Mean decrease in BP were SBP, 14.44 versus 8.22 mmHg (p = .030), and DBP 5.53 versus 1.93 mmHg (p = .032). The salt sensitivity was improved more in group A. There was no different between change in CAVI. From this study, salt meter in conjunction with dietary education, for self‐monitoring of salt intake is superior to education alone in hypertensive patients, and provided better blood pressure control. Salt meter should be considered in uncontrolled hypertensive patients.Salt intake over reference level would result in elevated blood pressure (BP) and long‐term morbidity. Salt meter is a device used to detect sodium content in daily food. This study aimed to evaluate the efficacy of salt‐meter addition to dietary education. The authors conducted a randomized‐controlled trial in hypertensive patients with uncontrolled BP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg). Patients were randomized to receive salt meter plus dietary education (group A) or education only (group B), and followed up for 8 weeks. The primary endpoint was change in 24‐h urinary sodium excretion. Changes in BP, salt taste sensitivity, cardio‐ankle vascular index (CAVI) were also analyzed. There were total number of 90 patients who had complete follow‐up, 45 in each group. Mean age was 62.9 years and 53% were females. Mean baseline 24‐h urine sodium was 151.6 mmol/24 h and mean SBP and DBP were 152.8 and 83.4 mmHg, respectively. Baseline characteristics were similar between two groups. At 8 weeks, mean change in urine sodium were –31.83 mmol/24 h and 0.36 mmol/24 h in group A and group B, respectively ( According to Health Data Center of Ministry of Public Health, the incidence of newly diagnosed hypertensive patients in Thailand was increasing each year, from 916.89 per 100000 populations in 2014 to 1370.25 per 100000 populations in 2018.High dietary salt intake was believed to be associated with hypertension and was demonstrated in many clinical studies. Each 1‐gram (g) sodium intake over the reference level would result in 2.11 mmHg increment in SBP and 0.78 mmHg increment in DBP.Dietary salt reduction campaigns have been launched in several countries; however, most of them, especially in low‐ and middle‐income countries,People who regularly consume high sodium diet are less sensitive to salty tasting and have higher salt taste threshold. This factor, in turn, results in the higher sodium intake afterwards.Salt meter is a device used to measure the sodium chloride content in any particular food and display the results to guide users. Salt meter, in conjunction with comprehensive health education would pave the way to the successful outcome, which could lead to better blood pressure control and lessen the risk of cardiovascular complications.This study aimed to evaluate the efficacy of self‐monitoring of salt intake by salt meter device in patients with uncontrolled hypertension by measuring changes in 24‐h urine sodium excretion which reflects the daily salt intake, blood pressure (systolic and diastolic BP), salt taste sensitivity, and estimating the vascular risk by cardio‐ankle vascular index22.1SMAL‐SALT study is a single‐center, randomized, controlled open‐labeled study with 8‐week treatment outcome. The study protocol had been reviewed and approved by the Ethical Committee of Human Rights Related to Research Involving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University  and our trial was conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki. This trial was registered at Clinicaltrials.gov, number NCT04286802.2.22, and able to collect 24‐h urine.Enrolled patients were at least 18 years of age and were diagnosed with hypertension for more than 3 months including either patients with antihypertensive naïve or currently on antihypertensive drug(s). The patients were eligible for study entry if the 24‐h urine sodium was more than or equal to 90 mmol per day (comparable to sodium intake over 2 g per day), average systolic blood pressure between 140 and 180 mmHg or diastolic blood pressure between 90 and 110 mmHg using last three consecutive hospital visits, no recent adjustment of antihypertensive agents (within 1 month), estimated glomerular filtration rate (eGFR) above 45 ml/min/1.73m2), hyponatremia , unable to collect 24‐h urine, or denied to enter the study. Adjustment of any antihypertensive agents during study period was not allowed to minimize the confounding to the measured outcome. Patients were excluded during the study if they had systolic blood pressure over 180 mmHg, had obligatory indication to adjust antihypertensive drug regimen, or presented with hypertensive emergency such as acute myocardial infarction, heart failure, or cerebrovascular event.The exclusion criteria were chronic kidney disease stage 3B and below (eGFR less than 45 ml/min/1.73 m2.3The primary objective was to compare the change in 24‐h urine sodium excretion (which represents daily consumption of sodium) from baseline between group of uncontrolled hypertensive patients using salt meter for self‐monitoring of salt intake plus dietary education and those receiving dietary education alone. The secondary objectives were to compare changes in systolic and diastolic blood pressure, salt taste detection threshold , and cardio‐ankle vascular index (CAVI). Patient‐reported adverse events, significant electrolyte abnormality, and hypertension‐related emergency condition were also monitored.2.4The study was conducted at Ramathibodi Hospital  during June 2017 to January 2020. Participants were recruited from outpatient department  at Ramathibodi Hospital, Mahidol university . All participants were evaluated for eligibility before randomization and follow‐up. All patients gave written informed consent before initiation of the protocol.Hypertensive patients whose blood pressure was uncontrolled were 1:1 randomly assigned, by computer‐generated random numbers, to receive salt meter device for self‐monitoring of salt intake in addition to dietary education by dietician (group A or device group) or receive only dietary education by dietician (group B or control group).Each patient was arranged to follow up at 4 and 8 weeks after recruitment and randomization. Patients received brief clinical interview and focused physical examination, measured weight and blood pressure, taken blood for serum sodium, creatinine and eGFR, collected urine for spot urine protein and creatinine at baseline and at 8‐week visits. Twenty four hour urine was collected within a day before placing specimen to a laboratory unit to measure 24‐h urine sodium excretion at baseline, 4, and 8 weeks Figure . We esti2.4.1Urine samples were collected on the day of completion for determination of urine volume, sodium and creatinine excretion. Urinary sodium was determined using the indirect ion‐selective electrode method and the enzymatic method for urine creatinine assay. Urine samples were considered incomplete and discarded if (a) total urine volume was less than 500 ml in 24‐h collection; (b) estimated daily urinary creatinine excretion was less than 0.98 g/day for males and less than 0.72 g/day for females2.4.2We, in collaboration with Faculty of Engineering, Mahidol University, Thailand, developed the user‐friendly version of salt meter devices using PPM/TDS meter with total dissolved solids expressed in parts per million (ppm) by measuring the electrical conductivity of sodium chloride in food and converting into ppm unit. The devices use the alternating electrical current, which has high frequency, to accurately determine the concentration of sodium chloride from a range of 0–5%. The display screen was developed to display the result in emotion or emotional face graphic that would be easy to understand for all users Figure . When th2  = 0.8559). We also performed device calibration at the follow‐up visit (week 4) for patients who received salt meter for self‐monitoring. After complete follow‐up, we collected the used devices to check for battery remaining and calibration with standard normal saline solution before giving them to the next patients.Validation of the salt meter could be performed by self‐calibration before each use by study participants. By applying the salt meter in standard normal saline solution and pressing the calibration button, it will automatically be calibrated to read at 0.9% salt. The participants were then informed how to do calibration when needed. Furthermore, we have compared results from our salt meter with the standard laboratory analysis for sodium in food using Inductively Coupled Plasma Optical Emission Spectrometer (ICP‐OES) Perkin Elmer Optima 8000, AOAC (2016) at the Institute of Food Research and Product Development, Kasetsart University, Bangkok, Thailand, which showed good correlation  and a salt solution (2–256 mM in 2‐fold steps). For each presentation, participants were informed to taste the samples in order from left to right by putting each sample solution all at once, gargling in their mouth and spitting. Between each series of presentations, participants rinsed their mouths with distilled water. Participants were asked to indicate which of the samples