P = 0.80) or MCAv . The change in CVR was different between groups . Total LBNP time was lower for CA (204 ± 92 s) vs. HC . During LBPP, the change in MAP was not different between groups . The change in MCAv  and CVR  were different between groups. CA exhibited impaired tolerance to LBNP and had a different cerebral vascular response to LBPP compared to HC.Concussions have been shown to result in autonomic dysfunction and altered cerebral vascular function. We tested the hypothesis that concussed athletes (CA) would have altered cerebral vascular function during acute decreases and increases in blood pressure compared to healthy controls (HC). Ten CA  and 10 HC  completed 5 min of lower body negative pressure  and 5 min of lower body positive pressure . Protocols were randomized and separated by 10 min. Mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) were continuously recorded. Cerebral vascular resistance (CVR) was calculated as MAP/MCAv. Values are reported as change from baseline to the last minute achieved (LBNP) or 5 min (LBPP). There were no differences in baseline values between groups. During LBNP, there were no differences in the change for MAP (CA: −23 ± 18 vs. HC: −21 ± 17 cm/s;  These techniques can therefore be used to investigate both cerebral blood flow responses and autonomic baroreflex function in individuals who have sustained a concussion. Unlike the sit-to-stand tests, which have been used to demonstrate impaired dynamic cerebral vascular function in concussed patients , 16, LBN2) and 10 healthy controls (HC)  completed the study. Using feasibility data, we calculated the a priori sample size based on the cardiovascular responses to a sympathetic stressor in 10 CA and 10 HC. We calculated we would need 8 participants in each group using an effect size (f ) of 0.38, alpha of 0.05, and power of 0.80 to observe a significant group x time interaction effect. CA completed the study within 10 days of concussion (5 ± 3 days) diagnosis by a University at Buffalo physician and while symptomatic . All concussions were sport-related and diagnosed using the most recent Concussion in Sport Group guidelines (via the Post-Concussion Symptom Inventory (n = 1), volleyball (n = 2), soccer (n = 2), and basketball (n = 2). Male athletes participated in football (n = 1), wrestling (n = 1), and lacrosse (n =1). The HC group self-reported to be physically active on most if not all days of the week via the International Physical Activity Questionnaire and self-reported no concussions within the previous year. We used healthy controls that did not participate in collegiate athletics to avoid the unknown effects of repetitive subconcussive head impacts on physiological function. Participants were excluded if they had a Glasgow Coma Score of <12, focal neurological deficit, used medications that affect blood pressure or the autonomic nervous system ; existing autonomic, cardiovascular, metabolic, respiratory, or endocrine disorder; major depression; pregnancy; or breastfeeding. The concussed athletes were studied while still reporting post-concussion symptoms based on a symptom severity inventory (Sport Concussion Assessment Tool−5th Edition (SCAT-5)) (Ten concussed college athletes (CA) ) . This 222 tension (capnography). Right MCAv was measured via transcranial Doppler sonography using a 2 MHz probe  while using insonation techniques described in detail by Willie et al. . The order of the protocols was randomized by a research team member prior to enrollment using Excel. Protocols were separated by 5 min of recovery and 5 min of quiet resting baseline (>10 min between protocols). Eight CA (5 women) and six HC (2 women) completed LBPP first. During the LBNP protocol, an acute decrease in blood pressure was achieved by applying 40 mmHg of LBNP for 5 min –27. If s2 tension (62.5 Hz) were continuously recorded using a data acquisition system . Stroke volume was estimated using Modelflow , beat-to-beat blood pressure , MCAv  and end-tidal COodelflow  and cardodelflow . Total Lodelflow .n = 3); excluded healthy controls (n = 2)] . Three minute and five minute recordings for LBNP and LBPP were included for analysis, respectively. Participants were excluded from LBNP analysis of cBRS if the test was terminated prior to reaching 3 min of negative pressure [excluded concussed athletes ((n = 2)] . The ECG(n = 2)] , 36. Fouas ≥0.85 . The timas ≥0.85 . Sequenct-tests to determine if resting baseline values for cardiovascular and cerebrovascular variables and total LBNP time were different between CA and HC. We used two-way repeated measures ANOVAs with time as a within-subject effect and group as a between-subject effect to compare responses for LBPP between CA and HC. Mixed-effects ANOVAs were used to compare responses between CA and HC during LBNP due to missing data from terminating the test early . All ANOVA assumptions were visually verified  prior to model interpretation and all assumptions were met and no corrections were made. If an ANOVA revealed a significant interaction or main effect . Statistical significance was set at P ≤ 0.05. Exact P-values are reported where appropriate. Values are reported as mean ± SD of the change from baseline.We used unpaired n effect , we usedThere were no differences between groups for all variables at baseline .P ≤ 0.006) and HC  during LBNP. Diastolic blood pressure decreased from baseline in CA at 2 min (P = 0.003), 3 min (P = 0.055), and 4 min (P = 0.003), whereas HC decreased at 3 min (P = 0.019), 4 min (P = 0.045), and 5 min (P = 0.002). Heart rate increased from baseline in CA  and HC  during LBNP. Stroke volume decreased from baseline in CA  and HC  during LBNP. Cardiac output decreased from baseline in CA at 1 min of LBNP (P = 0.014) and decreased in HC at 2 min (P = 0.012) and 3 min (P = 0.002). The change in cardiovascular variables were not different between groups  and HC (P = 0.002). Up-cBRS had a main effect of time (P = 0.015), but post-hoc-tests were unable to detect a difference from baseline in CA (P = 0.094) or HC (P = 0.239). Down-cBRS decreased from baseline in CA (P = 0.005) and HC (P = 0.005). The change in indices of cBRS were not different between groups  and HC  during LBNP. The change was not different between groups  and HC  during LBNP, but the change was not different between groups , whereas HC increased at 4 min (P = 0.037), and 5 min of LBNP (P = 0.008). The change in cerebral vascular resistance was different between groups at 4 min of LBNP  (P = 0.049) (P = 0.006)  and HC  . The Kap= 0.049) . CA expe= 0.006) .There were no differences between groups for all variables at baseline .P < 0.001) and HC  during LBPP. Heart rate increased from baseline in CA only at 5 min of LBNP (P = 0.006), whereas HC had an increase in heart rate at 2 min through 5 min of LBPP . Stroke volume decreased from baseline in CA  and HC  during LBPP. Cardiac output decreased from baseline in CA  during LBPP, but there was no change from baseline in HC (P > 0.999). The change in cardiovascular variables were not different between groups  but did not change in CA (P = 0.108). Up-cBRS did not change from baseline in CA (P = 0.358) or HC (P = 0.064). Down-cBRS was not different over time (P = 0.191) or between groups (P = 0.941). The change in indices of cBRS was not different between groups  and 2 min (P = 0.027) of LBPP, whereas HC decreased during LBPP .End-tidal COP ≥ 0.193), but decreased in HC at 2 min of LBPP (P = 0.039). The change in MCAv was different between groups at 2 through 5 min of LBPP  (P > 0.999), but increased in HC during LBPP . The change in cerebral vascular resistance was not different between groups  . CerebraP = 0.004, CA experienced an exacerbation of symptoms from pre-LBPP (2 ± 2) to post-LBPP  different cerebral vascular responses during an acute increase in blood pressure due to an increase in MCAv compared to healthy controls.We investigated the cardiovascular and cerebral vascular responses to acute periods of low and high blood pressure in symptomatic concussed college athletes and healthy controls. Our major novel findings are that concussed athletes demonstrated (1) greater orthostatic intolerance during an acute decrease in blood pressure During an acute decrease in blood pressure, symptomatic concussed college athletes had significantly lower orthostatic tolerance compared to healthy controls. As expected, a majority of healthy controls tolerated the 5 min LBNP protocol; however, two healthy controls did not complete the protocol due to the onset of presyncopal symptoms. These results are similar to previous findings of relatively low orthostatic tolerance to a moderate LBNP challenge in young, healthy adults , 40–42. The concussed athletes and healthy controls both exhibited reduced cBRS during the LBNP protocol, but we did not observe differences between groups. Previous evidence indicates that a concussion attenuates cBRS. La Fountaine and colleagues found that collegiate males diagnosed with a concussion have reduced spontaneous cBRS at 48 h and 1 wk post-injury compared to healthy matched controls during 5 min of quiet rest . SimilarP ≥ 0.065), the change in cerebral vascular resistance throughout LBPP was temporally different in concussed athletes and healthy controls. This was due primarily to lower MCAv responses in the healthy controls despite similar mean arterial pressure responses between groups  could have contributed to the group differences we observed in MCAv during LBPP. Although not statistically different, the concussed athletes had a reduction in end-tidal CO2 tension of ~1 mmHg whereas healthy controls exhibited a decrease of ~4 mmHg during LBPP  whereas concussed athletes did not (5 min only). We posit that the increase in heart rate along with the rise in mean arterial pressure was due to intramuscular pressure induced by LBPP that activated muscle afferents, which subsequently stimulated the cardiovascular control center. This response has been shown to override the baroreflex mediated decreased heart rate associated with increased blood pressure , 57–64. 