When comparing PPT between groups, statistically significant differences were found in the occiput (p = 0.039), low cervical (p = 0.035), trapezius (p = 0.037), second rib (p < 0.001) and medial epicondyle points (p = 0.006). Furthermore, there were statistically significant differences in both the trapezius and the forearm at the distal dorsal third SEL values (p ≤ 0.001) when comparing groups. Whole-body PBM produces changes in circadian blood pressure, the pain pressure threshold and the elasticity of tissue after a treatment program was carried out. However, more studies are needed to corroborate our findings as well as to better understand the underlying mechanisms.This study analysed circadian variation changes in blood pressure (BP), the pain pressure threshold (PPT) and the elasticity of tissue in patients with fibromyalgia (FM) after a whole-body photobiomodulation (PBM) treatment. This was a tripled-blinded randomized clinical trial including forty participants with FM. Participants using validated self-measurement BP devices attained readings that were used to calculate the circadian variation. Additionally, a standard pressure algometer of 1cm2 was used to assess 13 tender points by exerting a pressure of up to 4 kg, and strain elastography assessed the elasticity of tissue. Circadian variations in BP showed significant differences after the PBM intervention ( Chronic musculoskeletal pain (CMP) is one of the most common forms of chronic pain and has a profound impact on individuals and on society . FibromyA multifactorial understanding of FM is crucial in the development of new alternative treatments. An altered central nervous system response has been shown to exist in those suffering from FM, which may explain the association of FM with cardiovascular risks and explain a state of low-grade inflammation  and its A disrupted circadian clock has been associated with decreased health conditions  and can Therefore, alterations in circadian BP appear to be an additional risk factor in patients with FM, and treatments which focus on recovering BP patterns may be indicated, along with the assessment of tissue elasticity and pain pressure threshold (PPT).Circadian rhythms throughout the body are synchronized by the “master clock”, namely, the suprachiasmatic nucleus (SCN), via the retinohypothalamic path; hence, the diurnal/nocturnal BP ratio allows variations in blood pressure (BP) to be used as a method of assessing this clock . Neurohu2. The wave length range of 600–700 nm is used for superficial tissue treatments, and wave lengths ranging from 780 to 950 nm, which penetrate further because they are longer, can treat deeper-seated tissues [Photobiomodulation (PBM) therapy, previously named low-level laser therapy (LLLT), is a developing, non-invasive therapy for those suffering from FM. It has been proven to be effective in improving musculoskeletal and neuropathic pain in these patients, resulting in an improvement in the quality of their life . At wave tissues ,29,30.The biostimulation target for PBM could be the mitochondria , with trTherefore, we designed a tripled-blinded randomized clinical trial with 40 patients suffering from FM, based on the hypothesis that the circadian blood pressure rhythm, the perception of pain pressure and the elasticity of tissue are altered in FM sufferers. As far as we know, this is the primary research paper on the effects of PBM on circadian BP changes, pain pressure threshold and the elastic properties of tissue. FM and circadian rhythm are thought to be associated ; therefoThe research aim is to analyse changes in BP values, PPT and the elastic properties of tissue in subjects suffering from FM after a whole-body PBM treatment.This was a tripled-blinded randomized clinical trial, where subjects, therapists, evaluators and the statistician were all blinded to whether the whole-body PBM was active or in a placebo mode.All methods used followed the Declaration of Helsinki, and ethical approval was obtained from the local Ethics Committee of the University of Granada (1044/CEIH/2020). The study has been registered on ClinicalTrials.gov (NCT05113589) and conducted in accordance with the Declaration of Helsinki. The standard protocol items of the CONSORT Statement ,34A sample of forty-two participants who presented with FM was recruited from a private clinical practice. Participants were included in the study if they met the inclusion criteria when assessed by a research assistant, resulting in 40 participants being assessed.Each participant had to complete a consent form before their confidential information was password-protected and stored.i.Age: 34 to 64 years;ii.Rheumatologist diagnosed FM based on the classification criteria of the ACR (modified 2010/2011) . The folThe presence of any disorder of an inflammatory, neurological or orthopedic nature that may affect balance, hearing or vision. Additionally, any cognitive impairment that may impair the ability to answer questions or any muscle disorders of the fascia, such as trigger points, pain due to myofascial syndrome and neck pain.A whole-body PBM treatment or a placebo treatment was randomly assigned to the participants who were not allowed to take part in any other FM study nor receive any other treatment while in this study. Medically prescribed medication continued and any modifications made to it were recorded; hence, the placebo effect related only to the PBM session. Any participant who had had prior treatments, namely manual therapy and physical activity, were accepted, since FM patients need continuous care.® whole-body light bed  and subsequently after the treatment (T2). A flow diagram illustrates these assessment times .The circadian BP index (BPI) is defined as the nighttime reduction in BP relative to the mean daytime BP, and it is calculated using the following formula: 100 × (mean daytime BP−mean nighttime BP)/mean daytime BP; the mean BP is calculated as follows: diastolic BP + 1/3 (systolic BP−diastolic BP). This index was used to arbitrarily classify patients as normal dippers (ratio > 10%) or non-dippers (ratio < 10%). Recently, this allocation has been enhanced into four possible groups as follows: extreme-dippers (ratio ≥ 20%), normal dippers (ratio ≥ 10%), non-dippers (ratio < 10%) and inverse-dippers or risers  .The guidelines published by the International Society of Hypertension (ISH) were used as the basis for measurement procedures and were taught to the patients by the research assistant . Both daAfter receiving all data, the daytime and nighttime BP values for the 7 days were used to calculate the daily BP ratio and the mean diurnal/nocturnal ratio. In total, 560 BP measurements (280 daytime/280 nighttime) were carried out with the participants using validated self-measurement BP devices, following the aforementioned guidelines from the ISH and thus producing reliable values for scientific research ,38.2 was used to assess 12 tender points in accordance with the ACR criteria. The perpendicularly positioned algometer was used to apply continually increasing pressure until pain was perceived at the following tender points: (i) occiput—suboccipital muscle insertions; (ii) low cervical—anterior aspects of C5–C7 intertransverse spaces; (iii) trapezius—midpoint of upper border; (iv) supraspinatus—origins atop the scapula spine close to the medial border; (v) paraspinous—laterally 3 cm to the midline at mid-scapula; (vi) second rib—just lateral to the upper surface second costochondral junctions; (vii) lateral pectoral—anterior axillary line at the level of the fourth rib; (viii) lateral epicondyle—2 cm distal to the epicondyles; (ix) medial epicondyle; (xi) gluteal—anterior fold of muscle at the upper outer buttock quadrants; (x) greater trochanter—just posterior to the trochanteric prominence; (xi) knees—medial fat pad adjacent to the joint line; (xii) forearm—at distal dorsal third; (xiii) thumbnail and (xiv) midfoot—dorsal third metatarsal midpoint. At these tender points, two measurements were taken, and the mean was calculated and recorded for each participant [A standard pressure algometer , exerting up to 4 kg of pressure on 1 cmticipant ,40.A physiotherapist, with 10 years of experience and an expert in musculoskeletal imaging, used the Logiq S7 with 15 MHz linear probe  to carry out measurements on the subjects following the orientation guidelines used for tender point recognitions . Given t® Statistics version 21.0 . Data distribution normality was verified using the Kolmogorov–Smirnov test. The comparison of the clinical characteristics of the PBM intervention and the placebo groups at baseline and immediately post-intervention was carried out using a two-way repeated measures MANOVA, with each moment of assessment possessing two corresponding levels and with the two intervention groups as independent factors. A p-values < 0.05 was considered to be statistically significant.All analysis was carried out using SPSSThe Cohen d coefficient was employed to assess the size of the between group and within group effect for all qualitative variables, with greater than 0.8 being considered as large, approximately 0.5 considered as moderate and under 0.2 considered as small .In reference to the outcomes of earlier randomized clinical trials ,45 and eA total of 42 participants were recruited, but 2 participants were excluded due to not completing the proposed assessments. A final number of 40 participants were accepted and completed the baseline assessment, as shown in the flow diagram.Sample characteristics are shown in p = 0.036). When comparing PPT between groups, statistically significant differences were found in occiput (p = 0.039), low cervical (p = 0.035), trapezius (p = 0.037), second rib (p < 0.001) and medial epicondyle points (p = 0.006). Furthermore, there were statistically significant differences in both the trapezius and the forearm at the distal dorsal third SEL values (p ≤ 0.001) when comparing groups.Circadian variations in BP showed significant differences after the PBM intervention . When comparing PPT between groups, statistically significant differences were found in occiput (p = 0.039), low cervical (p = 0.035), trapezius (p = 0.037), second rib (p < 0.001) and medial epicondyle points (p = 0.006); nevertheless, there were no significant changes in the other points. In addition, there were statistically significant differences in both the trapezius and the forearm at the distal dorsal third. SEL values (p ≤ 0.001) when comparing groups, whereas no significant changes were presented in the rest of SEL assessment.Circadian variations in BP showed significant differences after the PBM intervention . Our results showed that the BP values of the whole group are non-dippers and inverse-dippers, which is in line with a recent study which showed people suffering from chronic musculoskeletal pain to have both non-dipper and inverse dipper values . MoreoveThis study, which has many strengths including being the first to report the effects of whole-body PBM on values such as BP, PPT and SEL in patients who suffer from FM, opens up new possibilities in the treatment and improvement of FM symptoms. Furthermore, a triple-blinded design was followed; thus, the results are more reliable. On the other hand, there are some limitations that must be acknowledged. The information given by the clinical measurement of blood pressure (BP) is known to be limited and its values can be influenced by other factors ; the smaThe results obtained in our study propose whole-body PBM intervention as a new possibility in the treatment of those suffering from FM, specifically in the perception of pain measured by PPT and the elasticity of tissue measured by SEL. Changes in circadian BP were also shown after the whole-body PBM intervention, and cardiometabolic profiles, insulin resistance and endothelial dysfunction may be improved. This could be a first step in designing new whole-body PBM treatments in terms of the number of sessions with the goal of increasing the beneficial effect on the body. Furthermore, the changes produced in PPT and SEL may be consequences of an improvement in vegetative symptoms, such as neuroinflammation and central nervous system dysfunction, which are characteristic in those suffering from FM.Future research with longitudinal designs studying changes in circadian BP, PPT and SEL in tender points after treatments are needed to corroborate our findings and to analyse how these changes persist. On the other hand, cardiometabolic profiles, insulin resistance and endothelial dysfunction biomarkers, together with cortisol and melatonin levels, should be studied in order to better understand changes in circadian BP values. Furthermore, gut microbiota, metabolomics and brain neurochemistry should be further studied in subjects with FM to better understand the relationship between the axis brain-gut microbiome and circadian rhythms. Finally, more studies combining whole-body PBM treatments, exercise and nutritional strategies, such as intermittent fasting or time restricted feeding, must be carried out.Whole-body PBM produced changes in circadian BP values, the pain pressure threshold and the elasticity of tissue after a treatment program of 12 sessions. However, more studies are needed to corroborate our findings and to better understand the underlying mechanisms.The trial has been registered at Clinicaltrials.gov with the following identifier: NCT05113589. Ethics approval and consent to participate: Ethical approval from the Ethics Committee of Human Research at the University of Granada, Spain (1044/CEIH/2020), was obtained for this study. All the participants accepted and signed an informed consent before beginning the study.