contained the taste (detection threshold) and to describe the taste (recognition threshold). If a participant perceived no difference between the three samples at any presentations, they were asked to choose one (forced choice). The individual best‐estimated detection and recognition thresholds (BETs) was calculated by the geometric mean of the last missed concentration and the next higher concentration detected, considering it as the first of all subsequent concentration correctly answered. The group best‐estimated detection and recognition thresholds were calculated considering the geometric means of the individual BETs. The salt taste sensitivity testing had been done at baseline and 8 weeks after enrollment in both intervention and control groups.2.4.5CAVI is a non‐invasive instrument that was used to predict arterial stiffness and is comparable with other parameters of atherosclerosis. It is measured by an electrocardiogram (ECG), phonocardiogram (PCG), and pulse‐wave velocity (PWV) from the starting point of the aorta from the heart to the ankle as well as blood pressure. This index is calculated from the heart–ankle pulse wave velocity (haPWV) adjusted for blood pressure based on a stiffness parameter. In our study, we used a VaSera CAVI instrument . The patients were in supine position; then the ECG, PCG, blood pressure, and pulse wave velocity were monitored and CAVI was derived from preset formulation.2.5n4studies program version 1.4.0.We did a primary analysis based on intention‐to‐treat populations. We calculated the sample size with the For the statistical analyses, we used the SPSS program version 18.0. Descriptive analysis was done and showed in terms of number, percentage, and mean ± standard deviation (SD). We used Chi‐square test for any independent categorical values. For continuous values, we used Student t‐test or one‐way ANOVA for any independent data. Two‐way ANOVA was used to determine interaction between independent factors for additional analysis. All tests were prespecified to the 5% significant level.32.A total of 100 patients were enrolled, with 90 patients who met the inclusion criteria and had complete follow‐up, 45 in group A or device group  and 45 in group B or control group (dietary education only). All patients were diagnosed as primary hypertension. There was no crossover between both groups. From all patients, mean age was 62.9 years old. 49 of 90 patients (53%) were females. 11.1% were antihypertensive‐naïve, and median number of currently received antihypertensive agents was two. Mean baseline 24‐h urine sodium was 151.6 mmol/24 h and mean baseline SBP and DBP were 152.8 and 83.4 mmHg, respectively. Mean serum creatinine and eGFR were 0.86 and 84.37 ml/min/1.73 mp > .05). There was no statistically different in classes of antihypertensive drugs between two groups. Mean CAVI was 8.08 in group A and 8.64 in group B without statistically significant (p = .103).Demographic data and baseline characteristics for each group were showed in Table p = .006). This signified lower daily sodium consumption in group A (device group) compared to group B (control group) (Table Table p) Table . We havep = .030). Mean change in diastolic blood pressure was –5.53 ± 7.3 mmHg in group A and –1.93 ± 8.1 mmHg in group B (p = .032) . All patients have more motivation to maintain low salt diet after completion of the study. No adverse event or critical laboratory abnormality was observed throughout the study.For secondary endpoints Table , mean ch) Figure . FurtherConcerning the adherence of salt meter device usage, all patients who received the salt meters were in good compliance, according to the salt meter diaries which they had reported to the investigators during the follow‐up period.4In uncontrolled hypertensive patients who are on antihypertensive medications or those who are treatment‐naïve, high dietary salt intake is considered to be an important contributing factor. Our study shows that, in addition to usual care and comprehensive dietary education about sodium reduction by dietician, salt meter device for self‐monitoring of salt intake has a superiority in efficacy to reduce 24‐h urine sodium excretion and blood pressure compared with dietary education alone. Reduction in 24‐h urine sodium excretion reflects the lowering in dairy sodium consumption. Additionally, there is a trend in improvement of salt detection threshold that potentially be the factor for maintaining low‐salt consumption behavior.Based on what we know, this is the first randomized‐controlled trial focusing on the role of salt meter device as an assisted tool to the salt reduction strategy and blood pressure control in uncontrolled hypertensive patients. Diuretics use, as a possible confounding factors of urinary sodium excretion, was similar between two groups Table . Our priRegulating salt intake behavior in hypertensive patients would finally result in better blood pressure control. Subsequently, better blood pressure control would affect any future morbidity and mortality associated with hypertension. There are many evidences revealed causal relationship of quantity of salt intake and blood pressure.Because of many possible confounding factors contributing to the blood pressure, we decided to use the less‐confounded objective outcome which is urinary sodium excretion as a primary endpoint instead of the blood pressure. With maximal effort to minimize the confounding factors, randomization showed similarity in baseline characteristics data between two groups. In term of blood pressure control, patients in group A or device group have pronounce magnitude in both systolic and diastolic blood pressure lowering; 14.44 and 5.53 mmHg, respectively. These numbers are significantly lower in those of control group with differences of 6.2 mmHg for systolic blood pressure and 3.6 mmHg for diastolic blood pressure. Despite the minimal change in 24‐h urine sodium excretion in group B, there was small decrement in blood pressure. We believed that the effect of BP lowering seen in this study was partly from Hawthorne effect. However, there would be Hawthorne effect in both groups, but more pronounced BP lowering in group A could be attributed by salt meter intervention. The effect size in our study is rather larger when compared to DASH diet which reduced systolic blood pressure by 2.8 mmHg and diastolic blood pressure by 1.1 mmHg more than control diet.In hypertensive patients, the salt taste sensitivity is worse compared to healthy populationConversely, this trial could not demonstrate the significant change in CAVI parameter between two groups at the end of follow‐up. This might be from the relatively short period of follow‐up to observe the vascular change. Longer duration of follow‐up may require to see the change in atherosclerotic outcome.Somehow, there were some limitations of our study such as non‐blinded study, since the salt meter device in the intervention arm could not be blinded, neither using placebo in the control arm which might be harmful and unethical. However, we used an objective outcome measurement rather than subjective outcome as well as many approaches to reduce the bias. Dietary education was arranged in the same directions for all participants with same dataset for teaching and certificated dietician who did not know for the patients’ allocation. Blood pressure measurement and salt taste sensitivity testing were done with protocol‐directed guidelines by the staffs who did not know for the patients’ allocation.Salt meter as a device for self‐monitoring of salt intake will facilitate hypertensive patients who have chronic high sodium consumption behavior to be more awareness, self‐learning to food with low sodium content, and will gradually improve their salt taste sensitivity. Due to technical design of salt meter that it cannot apply to the solid object or food, some food may be not suitable for testing with salt meter device. Nevertheless, we postulated that use of salt meter would habituate patients to learn which food has high or low content of sodium and subsequently results in eating habit adaptation. Eventually, people may not necessarily need the device for regular monitoring. Lowering salt intake could reduce salt‐water retention and regulate the renin‐angiotensin‐aldosterone system which finally result in blood pressure decrement.In conclusions, salt meter in conjunction with dietary education, for self‐monitoring of salt intake is superior to education alone in hypertensive patients, and provided better blood pressure control. Improvement in salt taste sensitivity will facilitate the long‐term benefit. Salt meter should be considered in patients with uncontrolled hypertension.None declared.Sirichai Wiriyatanakorn Project administration, Study design, Acquisition of data, Analysis of data, Drafting and revision of manuscript, Anucha Mukdadilok Acquisition of data, Surasak Kantachuvesiri Study conception and design, Revision of manuscript, Chusana Mekhora Acquisition of data, Analysis of data, Teerapat Yingchoncharoen Corresponding author, Study conception and design, Funding acquisition, Revision of manuscript.