2 and/or blood pressure. TCD does not provide a measure of artery diameter and thus the assumption is made that changes in cerebral blood velocity directly reflect changes in CBF . Giller et al. reported small changes in MCA diameter (~2-2.5%) with alterations in arterial CO2 (±10 mmHg) and blood pressure (±18 mmHg) during craniotomy . Fifth, women were tested at different phases of the menstrual cycle due to our criteria of testing within the first 10 days of injury while symptomatic. It is possible that menstrual cycle phase influenced our findings. Sixth, because of the relatively large number of early LBNP terminations in the CA group, we have a low number of participants for some of the statistical comparisions. Lastly, we did not reassess CA after they were clinically cleared to return to play. This approach would have allowed us to determine if CA returned to physiological function that is exhibited by healthy controls prior to their return to play. Important emerging evidence indicates that physiological dysfunction persists in concussed patients beyond symptom resolution (There are several experimental considerations that pertain to the interpretation of our data. First, we did not sport-match the physically active healthy controls to the concussed athletes so there might have been a difference in fitness that contributed to the attenuated LBNP tolerance in the concussed athletes. Highly trained endurance athletes tend to have lower tolerance to orthostatic stress due to structural and mechanical cardiac changes that result in reduced stroke volume due to a steeper slope of the left cardiac pressure-stroke volume relationship  or to ananiotomy . On the  ~8 mmHg . We cannsolution , 8, 73.Recently concussed athletes can exhibit signs of exercise intolerance . There i2 tension between groups, however MCAv was elevated only in symptomatic concussed athletes which could have contributed to concussion symptom exacerbation.Although our LBNP protocol was not designed to test orthostatic tolerance, we found that symptomatic concussed athletes experienced attenuated orthostatic tolerance compared to recreationally active healthy controls. Additionally, LBPP induced similar changes in mean arterial pressure and end-tidal COThe 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 University at Buffalo Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.ZS, BW, JL, and BJ conceived the study and designed the experiment. MO'L, JS, ZS, and BJ performed experiments and collected the data. MW, MO'L, and JS extracted and analyzed data. MW and BJ performed statistical analyses. MW drafted the manuscript. MW, MO'L, JS, ZS, BW, JL, and BJ edited and approved the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Atrial natriuretic peptide (ANP) is a cardiovascular and metabolic hormone that has been identified recently as being associated with chronic kidney disease (CKD) without diabetes. Cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and adiponectin (ADP) contribute to the development of type 2 diabetes (T2DM). The aim here was to investigate the relationships of ANP with cytokine levels and clinical variables in T2DM nephropathy patients.A total of 81 participants with T2DM were recruited, including 37 patients with normoalbuminuria, 23 patients with microalbuminuria and 21 patients with macroalbuminuria. Serum concentrations of ANP and cytokines were measured using enzyme-linked immunosorbent assay (ELISA) kits. The correlations between ANP and clinical variables were analyzed. Multiple linear regression and logistic regression models were constructed to test the associations between ANP and the severity and presence of albuminuria.r = 0.876, p < 0.001), IL-6  and ADP , independent of the duration of DM or the BUN concentration.The macroalbuminuria patients exhibited higher plasma levels of ANP, TNF-α, IL-6, and ADP; higher serum creatinine (Cr) and blood urea nitrogen (BUN); and longer duration of diabetes mellitus (DM) than the patients with normoalbuminuria and microalbuminuria. Plasma ANP level was significantly associated with TNF-α (ANP is higher in type 2 diabetes mellitus nephropathy subjects, especially those who have macroalbuminuria, which is associated with compensatory responses to inflammation. Diabetic nephropathy (DN) is an important microvascular-related diabetes complication that accounts for at least 50% of end-stage renal disease (ESRD) , 2. EarlBy analyzing fundamental cytokines, we may find markers that can identify T2DM and molecules that can be targeted for treatment, particularly those predictive of DN. Atrial natriuretic factor (ANP) refers to a member of a family of cardiac- and vascular-derived hormones primarily secreted from the atrial wall involved in the control of increased volume or elevated blood pressure . ANP hasNo data regarding the relationship between ANP levels and DN are available. The present study aimed to explore the association between ANP and DN. The effect exerted by ANP on T2DM albuminuria patients was analyzed. Moreover, the concentrations of ADP along with TNF-α and IL-6 were measured to elucidate the interaction, if any, of the mentioned cytokines and ANP in patients stratified by albuminuria degree.Eighty-one patients diagnosed with T2DM were recruited from the Department of Endocrinology of Nanjing First Hospital, Nanjing Medical University, from May to August 2016. The study complied with the Helsinki Declaration for the investigation of human subjects. The Ethics Committee of Nanjing First Hospital approved this study. Informed consent was obtained from each participant enrolled in the study. The subjects were divided into 3 groups according to the guidelines for chronic kidney disease : 21 withThe exclusion criteria were (1) history of overt cerebrovascular disease ; (2) severe, nonregulated high blood pressure, defined as systolic blood pressure > 160 mmHg/diastolic blood pressure > 100 mmHg; (3) severe dyslipidemia  urinary tract infection or any other acute inflammation or infection; (5) kidney diseases besides DN or the use of anticonvulsant drugs, anti-inflammatory drugs or nephrotoxic drugs; (6) diagnosed liver failure or malignancy under the previous diagnosis; (7) current pregnancy or lactation; (8) positivity for islet cell autoantibodies, indicating the possibility of type 1 diabetes mellitus; (9) current treatment with thiazolidinediones, which are known to increase the plasma ADP level.Physical examinations were performed, which included measurements of blood pressure, height, weight and other anthropometric parameters. Samples of venous blood were drawn from all patients after an 8-h fast before and after treatment. Biochemical and hematological properties were determined with routine technologies in one analyzing instrument. Blood was collected into 4 ml EDTA-containing tubes and centrifuged for 30 min at 3000 rpm for 10 min. Serum samples were stored as aliquots with no preservatives at − 80 °C for 3 months on average until the cytokine study.Serum ANP , ADP , IL-6  and TNF-α  levels were measured by using commercially available human ELISA kits according to the manufacturer’s instructions. The detection limits for ANP, ADP, IL-6 and TNF-α were 10 ng/L, 30 μg/L, 2 ng/L and 8 pg/L, respectively. The intratest and intertest coefficients of variation were 5 and 10%, respectively.Body mass index (BMI) was calculated as weight (kg)/square of height (m).p values < 0.05 were considered significant.SPSS  version 20.0 for Windows was used for statistical analysis. For continuous, normally distributed data, mean ± SD values are reported; otherwise, the median (interquartile range) is reported. To assess correlations of categorical variables with the Macro-MA and Nor-MA groups, the chi-square test was used. ANOVA compared variables between 3 groups. The Kruskal-Wallis test was used to compare three groups on nonnormal variables. Correlations were tested by conducting regression analysis. To determine the relationship between numerical variables for normally distributed groups, Pearson’s correlation coefficient was calculated, and Spearman’s test was used for abnormally distributed groups. Logistic regression analysis was conducted to assess the associations between ANP level and the other parameters assessed. Two-tailed p < 0.05). Glucose in the Macro-MA group was 6.35  mmol/L, which was distinctly lower than that in the other two groups. Macroalbuminuria patients showed markedly higher durations of DM, Cl, serum creatinine, and urea but lower plasma albumin levels .According to Table p < 0.001). Furthermore, the levels of TNF-α and IL-6 increased as nephropathy progressed, with median serum TNF-α levels of 13.49 pg/mL in the normoalbuminuric group, 15.22 pg/mL in the Micro-MA group, and 18.28 pg/mL in the Macro-MA group. The median serum levels of IL-6 were 2.13 ng/L in the normoalbuminuric group, 2.20 ng/L in the Micro-MA group, and 3.21 ng/L in the Macro-MA group . Interestingly, compared to the patients with normoalbuminuria, the macroalbuminuria patients had higher serum ADP , BUN , and plasma ADP    . There was no noticeable correlation between ANP and any other variable: BP, lipid levels, glucose, liver enzymes and urea (Table p < 0.05) after adjustment for the duration of diabetes and BUN.The above variables were assessed by multivariate statistical analysis Table . In the In this study of 81 T2DM participants, 44 had albuminuria and 40 did not. The blood inflammatory cytokines and ANP and the albuminuria levels were measured. Post hoc analysis showed as follows: (1) serum ANP was higher in the DN group than in the control (T2DM) group –20; (2) ANP is a cardiac hormone that provides negative feedback under elevated blood pressure and fluid volume . Robert ANP is capable of regulating lipolysis and lipid mobilization in humans. Moreover, it might regulate adipose tissue inflammation by regulating the secretion of inflammatory cytokines , 27. ThePatients treated with thiazolidinediones, which are known to partly increase the plasma ADP level, as well as those treated with thiazolidinediones, anticonvulsant drugs, anti-inflammatory drugs or nephrotoxic drugs, were excluded because these drugs affect the level of inflammation detected.Notably, HbA1c levels were decreased more in the macro-MA group than in the other 2 groups. This could be explained by the fact that patients with a longer duration of DM and diabetic complications are more diligent about managing their blood glucose. In addition, as suggested in a previous study, ANP may impact the etiology of diabetes primarily by inhibiting glucagon secretion  and the This study has some limitations. First, the cross-sectional design for the baseline group analysis and the restricted size of each group are likely to affect the result. Randomized studies with larger samples will be required for more in-depth exploration. Second, we cannot completely exclude the possibility that ANP influenced the clearance of renal or hepatic cytokines. Finally, only plasma cytokines were measured, but measuring ANP and other cytokines in urine might help in the interpretation of the results.In summary, increased circulating concentrations of plasma ANP, which were correlated with a longer duration of DM, could precede the development of type 2 diabetic kidney disease with no noticeable cardiovascular disease, revealing one likely effect exerted by such bioactive peptides that could be useful in monitoring the DN development process in the early phase. Further investigations on the molecular mechanism of ANP in the kidney and of inflammatory cytokines should be performed to prevent and delay renal disease development in T2DM patients.


