of medical history, comorbidities, and respiratory tests within 1 year prior to the index date were extracted as variables. Since a history of previous exacerbations is considered to be closely related to exacerbations during the follow-up period , 21, we For descriptive statistics, means (standard deviations) or medians (interquartile range) were calculated for continuous variables, and frequencies and proportions (%) were calculated for categorical variables. For each background, a chi-square test was conducted between the groups. For all tests, the significance level was two-tailed and set at 0.05.In the primary analysis, a self-controlled case series (SCCS) analysis was performed to examine the carefully monitored period regarding the first exacerbation after the index date. SCCS is a method for relative incidence , and “thIn the secondary analysis, we used a Cox proportional hazard model to estimate the hazard ratio (HR) and its 95% confidence interval (CI). Sex, medical histories/comorbidities, history of asthma exacerbation, prescription of SABA, change in the asthma treatment step at the time of switching, the performance of respiratory function tests, and switched medications were entered into the model as patient background for evaluation, and estimates were calculated with age, region, and month of switching as covariates.https://www.R-project.org/) was used for all statistical analyses. The results of the study were reported in accordance with the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [R  .As this study used only anonymized data, approval of a research ethics committee and informed consent were not required .Patient characteristics were categorized into exacerbation and non-exacerbation groups according to the occurrence of exacerbations during the follow-up period. Of the 1,951 patients included in the analysis, exacerbations occurred in 448 (23.0%). For each event, emergency care was provided to 16 patients (0.8%); hospitalization, 58 patients (3.0%); steroid/aminophylline injection administration, 203 patients (10.4%); SABA inhalation in medical institutions, 133 patients (6.8%); short bursts of oral steroids, 224 patients (11.5%) (including duplicates). The frequencies and proportions for sex, region, type of respiratory tests, asthma treatment management fee, the switched season, the asthma treatment step, comorbidity, medical history, asthma treatment, ICS dose before and after the switch, change of treatment (step up/down of asthma treatment), history of previous exacerbations, and the prescription of SABA are shown in The switching pattern of the ICS/LABA is shown in the Sankey diagram in In the primary analysis, the ORs derived from SCCS are shown in In the sensitivity analysis of the group who had an exacerbation before the index date, the risk decreased in 1–4 weeks immediately after the switch  and did not differ significantly consecutively with the control period until week 20 . For theIn the secondary analysis, the HR and its 95% CI for patients with chronic rhinosinusitis were 1.42 and 1.07–1.88; sleep disorder, 1.41 and 1.02–1.95; history of asthma exacerbation within 30 days before the index date, 7.89 and 5.97–10.43; between 31 and 91 days, 5.45 and 3.76–7.90; between 92 and 365 days, 3.96 and 2.87–5.45, respectively, which were significantly associated with asthma exacerbations .In this study, the SCCS design was used to explore the carefully monitored period after switching to another ICS/LABA in patients treated with ICS/LABA. The results showed that the risk decreased immediately after the switch from 1 to 4 weeks, and then increased again, with no significant difference compared to the risk before the switch until the week 32. Chronic sinusitis, sleep disturbance, and a history of exacerbations before switching were statistically significant factors associated with exacerbations. To our knowledge, this study is the first to explore the carefully monitored period itself rather than the exacerbating factors in a specific period after switching among patients with asthma. The guidelines recommend re-assessment within 1 month after treatment initiation, and step down of treatment may be considered appropriate after 3 to 6 months [The results of the primary analysis showed that the decrease in risk immediately after the ICS/LABA switch may have been influenced by inhalation technique guidance during the switch, improved adherence after the switch, and psychological effects of the switch. However, several factors are considered as possible reasons for the increased risk again in the subsequent period. First, the temporary effects of the ICS/LABA switch, such as improved inhalation technique and adherence, decreased. Second, the median date of the first visit after the switch was 29 days , and theIn this study, patients whose ICS/LABA was switched again after the switch were censored in the analysis. Therefore, patients who were assessed to be at risk were those who continued to use the same ICS/LABA during the study period. If control is insufficient after the switch, it should be reassessed at an early point, and ICS/LABA should be re-switched, or additional treatment should be considered. However, the fact that the carefully monitored period persisted for approximately 7 months (up to week 32) after the switch in the overall population, including patients with no history of exacerbations, suggests that the evaluation (follow-up) of the population after the switch was inadequate. Further studies on the timing, frequency, and options for appropriate evaluation are required.In this study, chronic sinusitis, sleep disorder, and a history of exacerbation in the past year were significant risk factors, all of