Arterial stiffness ), peripheral and central blood pressures were measured pre‐consumption, 30 min post‐consumption, and 120 min post‐consumption. Prior to each measurement period, beat‐to‐beat hemodynamic measures were collected. Changes in heart rate, blood pressure, and cardiac output from pre‐consumption did not differ between trials at any timepoint (p ≥ 0.06). Moreover, changes in peripheral or central blood pressures from pre‐consumption did not differ between trials (p ≥ 0.84). Likewise, changes in cfPWV from pre‐consumption to 30 min post‐consumption  and 120 min post‐consumption  did not differ. Changes in aortic augmentation pressure, augmentation index, augmentation index corrected to a heart rate of 75 bpm, and reflection magnitude did not differ between conditions at 30 min post‐ (p ≥ 0.55) or 120 min post‐ (p ≥ 0.18) consumption. In healthy young adults, ingesting 500 ml of a commercially available caffeinated soft drink sweetened with high‐fructose corn syrup does not acutely change indices of arterial stiffness and wave reflection.We tested the hypothesis that ingestion of a caffeinated soft drink sweetened with high‐fructose corn syrup acutely increases arterial stiffness. In a randomized counterbalanced, crossover design, fourteen healthy adults  reported to the laboratory for two experimental visits where 500 ml of tap water (H This study investigated whether the ingestion of a caffeinated soft drink sweetened with high‐fructose corn syrup acutely modified arterial stiffness. In a randomized counterbalanced, crossover design, fourteen young healthy adults consumed 500 ml of tap water or a caffeinated soft drink sweetened with high‐fructose corn syrup, after which carotid‐to‐femoral pulse wave velocity was measured. This study found that ingesting 500 ml of a commercially available caffeinated soft drink sweetened with high‐fructose corn syrup does not acutely change indices of arterial stiffness. Using this effect size, we estimated that thirteen participants were needed to detect differences in cfPWV using standard parameters of 1‐β = 0.80 and α = 0.05. Therefore, we recruited fourteen adults  to participate in this study. All participants self‐reported to be healthy, were non‐obese, normotensive, non‐tobacco users, reported no history of cardiovascular, kidney, autonomic, or metabolic diseases and were not taking any medications, except for hormonal contraceptives (n = 2). Participant physical characteristics were—height: 173 ± 9 cm, weight: 73.5 ± 13.9 kg, body mass index: 24.6 ± 3.6 m2/kg. Participants self‐reported to consume sugar‐sweetened soft drinks 1 ± 2 days/week. It is notable, however, that neither the inclusion nor exclusion criteria for this study considered habitual sugar‐sweetened soft drink consumption. All study procedures and informed consent documents were approved by the Indiana University Institutional Review Board. The study conformed to the standards set by the Declaration of Helsinki, except for registration in a database. Before completing any study‐related activities, each participant was fully informed of the experimental procedures and possible risks before providing informed, written consent.An 2.2Height was measured with a stadiometer , and body weight was measured using a digital scale . Urine specific gravity was measured using refractometry . Heart rate was measured via a 3‐lead electrocardiogram . Beat‐to‐beat blood pressure was measured via the Penaz method . Beat‐to‐beat blood pressure data were corrected to blood pressure measured via a manual auscultation of the brachial artery on their right arm. All manual blood pressure measurements were performed in duplicate by the same operator for both experimental trials within each participant. Pulse pressure was calculated by subtracting diastolic pressure from systolic pressure. Stroke volume was estimated from the arterial pressure waveform using the three element Windkessel model  was used to measure cfPWV by sequentially recording electrocardiogram gated carotid and femoral artery pressure waveforms  or 500 ml of Mountain Dew®  in their first visit and consumed the other beverage on their next experimental visit. Randomization was conducted in blocks of two to ensure trial order was counterbalanced. Outcome assessors were not blinded to the experimental conditions.The present study employed a randomized, counterbalanced crossover design. Participants visited the laboratory on three occasions. Visit 1 included a screening and familiarization visit, while visits 2 and 3 were the experimental trials. Participants consumed either 500 ml of tap water  at the same time of day for each experimental trial to control for any potential diurnal effects. Participants were instructed to refrain from ingesting caffeine in any form , soft drinks, exercise, and alcohol for 12 hr whereas food was restricted for 2 hr prior to the experimental visits. The standardization of caffeine consumption may have resulted in caffeine withdrawal, but it was expected that the extent of this withdrawal would have been consistent for each visit. Although not formally quantified, participants were encouraged to maintain their normal exercise routines and diet throughout the duration of the experimental period. Female participants were tested during the first 10 days following menstruation (5 ± 3 days) to standardize measurements to the follicular phase of the menstrual cycle, when sex‐hormone levels are relatively low  and to confirm a negative a pregnancy test for female participants. Participants then laid in the supine position for instrumentation.Participants reported to a temperature‐controlled laboratory (Hp < 0.01). Mountain Dew is a high‐calorie, high‐fructose, caffeinated soft drink sweetened with high‐fructose corn syrup. Mountain Dew was selected because it has one of the highest free fructose concentrations among commercially available soft drinks  with random effects to control for participant in the repeated measures design. From the results of the linear mixed models, estimated marginal means using Sidak's adjustment for multiple comparisons were used to test for differences between the HFCS and H2O trials at the measurement time points. A priori statistical significance was set at p ≤ 0.05. Data are reported as mean ± SD.Steady‐state hemodynamic data were collected at 1 kHz via a data acquisition system . Steady‐state hemodynamics data were analyzed using the average over the last minute of each data collection period. Data were analyzed and presented as absolute values and as the change from pre‐consumption (Δ), the latter of which was deemed necessary to isolate the effect of beverage consumption on changes in the dependent variables over time. All data were statistically analyzed using Prism software . A two‐way linear mixed model was used to examine any differences in the dependent variables over time  and between experimental trials . At 30 min post‐consumption, a difference in heart rate was observed between the HFCS and H2O trials (p = 0.05), but no other differences were shown in the remaining hemodynamic variables at 30 min post‐consumption (p > 0.13) or 120‐min post consumption (p ≥ 0.06).Steady‐state hemodynamic data during the H3.2p ≥ 0.99), diastolic (p ≥ 0.09), and mean arterial (p ≥ 0.39) pressures measured immediately preceding the calculation of central blood pressure were not different at pre‐consumption in the HFCS and H2O trials. This translated to no differences in central systolic (p ≥ 0.71) and mean arterial (p ≥ 0.22) pressures and a slightly elevated central diastolic  pre‐consumption in the HFCS trial versus the H2O trial. There were no differences in peripheral (p ≥ 0.25) or central (p ≥ 0.13) blood pressure at 30 or 120 min post‐consumption between HFCS and H2O trials. Further, there were no differences in peripheral or central pulse pressures (p ≥ 0.99) at 30 or 120 min (p > 0.92) post‐consumption between HFCS and H2O trials.Peripheral and central blood pressure data are presented in Table 3.3p = 0.69, Figure p = 0.96, Figure p = 0.22, Figure p = 0.94, Figure p = 0.89, Figure p = 0.31, Figure p = 0.05). cfPWV at 30 min post‐consumption was higher in the HFCS trial (5.7 ± 0.6 m/s) compared with the H2O trial  or 120 min post‐consumption  aortic augmentation pressure , augmentation index at 75 bpm , reflection magnitude , forward wave magnitude , or reflected wave magnitude . Likewise, the change from pre‐consumption to 120 min post‐consumption did not differ between the HFCS and H2O trials for the augmentation index  aortic augmentation pressure , augmentation index at 75 bpm , reflection magnitude , forward wave magnitude , or reflected wave magnitude .There were no differences in cfPWV  or decreases in vasodilators  are known to acutely increase arterial stiffness (Kinlay et al., 4.12O trial. This is supported by evidence that chronic consumption of sugar‐sweetened beverages is associated with a greater risk of developing cardiovascular morbidity and mortality (Arsenault et al., 2O trial, perhaps due to the novelty of the high‐fructose corn syrup in the soft drink.Our participants were young, healthy individuals who consumed approximately one sugar‐sweetened soft drink per week. Approximately half of American adults consumed one or more sugar‐sweetened beverages on any given day (Kit et al., Our participants arrived at the laboratory following a 2 hr fast and after abstaining from caffeine for at least 12 hr. This is important given evidence that fructose consumption in the fed state may augment cardiovascular risk owing to the potentiation of the postprandial increase in plasma triglycerides that is dependent on hepatic glycogen stores (Hengist et al., To enhance the external validity of our study, we employed a commercially available caffeinated soft drink, as we previously reported (Chapman et al., In the current study, we did not collect blood samples to elucidate the effect of consuming a caffeinated beverage on circulating vasoactive compounds that may have modified systemic cardiovascular responses. We do not think that this is a limitation because even if circulating vasodilator/vasoconstrictors were modified by consuming 500 ml a caffeinated soft drink sweetened with high‐fructose corn syrup, these changes did not translate to changes in arterial stiffness or systemic hemodynamics.4.2The present study demonstrates that, compared with an equivalent volume of water, consumption of 500 ml of a commercially available caffeinated soft drink sweetened with high‐fructose corn syrup does not modify arterial stiffness or systemic hemodynamics over the subsequent 120 min of observation in young healthy adults. Thus, under the experimental conditions employed herein, consumption of a soft drink sweetened with high‐fructose corn syrup does not acutely modify factors associated with heighted cardiovascular risk. This conclusion is likely contributed to by the healthy and lean participant population that completed this study in a relatively fasted state. Moreover, it remains plausible chronic intake of beverages sweetened with high‐fructose corn syrup may lead to modification of cardiovascular responses. This possibility is highlighted by a recent study demonstrating that one week of daily consumption of a glucose‐sweetened beverage induced vascular endothelial dysfunction independent of changes in fasting glucose or insulin concentrations (Bock et al., 5Compared with drinking an equivalent volume of water, consumption of 500 ml of a commercially available caffeinated soft drink sweetened with high‐fructose corn syrup did not acutely modify arterial stiffness or systemic hemodynamics in fasted, young healthy adults.No conflicts of interest, financial or otherwise, are declared by the authors.SJC, BDJ, and ZJS contributed to conception and design; JAF, JTG, TB, ZJS performed experiments; JAF, JTG, and ZJS analyzed data; JAF, SJC, JTG, BDJ, and ZJS interpreted results; JAF prepared figures; JAF and ZJS drafted manuscript; All authors edited and revised manuscript; approved final version of manuscript.