The reality of life in modern times is that our internal circadian rhythms are often out of alignment with the light/dark cycle of the external environment. This is known as circadian disruption, and a wealth of epidemiological evidence shows that it is associated with an increased risk for cardiovascular disease. Cardiovascular disease remains the top cause of death in the United States, and kidney disease in particular is a tremendous public health burden that contributes to cardiovascular deaths. There is an urgent need for new treatments for kidney disease; circadian rhythm–based therapies may be of potential benefit. The goal of this Review is to summarize the existing data that demonstrate a connection between circadian rhythm disruption and renal impairment in humans. Specifically, we will focus on chronic kidney disease, lupus nephritis, hypertension, and aging. Importantly, the relationship between circadian dysfunction and pathophysiology is thought to be bidirectional. Here we discuss the gaps in our knowledge of the mechanisms underlying circadian dysfunction in diseases of the kidney. Finally, we provide a brief overview of potential circadian rhythm–based interventions that could provide benefit in renal disease. Renal function is essential to maintaining systemic homeostasis. The kidneys filter the blood, maintain body pH, water, and electrolyte balance, and contribute to the regulation of blood pressure. The kidneys produce urine as a byproduct of maintaining fluid and electrolyte balance. The volume and composition of the urine can provide insight into health status. Indeed, analysis of the urine is thought to be the oldest medical test, dating back to the ancient Babylonians and Sumerians who recorded their observations on clay tablets more than 6000 years ago . This prIt was documented as early as the end of the 19th century (reviewed in ref. +-Cl− cotransporter (NCC) and prostasin in urinary exosomes varied over a 24-hour period  is defined as damage to the kidneys or decrease in renal function that is sustained over at least 3 months. CKD is associated with disordered circadian rhythms of sleep, blood pressure, and proteinuria. In human subjects, worsening renal function is associated with later onset, shorter duration, and increased fragmentation of sleep . ConsistCKD is also associated with non-dipping pattern of blood pressure, suggesting disrupted circadian rhythms of blood pressure. Clinically, non-dipping is defined as less than 10% difference between night and day blood pressure. The prevalence of non-dipping hypertension in CKD varies from 60% to 80% and increases with worsening kidney function . In patiThe renin-angiotensin-aldosterone system is upregulated in CKD. Angiotensin II acting via its cognate receptor AT1 modulates the activity of the suprachiasmatic neurons in vitro . WhetherCKD is associated with the development of long-term complications such as hyperphosphatemia, secondary hyperparathyroidism, vascular calcification, accelerated atherosclerosis, bone mineral disorders, and anemia. Serum phosphate levels exhibit a circadian rhythm in healthy individuals . While tThe signaling mechanisms that are perturbed in CKD can conceivably disrupt the kidney clock. However, disrupted sleep in human subjects with CKD and experimental evidence for disturbed activity and central clock output from animal studies discussed earlier suggest that the central clock in the suprachiasmatic nucleus is perturbed in kidney disease as well. This circadian dysfunction is likely to exacerbate the known complications of CKD . AlthougAlthough sleep disruption and fatigue are prominent complaints in patients with systemic lupus erythematosus (SLE) and negatively affect quality of life –57, the SLE is an autoimmune disease of unknown etiology that mainly affects women of reproductive age. LN is the most common end-organ manifestation of SLE and is the major cause of morbidity and mortality , 59. ImmSleep disturbances are commonly reported in SLE patients , 75, 76 Dysregulated immune responses are a cardinal feature of SLE/LN, and immune cells display a circadian effector pattern. Perturbations in immune cell circadian clock can influence outcomes of SLE/LN. In humans, natural regulatory T cell (Treg) number and function follow a rhythm across a 24-hour period. Sleep deprivation abrogated this rhythm and impaired Treg function . These fMacrophages are the harbingers of renal disease in LN and have been implicated in the pathology of several spontaneous and induced models of murine LN , 85–87. Cry1 and Cry2 have elevated serum IgG concentrations, serum antinuclear antibodies, and precipitation of IgG, IgM, and complement in glomeruli (Bmal1, Clock, Per, and Cry genes compared with the nephritic mice. There was also a significant reduction in BMAL1 protein expression at various time points in nephritic NZB/W mice compared with young mice.Few studies have examined the effect of genetic deletion of clock proteins in mice with spontaneous or drug-induced lupus. Mice deficient in the circadian clock genes lomeruli . This stlomeruli . In contlomeruli . The kidThe finding that the disturbances in circadian rhythm and dysregulated expression of key clock genes and proteins are associated with progression of SLE and LN is becoming well documented. Collectively, genetic mutations and sleep disturbance may synergize with systemic and local inflammation to worsen LN . NeverthBecause the kidneys play a critical role in blood pressure regulation, hypertension can be both cause and consequence of renal damage. Circadian disruption is likely to exacerbate these effects since it is known to negatively affect human health. Shift work is becoming more common in the 21st century . It is eMany patients diagnosed with essential hypertension have a normal day/night pattern of blood pressure rhythms, but the overall mean arterial pressure is shifted up. Hypertensive patients with a reduced day/night rhythm of blood pressure are classified as having non-dipping hypertension. The prevalence of non-dipping hypertension is difficult to estimate since it requires the use of 24-hour ambulatory blood pressure monitoring. It is of paramount importance to increase the use of this method, however, as non-dipping hypertension is a critical risk factor for adverse cardiovascular outcomes (reviewed in ref. Timed urine collections provide an opportunity to assess circadian disruption in a noninvasive manner. The loss of the nighttime dip in blood pressure has been linked to disruption of rhythms in urinary sodium excretion . It shouIt is well established that kidney function decreases with increasing age –110. AgeIn addition to overall changes in kidney structure and function, circadian rhythms in behavior, sleep/wake cycle, and other physiological parameters are negatively affected in older populations . ChangesA common symptom associated with aging is nocturia, which is defined as waking up one or more times at night to urinate . The preClinically, it is critical to determine the mechanisms behind dysregulation of the circadian clock in the aging kidney to improve quality of life and treatment strategies. For example, in a retrospective study using the US Renal Data System Dialysis Morbidity and Mortality Waves III/IV database, researchers examined the impact of the time of day at which dialysis was administered in a population of patients older than 60 years . Elderly1c (It is well established that loss of circadian rhythms in physiological functions can lead to disease. The evidence that this phenomenon occurs in patients with kidney disease is growing. As basic research brings us closer to understanding the pathophysiological mechanisms by which circadian disruption causes disease, the potential for circadian rhythm–based interventions is increasing. Using timed light therapy as an intervention, one small randomized controlled trial found that night shift workers had improved nighttime blood pressure dip with treatment. This increase in the nighttime blood pressure dipping status was associated with a decrease in serum glucose during oral glucose tolerance testing. There were no changes in serum insulin, melatonin, or cortisol, but plasma catecholamine levels were reduced . Early t1c . In term1c , 155. Wh1c . There i1c . With thIn the future, adoption of circadian-based therapies will require development of tests to assay the extent of circadian disruption to facilitate diagnosis and assess response to therapy. The use of timed urine collections could shed light on the incidence of circadian disruption and help assess the effectiveness of circadian-based therapies in a noninvasive manner. Measurement of clock gene expression in blood samples may also be useful as a prognostic and diagnostic biomarker in patients on dialysis, those with CKD, or those with or at risk for acute kidney injury –160. Alt


Osteoarthritis (OA) is the most common joint disease associated with pain and disability. OA patients are at a high risk for venous thrombosis (VTE). Here, we developed an interpretable machine learning (ML)-based model to predict VTE risk in patients with OA. To establish a prediction model, we used six ML algorithms, of which 35 variables were employed. Recursive feature elimination (RFE) was used to screen the most related clinical variables associated with VTE. SHapley additive exPlanations (SHAP) were applied to interpret the ML mode and determine the importance of the selected features. Overall, 3169 patients with OA (average age: 66.52 ± 7.28 years) were recruited from Xi’an Honghui Hospital. Of these, 352 and 2817 patients were diagnosed with and without VTE, respectively. The XGBoost algorithm showed the best performance. According to the RFE algorithms, 15 variables were retained for further modeling with the XGBoost algorithm. The top three predictors were Kellgren–Lawrence grade, age, and hypertension. Our study showed that the XGBoost model with 15 variables has a high potential to predict VTE risk in patients with OA. Osteoarthritis (OA) is the most common joint disease worldwide, with an age-associated increase in both incidence and prevalence ,2. It isVenous thrombosis is a relatively common and potentially fatal condition in patients, and an increased risk of VTE has been reported in arthritis, particularly in rheumatic arthritis (RA) ,14,15,16Thus, predicting the VTE risk among OA patients is critical to reduce morbidity and mortality from VTE in OA patients. Machine learning (ML) is a computer-based method of data analysis that is often used to construct predictive models based on large datasets . In thisWe performed a single-center cross-sectional study of OA patients in Xi’an Honghui Hospital between January 2018 and December 2020. Patients were consecutively recruited from joint surgery department and were examined by venous ultrasound of the legs to assess VTE risk. The inclusion criteria were as follows: (1) diagnosed with knee osteoarthritis (guidelines for the diagnosis and treatment of osteoarthritis (2018 edition)) [All patient demographics and laboratory data at admission were extracted manually from electronic medical records using a standardized case report form.To develop machine learning models, 35 parameters were used for the analysis. Before developing the ML models, laboratory indices, which were continuous variables, were converted into categorical variables based on their normal range values. In addition, the patient’s age was treated as a continuous variable, with missing values replaced by median values. All patients were randomly divided into a training set and test set at a ratio of 8:2.Six ML algorithms, namely logistic regression (LR), random forest (RF), extreme gradient boosting (XGBoost), adaptive boosting (AdaBoost), gradient boosting decision tree (GBDT), and light gradient boosting machine (LGBM), were used to predict the VTE risk. We used the receiver operating characteristic (ROC) curve as the evaluation metric to compare the performance of the ML