Introduction: Diabetic kidney disease (DKD) is the commonest cause of chronic kidney disease and end-stage kidney disease worldwide, consequently it has become an important productive implication to the healthcare system. This study was conducted to assess the prevalence of non-DKD (NDKD) in diabetic patients from south India.Objective: To assess the prevalence of NDKD in type 2 diabetes mellitus patients presenting to a tertiary care hospital from south India and also to analyze clinical clues to establish a diagnosis of NDKD.Patient and methods: It is a retrospective observational study of analyzing patient characteristics and renal biopsies. All Diabetic patients with a clinical suspicion of non-diabetic kidney disease who underwent renal biopsy during the study period between January 2012 and June 2017 were included. Based on the biopsy findings, the patients were classified into three groups  and patients’ characteristics were compared between the groups for analysis.Results: A total of 236 renal biopsies were analyzed for the study. Of that, 114 had features of DKD, 78 NDKD with diabetic nephropathy (DN) and 44 had isolated NDKD. Acute interstitial nephritis was the most common cause of NDKD.Conclusion: From the current study, the long duration of diabetes mellitus beyond five years and hypertension beyond two years reasonably predict DKD. Diabetic kidney disease (DKD) is defined as a clinical syndrome in a patient with diabetes mellitus (DM) characterized by persistent albuminuria (>300 mg/day or >200 μg/min) on at least two occasions 3-6 months apart, elevated blood pressure and progressive decline in renal function. DKD is the commonest cause of chronic kidney disease and end-stage kidney disease worldwide ; consequNDKD warrants special attention because when picked up early, interventions can often reduce the associated morbidity, mortality, or quality of life. The presence of biopsy-demonstrated NDKD in patients with diabetes varies from 8% to 85% in the published literature [It is a retrospective observational study analyzing patient characteristics and renal biopsies done on diabetic patients who had an atypical presentation. Indicators of kidney biopsy in diabetic patients are shown in Table The data were analyzed using WPS software and JMP Statistics. Numerical data were interpreted as mean ± standard deviation. Positive or negative values were interpreted as count/total sample number. Correlation between groups was analyzed using the Chi-square test, analysis of variance, unpaired t-test, and nonparametric test. Binary univariate and multivariate regression analyses were utilized to analyze the relationship between baseline characteristics and outcomes. A P-value < 0.05 was considered statistically significant.A total of 236 diabetic pts in whom renal biopsies were done for atypical features were analyzed for the study. Among these, 114 biopsies showed features of DKD, 78 had features of NDKD overlapped with DKD and 44 biopsies had features of isolated NDKD. We found a definitive yield based on clinical suspicion of 51.69% - 122 out of 236 in our study. The usual indicators for renal biopsy in our study were an unexplained renal failure - 33.4% not corroborating with the clinical scenario, followed by nephrotic range proteinuria being 28.35%, proteinuria without retinopathy of 18.14%, and active urine sediment of 16.08%  were 47.2% the commonest followed by membranous nephropathy - 10.4%, post infectious glomerulonephritis -10.4% and Ig A nephropathy - 7.2% and minimal change disease - 7.2%. Almost 85% of these patients - 200 were on follow up for a mean of three years and 67 of these patients required renal replacement therapy during the study period. The most common finding in patients with DKD and NDKD was AIN whereas it was post infectious glomerulonephritis in the group with isolated NDKD.In our study, the frequency of NDKD in diabetic cases was 51.69%. In various studies, NDKDs also isolated or overlapped on an underlying DKD, have been described to be 8% to 85% which reflects the wide array of clinical grounds for renal biopsy -11. KittWe found that patients with a longer duration of diabetes (>5 years) and hypertension (two years) were more likely to have DKD even though they have atypical features. Similar findings were found in the study by Yenigun et al. , those wSimilarly, unexplained renal failure which was 33.4%, and rapid worsening of renal function in diabetic patients were most likely associated with NDKD. This finding is similar to the results from Jin Kim , who repInterestingly none of the other parameters including the absence of diabetic retinopathy, 24-hour proteinuria levels, presence of hypertension, and degree of hypoalbuminemia found any statistical significance in our study. A similar finding was reported by Mak et al.  in theirAmong the NDKD, AIN was 47.2%, the commonest cause. This finding was similar to Soni et al.  from ourLimitations of the study being small study population and comprised regional population. Studies with larger numbers and different population groups will be helpful in authenticating the results.The clinical dilemma in differentiating DKD from NDKD still exists. The current clinical criteria do not effectively differentiate the two as the natural course of DKD in a population with type 2 DM is not well documented. From the current study, prolonged DM and hypertension of more than five years and two years, respectively, predict DKD. While unexplained renal failure was most likely with NDKD. Hence, there is a need to further refine the clinical criteria to suspect non-diabetic renal disease in diabetic patients.


In a stepwise multiple regression model, considering several variables, CCI was the only predictor of PWV-cf, whereas age and CCI were significant predictors of both CAVI and CAVI 0. In conclusion, all arterial stiffness indexes are associated with CCI and aging; the latter correlation is more evident for CAVI and CAVI 0 than for PVW-cf. Arterial stiffness parameters can complement the characterization of patients affected by a remarkable comorbidity burden across aging; arterial stiffening might mirror the complexity of these individuals.The aim of the study was to evaluate the relationships between carotid-femoral pulse wave velocity (PVW-cf), cardio-ankle vascular index (CAVI) and CAVI0 , age and comorbidity burden. Furthermore, 183 patients  referred to the Geriatric Ward and Outpatient Clinic at Verona University Hospital were included; demographic, clinical and blood analysis data were collected. Charlson Comorbidity Index (CCI), PVW-cf, CAVI and CAVI 0 were obtained. Significant correlations were found between CAVI, CAVI0, PVW-cf and both age (r = 0.698, r = 0.717, r = 0.410, respectively  Vascular aging is associated with arterial wall remodeling, with progressive stiffening and reduced compliance; arterial stiffness is an independent predictor of cardiovascular morbidity and mortality . It is tA massive number of pathological conditions have been shown to be related to increased arterial stiffening. For instance, PVW-cf is known to be associated to aging , cardiovInterestingly, although several comorbidities, as considered per se, are shown to be related to increased stiffness, less is known about the possible effect of the comprehensive comorbidity burden. The role of arterial stiffening in the characterization of complex patients with relevant comorbidity burden, considered across aging, is yet to be deeply explored; however, it may shed light on riveting pathophysiological issues. Furthermore, particular attention should be paid to cardiovascular comorbidities and risk factors, given their direct involvement in arterial structures. The aim of the study was to examine the correlation between arterial stiffness indexes, comorbidities and cardiovascular risk factors in a group of adults and older adults. The study population included 183 subjects, 119 females and 64 males, hospitalized at Geriatric Clinic of Verona University Hospital or referred to Outpatient Clinic . Exclusion criteria were: (I) limb amputation or history of surgical treatment to aorta, carotids, or femoral arteries; (II) severe peripheral arterial disease or proximal arterial stenosis; (III) atrial fibrillation or other major arrhythmias. A detailed clinical history, with particular mention to cardiovascular diseases and risk factors, and physical examination were recorded for each patient. To evaluate the comorbidity burden, Charlson comorbidity Index (CCI) was calculated for each patient, using anamnestic patient-reported data. The study was approved by the Ethical Committee of the University of Verona. All participants gave informed consent to be involved in the research study.2). With the subject barefoot and wearing light indoor clothing, body weight was measured to the nearest 0.1 kg , and height to the nearest 0.5 cm using a stadiometer ; whenever patients could not assume the erect position, the last anamnestic height was recoded. BMI was calculated as body weight adjusted by stature , and dP stands for diastolic blood pressure (DBP). By means of this device, heart-ankle PWV (haPWV) was calculated as the ratio between aortic valve to ankle length  and the time T taken by pulse wave to run this distance  [CAVI, blood pressure and heart rate were measured and mean arterial pressure (MAP) and pulse pressure (PP) were calculated using VaSera-1000 , as per the manufacturer’s recommendations. BP cuffs were placed simultaneously on the four limbs and inflated two by two (right and left side) to increase the accuracy of measurements. ECG was obtained by two electrodes placed on both arms; to obtain phonocardiography, a microphone was placed on the sternum (second rib space). This device calculates CAVI, on the basis of the Bramwell–Hill Formula ,28, mease waves) . CAVI 0 e waves)  followinThe pulse wave analysis was performed noninvasively using a portable device called PulsePen  , and itsVenous blood samples were obtained after the subjects fasted overnight. Plasma glucose was measured with a glucose analyzer . Cholesterol and triacylglycerol concentrations were determined with an automated enzymatic method . High-density-lipoprotein (HDL) cholesterol was measured by using the method of Warnick and Albers. LDL cholesterol was calculated using the Friedwald formula . CreatinResults are shown as mean value ± standard deviation (SD). Variables not normally distributed were log-transformed before analysis. Pearson correlation coefficient was used to estimate correlations between variables. Independent samples t-tests were used to compare baseline characteristics of female and male patients. Analysis of variance (ANOVA) was performed when comparing continuous data, after stratifying the population upon age classes and comorbidities and to evaluate the effect of independent variables included in regression models. A significance threshold level of 0.05 was used throughout the study. All statistical analyses were performed using SPSS 23.0 version for Windows . n = 119) female. The main characteristics of the study population are listed in The study population included 183 individuals, mean age 67.5 ± 14.3 years, 65% . Furthermore, CAVI, CAVI 0 and PVW-cf resulted correlated to higher comorbidities, as measured by CCI . Both CAVI and CAVI 0 showed a significant inverse relation with DBP , MAP  and a positive relation with PP .As shown by univariate analysis , all artp < 0.001) and both CAVI and CAVI 0 relate to PVW-cf .Moreover, CAVI 0 is directly correlated to CAVI . Mean CAVI, CAVI 0 and PVW-cf were also increased in diabetic patients, when compared to normoglycemic subjects . Furthermore, the subgroup of patients with previous CV events, as compared to subjects without, had increased CAVI and CAVI 0, whilst PVW-cf was not significantly different between groups . When stratifying the study population upon CCI, as CCI increased, we outlined a progressive increase in CAVI , accounting for 20.5% of its variance. Interestingly, when considering CAVI as dependent variable, and age, GFR, MAP, CCI, LDL and triglycerides as independent variables, both age and CCI resulted to be significant predictors , explaining almost 53% of CAVI variance. Likewise, as shown in the third model which considered CAVI 0 as dependent variable and again age, GFR, MAP, CCI, LDL and triglycerides as independent variables, age and CCI  could predict CAVI 0, accounting for 55.8% of its variance. Stepwise multiple regression models were performed  in orderThe present study shows significant positive correlations between all parameters of arterial stiffness and CV risk