which were consistent with the results reported in previous studies –29. PartThe strengths of this study include the clinical relevance of analyzing a large database of more than 1.7 million individuals, reflecting actual clinical practice and, thus, providing results with high generalizability. Second, the use of the SCCS design with the patients themselves as controls provided results that were controlled for unmeasured confounding. These results may provide information that supports the description of duration in the guidelines.This study has several limitations. First, the data used in this study were obtained from a specific health insurance association and are not representative of the Japanese population. In particular, the proportion of people aged 65 years or older was approximately 3.4%, which limits the generalizability of the results to the elderly. However, in terms of regional distribution, a comparison of the place of residence data published by the Statistics Bureau of the Ministry of Internal Affairs and Communications  and the Second, the data used in this study were submitted for insurance reimbursement, and the recorded disease names may have differed from the actual disease names. Therefore, there are limitations to the validity of the comorbidities assessed as variables and whether the outcomes actually occurred for asthma. Finally, inhalation instruction at the time of switching and subsequent adherence may be closely related to exacerbations; however, they could not be fully defined from this database, and the important factors may remain unmeasured confounders. In actual practice, there are various reasons for switching ICS/LABA, and instructions and confirmation of inhalation methods vary from physician to physician; nevertheless, it is important to carefully check the individual patient’s condition and consider the next treatment strategy . TherefoThe incidence of exacerbation events remained high for approximately up to 4 to 7 months after patients with asthma switched to another ICS/LABA. Therefore, patients who switched to another ICS/LABA are recommended to be followed up carefully for at least approximately up to 4 to 7 months. Reassessment should be performed at an earlier point in time if needed, and appropriate clinical intervention should be provided.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S1 Table(TIF)Click here for additional data file.S2 Table(TIF)Click here for additional data file.S3 Table(TIF)Click here for additional data file.S4 Table(TIF)Click here for additional data file.S5 Table(TIF)Click here for additional data file.S6 Table(TIF)Click here for additional data file.S7 Table(TIF)Click here for additional data file.


This study aimed to develop and validate a scoring system based on a nomogram of common clinical metrics to discriminate between active pulmonary tuberculosis (APTB) and inactive pulmonary tuberculosis (IPTB).A total of 1096 patients with pulmonary tuberculosis (PTB) admitted to Wuhan Jinyintan Hospital between January 2017 and December 2019 were included in this study. Of these patients with PTB, 744 were included in the training cohort , and 352 were included in the validation cohort . Data from 744 patients from the training cohort were used to establish the diagnostic model. Routine blood examination indices and biochemical indicators were collected to construct a diagnostic model using the nomogram, which was then transformed into a scoring system. Furthermore, data from 352 patients from the validation cohort were used to validate the scoring system.Six variables were selected to construct the prediction model. In the scoring system, the mean corpuscular volume, erythrocyte sedimentation rate, albumin level, adenosine deaminase level, monocyte-to-high-density lipoprotein ratio, and high-sensitivity C-reactive protein-to-lymphocyte ratio were 6, 4, 7, 5, 5, and 10, respectively. When the cut-off value was 15.5, the scoring system for recognizing APTB and IPTB exhibited excellent diagnostic performance. The area under the curve, specificity, and sensitivity of the training cohort were 0.919, 84.06%, and 86.36%, respectively, whereas those of the validation cohort were 0.900, 82.73, and 86.36%, respectively.This study successfully constructed a scoring system for distinguishing APTB from IPTB that performed well. Before the coronavirus disease pandemic, tuberculosis (TB) was one of the leading causes of mortality due to a single infectious agent. In 2020, there were approximately 10 million cases, nearly 5.8 million new cases of TB and 1.3 million fatalities from TB globally , and morFive methods, namely serum biomarker examination, immunological examination, histopathological examination, laboratory microbiological examination, and imaging examination, are valuable for diagnosing APTB. However, these methods have certain limitations. Regarding serum biomarker examination, no single biomarker is effective in determining TB activity; hence, serum biomarker examination produces a low level of evidence in activity judgments. The tuberculin skin test (TST) and interferon-release assay (IGRA) are two major immunological examinations employed and included in the World Health Organization guidelines for the diagnosis of LTBI. However, neither test can distinguish between LTBI and ATBI , let aloIn recent years, with the development of analytical approaches, the construction of mathematical models based on multiple markers has been increasingly applied in the field of medicine. A nomogram was used for developing a scoring system to identify malignant pleural effusion, and the scoring system exhibited good diagnostic performance . SimilarIn a variety of previous studies, routine blood examination indices and routine biochemical indicators commonly used in clinical practice have been proven to be of minor or moderate value in the diagnosis of TB . HoweverThis retrospective clinical study was performed between January 2017 and December 2019 at the Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology . The clinical features and radiological and laboratory examination results of all patients were collected. All patients were diagnosed with APTB or IPTB by three senior TB specialist doctors. SPSS software  was used to divide all participants into training and validation cohorts according to a ratio of 7:3. 