algorithm between the training and testing sets. The best performance model was chosen, and recursive feature elimination (RFE) was employed to screen the optimized variable combinations. For model interpretation, the Shapley additive exPlanations (SHAP) algorithm was used to calculate the Shapley value of each variable based on game theory to further explain the best performance model.2 test was conducted for binary variables, and Student’s t-test was used for continuous variables. Owing to the imbalance of the dataset, the synthetic minority oversampling technique (SMOTE) was used to deal with the training set. Six ML algorithms were used to screen for the best performance prediction model. Using the RFE algorithm, all variables were filtered one by one to obtain the best combination, which was then established in a selected ML prediction model. We also used the SHAP algorithm to interpret and evaluate the optimized model. Statistical significance was set at p ≤ 0.05.All statistical analyses were conducted using Python software (version 3.8). A Fisher’s exact test or an xWe excluded subjects with missing data and subsequently enrolled 3169 patients with an average age of 66.52 ± 7.28 years in the study . Of themThe patients were randomly stratified (8:2) into training and testing sets to evaluate the model performance. Finally, a total of 35 characteristics were enrolled in the six ML algorithms, including LR, RF, XGBoost, AdaBoost, GBDT, and LGBM, to identify the model with the best predictive performance. Our results showed that the XGBoost model demonstrated the best performance, with an area under the curve (AUC) of 0.741  A,B. The To further optimize the XGBoost model, the RFE method was used to screen the most important variables that can predict the VTE risk. Finally, 15 variables were employed to establish the final prediction model, and the new XGBoost model showed that the AUC of the testing dataset was 0.727  A,B.The SHAP method was also used to interpret the relative importance of each variable in the XGBoost model. Our results showed that age, eosinophil ratio (EOSR), hematocrit (HCT), mean platelet volume (MPV), thrombocytocrit (PCT), platelet-larger cell ratio (P-LCR), uric acid (UA), glucose, antistreptococcal hemolysin “O” (ASO), anti-cyclic citrullinated peptide antibody (ACPA), rheumatoid factor (RF), Kellgren–Lawrence grade (K–L grade), history of hypertension, diabetes, and coronary artery disease (CAD) were associated with the risk of VTE in OA patients. Particularly, K–L grade, age, and hypertension were the three vital variables A,B.Extensive efforts have been made to delay OA patients progress to the end stage. In this hospital-based cross-sectional study, we used the ML algorithm to predict VTE risk in patients with OA. We found that using the XGBoost model with 15 variables can predict VTE risk in OA patients, and this may have a growing prevalence due to the global ageing population.OA is not simply a matter of mechanical damage to the joint but involves several additional risk factors . NeverthMachine learning is a crucial branch of artificial intelligence that utilizes historical data to predict the likelihood of a future outcome ,25. As aThe present study has certain limitations. First, although ML algorithms are widely used in medical practice, the predictive value is limited due to the “black box” characteristic. Thus, rather than being used as a clinical judgment tool, an ML algorithm model should be used as a reference for physicians. Second, all the data analyzed in the present study were from a single institution, and the imbalance of gender ratio has limited the generalization of our results. Additionally, because of the nature of an observational study, some unmeasured confounding effects may persist; thus, additional validation and assessment of the relationship between the variables and VTE in OA patients should be performed in a large population. Nevertheless, despite such limitations, to our knowledge, this is the first study to use a machine learning method to predict VTE risk in OA patients.In conclusion, we developed a XGBoost model with a high accuracy in the prediction of VTE risk in patients with OA, which might supply a complementary tool for the screening of populations at high risk of VTE.


The present study aims to develop and validate a cuffless method for blood pressure continuous measurement through a wearable device. The goal is achieved according to the time-delay method, with the guiding principle of the time relation it takes for a blood volume to travel from the heart to a peripheral site. Inversely proportional to the blood pressure, this time relation is obtained as the time occurring between the R peak of the electrocardiographic signal and a marker point on the photoplethysmographic wave. Such physiological signals are recorded by using L.I.F.E. Italia’s wearable device, made of a sensorized shirt and wristband. A linear regression model is implemented to estimate the corresponding blood pressure variations from the obtained time-delay and other features of the photoplethysmographic wave. Then, according to the international standards, the model performance is assessed, comparing the estimates with the measurements provided by a certified digital sphygmomanometer. According to the standards, the results obtained during this study are notable, with 85% of the errors lower than 10 mmHg and a mean absolute error lower than 7 mmHg. In conclusion, this study suggests a time-delay method for continuous blood pressure estimates with good performance, compared with a reference device based on the oscillometric technique. Hypertension is a major risk factor for cardiovascular morbidity. It is generally defined according to doctor’s office blood pressure measurements (OBPM) that may not reflect true blood pressure (BP) levels and do not consider diurnal and nocturnal variations.Nowadays, thanks to the technological development, BP is becoming more and more non-invasively measured by the patient at home (HBPM) or automatically over 24 h (ABPM) .Patients may perceive the cuff pressure as being unbearable, especially during sleep, in the case of very high BP and if it is required to frequently repeat the readings;Avoiding false elevation or reduction in BP readings and obtaining an accurate measurement require the selection of an appropriate cuff size according to the users’ upper arm circumference;Readings by conventional devices may be insufficient indicators for hypertension since only intermittent measurements are provided. These devices cannot record time-varying BP or capture the dynamic state of the cardiovascular system throughout the day.The devices currently employed for HBPM and ABPM usually implement the oscillometric method, which involves an inflatable cuff during the measurement. These devices present several drawbacks:For these reasons, in the past few years, the interest in developing non-invasive BP measuring devices without an occluding cuff and that is able to return continuous estimations has increased.Cuffless methods are an improvement of the cuff-based ones, designed to overcome their main limitations.Several continuous cuffless methods were developed in the last years based on the photoplethysmographic (PPG) signal, a simple optical technique that can detect blood volume changes in the microvascular bed of tissues. Examples of methods using this physiological signal are represented by the volume-clamp method, the arterial applanation tonometry method and the time-delay method .In the past few years, several research groups have tried to develop continuous cuffless BP measurement techniques based on the guiding principle of the time that a blood volume takes to travel from the heart to a peripheral site, defined as time delay ,3.The time delay can be estimated with two different methods ,4: the pThese two quantities are related as follows: emotion . The eff emotion . There aSOMNOtouch NIBP , designeCareUp  is a smaSeismoWatch  is anothNo medical devices using the time-delay method seem to be currently available. After a literature analysis, some prototypal devices have emerged:This study aimed to develop and validate a non-invasive blood pressure measurement technique that provides continuous blood pressure estimations with a cuffless method.Among the identified continuous cuffless methods for BP estimation, the pulse arrival time (PAT) was chosen, where the time delay occurring from the R peak of the ECG signal and a characteristic point of the PPG signal is estimated. Necessary physiological signals were acquired thanks to an easy-to-wear wearable device developed by L.I.F.E. Italia S.r.l., consisting of a sensorized shirt and a prototypal wristband to be worn at the radial artery of the left wrist. This kind of device allows the subject to be monitored in daily-life activities without the interference of free cables or finger probes. In addition, the signals acquisition could be continuously performed simply wearing the device with no further actions required to the subject.From the extracted time-delay indicators, inversely related to blood pressure, linear regression models were implemented and the corresponding blood pressure values were estimated.The models’ performances was assessed by using dedicated data acquisition protocols designed to evaluate the reliability of the proposed method in detecting both provoked and daily blood pressure variations.The reference device was represented by the GIMA ABPM pulse rate monitor ,10, measA 12-lead ECG signal by using 10 ink-based dry electrodes;A 3-channel respiratory signal by using strain circumferential sensors positioned around the body at the thoracic level, xiphoid process, and abdominal level;Skin temperature by using a contact sensor near the left armpit;Activity level and body position by using one inertial measurement unit (IMU) on the back.The test device was represented by L.I.F.E. Italia’s IIa class medical device, a sensorized shirt that records several physiological signals with a common logic ,12:A 12-In order to acquire the PPG signal, a prototypal accessory wristband to be wear on the radial artery of the left arm was designed, using the Maxim Integrated MAX30102 optical module .Both the reference device and the wristband had to be worn on the same arm so that the sphygmomanometer occlusion generates a stop in the wristband PPG signal, due to a lack of blood pulsatile motion; this allows an easier synchronization between the two devices. In The target population consisted of healthy females and males with an age range between 18 and 80 years non presenting with upper limb impairments, dermatological problems or disabling surgery at the acquisition time. The Ethics Committee of Politecnico di Milano approved the study .The volunteers that met the pre-screening inclusion and exclusion criteria were enrolled. The enrolled subjects were also asked to fill in an anonymized questionnaire about anthropometrical data and health state. A total of 26 L.I.F.E. Italia’s employees decided to voluntarily participate in the different protocols.The volunteers involved in the study were asked to provide a written informed consent; then, they were provided with a subject’s specific code known only by the operator dealing with the procedure. The code had the structure of YYMMDDXX, where YYMMDD is the enrollment date and XX is a progressive two-digit number. Characteristics of the involved population are shown in HANDGRIP PROTOCOLIn order to assess the reliability of the test device against minor blood pressure variations, subjects were called to perform an isometric handgrip (IHG) exercise with the right arm . Three rThe subject had to be seated in rest position for 5 min, and then a blood pressure value was measured with the reference device. The exercise consisted of four 1.5 min contractions of an IHG exercise at 40% maximum effort, with 30 s of recovery periods. For the maximum contraction value determination, the subject was called to perform