factors, comorbidities, and aging. The positive correlation with age is stronger for CAVI and CAVI 0 than PVW-cf. Moreover, our data confirm and complement previous knowledge showing that age and comorbidity can predict arterial stiffness parameters.We could demonstrate a positive relationship between CAVI, CAVI 0, PVW-cf and the main CV risk factors, even after adjustment for age, sex, MAP and GFR. In line with previous evidence , in our As is predictable considering vascular involvement in the diabetes mellitus course , we descWe further outlined increased CAVI and CAVI 0 in patients with previous CV events, still in line with several studies that described increased CAVI in subjects with known coronary artery disease and cerebral ischemia ,41,42,43Although several conditions are known to be associated to worse values of CAVI and PVW-cf, the possible association with the comprehensive comorbidities burden is not entirely explored. In this regard, although less is known about increased comorbidity index, CAVI has already been depicted as increased among frail individuals; thus, our results confirm and complement previous evidence by Xue and colleagues who described higher CAVI values in elderly frail patients (relaying on Fried’s frailty definition) . NoteworAccording to consolidated knowledge , our stuA few limitations of the study should be recognized: this is a cross-sectional study, and therefore we were not allowed to test the power of arterial stiffness indexes in predicating long term cardiovascular risk. Our study was predominantly performed in female patients and given the increased prevalence of cardiovascular diseases in the male population, we need to test our hypothesis in a more represented male population. Further, information regarding medical therapy was not available, but we acknowledge that the possible effect of different medications on arterial stiffness may be of interest. As concerns arterial stiffness parameters, we acknowledge that the augmentation index, which is deemed to be an important parameter, was not significant in our findings, and therefore excluded from the results.In conclusion, our study, conducted on a relatively wide and heterogeneous cohort of patients, demonstrated that PVW-cf, CAVI and CAVI 0 are associated to CV risk factors and higher comorbidity burden, even after adjustment for several variables. Furthermore, our data outline a strong correlation between arterial stiffness indexes and age. Our findings might complement the pathophysiological understanding of the cardiovascular impairment in subjects with older age and remarkable comorbidity burden. Therefore, in the clinical setting, arterial stiffness evaluation, which is a feasible and easily available technique, may complement the characterization of complex patients.


Kidney transplantation is an effective treatment for end-stage renal disease (ESRD). Delayed graft function (DGF) is a common complication after kidney transplantation and exerts substantial effects on graft function and long-term graft survival. Therefore, the construction of an effective model to predict the occurrence of DGF is particularly important.Seventy-one patients receiving their first kidney transplant at the First Affiliated Hospital of Nanchang University from October 2020 to October 2021 were enrolled in the discovery cohort. Based on clinical characteristics and serum markers, a logistic regression model was used to simulate the risk of DGF in the discovery cohort. The DGF prediction model was named the prediction system and was composed of risk factors related to DGF. Thirty-two patients receiving a kidney transplant at the First Affiliated Hospital of Nanchang University from October 2021 to February 2022 were enrolled in the validation cohort. The validation cohort was used to verify the accuracy and reliability of the prediction model.Cold ischemia time (CIT), donor history of diabetes mellitus, donor interleukin-2 (IL-2) level and donor terminal creatinine level constitute the prediction system. In the validation test, the area under the receiver operating characteristic curve (AUC) was 0.867 for the prediction system, and good calibration of the model was confirmed in the validation cohort.This study constructed a reliable and highly accurate prediction model that provides a practical tool for predicting DGF. Additionally, IL-2 participates in the kidney injury process and may be a potential marker of kidney injury. Kidney transplantation is an effective treatment for end-stage renal disease. However, the demand and supply disparity among patients waiting for kidney transplants and the availability of donor organs is widening. Expanded criteria donors (ECDs) are increasingly used for transplantation to alleviate the shortage of organs. However, the use of these donors has resulted in a significant increase in postoperative complications ) . DelayedIn recent years, transplant centers around the world have begun to build models to predict DGF by collecting preoperative information. Irish et al.  first puClinical characteristics and preoperative kidney injury markers are also important for predicting the occurrence of DGF. Most studies have shown that acute kidney injury (AKI) caused by ischemia–reperfusion injury (IRI) is the main factor contributing to DGF because the production of cytotoxic mediators and activation of innate and adaptive immune responses after reperfusion all cause damage and necrosis of renal tubular cells –11. InteHere, we discuss the involvement of serum markers in renal function impairment, construct a novel, reliable and highly accurate prediction model combine with serum markers, aiming to provide new insights for the DGF prediction after kidney transplantation.Sample and data collection were approved by the First Affiliated Hospital of Nanchang University ethical committees and were performed according to the Declaration of Helsinki. This study retrospectively collected the clinical characteristics of 39 donors and 77 recipients who underwent transplant surgery at the First Affiliated Hospital of Nanchang University from October 2020 to October 2021. The following classes of renal allograft donor organs or recipients were excluded from the study: (1) they had undergone retransplantation or were transplanted with organs other than the kidneys; (2) had a positive crossmatch or positive panel-reactive antibody (PRA > 10%); (3) had abnormal hepatic function; (4) patients who had autoimmune disease or received immunosuppressive therapy before the transplant procedure; (5) living related donor; (6) patients who displayed less than seven days of patient-and-graft survival (the diagnosis of DGF takes 1 week); and (7) patients who underwent a double-kidney transplant. Five recipients were excluded due to retransplantation, one recipient was excluded due to double kidney transplants. Finally, 71 recipients were included in the discovery cohort.In addition, we collected information on 17 donors and 32 recipients who underwent transplant surgery at the First Affiliated Hospital of Nanchang University from October 2021 to February 2022 as a validation cohort to validate the predictive value of our model  Sample collection: ① Donor blood sample collection: When donor death was declared, donor peripheral blood samples (10 ml) were collected into a tube containing EDTA. ② Recipient blood sample collection: Recipient peripheral blood samples were collected into tubes (10 ml) containing EDTA before the induction of immunosuppression.(2) Flow cytometry experimental procedure: The frequency of Tregs was measured using flow cytometry. The main experimental equipment includes: CTYOMICS FC 500 flow cytometer, lysis solution ; CD4-FITC, CD25-PC5, and CD127-PE antibodies ; and phosphate-buffered saline .(3) ELISA experimental procedure: Plasma levels of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), cytotoxic T-lymphocyte-associated protein-4/cluster of differentiation 152 (CTLA-4/CD152), interleukin-35 (IL-35), and high mobility group Box 1 protein (HMGB1) were measured in the groups using commercially available enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer’s instructions. The main experimental equipment included IL-2, IL-4, IL-6, IL-10, CTLA-4/CD152, IL-35, and HMGB1 ELISA kits .DGF was defined as a need for dialysis in the first week after transplantation. Dialysis with heart failure was excluded. Patients who displayed less than seven days of patient-and-graft survival were excluded.Continuous variables are presented as the means ± standard deviations (SD) or medians (interquartile ranges [IQRs]), and categorical data are presented as percentages. Differences in continuous variables were analyzed using Student’s t tests or the Mann–Whitney U test. Categorical data were evaluated using the chi-square or Fisher exact test, as appropriate.(1) Construction of the prediction model: This analysis was performed based on the discovery cohort (n=71) using a multivariate logistic regression analysis. The independent predictors of DGF were identified if their P value was less than 0.05. The regression coefficients of the predictive variables in thelogistic regression model were used to establish the nomogram to predict DGF.(2) Validation of the prediction model: Model efficacy was verified by analyzing the data from the discovery cohort  and the validation cohort . ① Internal validation: The predictive ability of the prediction model was assessed using a c‑statistic of the receiver operating characteristic curve (ROC), and the 95% Confidence Interval (CI) of the areas under the ROC curves (AUCs) were nonparametrically obtained bybootstrap resampling (1000 bootstraps). The model prediction threshold was compared by performing decision curve analysis (DCA). By drawing a calibration diagram (1000 bootstraps), the performance characteristics of the model are shown graphically. We calculated the Brier score and R-squared values of the model. ② External validation: This analysis was repeated using data from the validation cohort. The validation cohort was divided into ten groups, and the DGF prediction model calibration was evaluated using the Hosmer‑Lemeshow statistic.The statistical analyses were performed using SPSS software version 24.0 , MedCalc statistical software version 19.6  and R version 4.12 .n = 71) and validation cohort (n = 32). Table P = 0.001). The proportion of patients with a donor history of hypertension in the IGF group (17 (35.4%)) was lower than that in the DGF group (15 (65.2%)) (P = 0.018). The proportion of donors with a history of diabetes mellitus in the IGF group (6 (12.5%)) was also lower than that in the DGF group (10 (43.5%)) (P = 0.003). The CIT in the IGF group (8.36 ± 2.27) was significantly shorter than that in the DGF group (10.61 ± 2.82) (P = 0.001). In contrast, the proportion of a recipient history of hypertension in the IGF group (44 (91.7%)) was higher than that in the DGF group (17 (73.9%)) (P = 0.044). Table P = 0.001). No significant differences in the levels of other serum markers or Tregs were observed between the groups.A total of 103 patients were enrolled in the discovery cohort , and clinical impact curve (CIC) to evaluate the predictive power of the prediction system. The relative efficiencies of the KDRI, delayed graft function score (DGFS) and the prediction system for predicting DGF are shown in Figs. t) is 0–0.88, the positive probability of DGF is higher with our prediction model, while the threshold value of KDRI(Pt = 0–0.75) and DGFS (Pt = 0–0.77) are narrower. Figure In the discovery cohort, the AUCs were 0.894 for the prediction system, 0.764 for the KDRI and 0.720 for the DGFS  than in the DGF group (9.5 ± 1.23). The proportion of donors with a history of diabetes mellitus in the IGF group was lower than that in the DGF group. The donor IL-2 level in the IGF group (76.22 (63.25–95.64)) was lower than that in the DGF group (97.70 (89.56–113.83)). The donor terminal creatinine level was significantly different between the DGF (1.37 (0.92–1.74)) group and IGF (0.67 (0.56–0.8)) group. Figure t = 0.16–0.62) and DGFS (Pt = 0.3–0.59) thresholds were still low. Our prediction model was better than KDRI in terms of decision-making ability. Figure P = 0.4117, > 0.05 indicates good calibration).In the validation cohort, the AUC calculated using the prediction system was 0.879, the KDRI was 0.829, and the DGFS was 0.667  to provide clinicians with a useful tool that helps clinical decision-makers intervene more quickly and reduce the occurrence of DGF. IL-2 also participates in the kidney injury process and may be a potential marker of kidney injury.