To find risk markers and develop new clinical predictive models for the differential diagnosis of hand-foot-and-mouth disease (HFMD) with varying degrees of disease.  19766 children with HFMD and 64 clinical indexes were included in this study. The patients included in this study were divided into the mild patients' group (mild) with 12292 cases, severe patients' group (severe) with 6508 cases, and severe patients with respiratory failure group (severe-RF) with 966 cases. Single-factor analysis was carried out on 64 indexes collected from patients when they were admitted to the hospital, and the indexes with statistical differences were selected as the prediction factors. Binary multivariate logistic regression analysis was used to construct the prediction models and calculate the adjusted odds ratio (OR). β2MG, Glu, and Ca could be used for the differential diagnosis of severe/severe-RF (AUROC > 0.76).  SP, DP, NEUT#, NEUT%, RDW-SD, RDW-CV, GGT, CK/CK-MB, and Glu were risk markers in mild/severe, mild/severe-RF, and severe/severe-RF. Glu was a diagnostic marker for mild/severe-RF ; the predictive model constructed by temperature, SP, MOMO%, EO%, RDW-SD, GLB, CRP, Glu, BUN, and Cl could be used for the differential diagnosis of mild/severe (AUROC > 0.84); the predictive model constructed by SP, age, NEUT#, PCT, TBIL, GGT, Mb,  By analyzing clinical indicators, we have found the risk markers of HFMD and established suitable predictive models. Hand-foot-and-mouth disease (HFMD) is a common viral illness mainly caused by enterovirus 71 (EV71) and coxsackie A16 (CA16), which mainly affects children under 5 years of age . Most paAlthough many previous studies have focused on investigating the risk markers and exploring prediction models of HFMD –10, therhttp://www.nhc.gov.cn/wjw/gfxwj/201304/4a5c8d7485c64d189afd5392a390bd84.shtml/; http://www.nhc.gov.cn/yzygj/wslgf/201306/6d935c0f43cd4a1fb46f8f71acf8e245.shtml/; http://www.nhc.gov.cn/yzygj/s3594q/201805/5db274d8697a41ea84e88eedd8bf8f63.shtml/). Inclusion criteria were positive enterovirus-specific nucleic acid test  or isolated enterovirus and identified as CV-A16, EV-A71, or other enterovirus causing HFMD. We also excluded several children with erupting diseases . The data used in this study were all detected at the first visit of patients. This retrospective study was approved by the ethics committee of Jiangxi Provincial Children's Hospital.From April 2009 to January 2020, patients with HFMD admitted to Jiangxi Children's Hospital were selected as the study objects, and the definition diagnosis of HFMD was based on the guidelines for the diagnosis and treatment of hand-foot-and-mouth disease , tachycardia, cyanosis of the mouth, coughing pink foaming sputum or bloody fluid, decreased blood pressure, or shock. All data were collected independently of the evaluation of the study results.U test was used, and for variables that conform to the normal distribution, the independent-sample t-test was used. A P value < 0.05 was regarded as being statistically significant for all of the analyses. The adjusted odds ratio (OR) of each variable was obtained by logistic regression analysis. To estimate the ability to discriminate between patients with different diagnoses, we used the receiver operating characteristic (ROC) curve analysis for pairs of patients [Gender, age, clinical blood test indicators, and other information collected at the first visit of HFMD patients were taken as potential predictive variables, and cases with blood test indicators missing more than 30% and variables with data missing more than 10% were eliminated. The processing method of missing values in the data was as follows: mode was used for interpolation of classified variables and mean was used for interpolation of continuous variables. For variables that do not conform to the normal distribution, the Mann–Whitney patients . All anaGenerally, 19766 children with HFMD met the inclusion criteria of this study, and 3091 children were excluded. The patients included in this study were divided into the mild patients' group (mild) with 12292 cases, severe patients' group (severe) with 6508 cases, and severe patients with respiratory failure group (severe-RF) with 966 cases. 64 predictive variables met the requirements and 24 variables were excluded. Some basic information and information on variables of subjects in each group are shown in β2MG, CRP, K, Na, and Cl.Through the statistical analysis of all the indicators included in the study, we found that 52, 44, and 51 indicators showed statistical differences between mild/severe, severe/severe-RF, and mild/severe-RF, respectively, and 30 indicators showed significant differences among the three groups . With thCalculating the adjusted OR values between the mild/severe, mild/severe-RF, and severe/severe-RF groups, we found that a total of 19 indicators may be risk factors of mild development to severe (adjusted OR > 1.0), where temperature  and Glu  performed better . A totalROC curve analysis was used to investigate the diagnostic performance of each difference indicator. The top 10 indicators with good performance among each group are shown in To improve the diagnostic distinction effect between mild/severe and severe/severe-RF, we further established prediction models. Two-thirds of the participants were randomly assigned to the model development data set, and one-third was kept as the independent validation data set. The variables with significant differences in mild/severe and severe/severe-RF were used as the prediction variables, and binary logistic regression analysis was used to establish the prediction models. The inclusion criterion of model variables was the Akaike Information Criterion (AIC) , and steP = exp(K)/(1 + exp(K)) and K = 0.987 × temperature + 0.026 × SP − 0.073 × MOMO% − 0.291 × EO% + 0.089 × RDW − SD + 0.061 × GLB − 0.020 × CRP + 0.279 × Glu − 0.213 × BUN − 0.096 × Cl − 34.858; P > 0.5 was identified as a severe patient. Finally, in the model development data set, the AUROC was 0.845 (95% CI: 0.838-0.852) and the sensitivity and specificity were 72.19% and 81.84%, respectively /(1 + exp(K)), K = 0.047 × SP − 0.001 × age + 0.078 × NEUT#+2.621 × PCT − 0.068 × TBIL + 0.013 × GGT + 0.013 × Mb − 0.705 × β2MG + 0.154 × Glu − 2.060 × Ca − 1.790; P > 0.5 was identified as severe-RF patients. Finally, in the model development data set, the AUROC was 0.766 (95% CI: 0.745-0.786) and the sensitivity and specificity were 59.08% and 80.70%, respectively , which will lead to death , 4. TherWe analyzed the clinical data of patients with HFMD and found that temperature and Glu performed the best for warning of mild development into severe and severe-RF, and Glu performed the best for warning of severe development and severe-RF. Also, temperature and Glu as risk factors for HFMD have been reported in many pieces of literature , 13–15. Although China has issued diagnosis and treatment guidelines for HFMD, scholars have established various prediction models based on local climate conditions, seasons, and other information –18, usinDuring the development of the model, we tried to build a model with the indicators of significant differences between the mild/severe and severe/severe-RF groups as the predictive variables to differentiate and diagnose the mild/severe and severe/severe-RF at the same time, but the discrimination was not good. For example, the temperature has a significant difference in mild/severe, but no difference in severe/severe-RF. However, when developing the prediction model of mild/severe, there is a large difference in the AUROC of whether to include temperature in the model built for prediction variables (included/excluded = 0.845/0.802). Temperature is not included here, and the modeling data is only obtained during model development and no detailed data is provided in this paper. The severity of disease of mild, severe, and severe-RF is different, and the importance of different predictive variables in establishing the prediction model of mild/severe and severe/severe-RF is different. Therefore, we chose different prediction factors for mild/severe and severe/severe-RF to build two different prediction models.The advantage of our study is that, compared with the existing literature reports, the number of cases included in this study is more (19766 cases), covering mild, severe, and severe-RF patients, and for the first time, blood test indicators are used to establish the prediction model of severe and severe-RF. The limitations of this study, the lack of virus types in the data leading to HFMD, may lead to bias and limit clinical practice. Moreover, this study is a single-center retrospective study conducted in Jiangxi Province, China. We are not sure whether our results can show similar results in other ethnic groups in other regions. Finally, some qualitative indicators  also play a certain role in the diagnosis of HFMD with different conditions, but this study is not included. In the follow-up study, we will investigate whether combining these indicators will optimize our model.For the HFMD patients with mild, severe, and severe-RF, we have found appropriate risk factors and developed appropriate predictive models to help clinicians diagnose severe and severe-RF HFMD patients early.