70% of PTB individuals are designated as training cohort, and 30% are validation cohort. A diagnostic model and scoring system to differentiate APTB from IPTB were constructed from those in the training cohort. The diagnostic performance of the scoring system was validated in a validation cohort. The diagnosis of APTB included microbiological and clinical diagnosis according to the Chinese expert consensus. , and theDemographic variables (age and sex), objective symptoms , and the results from radiographic and laboratory examinations, such as routine blood examinations, biochemical measurements, and microbiological examinations, were all obtained from the electronic medical record (EMR) system. In addition, several ratios, including the monocyte-to-high-density lipoprotein ratio (MHR), lactate dehydrogenase-to-adenylate dehydrogenase ratio (LAR), high-sensitivity C-reactive protein-to-albumin ratio (HSCAR), high-sensitivity C-reactive protein-to-prealbumin ratio (HSCPR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and high-sensitivity C-reactive protein-to-lymphocyte ratio (HSCLR), were calculated and included in the present study.SPSS software  was used to perform a statistical analysis of the data. Student’s t-test or Mann-Whitney U test was used to compare the continuous variables between groups, the results of which are presented using the mean ± standard deviation (SD) or median , and the chi-square (2) test was used to compare the categorical variables between groups, the results of which are presented as the absolute value (n) and percentage (%). Additionally, the cutoff values for the reference ranges of the laboratory indices or the optimal cutoff values of the receiver operating characteristic (ROC) curves were used to transform all continuous variables into binary variables. In the training cohort, univariate logistic regression analysis and ROC analyses were performed to identify the variables with a P-value of <0.05 and an area under the curve (AUC) value greater than 0.6. Subsequently, significant variables were analyzed using multivariable logistic regression analysis (MLRA), which was performed to construct the predictive model. The nomogram of the scoring system was created using the RMS tool in R and independent variables in the MLRA. The corresponding score of each parameter is based on the regression coefficient in the results of the multivariate logistic analysis, and the specific methods are as follows: (1) Parameter with the largest coefficient in the logistic regression analysis was defined as 100 points, and the scores of the remaining parameters were obtained through the regression coefficient of equal ratio calculation; (2) Dividing all scores by 10, and when there is a non-integer score, we round up the whole number to get the final score. The model score was automatically computed and evaluated for each patient using the ROC curve analysis. A two-sided p value was computed, and statistical significance was defined as p < 0.05.A total of 1096 patients with PTB admitted to Wuhan Jinyintan Hospital were included in this study. Of these patients with PTB, 744 were included in the training cohort  and 352 were included in the validation cohort . A detailed flowchart of the participant selection protocol and steps performed in this study are shown in There were no significant differences in age and sex among different groups. Additionally, the number of APTB patients with typical symptoms was significantly higher than those of IPTB patients in the training and validation set (P<0.001). Importantly, the number of APTB with Diabetes mellitus (DM) also was significantly higher than those in IPTB patients with DM in the training set (P=0.033), however, there was no significant difference between the number of APTB with DM and IPTB with DM in the validation set (P=0.204). The results suggested that APTB patients were more prone to comorbid DM. The clinical and demographic characteristics of patients are shown in In the training cohort, 41 parameters in this study were significantly different between the APTB and IPTB groups using the Student’s t-test or Mann-Whitney U test Table 2.This nomogram is easy to use in clinical practice in TB high burden countries, especially in remote areas and economically underdeveloped areas. A scoring system was established based on the nomogram with integer points as follows: MCV (6 points), ESR (4 points), ALB (7 points), ADA (5 points), MHR (5 points), and HSCLR (10 points) Table 3.To evaluate the diagnostic performance of the scoring system, the specific score of each parameter was integrated to obtain the total score. Then the ROC analysis was carried out. The total score corresponding to the maximum Jordan index was selected as the cut-off value. This scoring model exhibited good discriminative power in the validation cohort, as evidenced by an AUC of 0.900 (95% CI:0.869-0.931) , Scientific Research Fund of Wuhan in Hubei Province (WX16C33), and Scientific Research Fund of Wuhan in Hubei Province (WX12C02).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.