It is well known that sarcopenia is a common risk factor in patients with gastrointestinal tumours, which may negatively affect the clinical outcome and prognosis. Recent studies suggest that serum creatinine-cystatin C (Cr/CysC) ratio may be associated with sarcopenia, but this association lacks sufficient evidence in patients with gastrointestinal stromal tumours (GIST). Therefore, this study aimed to investigate whether the Cr/CysC ratio was associated with sarcopenia and recurrence-free survival (RFS) in patients with GIST.The study retrospectively analysed 413 patients with GIST who underwent surgical resection from January 2016 to January 2020. The serum Cr/CysC ratio was determined as a proxy for sarcopenia by comparing it with various biomarkers and Cox multifactorial analysis was used to determine the relationship between Cr/CysC ratio and prognosis.r = 0.256, p < 0.001), skeletal muscle index (SMI) , and hand grip strength (HGS) . The area under the receiver operator characteristic curve for sarcopenic subjects with serum Cr/CysC ratio was significantly greater than other biomarkers . The optimal cut-off value for Cr/CysC was 0.65, and patients in the high Cr/CysC group had a higher 3-year recurrence-free survival (RFS) than those in the low Cr/CysC group . Cox multifactorial analysis found that the Cr/CysC ratio was an independent risk factor for RFS in GIST patients .Serum Cr/CysC was positively correlated with skeletal muscle area (SMA) (Serum Cr/CysC ratio has satisfactory and comparable diagnostic accuracy, and prognostic value for sarcopenia in patients with GIST. Therefore, it can be a simple and practical clinical tool to screen sarcopenia in GIST patients. However, further studies are required to validate these findings. Gastrointestinal stromal tumours (GIST) are the most common type of mesenchymal tumour, occurring mainly in the stomach 40–60%) followed by the small intestine 20–30%) , 2. Rece0–30% , 20–60% folCurrently, the published international consensus diagnosis of sarcopenia considers that it is necessary to measure muscle function and to evaluate the patient’s physical performance, in addition to the assessment of muscle mass –8. SeverIt is well known that serum creatinine (Cr) and cystatin C (CysC) are commonly used to assess renal function in cancer patients. In recent years, researchers have found that the ratio of Cr and Cyc in peripheral blood can be used to predict muscle mass. Cr is an index reflecting the function of glomerular filtration, which is mainly affected by the metabolism of muscle tissue in the body and is mainly excreted by glomerular filtration , 14. MeaTherefore, the aim of this study was to investigate whether Cr/CysC can be utilised for screening sarcopenia in GIST patients and to determine its optimal cut-off value and impact on recurrence-free survival (RFS) in GIST patients.This retrospective cohort study was conducted in the Fourth Hospital of Hebei Medical University. The clinical data of GIST patients who were consecutively admitted to the Three Departments of Surgery were analysed from January 2016 to January 2020. The inclusion criteria were as follows: age ≥ 18 years, pathological diagnosis of GIST, treatment with surgery, serum Cr and CysC measured within 1 week before surgery and computed tomography (CT) of the abdomen and pelvis within 2 weeks. Exclusion criteria were as follows: receiving targeted therapy, concurrent presence of other types of tumour, diagnosis of metastatic GIST, incomplete clinical data, reduced preoperative glomerular filtration, and absent abdominal and pelvic CT images. A total of 449 patients were enrolled in the study, of whom 36 were excluded for the following reasons: 18 patients had missing abdominal and pelvic CT images, 10 patients received preoperative imatinib-targeted therapy, and 8 patients had impaired preoperative glomerular filtration function. Ultimately, data from 413 patients were analysed. Informed consents were obtained from all participants and the study protocol was ethically approved by the biomedical research ethics committee of the Fourth Hospital of Hebei Medical University (Ethics number: 2019049).In all patients, within 1 week before the procedure, peripheral venous blood was collected after fasting for 8 h. The blood creatinine level and CysC level were measured using an automated haematology analyser (Beckman Coulter AU5800). According to previous research reports –24, the Abdominal and pelvic CT images of all recruited patients before the surgery were analysed retrospectively. Numerous studies have confirmed that the area of skeletal muscle and adipose tissue in CT cross-sectional images of the L3 vertebral level scan performed in the supine position is closely related to the total body muscle and fat mass , 26. The2/m2) = SMA/height2.The 5-mm flat-scan images were uploaded to the Picture Archiving and Communication System  after image acquisition. The following tissue Hounsfield unit (HU) thresholds were used: skeletal muscle had an attenuation range of -29 to 150 HU . The sofThe handgrip strength (HGS) was evaluated using a Camry dynamometer , both hands were alternately measured twice, and the maximum value was used for further analysis.2/m2 in men and SMI < 34.9 cm2/m2 in women as muscle loss, and HGS < 26 kg in men and HGS < 18 kg in women as sarcopenia.The definition of sarcopenia in this study was assessed using the European working group on sarcopenia in older people (EWGSOP)  and the Recurrence-free survival (RFS) was defined as the time from the start of initial recruitment to the date of documented relapse or death from any cause during the follow-up, and the follow-up deadline for this study was May 31, 2022. All patients were recommended to have an enhanced CT scan of the abdomen and pelvis every 3 months for the first 3 years postoperatively and every 6 months for the 4th to 5th postoperative years. Follow-up methods mainly included telephone encounters, outpatient visits, and hospitalisation.X2 test or Fisher’s exact test. Continuous variables were expressed as mean with standard deviation (SD) or median with interquartile range (IQR). All continuous data in this study were non-normally distributed according to the Kolmogorov–Smirnov test, so the Wilcoxon rank-sum test was used to compare differences between groups. Scatter plots and Pearson’s correlation coefficient were used to assess linear correlations. Multivariate logistic regression was used to analyse the effect of various factors on the prevalence of sarcopenia. The subject receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to assess the ability of the Cr/CysC ratio, CysC and Cr to screen for sarcopenia. Differences in subject working characteristic (ROC) curves were compared using DeLong test. The Youden index (sensitivity + specificity-1) was calculated to determine the optimal cut-off point for determining the Cr/CysC ratio in men and women. Kaplan–Meier curves were performed to estimate RFS, and a log-rank test was used to compare the difference between groups. Cox regression models were used to identify independent prognostic factors. A P-value < 0.05 was considered to show statistical significance.All statistical analyses were performed using IBM SPSS Statistics for Windows, version 26.0  and MedCalc Statistical Software v15.2 . Categorical variables were expressed as numbers and proportions, using the p = 0.002) remained as an independent predictor of sarcopenia.In this study, a total of 87 patients (21.07%) had sarcopenia, including 44 (50.57%) men and 43 (49.43%) women. The characteristics of patients with sarcopenia compared to those without sarcopenia are shown in r = -0.0405, p = 0.359), SMA , or HGS , whereas serum Cr was positively correlated with SMI , SMA , and HGS . In addition, the Cr/CysC ratio correlated more strongly with SMI , SMA , and HGS  than between Cr and SMA, SMI, and HGS, respectively.As shown in p = 0.021 and p = 0.016). Moreover, a serum Cr/CysC cut-off value of 0.65 for all patients was calculated using the Youden-index, and the same cut-off values were obtained for the subgroup analysis of male and female patients. Based on the cut-off values, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated as 0.777, 0.773, 49.28, and 92.42%, respectively in the male group. In the group, the sensitivity, specificity, positive predictive value and negative predictive value were 0.799, 0.814, 48.22, and 94.41%, respectively (p < 0.001).We analysed the diagnostic value of serum Cr, CysC, and Cr/CysC ratio for sarcopenia by using ROC curves, and the validity of each biomarker as a predictor of sarcopenia was examined by using DeLong test . The patectively . Sarcopep < 0.001). The same results were obtained when subgroup analysis was carried out according to gender  (p = 0.011) , and the 3-year RFS was 85.96%. The Kaplan–Meier curve was plotted using the calculated optimal cut-off value of serum Cr/CysC ratio, and it was found that the 3-year RFS of patients in the low serum Cr/CysC ratio group was significantly lower than that in the high Cr/CysC ratio group  . We perf= 0.011) .This study shows that the serum Cr/CysC ratio in GIST patients is positively correlated with muscle mass and grip strength. In addition, the serum Cr/CysC ratio was also an independent predictor of the development of sarcopenia after adjusting for potential confounders, it indicates a high predictive value for sarcopenia in GIST patients. An optimal serum Cr/CysC cut-off value of 0.65  was calculated, the percentage of sarcopenia in the low serum Cr/CysC ratio group (50.00%) was significantly higher than that in the high serum Cr/CysC ratio group (6.55%) based on the cut-off value. Meanwhile, Cox multivariate regression analysis revealed that serum Cr/CysC ratio was an independent predictor of RFS in GIST patients. Therefore, these findings suggest that serum Cr/CysC ratio can be used as an alternative biomarker for screening sarcopenia in GIST patients.According to the published consensus reports of EWGSOP  and AWGSr = 0.300, p < 0.001), SMA , and HGS , which is consistent with previous studies , SMA , and HGS . The study showed that Cr/CysC ratio  remained an independent predictor of sarcopenia in GIST patients after adjustment of BMI, tumour size, risk classification and Cr by multivariate logistic regression analysis, which is consistent with previous findings in gastric cancer patients  (p < 0.001), suggesting that the results of the Cr/CysC ratio can also be used to predict prognosis in GIST patients.Currently, the relationship between the Cr/CysC ratio measured at the first diagnosis of cancer patients and the prognosis of cancer patients has attracted increasing attention. A retrospective study of 3,060 cancer patients found that an increase in the Cr/CysC ratio at diagnosis was significantly associated with lower 6-month mortality in patients . Further= 0.004) . In addi= 0.004) –37. The Presently, the risk of postoperative recurrence in GIST patients is usually assessed by tumour-specific factors, such as tumour diameter, risk classification, and tumour mutation type. However, our previous study found that the nutritional status of GIST patients also significantly affected prognosis , 39. AltThis study has several limitations. First, this was a single-centre retrospective study with a small sample size and the selection of GIST patients may have been biassed, which would have limited the generalizability of the results. Second, the calculated cutoff values for serum Cr/CysC ratio were not verified in other cohorts to further confirm its validation as a convenient screening tool for sarcopenia in GIST patients. Therefore, further prospective studies with multi-centre and large-sample size are needed. Third, Cr level could be altered in patients with acute kidney injury (AKI) and chronic kidney disease (CKD). Although a previous study found that serum Cr/CysC ratio could predict muscle wasting in CKD patients , the optIn conclusion, this study suggests that the serum Cr/CysC ratio may be a simple, cost-effective, and efficient screening tool for sarcopenia in GIST patients. Furthermore, a lower serum Cr/CysC ratio is associated with poorer RFS, indicating its promising prognostic value for long-term survival. However, further studies with larger sample size and different patient groups are required to validate these findings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All patients were informed about the adverse effects accompanying therapies and they all signed informed consent forms. All procedures performed in studies involving human participants were following the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study design was approved by the Ethics Committee of The Fourth Hospital of Hebei Medical University. The patients/participants provided their written informed consent to participate in this study.QZ conception and design and administrative support. PD, PY, YT, and HG: provision of study materials or patients and collection and assembly of data. PD and CS: data analysis and interpretation. All authors contributed to the manuscript writing and final approval of manuscript.