Iron deficiency is prevalent in chronic heart failure (CHF) patients. Nonetheless, the diagnosis is often overlooked and, often, the treatment is commenced just when overt anemia has ensued. Therefore, a better appreciation of this disease is needed, and all seasoned cardiologists should know how to approach CHF patients with iron deficiency correctly, as mandated by clinical practice guidelines. In this comprehensive review, we describe iron homeostasis, the pathophysiologic changes of iron homeostasis, and the clinical implications of iron deficiency on CHF patients. In addition, we delineate the evolution of clinical trials, ranging from the inception to the ongoing clinical trials of iron deficiency treatment in CHF patients. Iron deficiency contributes to the worse clinical outcome of the patients. Numerous studies have reported the clinical benefit of iron supplementation, particularly in intravenous preparation, in heart failure patients regarding symptoms, functional capacity, and quality of life (QoL) improvement. Therefore, the current guidelines recommend routine screening of iron status in all newly diagnosed heart failure patients. Eventually, intravenous iron replacement is recommended for symptomatic heart failure patients with iron deficiency, irrespective of anemia. Heart failure is one of the most important cardiovascular diseases owing to its significant impact on mortality, morbidity, hospitalization rates, and quality of life (QoL) . DespiteHeart failure is a clinical syndrome caused by structural abnormality and/or ventricles systolic or diastolic dysfunction, which renders the inability of heart tissues to meet and maintain metabolic demands due to inadequate systemic and peripheral oxygenation . PresentConsequently, other than causing myocardial damage and injury, these maladaptive systemic responses inflict damage and disturbances to the vascular endothelium, kidney, skeletal muscles, bone marrow, lungs, and liver. These systemic pathomechanisms will manifest clinically as heart failure syndromes with their respective potential comorbidities in the course of illness. Various comorbidities and complications that accompany CHF will ultimately influence the progressivity, clinical symptoms, and prognosis of heart failure ,7.Iron deficiency is one of the comorbidities worthy of recognition in CHF patients and holds a promising and potential treatment target . HoweverIron homeostasis derangement is a common event in chronic diseases, especially CHF . SeveralAnother controversy is whether low serum iron is a consequence of protracted CHF or a comorbid factor that influences CHFs progressivity. Moreover, the diagnostic utility of serum iron monitoring in non-anemic CHF populations is not extensively studied and rarely checked in clinical practice.Cardiomyocyte’s metabolism and energetics in chronic heart failureThe process of energy metabolism in cardiomyocytes proceeds in three stages, i.e., substrate uptake and utilization, energy generation through oxidative phosphorylation, and energy transfer through creatinine kinase. Any derangement of these steps will ultimately cause contractility dysfunction. In CHF, several principal components needed for cardiomyocytes' energy metabolism are downregulated . A studyIn a physiologic condition, the primary substrate for cardiomyocyte's energy metabolism is the oxidation of fatty acids in the mitochondria . The invOther causes of diminished cardiomyocyte ATP production are the abnormality of mitochondrial structures and functions. Evidence points out that in dilated cardiomyopathy, hibernating myocardium, and advanced heart failure, the mitochondria were smaller and fragmented. Furthermore, mitochondria in failing heart cardiomyocytes experienced an imbalance in dynamics between mitochondrial fusion and division . The redSeveral studies have shown that mitochondrial dysfunction played a prominent role in the progressivity of heart failure . TherefoIron metabolism and regulationIron is an essential micronutrient and plays a multitude of functions in all of the human cells, which are metabolic and cellular proliferation, hemoglobin synthesis, DNA synthesis, oxygen transport and reserve, a cofactor of oxidative reaction, and cellular electron transfer. Moreover, iron plays a crucial part in a myriad of cellular enzymes, including the cytochrome system in mitochondria . On the The total iron in the human body is approximately 3-4 grams, and it varies between genders and ages. Erythrocytes and turnover products from erythrocytes destruction constitute two-thirds of the total body iron, and the rest is stored in the form of ferritin/hemosiderin. Therefore, erythrocytes dominate the total human body iron in the form of hemoglobin Table  23]. Ap. Ap23]. Iron metabolism in the human body is a semi-closed system that is strictly regulated, and it is designed to preserve iron concentrations via recycling so that it is available for another metabolic process . The humEvery stage of iron metabolism involves various molecules at the cellular level, i.e., gastrointestinal system iron absorption, bone marrow iron uptakes, reusing iron from the destruction of erythrocytes, iron storage, particularly in the liver, and its systemic regulation . Iron coIron absorption primarily occurs in the duodenum and the proximal part of the small intestines through the active process of intestinal villi, especially the luminal cells ,23. WithThe ferrireductase enzyme on enterocytes brush border reduces Fe3+ to Fe2+. Then, via the divalent metal transporter 1, Fe2+ will be transported through the cell membrane ,23. SomeIt is important to note that iron absorption is a dynamic process that is influenced by several physiologic conditions . In hypoApart from diet, another source of iron is recycled heme iron derived from erythrocytes breakdown. Each millimeter of blood contains 0.5 mg of iron. The average erythrocyte's life span is about 120 days, and subsequently, they got destroyed by macrophages in the reticuloendothelial system. The heme catabolism of degraded erythrocytes by HO-1 will generate free irons, which subsequently return into the circulation through ferroportin and bind with transferrin, to be used for another erythropoiesis . In patiIt has been previously mentioned that the circulating iron binds with a glycoprotein called transferrin. The majority of iron-transferrin complexes will get into the bone marrow and will be utilized for erythropoiesis . The turMoreover, circulating iron-transferrin complexes will interact with specific transferrin receptors ,32. To dThe interaction between iron-transferrin complexes and their corresponding receptors will cause endocytosis and internalization of the complexes within endosomes. In erythroblasts, the iron component will subsequently be utilized for heme synthesis, whereas transferrin will be returned into the circulation ,33. AfteHepcidin, a peptide that regulates systemic iron metabolism, is a negative regulator that restricts gastrointestinal iron absorption and prevents its release from the reticuloendothelial system -24,28-29The role of myoglobin in cellular energy metabolismMyoglobin is a cytoplasmic hemoprotein consisting of a single polypeptide of 154 amino acids. It is structurally and functionally similar to hemoglobin. The concentration of myoglobin varies among species and tissue. Myoglobin, as a cellular component in the human body, is abundantly found within the cardiomyocyte and oxidative skeletal muscle fiber .Myoglobin has an essential role in cardiac and skeletal muscle physiological function. It plays an important role at the cellular level, especially in oxidative metabolism and to bind, transport, and store oxygen intracellularly . Heme reMyoglobin is the most critical protein component of muscle to keep oxygen storage (oxymyoglobin/MbO2). Myoglobin also plays a role as intracellular partial oxygen pressure (PO2) through its capacity as an oxygen reservoir and transport in tissue. This buffer function allows intracellular concentration to remain reasonably constant and homogeneous despite an increase in muscle activity, permitting an optimal oxidative metabolism within mitochondria . The myoMyoglobin participates in facilitating oxygen diffusion to mitochondria, thus increasing oxygen influx to mitochondria, other than through a simple diffusion process -36. The Another study reported the function of myoglobin as a cellular antioxidant through its ability to bind to nitric oxide (NO), a molecule with both an advantageous and a disadvantageous cellular effect . NO can A study on mice found a shift of myocardial metabolism from fatty acid to glucose in myoglobin-deficient mice. This shift in metabolism happens as a compensatory mechanism, as myoglobin plays a part in the binding and facilitation of fatty acid diffusion through sarcoplasm . Other aPathomechanism of iron homeostasis in chronic heart failureDisruption of iron homeostasis is often found in various chronic diseases with systemic manifestation, such as connective tissue disease, inflammatory bowel disease, chronic kidney disease, including CHF . FurtherIn an exaggerated inflammatory state, the concentrations of hepcidin will rise. This acute-phase protein is solely responsible for functional iron deficiency by reducing ferroportin expression, limiting gastrointestinal tract iron absorption, iron redistribution from circulation to tissue iron reservoir, and iron retention within the reticuloendothelial system . NumerouIn the early stage of CHF, circulating iron decreased by 15%-30%. In comparison, the tissue iron reservoir or