three grips at the maximum intensity with 10 s rest periods to avoid fatigue; then, the maximum contraction value was given by the average. At the end of the four trials, while the test device was still recording both PPG and ECG signals, the blood pressure was being measured with the reference device. Two minutes after the end of the exercise, with the subject still in rest position, blood pressure was measured with the reference device.RUNNING PROTOCOLIn order to assess the reliability of the test device to more significant blood pressure variations, the subjects were asked to perform running repetitions alternated with walking recovery periods  for a toThe subject had to be seated in rest position for 5 min, and then a blood pressure value was measured with the reference device. After that, the exercise started: 5 min of warm-up walking; 2 min of running at maximum speed; additional 2 min of running at maximum speed; 4 min of recovery walking; 3 min of sprint running; 6 min of recovery walking; 1 min of skipping; 10 min of recovery walking. After each of the aforementioned steps, a BP measurement was performed with the reference device with the subject in a standing position. The subject had to be seated again in the rest position immediately after the recovery walking, and their blood pressure was measured with the reference device. After 2 min in the same position, we proceeded with another measurement. Two acquisition protocols were designed to assess the reliability of the test device in identifying blood pressure variations due to specific stimuli.DAILY PROTOCOLThe reference device occlusion occurred automatically every 15 min. At the beginning of each reference device occlusion and for its duration, subjects had to stop and maintain their position to reduce measurement artefacts.daily protocol, both devices could also be worn during the night to assess the reliability of the test device against the detection of blood pressure variations during sleep. In this case, the reference device occlusion occurred automatically every 15 min.As an extension of the daily protocol were valuable to understand the reliability of the test device in a real scenario, continuously monitoring blood pressure during daily activities. For this reason, and for the uncontrolled conditions of the protocol, these data were used only for model test. In addition, real use-case scenario data trends were implemented. Data from the In addition, in order to assess the reliability of the test device against blood pressure variations not due to specific stimuli, the subjects were asked to perform their daily working activities wearing both the reference and the test devices for at least 5 h:handgrip protocol or running protocol). Optionally, each subject could also participate in the protocol designed to identify blood pressure variations in a real scenario (daily protocol).Each subject was required to participate in at least one of the two protocols designed to understand blood pressure variations due to specific stimuli .Maximum of the waveform, representing the systolic peak (P).Minimum of the waveform, representing the diastolic valley (V).According to Refs. ,16, fromMd).Pulse arrival time at the maximum of the waveform’s first derivative (PATP).Pulse arrival time at the systolic peak (PATV); it is important to highlight that, for this feature, it is necessary to consider the minimum within the following RR period.Pulse arrival time at the diastolic valley : representing the time occurring from the wave start  to the systolic peak;Diastolic time (𝐷𝐼𝐴𝑇𝐼𝑀𝐸): representing the time from the systolic peak to the diastolic valley;Duty cycle (DC): representing the ratio of the systolic time and the total PPG wave duration, given by the sum of the systolic and diastolic times , could be used as time-delay indicators to estimate blood pressure. In order to consider also the PPG wave morphology, additional features were extracted b:SystoliThe used features extraction algorithm flowchart is summarized in Blood pressure values in terms of SBP and DBP were obtained from the reference device with information about the occlusion starting time. The number of collected measurements depend on the adopted protocol.ECG and PPG signals, imported from the data logger, are continuous signals synchronously recorded by a standard microcontroller at a sampling frequency of 500 Hz and 250 Hz, respectively. A single lead for the ECG signal was selected, in general, the pericardial V6 because it is characterized by the highest quality, and the PPG infrared wave. The ECG signal was then under-sampled at the same PPG frequency (250 Hz) and, if necessary, lower and upper trimmed.Signals filtering was then performed. The PPG signal passed through a 5th order band pass Butterworth filter with a high pass cutting frequency of 0.5 Hz and a low pass cutting frequency of 10 Hz. The ECG signal passed through a notch filter to remove the 50 Hz interference, and a 5th order band pass Butterworth filter with a high pass cutting frequency of 0.5 Hz and a low pass cutting frequency of 40 Hz.Given that the reference device provided intermittent measurements, conversely, the test device measurements were continuous, a 30 s window of the test device signals around each reference device measurement was considered in the analysis. PREVIOUS LOGICprevious logic selects a 30 s window before the occlusion starting time, removing the first 5 s to avoid possible artefacts in the PPG wave due to the occlusion. This logic was used for the handgrip protocol, in which the subject was in the rest position throughout the protocol, and the stimulus entity was small. Following this logic, it was possible to consider the test device signal during the stimulus occurrence.The FOLLOWING LOGICfollowing logic selects a 30-s window after the occlusion starting time, removing the first 45 s to wait for a normal PPG signal after the end of the occlusion. This logic was used for the running protocol, in which subjects needed to stop the activity before the reference device measurement. Because of the larger entity of the stimulus, also a signal window immediately after the end of the activity could be appropriate.The PREVIOUS AND FOLLOWING LOGICprevious and following logic selects two 30 s windows, one following the previous logic and the other one, the following logic. This logic was used for the daily protocol, in which the subjects’ activity immediately before and after the occlusion could be considered equivalent.The According to the different protocols, the 30 s window was extracted with different logic :PREVIOUprevious logic.In From now on, the algorithm considered the 5-s sub-windows of the selected 30 s one at a time.First of all, for each 5 s window, a signals quality check logic was implemented. The ECG signal quality assessment was performed, using logic related to the signal range, standard deviation (STD) and kurtosis statistical index . In addiIf the quality checks are satisfied, each 5 s window is further spitted into other windows between two consecutive R peaks. Each of these windows has only one PPG wave so that the corresponding features could be extracted.For each 5 s window, as many values for each feature as the number of R peaks minus one could be obtained. In order to avoid possible outliers, the minimum and maximum values were removed, and an averaging operation was performed. In the end, for each 5 s window, a mean value for each feature was obtained.previous and following, the two vectors from each 30 s window had to be averaged. A summary of the exposed logic is shown in All the features’ values, extracted from the same 30 s window, were averaged and collected in a vector with the corresponding reference device values in terms of SBP and DBP. If the windowing logic was According to , to obtaMd) is the most relevant time-delay feature, it was considered for the statistical data analysis; the necessity of additional features was investigated for the linear regression model implementation. As the pulse arrival time at the maximum of the first derivative  with an average age of 35 (±11 std) years were enrolled. All the enrolled subjects successfully completed the protocol on the first day. Four subjects did not repeat the protocol on the second day because they were unavailable during the second acquisition period. The quality of one subject’s signals was insufficient for the ECG and PPG signals quality check block of the features extraction algorithm that was not able to extract good quality windows close to the reference device measurement; therefore, this subject was subsequently removed from the dataset. The low quality, in particular of the PPG signal, can result due to an unsuitable sensor’s position or exerted pressure. The handgrip protocol dataset consisted of 25 subjects for the first day and 21 subjects for the second day. The dataset dimension is compliant with the validation study sample size of 20 subjects required by the Institute of Electrical and Electronics Engineers (IEEE) standard [For the RUNNING PROTOCOLrunning protocol, three subjects (one man and two women) with an average age of 30 (±6 std) years were enrolled. All the three enrolled subjects successfully completed the protocol on both days, and all the data were included in the dataset.For the DAILY PROTOCOLdaily protocol, 20 subjects (12 men and eight women) with an average age of 36 (±11 std) years were enrolled. A total of 12 subjects (six men and six women) successfully completed the protocol, with an acquisition period higher than the required five hours. The other eight subjects had lower acquisition periods due to technical problems during the acquisitions. A 24-year-old woman assessed the reliability of the device also during the night.For the Since L.I.F.E. Italia’s employees represent the enrolled population, the currently available data do not include a large variability of age, anthropometric measures, smoke, physical activities, and cardiovascular diseases.handgrip protocol. In fact, after the outliers’ removal process (see details at the end of this section), the handgrip protocol dataset includes 24 subjects for the first acquisition day and 19 for the second acquisition day, for a total amount of 129 features’ vectors.A preliminary statistical analysis was conducted because of the significant amount of data available for the Md feature (ΔPATMd).Due to the time-delay method characteristics, the data were analyzed in terms of differential values, allowing the mitigation of subject-specific dependencies. From the reference device, differential systolic (ΔSBP), diastolic (ΔDBP) and mean (ΔMBP) blood pressure values were considered; from the test device, differential PAThandgrip protocol, three reference blood pressure measurements were performed: one at rest, one immediately after the exercise and the last after a recovery period. Consequently, the following differential values were established:Md decrease are expected.The difference between effort and rest values, called ΔEffort: a blood pressure increase and a corresponding PATMd increase are expected.The difference between recovery and effort values, called ΔRecovery: a blood pressure decrease and a corresponding PATThe difference between recovery and rest values, called ΔRest: these two values are expected to be very similar, so the difference needs to be around zero.In the V-shape is expected for all the considered variables: in physiological conditions, the blood pressure increases after the exercise, then decreases in recovery and returns to rest values after recovery. Conversely, according to the literature evidence [Md behaves oppositely: it decreases after having completed the exercise and increases during the recovery. In A characteristic evidence , the PAThandgrip protocol dataset scatter plot is shown to understand the relation between test device values, in terms of PATMd variation, and reference device values, in terms of systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure variation. In