In multivariate analysis, age, ever-smoker, and initial systolic blood pressure were significantly associated with hemoptysis of unidentified causes. Although further studies are needed, our findings suggest a possible association between high blood pressure and cryptogenic hemoptysis.Hemoptysis is a common cause of emergency department (ED) visits. There is little data about the role of systemic hypertension as a cause of hemoptysis. The aim of this study was to evaluate the association between systemic blood pressure and the unknown etiology of hemoptysis. This retrospective study included consecutive patients who visited the ED owing to hemoptysis and underwent a chest computed tomography between January 2011 and June 2021. Details of the initial blood pressure at the ED visit were compared between two groups with identified and unidentified causes of hemoptysis. In total, 1105 adult patients were included. The etiology of hemoptysis was identified in 1042 patients (94.3%) and remained unidentified in 63 patients (5.7%). The percentage of patients with severe hypertension was significantly higher in patients with unidentified causes of hemoptysis than in those with identified causes (35% vs. 11%,  Hemoptysis is the expectoration of blood from the lower respiratory tract and is usually an alarming respiratory symptom requiring further evaluation ,2. HemopThe incidence of cryptogenic hemoptysis varies widely from 5% to 34%, depending on the studies ,7,8,9,10The lungs have dual blood supply known as pulmonary and systemic circulation . Owing tThis study was conducted at Kyungpook National University Hospital, a tertiary referral hospital in South Korea. We retrospectively reviewed the records of all consecutive patients who visited the emergency department (ED) for hemoptysis between January 2011 and June 2021. Adult patients who underwent chest CT for the diagnostic evaluation of hemoptysis were enrolled in this study. Patients with pseudo-hemoptysis who were found to have upper respiratory tract bleeding or upper gastrointestinal bleeding based on the results of laryngoscopy or endoscopy were excluded.The etiology of hemoptysis was determined by the patient’s clinical and medication history; available laboratory findings including hemoglobin level, platelet count, prothrombin time, activated partial thromboplastin time, creatinine level, antinuclear antibodies, antineutrophil cytoplasmic antibodies, and anti-glomerular basement membrane antibodies; microbiological examination of sputum; chest CT findings; and bronchoscopic results. Cases with no objective evidence of disease or condition causing hemoptysis at the initial examination and throughout the follow-up period were classified as hemoptysis of unidentified causes. We collected detailed data from the medical records—including age, sex, smoking history, initial blood pressure at the ED visit, number of repeated ED visits owing to hemoptysis, the need of BAE or surgical treatment, and hemoptysis-related death—and compared between two groups with identified and unidentified causes of hemoptysis. Severe hypertension was defined as systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥120 mmHg upon arrival at the ED [t-test or Mann–Whitney U test. Categorical variables were expressed as absolute values and percentages and analyzed using the χ2 test or Fisher’s exact test. Multivariate logistic regression analysis was conducted using variables with p-value < 0.05 in univariate analysis to identify the factors associated with hemoptysis of unidentified causes.Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 22.0 . Continuous variables were expressed as the mean (standard deviation—SD) or median (interquartile range—IQR), and differences between the groups were analyzed using the p = 0.093). Bronchiectasis (40.2%) was the most common cause of hemoptysis, followed by active tuberculosis (6.9%), malignancy (6.3%), and pneumonia or lung abscess (6.2%). The other identified causes of hemoptysis are listed in In this study, 1105 adult patients with true hemoptysis and available chest CT data were enrolled from all 1896 patients who visited the ED for hemoptysis during the study period. Among them, the etiology of hemoptysis was identified in 1042 patients (94.3%), but the possible cause of hemoptysis was not identified even after precise evaluation, including a drug history and contrast-enhanced chest CT and/or bronchoscopy, in the remaining 63 patients (5.7%). Bronchoscopy was performed in 235 (23%) and 20 (32%) patients with identified and unidentified causes of hemoptysis, respectively (p < 0.001), and male sex was more common  . In particular, the percentage of patients with severe hypertension was significantly higher among those with unidentified causes of hemoptysis . The clinical characteristics and outcomes were compared between patients with identified and unidentified causes of hemoptysis. Patients with unknown causes of hemoptysis were significantly younger than those with identified causes of hemoptysis  . Both grp = 0.053). Additionally, 41 (4%) of 1042 patients with identified causes of hemoptysis underwent surgery for treating the underlying etiology or bleeding control, while no patient in the cryptogenic hemoptysis group required surgery. The total number of repeated ED visits and the percentage of patients who visited the ED more than twice owing to recurrent hemoptysis were significantly higher in patients with identified causes of hemoptysis than in those with unknown causes . No hemoptysis-related deaths were reported in patients with unidentified causes of hemoptysis during the follow-up period.In patients with unidentified causes of hemoptysis, BAE was less required to stop hemoptysis , ever-smoker , and initial systolic blood pressure  were significantly associated with hemoptysis of unidentified causes.Univariate and multivariate regression analyses were performed to determine factors associated with hemoptysis due to unidentified causes . Univarip = 0.005). Among the 12 patients with a prior history of hypertension presenting with severe hypertension, only seven (58%) had been taking antihypertensive drugs regularly, while five (42%) did not take medication despite knowing their high blood pressure status. Hypertension was diagnosed first after the development of hemoptysis in the remaining ten patients in the severe hypertension group.The clinical and radiological characteristics of 63 patients with hemoptysis of unidentified causes were compared according to the presence or absence of initial severe hypertension . A previNone of the patients in the severe hypertension group experienced BAE or recurrent hemoptysis. Chest CT findings were comparable between the severe hypertension and non-severe hypertension groups among patients with unidentified causes of hemoptysis. In this study, the common causes of hemoptysis were bronchiectasis, tuberculosis, and malignancy. Despite comprehensive evaluation, the causes of hemoptysis remained unidentified in 5.7% of patients. Higher systolic blood pressure, young age, and ever-smoking status were independently associated with an unknown etiology of hemoptysis. Conservative treatment led to satisfactory outcomes in patients with cryptogenic hemoptysis, and no hemoptysis-related deaths were reported, suggesting a benign prognosis. Compared with that of previous studies, our study had a relatively low percentage of patients with unknown causes of hemoptysis. This is probably because all of the patients included in the current study underwent chest CT, which contributed to the identification of the etiology of hemoptysis in more patients. However, our findings were consistent with those of several previous studies addressing the causal relationship between smoking and cryptogenic hemoptysis ,12. SmokAlthough uncontrolled hypertension may be a risk factor for hemoptysis as in bleeding of other organs—such as intracerebral hemorrhage, retinal hemorrhage, or epistaxis—the data regarding the association between hypertension and hemoptysis are sparse. A few studies have suggested a possible relationship between high systemic blood pressure and hemoptysis. A study indicated that systemic hypertension was the sole cause of bleeding in two out of 208 patients with hemoptysis, and bleeding was closely related to the fluctuation of blood pressure . The stup < 0.001). Additionally, the initial systolic blood pressure was independently associated with unidentified causes of hemoptysis. Therefore, it can be deduced that uncontrolled hypertension might have contributed to the development of hemoptysis in patients with unidentified causes of hemoptysis.It may be argued that high blood pressure is a physiological response to hemoptysis, followed by anxiety-induced adrenergic activation. Similarly, incident severe hypertension is common during admission unrelated to hypertension ,24. The Diffuse alveolar hemorrhage (DAH) with hemoptysis caused by systemic hypertension or hypertensive emergency has been discussed in several studies ,17,18,19Despite the broad clinical spectrum of cryptogenic hemoptysis, from benign to life-threatening, clinical outcomes have been reported to be favorable ,29. SimiThe current study has several limitations. First, although only patients with available chest CT data were included in this study, not all patients with hemoptysis underwent bronchoscopy. Therefore, some patients may have been misclassified under the cryptogenic hemoptysis group. However, considering the minimal role of bronchoscopy in patients with hemoptysis who have unremarkable chest CT findings and a benign clinical course, it may not have a significant impact . Second,Young age, smoking, and high systolic blood pressure were associated with an unknown etiology of hemoptysis. Although further studies are needed, our findings suggest a possible association between high blood pressure and cryptogenic hemoptysis.