ferritin can increase by 24% . This siA low circulating iron level consequently disrupts active erythropoiesis in bone marrow, causing anemia. Moreover, iron deficiency exclusively can also cause organ dysfunction without full-blown anemia. A previous study found that cardiomyocyte's iron content is decreased in CHF patients because of neurohormonal activation, which reduces mRNA expression, downregulates Tfr1, and ultimately prevents iron uptake . Low carDysfunctional cardiomyocyte's cellular metabolism relating to iron deficiency can potentially cause cardiomyocyte contractility dysfunction . The decClinical implication of iron deficiency in chronic heart failureStudies in the past decade have found that iron deficiency is important comorbidity often found in CHF . HoweverThe prevalence of iron deficiency in CHF regardless of anemia is relatively high, around 30-50% ,48,50. AIron deficiency is also thought to contribute to the progressivity of structural dysfunction and remodeling in CHF. In an experimental animal model of iron deficiency studied for 12 weeks, it was found that there were left ventricular dilatation, mitochondrial macro-structure abnormalities, sarcomere structure irregularities, and an increase in oxidative stress response, including an increase in mitochondrial C cytochrome and reactive nitrogen species (RNS) .Several studies in the last few years reported the link between iron deficiency and worse clinical outcomes in CHF patients. Univariate and multivariate analysis in 546 systolic heart failure patients, ranging from mild to severe delineated iron deficiency as a strong independent predictor towards mortality and heart transplant ,48. AnotOwing to the significant impact of CHF on mortality, morbidity, and QoL, the issue of iron deficiency should not be underestimated, and adequate therapy with proven clinical efficacy and safety needs to be known by all cardiologists. Thus, we summarized the relevant evidence from randomized clinical trials and systematic reviews/meta-analyses. Numerous studies have demonstrated the clinical benefit of intravenous iron administration in CHF patients. A randomized clinical, prospective, double-blind study by Toblli et al. reported that the intravenously administered iron sucrose  lowers NT-proBNP and CRP levels significantly compared with placebo . The subThe Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) study, a large scale clinical trial of intravenous iron administration in chronic heart failure study, compared intravenous FCM preparation administration from placebo in a prospective, randomized, double-blind, multicenter trial of 459 heart failure patients with the NYHA functional class of II-III . Iron deThen, after four years of hiatus regarding iron therapy clinical trials in CHF patients, several studies started to emerge. The IRON-HF study in 2013 was a multicenter, randomized, double-blind, placebo-controlled trial that aimed to compare the effects of intravenous iron versus oral iron supplements in anemic heart failure patients . The intFerric Carboxymaltose (FCM) Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic Heart Failure (CONFIRM-HF) in 2015 was a multicenter, double-blind, double-blind, placebo-controlled trial that enrolled 304 symptomatic, iron-deficient HF patients to assess the potential long-term impact of intravenous iron therapy . PatientA study in CHF patients with chronic kidney disease and iron deficiency anemia as comorbids demonstrated the benefit of 200 mg/week intravenous iron administration for five weeks to improve cardiac structure and function, aside from clinical improvement . By the The Effect of FCM on Exercise Capacity in Patients with Iron Deficiency and Chronic Heart Failure (EFFECT-CHF)  study inThe European Society of Cardiology in 2016 recommended that iron status should be evaluated as part of the initial work-up of all newly diagnosed heart failure patients . FerritiThe iron preparation recommended for CHF patients is in the form of intravenous iron . The useTable The long-term effectivity and safety profile of intravenous iron therapy in CHF patients with iron deficiency still need to be confirmed by future large-scale studies. Some clinical questions regarding iron therapy yet to be answered by future studies include the benefit of oral iron therapy compared to intravenous therapy, the benefit and long-term effect of iron therapy in the clinical course of heart failure , the useIron deficiency is prevalent in CHF, but it is often overlooked, especially without existing anemia. This comorbid might contribute to a worse clinical outcome in patients. Numerous studies have reported the clinical benefit of iron supplementation, particularly in intravenous preparation, in HF patients with regards to symptoms, functional capacity, and QoL improvement. Therefore, the current guidelines recommend routine screening of iron status in all newly diagnosed heart failure patients. Eventually, intravenous iron replacement is recommended for symptomatic HF patients with iron deficiency, irrespective of anemia.


Moderate to severe obstructive sleep apnea (OSA) is associated with cardiovascular disease. Polysomnography is time intensive and difficult to access for diagnosis of OSA. Neck computed tomography (CT) provides upper airway delineation but not diagnostic criteria for moderate to severe OSA. We explored neck CT with computational fluid dynamics (CFD) study for airway pressure and airflow velocity to predict moderate to severe OSA.Enrolled from February 1, 2020, to June 30, 2021, patients with OSA with overnight oxygen desaturation (sPO2 <90%) received awake neck CT with a CFD study of their airway pressure and airflow velocity. CTL12 and CTL34 were defined as airflow velocity <3 and ≥3 m/s, respectively, and airway pressure <10 and ≥10 pa, respectively, in the narrowest upper airway.P = 0.004) and longer duration of sPO2 <90% at overnight oximetry  than those with CTL12. The values of the area under the receiver operating characteristic curves of airway pressure and of airflow velocity at the narrowest upper airway were 0.788 and 0.733, respectively.Sixty-two patients  were included; 12 and 50 patients had mild OSA and moderate to severe OSA, respectively. The minimum sPO2 in the supine position was 80.7 ± 9.1%. The total time of sPO2 <90% at overnight oximetry was 29.3 ± 51.1 min. Most (85.5%) neck CT examinations with CFD study presented CTL34. Patients with CTL34 had a lower minimum sPO2 in the supine position (78.4 vs. 88.1%, Neck CT with CFD study of airway pressure and airflow velocity may provide a quick prediction of moderate to severe OSA. Obstructive sleep apnea (OSA) is a so-called invisible killer disorder characterized by repetitive pauses of airflow through the upper airway with hypoxia during sleep . IntermiThe reference standard for diagnosis of OSA is a full-night polysomnography, a level 1 study, in a sleep center. However, patients with OSA experience substantial wait time (2–36 months) for sleep studies because OSA has become increasingly prevalent and diagnostic capacity remains limited –11. A fuThe pathogenesis of OSA may result from pharyngeal collapse during sleep. Pharyngeal collapse can occur at the retropalatal level (uvula), the retroglossal level (tongue base), and at the oropharyngeal lateral walls and the hypopharynx (epiglottis) . IdentifThe patients in the study were diagnosed as having OSA (AHI ≥ 5 episodes per hour) with overnight oxygen desaturation (sPO2 <90%) in a full-night level-1 polysomnography session in a sleep center of the Taichung Hospital from February 1, 2020, to June 30, 2021. All patients received awake neck CT to evaluate the obstruction level of the upper airway from the skull base to the thoracic inlet by using a 160-slice Toshiba AQUILION PRIME scanner  with the following settings: 120 kVp, automatic mA, 1-mm slice thickness, 5-mm reconstruction interval, 1:1 helical pitch, and 30-cm display field of view with an approximately 5-s scan time (approximately 5 mGy of radiation exposure). We further constructed a 3-dimensional mesh model and geometry of upper airway from CT Digital Imaging and Communications in Medicine (DICOM)  images (image size 512 × 512). We excluded those patients who slept for <4 h. All personally identifiable information was digitally encrypted by a system used in the hospital. The study was approved by the Institutional Review Board of Tsaotun Psychiatric Center, Ministry of Health and Welfare (110008).The generation of an unstructured surface mesh, which was then saved in a stereolithography file, required the delineation of the upper airway and importation of the images into Soteria OPZ  and further construction of CFD airflow simulation . The unst) was imposed at the inlet of the airway asThe 3-dimensional incompressible flows in turbulence were determined by the Reynolds-averaged Navier–Stokes equations (RANS) inside the upper airway. The gravitational effect, heat source, heat transfer, phase change, and chemical reactions were disregarded. Turbulence closure was obtained using the standard shear stress transport k–ω model . The velwhere Ui and f are the amplitude and frequency, respectively, of the variation in velocity . The traThe density and dynamic viscosity of inhaled fluid were set at 1.1614 kg/m3 and 1.846e−5 kg/ms, respectively, because we expected normal air inhalation from the nose. The inlet boundary was located at the nasopharynx and the velocity of the flow was variably set to represent normal breathing; the outlet boundary was positioned at the hypopharynx where the pressure was set at 0 Pa