p-values are shown.In Md values. Symmetrically, ΔRecovery values (in blue) fell into the fourth quadrant, in which the blood pressure drops and PATMd increases. Finally, the ΔRest values (in green) were centered around zero. In As expected, ΔEffort values (in red) fell into the second quadrant, corresponding to an increase in blood pressure and a decrease in PAThandgrip protocol dataset’s outliers removal process had the aim of removing the subject’s acquisitions in which the majority of the three recorded values fell in the wrong quadrants. According to this logic, both the acquisitions of one subject and the second day acquisition of another subject were removed.The handgrip protocol and running protocol data for most significant blood pressure variations identification. The selected dataset consisted of 174 feature vectors: 129 from the handgrip protocol dataset and 45 from the running protocol dataset after the outliers’ removal process. In the running protocol, values were expected to fall in the second quadrant or to be close to zero. In fact, both during the exercise and the recovery periods, blood pressure values higher than the ones in rest position were expected. For this reason, data coming from the first day acquisition of one subject (a 24-year-old woman) and falling in the first quadrant were removed.The training dataset included the running protocol data inclusion was essential to cover larger BP variations. In addition, since the proposed model is based on features, the 10 values for each feature coming from the running protocol acquisitions allowed us to consider consistently the available data amount.Despite being aware of the unbalancing between the two datasets, the running protocol data, according to the physiological inverse linear relation between blood pressure and time-delay [Md variations in the negative direction. In handgrip protocol in green and running protocol in pink; the corresponding Pearson’s correlation coefficients and p-values are shown in Including also the me-delay , the traMd), PAT at the diastolic valley (PATV) and diastolic time (DIATIME).For each blood pressure value to be estimated , a specific multiple linear regression model was implemented, including PPG features with a significant correlation with blood pressure  starting from the initial calibration value (BPreference) to reproduce a real use case scenario:Blood pressure variations provided by the models (ΔBP) can be used to obtain corresponding absolute blood pressure values .Being that the proposed regression models are linear, their performances could be improved by implementing a more complex, higher-order model.Finally, only healthy subjects were enrolled so far: dedicated clinical trials could allow investigating the proposed method adequacy in the case of hypertension or related pathologies.In conclusion, the results of the study are notable because it is proposed a time-delay method for blood pressure estimations with good performance, compared with a reference device based on the oscillometric technique. In a real-case scenario, through L.I.F.E. Italia’s wearable device and thanks to the proposed cuffless method for blood pressure variations estimation, subjects could monitor their blood pressure values without the inconvenience of a sphygmomanometer.


The goal of this study was to investigate the association between total epinephrine dosage during resuscitation and acute kidney injury after return of spontaneous circulation in patients with cardiac arrest. We performed a secondary analysis of previously published data on the resuscitation of cardiac arrest patients. Bivariate, multivariate logistic regression, and subgroup analyses were conducted to investigate the association between total epinephrine dosage during resuscitation and acute kidney injury after return of spontaneous circulation. A total of 312 eligible patients were included. The mean age of the patients was 60.8 ± 15.2 years. More than half of the patients were male (73.4%) and had an out-of-hospital cardiac arrest (61.9%). During resuscitation, 125, 81, and 106 patients received ≤2, 3 - 4, and ≥5 mg epinephrine, respectively. After return of spontaneous circulation, there were 165 patients (52.9%) and 147 patients (47.1%) with and without acute kidney injury, respectively. Both bivariate and multivariate analysis showed a statistically significant association between total epinephrine dosage and acute kidney injury. The subgroup analysis showed that the strength of the association between epinephrine dosage and acute kidney injury varied by location of cardiac arrest. Further multivariate regression analysis found that the association between epinephrine dosage and acute kidney injury was only observed in patients with in-hospital cardiac arrest after adjusting for multiple confounding factors. Compared with in-hospital cardiac arrest patients who received ≤2 mg of epinephrine, patients with 3–4 mg of epinephrine or ≥5 mg of epinephrine had adjusted odds ratios of 4.2  and 11.3 , respectively, to develop acute kidney injury. Therefore, we concluded that a higher epinephrine dosage during resuscitation was associated with an increased incidence of acute kidney injury after return of spontaneous circulation in adult patients with in-hospital cardiac arrest. Cardiac arrest (CA) is defined as the sudden cessation of myocardial contractions and circulation to the cardiac tissue, which is determined by a lack of pulse and loss of consciousness . CA is aPrevious studies have shown that the pathological process of return to spontaneous circulation (ROSC) after CA involves hypoxic-ischemic encephalopathy, myocardial dysfunction, and ischemia-reperfusion injury , all of Compared with the number of studies focused on mortality and neurological function following CA , the numEpinephrine is the most important medication used during CPR. Based on the recommendation from the American Heart Association and European Resuscitation Council guidelines for adult patients with CA, the standard dose of epinephrine administration is 1 mg per 3–5 min . Epinephhttps://datadryad.org/) for free access and analysis (https://doi.org/10.5061/dryad.qv6fp83)  at Erasme Hospital, Brussels, Belgium, and was approved by the local Ethical Committee . The original data from that study are stored in a public domain (qv6fp83) . The iniIn the present study, we further excluded patients <18 years old, with history of chronic kidney failure, or having missing data on the AKI diagnosis. The definition of AKI was based on the Acute Kidney Injury Network criteria. Briefly, the diagnostic criteria of AKI was defined as an absolute increase of serum creatinine more than or equal to 0.3 mg/dl, a 1.5-fold increase in serum creatinine level from baseline, or a reduction in urine output to less than 0.5 ml/kg per hour for more than 6 hours .Trans-oesophageal and/or transthoracic echocardiography were used to evaluate the cardiac function. The mean arterial pressure was maintained at > 65–70 mmHg via volume resuscitation and dobutamine and/or noradrenaline infusion. Intra-aortic balloon counterpulsation (IABP) or extracorporeal membrane oxygenation (ECMO) was applied in patients with severe cardiogenic shock. The normocapnia and SpO2 > 94% was supported by mechanical ventilation. Blood glucose was controlled between 110 and 150 mg/dl. Enteral nutrition was started during TTM and adjusted according to the gastric tolerance.CPR was performed following the standard recommendations . The posData included demographics , comorbidities , CPR information , and lactate and C-reactive protein (CRP) levels at admission.U test was applied for continuous variables when appropriate.Mean ± standard deviation  or median Q1-Q3 (skewed distribution) was used for continuous variables. Numerical values and percentages were used for categorical variables. To determine significant differences among groups with different epinephrine dosages, the Chi-square test was applied for the categorical variables and one-way ANOVA or the Mann-Whitney The association between different variables and AKI was first investigated using bivariate analysis. The effect of epinephrine dosage on AKI under other potential confounders was evaluated using multivariate logistic regression analysis. The criteria of selecting confounding variables were as follows: 1) There were 165 patients diagnosed with AKI. We selected less than 16 variables to avoid over-fitting the model. 2) Clinical significance of variables was related to AKI after CA. The clinical significance was determined by searching the literature  and our Interaction and stratified analysis were conducted according to age , shock, and out-of-hospital cardiac arrest. The test for linear trend was also performed by entering the median value of each category of selected variables as continuous variables in the models.http://www.R-project.org, The R Foundation) and EmpowerStats . A p-value < 0.05 in a two-tailed test was considered statistically significant.All analyses were conducted in statistical software packages R , history of chronic kidney failure, and missing data, respectively, 312 patients met the inclusion criteria of the present study . There wThe results of bivariate analysis are presented in Multivariate logistic regression was applied to construct three models to investigate the independent effect of epinephrine dosage on AKI after CA. The results are listed in p value for interaction <0.05). For in-hospital CA patients, an increase in the epinephrine dose was significantly correlated with an increased incidence of AKI .As shown in Epinephrine is the most important medication used during CPR in CA patients. Epinephrine administration during CPR has been recommended by the current American Heart Association and European Resuscitation Council guidelines for adult CA  and numep values in each group and for the trend and interaction were >0.05). Chua’s study claimed that more than half (51.7%) of the patients with post-resuscitation cardiogenic shock had AKI, while only 6.4% of patients without post-resuscitation cardiogenic shock developed AKI . In-hospital CA patients received more epinephrine, and their chance of developing AKI was higher accordingly  (The association between epinephrine dose and AKI was varied by CA location (ordingly . Howeverd >0.05) . Theoretd >0.05) . Thus, mWe performed a multivariate regression analysis and considered the influences of multiple potential confounders on the relationship between epinephrine use and AKI. However, our study was limited by the observational study design, which was hard to establish a causal relationship between epinephrine dosage and AKI. We performed secondary analysis using a previously collected dataset and were not able to access detailed information, such as the duration of shock and quality or duration of resuscitation, which might be potential confounding factors. The diagnosis of kidney failure was based on the AKIN criteria, but not on the latest Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Further prospective studies should be conducted to verify our results. In addition, although the standard dose of epinephrine administration is 1 mg per 3–5 min, the actual situation might be different due to complexities in the clinical practice, especially under emergent situations. The relationship between epinephrine administration and AKI might vary with each dose and interval during CPR. Unfortunately, the original data did not provide information about these factors. Further studies should focus on the epinephrine dose and interval during resuscitation and investigate their effects on AKI.In conclusion, after adjusting for multiple confounding factors, a higher epinephrine dosage during resuscitation was associated with an increased incidence of AKI after ROSC in adult patients with in-hospital CA. As epinephrine is an essential medication during CPR, more dedicated studies to optimize epinephrine dosage, frequency, or timing during resuscitation are warranted.