Hypertension increases the global burden of disease and mortality. Iron metabolism is considered to be an important factor in hypertension. However, as an indicator of iron metabolism, little is known about the associations of soluble transferrin receptor (sTfR) with hypertension. We studied the relationship between sTfR and hypertension.We studied 7,416 adults aged 20 years old or above from the National Health and Nutrition Examination Survey (NHANES), a nationally representative, cross-sectional, population-based study. Weighted logistic regression was used to examine the association between markers of iron metabolism and hypertension. The restricted cubic spline (RCS) was used to characterize the association between sTfR and blood pressure.p = 0.001) after adjustment for all the potential confounding factors. Meanwhile, weighted logistic regression analyses indicated independent associations of high sTfR (p = 0.009) with systolic hypertension after adjusting for various different confounders. The result of restricted cubic splines showed a non-linear association between sTfR and systolic blood pressure among U.S. adults.Weighted logistic regression showed that higher sTfR level was associated with higher odds of hypertension (OR = 1.05; 95% CI: 1.01–1.05; Soluble transferrin receptor was found to be an independent factor in systolic hypertension. And, a non-linear relationship between sTfR and systolic blood pressure was discovered. The prevalence and absolute burden of hypertension are rising globally, and hypertension is the leading cause of cardiovascular disease, including coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, peripheral artery disease, chronic kidney disease (CKD), and cognitive impairment –3. AccorAccumulating evidence has demonstrated that iron metabolism appears to play a significant role in the development of hypertension –9. HowevIn current study, soluble transferrin receptor (sTfR) and serum ferritin are commonly adapted to present the iron status. Compared with sTfR, serum ferritin was susceptible to other factors  . sTfR waThis study adapted the data from National Health and Nutrition Examination Surveys (NHANES) 2007–2010 and NHANES 2015–2018. The NHANES survey used a stratified multistage random sample that was representative of the uninstitutionalized civilian population in U.S. The sample was drawn from a county, a neighborhood, a household, and the members of that household. To offer sufficient estimates of these racial groupings, it also included non-Hispanic blacks and Mexican Americans. Prior to participating, the subjects must sign a permission form and gain ethical clearance from the U.S. Department of Health and Human Services’ Human Subjects Committee .n = 8,738); missing data for markers of iron metabolism ; participants less than 20 years old ; missing data for self-reported a history of smoking and drinking (n = 691); pregnant women (n = 190); liver disease ; chronic kidney disease  (n = 10). With the foregoing exclusion criteria in place, 7,416 individuals were included in the study, with 1,077 (14.5%) of them having hypertension  were measured using a mercury sphygmomanometer after participants sat quietly for 5 min , 21. BloIn 2007–2010 and 2015–2018, serum ferritin concentration was measured by two methods. In 2007–2008, the measurements of serum ferritin concentration used the Roche Tina-quant serum ferritin immunoturbidimetric assay with the Hitachi 912 clinical analyzer . The method for measurement of serum ferritin concentrations was the Roche Elecsys 170 clinical analyzer in 2009–2010 and 2015–2018.For NHANES 2007–2010 and 2015–2018, sTfR concentrations were measured at the National Center of Environmental Health, Center for Disease Control and Prevention. The Tina-quant sTfR test  was used to quantify sTfR concentrations with an automated homogeneous immunoturbidimetric assay. There was no change in laboratory procedure or site, but the test was run on three different chemical analyzers as follows : Hitachi 912 (NHANES 2007–2008), Hitachi Mod P (NHANES 2009–2010 and 2015), and lastly, Roche c501 analyzers (NHANES 2016–2018). As a consequence of the same results for all three devices, no adjustments were necessary .From 2003 to 2012, hemoglobin concentrations were tested by the mobile examination center using a Beckman Coulter MAXM hematology flow cytometer , then switched to a Beckman Coulter Unicel DxH 800 Analyzer in 2013. To provide blood cell distribution for all participants, Beckman Coulter MAXM equipment was used to assess the complete blood count, including white blood cell count, at the NHANES Mobile Examination Center.Serum iron was part of the standard biochemistry profile, which was measured at Collaborative Laboratory Services using a Beckman UniCel DxC800 Synchron for NHANES 2015–2016 and Beckman Synchron LX20 for NHANES 2007–2010, and at the University of Minnesota Advanced Research Diagnostics Laboratory using a Roche Cobas 6000 (c501 module) analyzer for NHANES 2017–2018.To remove the difference of labs and assay techniques during data collection period. The NHANES group conducted crossover experiments to compare the data due to method changes amongst various assays, and adjustments were made accordingly based on the comparison before the data were released to the public –25.2) was computed by dividing the weight in kilograms by the height in meters squared. Waist circumference (cm), triglycerides (mmol/L), total cholesterol (mmol/L), high-density lipoprotein (HDL) cholesterol (mmol/L), albumin (g/dL), total white blood cell count (SI), glycohemoglobin (%), and plasma fasting glucose (mmol/L) were also included as covariate. At the NHANES website, details regarding the measurement of the covariate were obtained . The levels of serum iron, serum ferritin, hemoglobin, and sTfR were categorized into quartiles. We utilized the lowest quartile as a reference and used weighted logistic regression models to calculate the odds ratio (OR) and 95 percent confidence interval (CI) for hypertension in each quartile. Simultaneously, p-trend analysis was performed in the weighted regression analyses by considering the quartiles as a continuous variable. Four models were developed: model 1 was adjusted for age and sex; model 2 was further adjusted for ethnicity, educational level, income, smoking, drinking, physical activity, BMI and waist circumference; model 3 was further adjusted for triglycerides, total cholesterol, HDL cholesterol, plasma fasting glucose and glycohemoglobin; and model 4 was further adjusted for white cell count and albumin. Collinearity diagnostics were carried out using the variance inflation factor (VIF). In order to further explore the relationship between iron metabolism markers and systolic and diastolic hypertension, weighted regression analysis was performed on iron metabolism markers and systolic and diastolic hypertension, respectively, and other covariates were adjusted. All the regressions above were statistically weighted  and weighted Student’s weighted .p-value < 0.05 was considered statistically significant.Subgroup analyses were performed according to age, gender, menopause status, poverty income ratio, and physical activity to investigate the relationships between sTfR and systolic hypertension; and potential interactions were tested. Using exploratory data analysis techniques with R, we examined monotonic relationships between sTfR and systolic blood pressure in all participants, stratified by age. To further illustrate the correlation between sTfR and systolic blood pressure, we modeled sTfR against systolic blood pressure and also used a restricted cubic spline with five knots located at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles to flexibly model the underlying relationship. All analyses were performed using R version 4.1.2, and a High blood pressure was present in 1,077 of the 7,416 participants. p = 0.001) after adjustment for all the potential confounding factors, including age, sex, ethnicity, educational level, income, smoking, drinking, physical activity, BMI, waist circumference, triglycerides, total cholesterol, HDL cholesterol, fasting glucose, glycohemoglobin, white cell count, and albumin. The model for evaluating the trend of this association was also statistically significant (p < 0.05). Hemoglobin, ferritin and serum iron had a non-significant effect on the risk of hypertension. Additionally, weighted logistic regression analysis was performed to assess the association between markers of iron metabolism and systolic/diastolic hypertension. As shown in p = 0.009) after adjustment for the variables. The model for evaluating the trend of this association was also statistically significant (p < 0.05). However, there were no significant relationships between sTfR level and diastolic hypertension, as shown in p = 0.148). Linear regression was performed to evaluate the association of sTfR with SBP and DBP, respectively. The result showed that sTfR was statistically significantly correlated with SBP (p < 0.05). To the left of the inflection point, the influence was substantially enhanced; to the right, the effect was flat. In adults over 50, the association between sTfR and systolic blood pressure was likewise non-linear (p < 0.05). Similarly, the influence was greatly boosted on the left side of the inflection point, while the effect was flat on the right.As shown in with SBP , while swith SBP . The empwith SBP . Restricwith SBP . In adulwith SBP , and then-linear , with thSubgroup analyses were performed to further assess the robustness of the association between sTfR and systolic hypertension. All analyses were adjusted for age, gender, ethnicity, poverty income ratio, smoking status, drinking status, level of education, physical activity, BMI, waist circumference, triglycerides, total cholesterol, HDL, albumin, total white blood cell count, glycohemoglobin, plasma fasting glucose, and menopause status, except for the variable that was stratified. In female participants, those with the highest quartile of sTfR levels had a significantly higher risk of systolic hypertension when compared to the lowest group . HoweverThis nationwide population-based study indicated that transferrin, serum iron, and hemoglobin levels had no significant effect on the risk of hypertension. sTfR was positively associated with systolic hypertension but not diastolic hypertension. Furthermore, this study found a non-linear association between sTfR and systolic blood pressure. Our findings showed that sTfR was a significant independent risk factor for the hypertension in the American population.This study showed that hemoglobin and serum iron levels were not associated with hypertension. However, according to a Dutch study, hemoglobin had a substantial positive relationship with blood pressure . SamuelsThe cross-sectional study from the U.S. showed sTfR was the biomarker associated with the risk of uncontrolled hypertension compared to controlled hypertension . RecentlOur study showed that sTfR was an independent risk factor for systolic hypertension but not diastolic hypertension, and it also presented a curvilinear relationship between sTfR and systolic blood pressure. A cross-sectional study in Spain showed that sTfR was correlated with systolic blood pressure, but not diastolic blood pressure . Even afvia nitric oxide (NO), a regulatory chemical that promoted vascular smooth-muscle cell relaxation. NO synthase was responsible for the production of NO, and iron was a necessary component  was adapted to replace CRP measurements (2007–2010). Therefore, this indicator was not adjusted.In conclusion, this study indicated that sTfR was an independent factor in systolic hypertension. And, we found that the relationship of sTfR with systolic blood pressure was non-linear among U.S. adults. Our results might provide a new point of view on the roles of markers of iron status in hypertension related metabolic dysfunctions.https://www.cdc.gov/nchs/nhanes/index.htm.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The NHANES implementation protocol was approved and conducted by Centers for Disease Control and Prevention (CDC) National Center for Health Statistics (NCHS). The patients/participants provided their written informed consent to participate in this study.HW wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript, contributed to the study conception and design, performed material preparation, data collection, and data analysis, read, and approved the final manuscript.