with the reference pressure of 1 atm. A no-slip condition was imposed on the surface of the trachea. Null initial velocity and pressure were set in the trachea. The simulation condition involved a breathing period (T = 1/f) of 3.75 s and a tidal volume of 500 ml. The RANS was solved using the finite volume method in Soteria OPZ software.Airflow velocity was used to indicate a normal (<1 m/s), mild severity (1–3 m/s), moderate severity (3–5 m/s), or severe severity (>5 m/s) condition. Airway pressure was used to indicate a normal (<3 pa), mild severity (3–10 pa), moderate severity (10–20 pa), or severe severity (>20 pa) condition. We defined CTL12 and CTL 34 as airflow velocity <3 and ≥3 m/s, respectively, and airway pressure <10 and ≥10 pa, respectively, in the narrowest upper airway. We evaluated airway pressure and airflow velocity by using area under the receiving operating characteristic curve (AUROC) to predict moderate to severe OSA.U test was used to compare the continuous variables of both groups. The P < 0.05 was represented as a statistical significance level for all tests. We also computed the AUROC for a determination of prediction discrimination of airway pressure and airflow velocity for diagnosing moderate to severe OSA.We conducted statistical analyses by using SPSS Version 22.0 . The Chi-square test was used to compare and test the differences in categorical variables between both groups. The Mann–Whitney 2, 38.5 ± 3.5 cm, and 96.9 ± 8.7 cm, respectively. The average AHI was 34.7 ± 24.1 episodes per hour. In total, 12 patients with mild OSA and 50 patients with moderate to severe OSA participated. The minimum sPO2 of overnight oximetry was 80.3 ± 8.9%. The minimum sPO2 in the supine position was 80.7 ± 9.1%. The total duration of sPO2 <90% at overnight oximetry for each participant was 29.3 ± 51.1 min. The mean airway pressure was 40.3 ± 55.9 Pa and the mean airflow velocity was 9.7 ± 7.3 m/s. Most (85.5%) neck CT examinations with CFD study were of CTL34  were included in the analyses. Most of the study patients  were never smokers. Seven patients were current smokers and four patients were ex-smokers. Their mean age was 50.4 ± 14.6 years. Their body mass index (BMI), neck circumference, and waist circumference were 27.6 ± 4.0 kg/mof CTL34 .P = 0.004) and more shallow sleep  than did the patients with mild OSA. Furthermore, patients with moderate to severe OSA had substantially lower sPO2  and a longer duration of sPO2 <90% at overnight oximetry  than did the patients with mild OSA. The patients with moderate to severe OSA carried substantially higher airway pressure  and airflow velocity  in the narrowest upper airway than did the patients with mild OSA.P = 0.037) and higher AHI  than did the patients with CTL12. The patients with CT34 had lower minimum sPO2 in the supine position  and longer duration of sPO2 <90% at overnight oximetry  than did the patients with CTL12. We illustrated neck CT with CFD study for CTL12 in the . Concomitant airway pressure and airflow velocity provided a sensitivity of 92% and a specificity of 42%. Awake neck CT provides a quick screening modality not only for moderate to severe OSA but also for the anatomic obstruction site of the upper airway. However, awake CT may not completely reveal upper airway collapse caused by decreased muscle tone during sleep, and this limitation may result in relatively low specificity. Albeit previous studies indicated that Berlin questionnaire and Epworth sleepiness scale may be helpful to screen OSA , 24. HowBarkdull et al. reported that patients with OSA exhibited smaller cross-sectional areas in the retroglossal airway and a larger distance between the mandible and hyoid . AlthougAlthough overnight polysomnography in a sleep center is considered a diagnostic standard for OSA , the metWe further evaluated patients by using neck CT with a CFD study of airway pressure and airflow velocity and categorized the readings as indicating CTL12 or CTL34. The patients with CTL34 exhibited a larger waist circumference than did the patients with CTL12. Waist circumference was strongly correlated with total amount of visceral fat, which may result in increased adipose tissue within the airway and a reduced upper airway size , 30. TabA primary strength of this study is that it is the first to conduct an awake neck CT with CFD study of airway pressure and airflow velocity that provides acceptable diagnosis of moderate to severe OSA. This study's findings suggest that awake neck CT shortens examination wait time (~5-s scan time) and reduces the need for sedative medications. Relevant studies have used DISE to evaluate the upper airway condition of patients with OSA , 32. BotThis study reports that neck CT with a CFD study of airway pressure and airflow velocity may provide an acceptable prediction of moderate to severe OSA. Moreover, neck CT can shorten diagnostic examination wait time and provide good measurements of upper airway anatomy.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Institutional Review Board of Tsaotun Psychiatric Center, Ministry of Health and Welfare (110008), Taiwan. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.W-SC: conception and design and administrative support. All authors collected, assembly of data, data analysis, interpretation, manuscript writing and final approval of manuscript.This study was supported by Taichung Hospital, Ministry of Health and Welfare (TAIC110-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Additionally, were assessed nighttime systolic dipping and pulse pressure separately for daytime, nighttime, and 24 h. Serum E-selectin was measured using the enzyme-linked immunosorbent assay technique. We found that E-selectin was consistently associated with 24 h diastolic blood pressure variability  and daytime diastolic blood pressure variability , after adjustment for confounding factors. No association of E-selectin with office blood pressure and other 24 h ambulatory blood pressure parameters was observed. In conclusion, endothelial activation indicated by elevated serum E-selectin is associated with increased ambulatory diastolic blood pressure variability in patients with type 2 diabetes.E-selectin is an endothelial cell adhesion molecule involved in vascular inflammation. Elevated E-selectin has been reported in patients with high blood pressure and diabetes. Given the increasing clinical relevance of parameters derived from ambulatory blood pressure monitoring, further investigation of their relationships with E-selectin is of interest. In this study, we aimed to investigate the association between serum E-selectin, office blood pressure and 24 h ambulatory blood pressure parameters in patients with type 2 diabetes. Blood pressure variability was assessed by computing the standard deviation of mean systolic and diastolic blood pressure separately for daytime and nighttime during 24 h ambulatory blood pressure monitoring in a cohort of patients with type 2 diabetes ( The investigation of inflammatory mechanisms of high blood pressure (BP) has gained increased interest in recent decades. Numerous cytokines regulate vascular tone and maintain the appropriate balance between pro- and anti-inflammatory factors involved in hypertension and vascular disease . ExistinSelectins are a family of endothelial leukocyte cell adhesion molecules involved in vascular disease progression by causing a local inflammatory response through stimulation of the migration of immune cells across the endothelial barriers ,6. The eRecently, increased short-term BP variability within 24 h has been associated with a higher incidence of cardiovascular events, increased risk of end-organ damage, and increased all-cause mortality in patients with hypertension, independent of average systolic and diastolic BP values ,16,17. STypically, BP has a circadian variation with the lowest levels observed during sleep . An arbiPulse pressure represents the difference between the systolic and diastolic BP and results from the interaction of arterial stiffness (increased due to atherosclerosis or age) and cardiac ejection . IncreasVascular inflammation indicated by elevated E-selectin levels was associated with increased office BP , mean BPn = 132) presenting at Emergency Clinical County Hospital, Department of Diabetes and Nutrition in Cluj-Napoca, Romania. The diagnosis of type 2 diabetes and its chronic micro- and macrovascular complications  was established according to the American Diabetes Association criteria [This was a cross-sectional study that included data from adult patients with type 2 diabetes . All participants provided written informed consent before any study procedure.Age, sex, height, weight, abdominal circumference, smoking status, duration of diabetes, duration of hypertension, as well as chronic complications of diabetes were collected by patient interviews, physical examination, and from patients’ medical files. Body mass index was calculated as Biochemical laboratory investigations and HbA1c were assessed on the day of blood collection using commercially available methods at Central Laboratory of the Emergency Clinical County Hospital Cluj, Romania . After blood collection, all study participants underwent 24 h ambulatory BP monitoring using a verified automatic device based on the oscillometric method, HolCARD CR-07 . The BP measurement was performed at the arm with the highest BP and values were recorded every 30 min during daytime and every 60 min during nighttime. Patients were permitted to engage in their normal daily activities during the 24 h ambulatory BP monitoring