Blood pressure (BP) monitored within 24 h from the beginning of intravenous thrombolysis (IVT) with alteplase, is one of the important factors affecting the prognosis of patients with acute ischemic stroke (AIS). This study aimed to explore longitudinal BP trajectory patterns and determine their association with stroke prognosis after thrombolysis. From November 2018 to September 2019, a total of 391 patients were enrolled consecutively during the study period, and 353 patients were ultimately analyzed. Five systolic (SBP) and four diastolic blood pressure (DBP) trajectory subgroups were identified. The regression analysis showed that when compared with the rapidly moderate stable group, the continuous fluctuation‐very high level SBP group  was associated with early neurological deterioration (END). Both the rapid drop‐high level SBP  and DBP groups  were associated with early neurological improvement (ENI). Moreover, there was a U‐shaped correlation between the OR value of SBP trajectory group and favorable outcome  at 3 months: the slow drop‐low level SBP group represent a well‐established unfavorable outcome risk factor , and extremely high SBP—the continuous fluctuation‐very high level SBP group, are equally associated with elevated unfavorable outcome risk . The continuous fluctuation‐very high level DBP group was statistically significant in mRS . The BP trajectory groups show varying clinical features and risk of neurological dysfunction. The findings may help identify potential candidates for clinical BP monitoring, control, and specialized care. Several observational studies have found that approximately 75%–80% of patients have elevated BP in response to stroke episodes,In comparison, much less is known about the importance of changes in BP over time  in patients with AIS. A study on this topic showed that different BP trends were associated with the occurrence of cerebrovascular events.Stroke guidelines indicate that monitoring BP within 24 h from the beginning of IVT in patients with AIS is essential due to the high incidence of complications.Several studies have shown that high SBP or DBP levels are associated with the prognosis of patients with AIS, such as changes in neurological function, hemorrhaging‐related complications, and mRS scores.In most similar studies, the BP values at a single time point, its mean value, the variation coefficient, and other indicators at multiple time points were used to describe BP and to explore the correlation between BP and stroke prognosis.According to BP data obtained at multiple time points in patients with AIS treated using thrombolysis, the group‐based trajectory model can be used to assess patterns of BP fluctuations.SBP and DBP showed different patterns as the time to thrombolytic therapy increased.There were differences in clinical characteristics among patients with different patterns of BP changes as well as in the degree of correlation with stroke prognosis, which was one of the independent influencing factors.Compared with these parameters, the BP values at a single time point, its mean value, the variation coefficient, and other indicators at multiple time points, which were used to describe BP in similar articles, BP trajectories are equally important values for predicting stroke prognosis.Hypertension is a heterogeneous condition in patients with AIS, and available data support the importance of both systolic (SBP) and diastolic (DBP) BP monitoring. We designed our analysis using an unsupervised cluster approach, group‐based trajectory modeling(GBTM) approach that may provide an alternative method for summarizing long‐term BP values accounting for the dynamic nature of BP over time, to group similar longitudinal BP response patterns. We then evaluated the associations of these clusters, or most commonly BP parameters in similar articles, with neurological function changes and status using a standard multivariate regression approach. Improved knowledge of BP trajectories is critical in understanding the role of BP as a risk factor for adverse outcomes.22.1We prospectively identified 353 consecutive patients between November 2018 and September 2019 who were diagnosed with AIS and subsequently treated with IVT using alteplase, a thrombolytic medication, within 4.5 h after symptom onset and were then followed up for 3 months at one comprehensive stroke center . All patients were evaluated according to the American Heart Association guidelines and 2018 American Stroke Association guidelines for enrollment and contraindications before thrombolytic therapy was administered. All enrolled patients received 10% of the total dose of alteplase , which was calculated as 0.9 mg/kg (maximum 90 mg), as an intravenous bolus, with the remaining 90% given as an infusion over the course of 1 h. Inclusion criteria were age ≥18 years, being treated with intravenous alteplase according to clinical guidelines, and follow‐up magnetic resonance imaging (MRI) or computed tomography performed 24 h after intravenous alteplase thrombolysis.2.2BP measurements were made during the routine care of patients with AIS. We used an electrocardiogram monitor  to measure BP with patients lying in the supine position. All BP recordings and measurement time points were collected and stored in the electronic health record systems of the participating center. BP was monitored every 15 min for 2 h from the start of alteplase therapy, then every 30 min for 6 h, and then every hour for 16 h. Patients with BP higher than 185/110 mmHg before thrombolysis therapy or higher than 180/105 mmHg within 24 h from the beginning of IVT were treated by intravenous pumping of urapidil or nicardipine using the same protocol. In similar articles, we have seen that the time points focus on the admission, immediate completion of thrombolysis, 24 h, daytime and nightime in 24 h, and the most commonly used parameters are average value (mean), maximum value (max), minimum value (min), range (maximum–minimum), standard deviation (SD), and successive coefficient of variation (SV).2.3The primary functional outcome was the mRS score at 90 days after stroke onset. Three months after the occurrence of ischemic stroke, the neurological impairment caused by stroke can be basically terminated. Walking function is the necessary function basis for patients to carry out daily living activities, and the improvement of walking ability in stroke patients is positively and linearly correlated with the future quality of life. Since the mRS scale takes the walking ability as a clear scoring standard, which was used the mRS score > 2 as the demarcation value of disability, it is widely used in stroke‐related studies and is one of the gold standards for evaluating the independent living ability of stroke patients. A favorable outcome was defined as an mRS score of 0–2 points, whereas an unfavorable outcome was defined as an mRS score of 3–6 points.sub‐item that occurred at 24 h following alteplase infusion; these criteria were previously used to define significant deterioration.The secondary outcome events included early neurological deterioration (END) and improvement (ENI). END was defined as an increase in the National Institutes of Health stroke scale (NIHSS) score ≥4 points or as an increase ≥2 points in one 2.4Medical records were retrospectively reviewed by a nurse who was blinded to patients' outcomes and the following information was retrieved: demographic data , medical history , vascular risk factors defined by our research team  to identify superior BP trajectories.2.7p < .1). All statistical tests were two‐sided, and statistical significance was considered at p < .05. Statistical analyses were performed using SPSS v.22.0 .Continuous data were reported as means ± standard deviation and were analyzed using one‐way ANOVA or Kruskal‐Wallis tests as appropriate. Categorical data were presented as frequency and percentages and were analyzed using the chi‐square test. Logistic regression analysis and area under the curve (AUC) were used to determine the association between neurological damage and different BP trajectory groups, previous BP parameters. The strengths of the associations were determined by estimating the odds ratios (OR) and their 95% confidence interval (CI). To detect changes in associations between outcome and main exposures, the following multivariate logistic models were constructed: model 1 = no covariates; model 2 = statistical demographic indicators; model 3 = model 2 + all statistical indicators  were male, 96 (27.2%) were female, and the mean age was 62.49±11.79 years.3.1n = 22, 6.2%); group 2 ; group 3 ; group 4 ; and group 5 . In group 1, BP was relatively low with the highest point being below normal, and it fluctuated widely during the first 3 h. Groups 2, 3, and 4 showed stable BP after a rapid and steady decline within 1.5–2 h, whereas groups 2 and 3 had normal to high BP; the BP in group 4 remained stable at about 150 mmHg. In group 5, BP declined rapidly and steadily for the first 1.5 to 2 h, followed by wavy fluctuations.Five groups were identified based on the SBP trajectory during the first 24 h after the beginning of IVT Figure . The groPatients in these five SBP trajectory groups had distinct clinical profiles and laboratory results Tables , 2. Pati3.2n = 67, 19.3%); group 2 ; group 3 ; group 4 . The only difference between groups 1–3 was the DBP level reached after the BP dropped.Four groups were identified based on the DBP trajectory Figure . Group 1Patients in these four DBP trajectory groups had distinct clinical profiles and laboratory results Tables , 2. GrouThe trend of the graph in Figure 3.3After IVT, there were 67 (19.0%) cases of END, 131 (37.1%) cases of ENI, and 242 (68.6%) patients with an mRS score 0–2 at the 3‐month follow‐up. To examine the association between BP trajectory groups and outcomes, the groups were included as independent variables in a logistic regression model, and the moderate stable BP trajectory groups  were considered as the control groups (Table 3.4p < .05). At the same time, the diagnostic value of SBP trajectory is not inferior to other BP parameters. With regard to the 3‐month MRS score, only BP trajectory showed a strong correlation with it. Other BP parameters could not be used as an indicator to predict the stroke functional status after 3 months; however, the mean and maximum values at any time point were more valuable for its diagnosis , fluctuating high SBP/DBP (162–173/92–101 mmHg), or rapidly high stable SBP/DBP (150–157/82–88 mmHg) groups was an independent predictor of adverse events. The clinical significance of this study is that our findings may help identify patients at a high risk of future vascular events and those requiring intervention.This study does not need any fund support, and all the work is completed within the normal work content and time. The data used in the study is also easy to access.There are no conflict of interest.Conceptualization: Kaiting Fan, Jie Zhao, Hong Chang, xin Yang.Data curation:Kaiting Fan, Jie Zhao, Hong Chang.Investigation:Kaiting Fan, Xiaojuan wang, Xiaoxia yao.Methodology:Kaiting Fan, Jie Zhao.Project administration:Kaiting Fan, Hong Chang, Hui Yao, xin Yang.Supervision: Kaiting Fan, Hong Chang, Hui Yao. xin Yang.Visualization:Kaiting Fan.Writing – original draft: Kaiting Fan.Writing – review & editing: Kaiting Fan, Jie Zhao, Hong Chang.