The purpose of this study was to compare changes in blood pressure variability (BPV) and blood pressure (BP) values occurring in response to concurrent training (CT) between the two genders. A total of 35 males and 20 women aged 55–80 years, with hypertension and coronary artery disease, were included. They underwent a 12-week CT program. The aerobic component of CT was performed according to the rate of perceived exertion while the intensity of the resistance component was set at 60% of 1 repetition maximum for the first 4 weeks and then increased to 80%. BP and BPV were evaluated at baseline and at the end of the CT program through 24 h ambulatory blood pressure monitoring. After 12-weeks, 24 h and daytime systolic BPV decreased in both men and women without significant between-groups differences. Twenty-four-hour daytime and nighttime diastolic BPV decreased in both genders with a significantly greater decrease in women compared to men. Twenty-four-hour daytime systolic and 24 h diastolic BP decreased in men while they were unchanged in women. In conclusion, CT induced similar reductions of systolic BPV in men and women and a greater decrease in diastolic BPV in women. Conversely, CT decreased BP values in males but not in females. CT appears to be an effective intervention for reducing BPV in both genders. Hypertension is the most common comorbidity encountered in patients with coronary artery disease (CAD) undergoing secondary prevention programs. Despite available data underlining the importance of obtaining an optimal blood pressure (BP) control in such high-risk patients, it has been estimated that this goal is reached in just over half of them . Aside fThe study included a total of 55 patients, 35 males and 20 females, evaluated for being enrolled in a cardiac rehabilitation program at the cardiac rehabilitation centre of S. Raffaele IRCCS, Rome. The following inclusion criteria were adopted: diagnosis of hypertension; underlying coronary artery disease; patients being in stable clinical conditions and stable pharmacological therapy (without changes occurring in the last three months); sedentary lifestyle: patients not being enrolled in exercise training programs in the previous six months; age between 55 and 80 years. Exclusion criteria were: BP levels exceeding 160/100 mmHg; significant heart valve diseases; hypertrophic cardiomyopathy; signs and/or symptoms of myocardial ischemia during a preliminary ergometric test; uncontrolled arrhythmia; neurological and/or orthopedic conditions contraindicating or limiting exercises; significant chronic obstructive pulmonary disease (FEV1 < 50%); symptomatic peripheral arterial disease. Moreover, patients were excluded if they changed their pharmacological treatment during the study period.n = 25/20). All patients gave informed consent to participate in the study, which conformed to the principles outlined in the Declaration of Helsinki. Patients meeting the inclusion/exclusion criteria, after signing informed consent, underwent a baseline evaluation including clinical and pharmacological history, assessment of body mass index, and waist circumference. On the same day, patients performed an ergometric symptom-limited test in order to rule out exercise-induced ischemia and ventricular arrhythmias during exercise. The ergometric test was performed on a treadmill  and a standard Bruce protocol was adopted for each patient. At each stage of the test, RPE was assessed through the Borg 6–20 scale. On the same day, patients had an adaptive session during which they familiarized themselves with the gym equipment and the established exercise modality. At the end of this adaptive session, patients underwent the assessment of 1-repetition maximum (1-RM) for the different muscle groups involved in the resistance phase of the training. Within ten days from the first visit, all subjects started an exercise training program lasting 12-weeks and including three sessions every week. Within a week from the first visit and up to three days before the first planned exercise session, all subjects underwent 24 h ambulatory blood pressure monitoring (ABPM). Within a week from the last session, they were re-evaluated and performed another ergometric test and 24 h ABPM. The effects of the exercise training protocol on functional capacity were also evaluated by the six minute walk test (6MWT) [The study was conducted as a prospective, longitudinal single-center open pilot study, with two arms corresponding to the two genders. It was preliminarily approved by the ethical committee of S. Raffaele IRCCS, Rome (prot t (6MWT)  and the ABPM was performed with a validated oscillometric device , with the BP cuff placed on the non-dominant arm. The recording was programmed to obtain BP readings at 15 min intervals from 6.00 a.m. to 10.00 p.m. and 20 min intervals from 10.00 p.m. to 6.00 a.m. BP readings considered for data analysis included only those obtained from 8:00 a.m. to 8:00 p.m. (daytime) and from midnight to 6:00 a.m. (nighttime) for excluding transition periods from daytime and nighttime. On the day of the ABPM, patients were instructed to maintain their usual activities and medications. All ABPMs were performed on working days. The majority of our patients were retired workers and were engaged in low-intensity activities during the working days in which they performed ABPM . Twelve out of forty (30%) patients were still active workers at the time of the study protocol. All of them were office employers and were not engaged in physically demanding jobs. In the days of ABPM, they spent 6–8 h at work, mostly seated behind a desk. Data from ABPM were accepted if at least 75% of the measurements were obtained successfully. The following parameters were considered: 24 h systolic BP, daytime systolic BP, nighttime systolic BP, 24 h diastolic BP, daytime diastolic BP, nighttime diastolic BP, and their respective time-related variability (BPV). BPV has been evaluated by means of average real variability (ARV), according to the formula reported by Mena et al. . StandarExercise training sessions were performed in the gym of our hospital. Patients performed aerobic exercises before resistance exercises in each session. Each session lasted 60 min and was preceded by 10 min of warm-up and followed by 10 min of cool-down. Exercise sessions were planned as follows: 40 min of aerobic training on a treadmill; 20 min of resistance training . The intensity of the aerobic component of the whole study training was established by means of the RPE method with an intensity target of 13–14 during the whole study. Regarding the resistance component of the sessions, it consisted of the following exercises: leg press and extension, shoulder press, chest press, low row, and vertical traction. The intensity of each resistance exercise was established through the assessment of the corresponding 1-RM: for each exercise, patients performed a warm-up set (8–0 repetitions) at 50–60% of their perceived 1-RM. Then they were asked to perform one repetition at their maximal effort. This last movement was carried out three times, with 2–3 min rest between efforts, and the highest value of strength registered was used as 1-RM . For eacp < 0.05. Data were analyzed using SPSS software .By considering the lack of previous studies confronting exercise-induced changes in BPV between the two genders we did not assess a sample size. Data are expressed as mean ± SD. The assumption of normality was checked using the Shapiro–Wilks hypothesis test. Pre- and post-exercise data of normally-distributed variables were assessed using a repeated measure two-way ANOVA, with Bonferroni corrections for post hoc testing. Not normally-distributed variables were assessed using the Kruskal–Wallis test and Bonferroni corrections for post hoc testing. The level of significance was set at p = 0.0001, women from 366.5 ± 46 s to 432.3 ± 54 s, p = 0.0011); without significant between-groups difference (p = 0.11). Distance at 6MWT increased significantly in both groups ; without significant between-groups difference (p = 0.07). The Borg’s scale score decreased from 10.9 ± 2.2 to 7.3 ± 1.9 in males and from 11.5 ± 2.7 to 7.9 ± 2.4 in females between-groups, p = 0.36). BMI did not change in comparison to baseline values in both groups  and daytime  systolic BPV decreased in both genders without significant between-groups differences . Nighttime systolic BPV was unchanged in both groups. Twenty-four hour , daytime  and nighttime  diastolic BPV decreased in both groups, but to a greater extent in the female group. According to SD: similarly to ARV, we observed reductions of BPV at 12-weeks in both males and females; with significant between groups differences regarding diastolic BPV.Changes in BPV are summarized in p 0.008 and p 0.003, respectively). Nighttime systolic BP decreased (−4.4 ± 1.9) in men and presented a non-significant increase in women (+1.4 ± 0.4), . Twenty-four hour and daytime diastolic BP decreased in men  and women (−1.5 ± 0.4 and −2.1 ± 0.6 respectively) without significant between-groups differences. Nighttime diastolic BP decreased in men (−3.8 ± 1.7) while it was unchanged in women (between groups p 0.02).Twenty-four hour and daytime systolic BP decreased in men  while they were unchanged in women (between groups, The most important finding of the present study is that a CT program lasting 12-weeks effectively reduced short-term BPV in both males and women patients with hypertension and underlying CAD with a significantly greater decrease in diastolic BPV in women compared to males. To our knowledge, this is the first study showing a positive impact of an exercise training modality on short-term BPV in women. This result appears to have potential implications in the clinical practice: an elevated BPV has been associated with an increased risk of cardiovascular events in patients with already diagnosed CAD ,24. RegaIn this preliminary study, we observed that a 12-week CT program was effective in reducing BPV in both genders while it reduced BP values only in men. We think that our results go in the direction of more individualized treatment of hypertension and high BPV in patients with cardiovascular diseases. However, considering the preliminary nature of our data they need to be confirmed in other larger studies.