Background: Poor cognitive function can predict poor clinical outcomes. Intensive blood pressure control can reduce the risk of cardiovascular diseases and all-cause mortality. In this study, we assessed whether intensive blood pressure control in older patients can reduce the risk of stroke, composite cardiovascular outcomes and all-cause mortality for participants in the Systolic Blood Pressure Intervention Trial (SPRINT) with lower or higher cognitive function based on the Montreal Cognitive Assessment (MoCA) cut-off scores.Methods: The SPRINT evaluated the impact of intensive blood pressure control (systolic blood pressure <120 mmHg) compared with standard blood pressure control (systolic blood pressure <140 mmHg). We defined MoCA score below education specific 25th percentile as lower cognitive function. And SPRINT participants with a MoCA score below 21 (<12 years of education) or 22 (≥12 years of education) were having lower cognitive function, and all others were having higher cognitive function. The Cox proportional risk regression was used to investigate the association of treatment arms with clinical outcomes and serious adverse effects in different cognitive status. Additional interaction and stratified analyses were performed to evaluate the robustness of the association between treatment arm and stroke in patients with lower cognitive function.Results: Of the participants, 1,873 were having lower cognitive function at baseline. The median follow-up period was 3.26 years. After fully adjusting for age, sex, ethnicity, body mass index, smoking, systolic blood pressure, Framingham 10-year CVD risk score, aspirin use, statin use, previous cardiovascular disease, previous chronic kidney disease and frailty status, intensive blood pressure control increased the risk of stroke  in patients with lower cognitive function. Intensive blood pressure control could not reduce the risk of composite cardiovascular outcomes  and all-cause mortality  in lower cognitive function group. In patients with higher cognitive function, intensive blood pressure control led to significant reduction in the risk of stroke , composite cardiovascular outcomes  and all-cause mortality  in the fully adjusted model. Additionally, after the full adjustment, intensive blood pressure control increased the risk of hypotension and syncope in patients with lower cognitive function. Rates of hypotension, electrolyte abnormality and acute kidney injury were increased in the higher cognitive function patients undergoing intensive blood pressure control.Conclusion: Intensive blood pressure control might not reduce the risk of stroke, composite cardiovascular outcomes and all-cause mortality in patients with lower cognitive function. With aging of the global population, the incidence of hypertension and cognitive impairment has gradually increased, leading to a large social and economic burden –3. The rPrevious studies have reported that populations with poor cognitive function have a higher mortality rate. Batty et al. assessed the cognitive function of more than one million men at age 18, and followed them for an average of 20 years; thus, they found a dose-response relationship between mortality and cognitive function with worse cognitive function and a higher risk of mortality . In a poPrevious studies found benefits of intensive blood pressure control, including decreasing the risk of primary cardiovascular events and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT) and stroke in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial , 16. Coghttps://biolincc.nhlbi.nih.gov/studies/sprint/). We obtained baseline demographic data, laboratory data, physical examination data, baseline Montreal Cognitive Assessment (MoCA) score, prior disease and medication history, and endpoints from the dataset provided by the SPRINT research group. The SPRINT research was conducted in 102 clinical sites in the United States and enrolled 9,361 participants (2), Framingham 10-year CVD risk score ≥15% on the basis of laboratory examination in the last 12 months, or age ≥75 years. Patients with type 2 diabetes mellitus, prior stroke, polycystic kidney, and participants with a standing systolic blood pressure of <110 mmHg at baseline were excluded. The intervention was stopped after a median follow-up of 3.26 years owing to a significant reduction in primary cardiovascular events and all-cause mortality in the intensive treatment group compared with that in the standard treatment group  . The fraThe primary outcome of our study was stroke. The secondary outcomes included composite cardiovascular outcomes and all-cause mortality. The composite cardiovascular outcomes were the first occurrence of cardiovascular events after randomization, including myocardial infarction (MI), non-MI acute coronary syndrome (non-MI ACS), new-onset stroke, heart failure, and death attributable to CVD. The definition of clinical outcomes was previously published in the SPRINT protocol . The secSerious adverse events were defined as fatal or life-threatening events that resulted in a severe or persistent illness requiring hospitalization, prolonged hospitalization, or a medical event determined by the investigator to be a significant hazard or injury to the participant and requiring medical or surgical intervention to prevent injury. Serious adverse events observed in this study included hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, and acute kidney injury.t-test  or Mann-Whitney U-test (skewed distribution) were used to determine any significant differences between the means or medians of the two groups. The normal distribution of data was assessed using a normal Q–Q plot.Categorical variables are expressed as frequencies or percentages. Means ± standard deviations or medians (interquartile ranges) were used for continuous variables based on the distribution of data. We compared the baseline characteristics between intensive and standard blood pressure control in LOWER_CF and HIGHER_CF, respectively. Differences in categorical variables between the treatment arms were evaluated using the Chi-square analysis. The two-tailed To determine whether the benefits of intensive blood pressure control remain robust in different cognitive status, the Cox proportional risk regression was used to compare the clinical outcomes and serious adverse effects of intensive and standard blood pressure control within the lower or higher cognitive functions, respectively. According to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement , Model 1The robustness of the results in various subgroups  were also evaluated by stratified analyses and interaction tests.http://www.R-project.org) and EmpowerStats . Statistical significance was set at P < 0.05.All analyses were performed using the statistical software packages R . We also investigated the association between intensive blood pressure control and stroke in patients with lower cognitive function based on other MoCA cut-offs  and syncope  in patients with lower cognitive function. In the higher cognitive function group, intensive blood pressure control could increase the risk of hypotension , electrolyte abnormality  and acute kidney injury . The results of the relationship between the treatment arms and other serious adverse effects within different cognitive status were shown in After full adjustment for all covariates in Model 3, the intensive blood pressure control was associated with an increased risk of hypotension (HR: 2.05, 95% CI: 1.03–4.08, post-hoc analysis of SPRINT, we observed that lower cognitive function might attenuate the benefit of intensive blood pressure control for stroke, composite cardiovascular outcomes and all-cause mortality. In old hypertensive patients with lower cognitive function, the intensive blood pressure control could increase the risk of stroke in all models. For patients with higher cognitive function, intensive blood pressure control could reduce the risk of stroke, composite cardiovascular outcomes and all-cause mortality.In this A large number of studies have investigated the effect of antihypertensive strategies on CVD and mortality in different populations. The benefits of intensive blood pressure control include decreasing the risk of primary cardiovascular events and all-cause mortality in the SPRINT and stroke in ACCORD blood pressure trial , 16. A pIn our study, intensive blood pressure control increased the risk of stroke in patients with lower cognitive function. A possible explanation for the increased risk of stroke is that intensive antihypertension might reduce cerebral blood flow. The results of the Secondary Prevention of Small Subcortical Strokes trial showed a J-shaped association between blood pressure and the risk of stroke among patients with recent lacunar infarcts. Systolic blood pressure <120 mmHg and diastolic blood pressure <65 mmHg were associated with an increased risk of stroke . It is wThis study also found that intensive blood pressure control could not reduce the risk of cardiovascular outcomes and all-cause mortality in patients with lower cognitive function, which conflicted with findings from the SPRINT. This might be mainly attributed to the vulnerability and frailty of patients with lower cognitive function. Several studies have reported that poor cognitive function is associated with a significantly increased risk of mortality , 28–31. post-hoc analysis of the North American population. The results might not be applicable to other regions and countries because of the impact of race and culture on cognitive assessment.Our study had some limitations. The main limitation of our study was that it was a secondary analysis of the SPRINT. Although we adjusted as much as possible for a large number of risk factors that might have altered the clinical outcome, we were not able to adjust for all variables that might affect the outcomes due to the limited database available. Additionally, MoCA was a cognitive screening test and insufficient to reflect true impaired cognitive function. This study was a In hypertensive patients with lower cognitive function, intensive systolic blood pressure control might increase the risk of stroke, hypotension and syncope. However, composite cardiovascular outcomes and all-cause death did not differ between the treatment arms. Therefore, the management of hypertensive patients with lower cognitive function should be carefully considered, and individualized treatment should be sought.https://biolincc.nhlbi.nih.gov/studies/sprint/.Publicly available datasets were analyzed in this study. This data can be found here: JY and KZ statistically analyzed the data and wrote the manuscript. JY, KZ, and AL prepared the figures and tables. WC provided the ideas and revised the manuscript. All the authors agree with the published version of the manuscript.This study was supported by the Capital Health Development Scientific Research Project 2020-2-2064.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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