As the elderly population is growing rapidly, management of hypertension in South Korea faces major challenges because the proportion of elderly hypertension patients is also increasing. The characteristics of this population are also much more complex than younger patients. Elderly hypertension is characterized by wide variations in (1) fitness or biological age, (2) white-coat effect, (3) poor functional status or frailty, (4) dependency in activities of daily living or institutionalization, (5) orthostatic hypotension, and (6) multiple comorbidities. All of these should be considered when choosing optimal target blood pressure in individual patients. Recent randomized clinical trials have shown that the benefits of intensive blood pressure control for elderly patients is greater than previously thought. For generalization of these results and implementation of the guidelines based on these studies, defining the clinician’s role for individualization is critically important. For individualized decisions for target blood pressure (BP) in the elderly with hypertension, four components should first be checked. These consist of (1) the minimum requirement of functional status and capability of activities of daily living, (2) lack of harmful evidence by the target BP, (3) absence of white-coat hypertension, and (4) standing systolic BP ≥ 110 mmHg without orthostatic symptoms. Risk of decreased organ perfusion by arterial stenosis should be screened before starting intensive BP control. When the target BP differs among comorbidities, the lowest target BP should be given preference. After starting intensive BP lowering therapy, tolerability should be monitored, and the titration should be based on the mean level of blood pressure by office supplemented by out-of-office BPs. Applications of the clinical algorithms will be useful to achieve more standardized and simplified applications of target BP in the elderly. Hypertension (HTN) is the most important controllable risk factor for cardiovascular (CV) events and mortality in the world . There hAging is a global issue, and HTN is the second most common chronic disease or disability other than mobility impairment . South KIn a meta-analysis, elderly HTN is characterized by much higher absolute risk for CV events and mortality . DespiteIn the elderly, (isolated) systolic HTN is common, and it is closely related to increased aortic stiffness . Aortic The prevalence of white-coat HTN (WCH) has been reported as 22.7% in a study of elderly HTN patients in clinics . White-cIn the elderly, the prevalence of orthostatic hypotension (OH) is high (10–22%) and is associated with frailty, CV prognosis, and longitudinal cognitive function deterioration –18. DizzIn addition to the white-coat effect (WCE) and OH, special considerations are needed for applying guidelines in the elderly, such as multiple comorbidities, frailty, and dementia or cognitive impairment .There were reports regarding the indicators of biological age such as telomere length, epigenetic clock . HoweverRecent HTN clinical trials for target BP more frequently include the end points such as heart failure and dementia prevention , 26. RecThere are large discrepancies among guidelines in terms of target BP in the elderly. In the 2017 American College of Cardiology/American Heart Association HTN guidelines, 130 mmHg of systolic BP (SBP) was recommended ; HoweverIn patients with a transient ischemic attack or stroke, the target BPs differ among the guidelines mainly because the benefits of the lower target are not supported by clinical trial evidence. However, more recent guidelines consider 130 mmHg, previously considered for lacunar infarction, as the general target BP . ConcernIn diabetes mellitus patients, 140 mmHg is suggested as the general target, but target BPs can vary according to the underlying risk profiles; for example, 130/80 mmHg was suggested as the target BP for high atherosclerotic CV disease risk, the presence of CV diseases or chronic kidney diseases , 32. TheIn chronic kidney diseases, the 2021 Kidney Disease: Improving Global Outcomes guidelines recommended < 120 mmHg in SBP as the general target BP if it is tolerable and standardized BP measurement is available considering Systolic Blood Pressure Intervention Trial (SPRINT) , 34. TheIn the HTN in the very elderly trial (HYVET), patients aged > 80 years with a sitting SBP ≥160 mmHg were enrolled . PatientHowever, in an observational study for community-dwelling elderly HTN patients with 120 / 80 mmHg as the target BP, a 5-fold increase in injurious falls and syncope was reported compared to SPRINT . This diFrailty is a multidimensional syndrome of physical, cognitive, physiological, and social function decline whereas functional status in the conventional definition is restricted to physical function. There are many challenges to comprehensively define frailty. The clinical frailty scale, which was developed from the Canadian Study of Health and Ageing, can easily represent the frailty status of older patients . Even thTo more effectively care for this population, the minimal requirement for starting AHM or escalating AHM needs to be defined. Benetos et al. , 47 suggPreserved functional status with routine walking is essential to start intensive BP control. Residence in nursing home was an exclusion criterion, but wheelchair dependency itself was not an exclusion criterion for SPRINT. Slowing in routine walking itself cannot exclude the benefit of intensive BP lowering . HoweverUntil now, frailty status has not been considered when we start or intensify AHM. However, considering the importance of frailty status in managing older hypertensive patients, a frailty assessment should be included for the initial evaluation. Simple tests evaluating frailty status, such as gait speed, questionnaire in Korea, the so-called K-FRAIL  score, and the clinical frailty scale, can be used as screening tools for evaluating the frailty status of older patients , 50, 51.Even though all medications carry an intrinsic risk of side effects and drug interactions, especially in older patients, most evidence of harmful effects used in RCT have been serious ones, such as major adverse CV events or functional deterioration of the organ levels. According to the “First do no harm” principle, clinical trial evidence of serious harm is a contraindication for intensive target BP, which has proved to be beneficial in the other comorbidities. Evidence of harm can be exemplified as a J-curve phenomenon in multi-vessel coronary artery stenosis or combination therapy using both an angiotensin converting enzyme inhibitor and angiotensin receptor blocker.Without evidence of such serious harm, the higher target BP recommended just by the lack of benefit in one comorbidity can be disregarded when benefits of the lower target BP in other comorbidities were proved by RCT, as shown in Table In terms of the evidence of harm, most of the current evidence for serious harm is presumptive but inconclusive. As shown in Fig. Unless WCH and/or WCE are excluded by AOBP, home BP monitoring (HBPM), or ambulatory BP monitoring (ABPM), BP control to the intensive target cannot be safely implemented for elderly HTN patients. If WCH and/or WCE cannot be excluded, the SBP target should be conservative and < 150 mmHg as long as the standing SBP is ≥140 mmHg at the time of starting AHM, as shown in HYVET in patient aged over 80 .At the time of starting AHM, only patients with an asymptomatic standing SBP ≥110 mmHg should receive intensive target BP with the exclusion of potential WCE, as shown in SPRINT , 38. OthTherefore, routine screening of OH by measuring standing BP and by its symptom is critical. Typical orthostatic symptoms include dizziness, lightheadedness, blurred vision, weakness, nausea, and palpitations within a few minutes of standing . OH can If there is no evidence of harm, the lowest target BP should be chosen with the above mentioned four essential components screened and integrated for decision making, as shown in Fig. During intensive BP control for potential benefit without RCT evidence, for example, intensive BP lowering in stroke patients only showing benefit in SPRINT eligible lacunar infarct patients in post-hoc analysis of the SPS3 trial, close monitoring for side effect is mandatory . When inThe speed of titration of AHM to achieve the target SBP can vary among patients to patients. All side effects including symptomatic OH and the impact of intensive treatment on functional status and ADL should be routinely checked during follow-up. In elderly patients > 80 years, reduction of weight, oral intake, physical activity, or cognitive function should be closely assessed because sarcopenia, dental problems, mental health problems, and cachexia can be common during the natural aging process. Programmed physical training and a supply of adequate protein and calories should be considered positively. Whether excessive reduction of salt intake could result in a reduction of oral intake and/or weight should also be assessed. During the monitoring period, in patients in whom intake and weight are decreasing, de-escalation of AHM can be based on the level of standardized office BP. The presence of symptomatic OH with uncontrolled office BP does not necessarily mandate immediate down-titration for older, community-dwelling hypertensive patients and out-of-office BP measurement will be useful for titration.In SPRINT, patients with a 10-year risk of CV disease of 15% or greater on the basis of the Framingham risk score were enrolled. For Korean patients, the risk stratification equation is reported to be much more dependent on age so that most of the hypertensive elderly are classified as a high-risk group. If there are no limiting factors for tolerability, there is greater opportunity to try intensive BP control in Korean elderly patients. However, because of the limitations of the current risk stratification system for Koreans, more evidence for an atherosclerotic CV disease risk-based strategy for intensive BP lowering is needed. In addition, the risk stratification model overestimates the CV risk of Asian patients . AccordiExclusion of the WCE or WCH is mandatory to make the decision for intensive BP lowering in the elderly. In general, strictly standardized office BP measurement is sufficient for starting and monitoring intensive BP lowering. In the case of the elderly, however, it is reasonable to use HBPM or ABPM to ensure the safety of vulnerable patients. When HBPM or ABPM is not available, AOBP can be useful to exclude WCH at the time of diagnosis of HTN. In Korea, routine AOBP does not seem to be feasible because of limited space in the clinic. Practical solutions for HBPM or application of smart devices in clinical practice are useful to determine individualized target BP in the elderly.Once a patient for intensive BP control is selected by clear screening of the four elements of tolerability, clinicians need to know that both the research level office BP measured using automated device and AOBP had a significant masked effect greater than 5 mmHg when SBP was maintained at around 120 mmHg safely, as shown in the SPRINT and STEP study. When BP is maintained at 130 to 135 mmHg, HBPM and daytime ABPM are the most equivalent to office BP or AOBP .With population aging, we should prepare for the increase of the oldest old or frail elderly patients. Frail older adults are highly vulnerable to external stresses. Thus, they are high-risk groups for adverse CV events. Frailty is common among institutionalized older adults. Previously, it has been reported that the prevalence of frailty and pre-frailty in nursing homes was 52.3% and 40.2%, respectively . It remaIn conclusion, for individualized decisions for target BP in the elderly with hypertension, using a clinical algorithm considering functional status, WCH, OH, evidence of harm and multiple comorbidities will be useful to achieve more standardized and simplified applications of target BP in the elderly.