evaluation, but to refrain from intense physical activity and to keep their arm still and relaxed during BP measurements . All patolic BP) ,39. Pulsolic BP) . N is the number of valid BP measurements in a participant, kBP represents the BP value at moment k and BP for the time assessed [BP, its variability for 24 h was computed as the weighted mean of daytime and nighttime SD of BP [Descriptive statistics used were number and percentages, mean ± standard deviation, median or percentile (25th and 75th) after assessing the normal distribution using the Shapiro–Wilk test. BP and BP variability parameters were analyzed for 24 h and separately for daytime and nighttime. Daytime BP consisted of all BP values recorded between 7:00 and 22:00; nighttime BP consisted of all BP values recorded between 22:00 and 7:00. For daytime BP measurements, we calculated individual means for each hour. These means were further used to compute mean systolic and diastolic BP during daytime as the average of the computed means. The 24 h mean systolic and diastolic BP were computed as the average of computed means during daytime and hourly recorded data for nighttime . The varassessed . To accoSD of BP ,43.p < 0.05.Univariate linear regression analysis unadjusted and adjusted for age, sex, smoking status, body mass index, duration of diabetes and hypertension, fasting glycemia, and HbA1c was performed to assess the association of E-selectin (as dependent variable) with office BP and 24 h ambulatory BP parameters . E-selectin had a non-Gaussian distribution and therefore was logarithmically transformed (lgE-selectin) before inclusion in the regression analysis. Collinearity diagnostic was performed for BP mean, BP variability parameters, nocturnal dipping, dipper status, and pulse pressure before linear regression analysis. Several variables included as predictors displayed variation inflation factors >10 when included in the multivariate regression, indicating potential collinearity issues among predictors. Thus, it was decided not to perform multivariate regression analysis with office BP and 24 h ambulatory BP parameters included as predictors in a single model. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 22.0 . The statistical significance threshold was considered 2, fasting glycemia 156.5 mg/dL, a median HbA1c 9.2% and a median diabetes duration 8.0 years. Hypertension was previously diagnosed and treated with medication in 88.6% of all patients and had a median duration of 8.0 years. Median E-selectin levels were 2.5 ng/mL .Of the 24 h ambulatory BP parameters, lgE-selectin was significantly associated with daytime and 24 h diastolic BP variability in unadjusted linear regression analysis . No association was observed with other 24 h BP parameters assessed (In linear regression analysis adjusted for age, sex, smoking status, fasting glycemia, HbA1c, body mass index, diabetes, and hypertension duration, lgE-selectin remained significantly associated with daytime and 24 h diastolic BP variability in patients with type 2 diabetes (β = 0.258, assessed .In the present study, we addressed the issue of E-selectin levels in hypertension and diabetes and sought to understand its relationship with parameters evaluated during 24 h ambulatory BP monitoring. We found that elevated serum E-selectin was associated with daytime and 24 h diastolic BP variability in patients with type 2 diabetes. Previous studies described the role of E-selectin in the inflammation and activation of vascular endothelial cells in response to certain pro-inflammatory stimuli ,13,33,34Hypertension is found at higher rates in people with diabetes and it represents a clear risk factor for cardiovascular disease, while diabetes itself also confers an independent risk . BP variEpidemiological data show a linear association between elevated office BP and risk of acute cardiovascular events . Given tWe did not find a significant association of E-selectin with pulse pressure during daytime, nighttime and 24 h periods. High values of pulse pressure indicate elevated arterial stiffness, a feature frequently found in persons with diabetes  and hypePersons presenting with reduced BP fall during nighttime, defined as non-dipper, have been proven to have an increased cardiovascular risk  and a laOur study investigating E-selectin associations with parameters evaluated during 24 h ambulatory BP monitoring brings new and relevant data supporting the involvement of endothelial dysfunction and inflammation in worsening of cardiovascular risk. In addition, these results are representative for patients with type 2 diabetes presenting with multiple comorbidities and chronic complications of diabetes, in comparison with previously mentioned studies enrolling persons from the general population, with metabolic syndrome or hypertension only. Current therapeutic strategies targeting hypertension, hyperglycemia, or hypercholesterolemia that improve atherosclerotic cardiovascular diseases outcomes are available. Data is also accumulating regarding their role in lowering proinflammatory cytokines and endothelial dysfunction ,65. HoweOur observational study suggests that E-selectin is associated with diastolic BP variability, but the causality could not be assessed due to its cross-sectional design. Another limitation of this study is the arbitrary definition of night and day, similarly to those previously reported in other studies ,36,44. WThe association of serum E-selectin with daytime and 24 h diastolic BP variability indicates that endothelial activation might be linked to increased BP variability in patients with type 2 diabetes. Increased short-term BP variability might stimulate vascular inflammation indicated by high E-Selectin levels, which may, in turn, determine pathological changes in the arterial wall.


To evaluate the performance of the NoSAS  score, the STOP-Bang  questionnaire, and the Epworth sleepiness score (ESS) as a screening tool for obstructive sleep apnea (OSA) severity based on the apnea-hypopnea index (AHI) and the oxygen desaturation index (ODI).Data from 235 patients who were monitored by ambulant polysomnography (PSG) were retrospectively analyzed. OSA severity was classified based on the AHI; similar classification categories were made based on the ODI. Discrimination was assessed by the area under the curve (AUC), while predictive parameters were calculated by four-grid contingency tables.The NoSAS score and the STOP-Bang questionnaire were both equally adequate screening tools for the AHI and the ODI with AUC ranging from 0.695 to 0.767 and 0.684 to 0.767, respectively. Both questionnaires perform better when used as a continuous variable. The ESS did not show adequate discrimination for screening for OSA (AUC ranging from 0.450 to 0.525). Male gender, age, and BMI proved to be the strongest individual predictors in this cohort.This is the first study to evaluate the predictive performance of three different screening instruments with respect to both the AHI and the ODI. This is important, due to increasing evidence that the ODI may have a higher reproducibility in the clinical setting. The NoSAS score and the STOP-Bang questionnaire proved to be equally adequate to predict OSA severity based on both the AHI and the ODI.The online version of this article (10.1007/s11325-020-02219-6) contains supplementary material, which is available to authorized users. Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by repetitive partial or complete upper airway obstruction which often results in decreased arterial oxygen saturation and arousal from sleep . OSA sevSeveral instruments have been developed over the years including the STOP-Bang questionnaire , 7 and tThe present study reviewed and analyzed a cohort of 235 patients who underwent PSG, using in each case all three instruments: the STOP-Bang questionnaire , the NoSRecently, it has been suggested that the AHI is susceptible to variability in the clinical setting and that there is a need for an alternative parameter to indicate OSA severity , 19–21. Data from 235 patients who were monitored by ambulant PSG were retrospectively analyzed. Patient inclusion criteria were patients aging 18 years of age or older, completed clinical data, and completed STOP-Bang questionnaire and NoSAS score. Patient exclusion criteria were previously diagnosed OSA, use of portable sleep studies or respiratory polygraphy, incomplete clinical data, and technically inadequate PSG. In the outpatient clinic, the following clinical parameters were collected for all patients: gender, age, height, weight, body mass index (BMI), neck circumference (NC), self-reported complaints , and self-reported comorbidities . The ESS was completed. The clinical parameters were used to calculate the NoSAS score and the STOP-Bang questionnaire.2, age > 50 years old, neck circumference > 40 cm, and male gender. For each question, answering ‘yes’ scores 1, a ‘no’ scores 0. With a total range of 0–8, a total score of ≥ 3 points is considered as a high probability for OSA [2, 5 points for BMI ≥ 30 kg/m2, 2 points for snoring, 4 points for age > 55 years old, and 2 points for male gender. The total score of ≥ 8 points is considered as a high probability for OSA [The STOP-Bang questionnaire consists of four questions used in the STOP questionnaire—snoring, tiredness, observed apneas, and hypertension—plus four demographic queries—BMI > 35 kg/m for OSA . The NoS for OSA .2), baseline arterial oxygen saturation (baseline SpO2), average arterial oxygen saturation (average SpO2), and percentage of sleep time with arterial oxygen saturation time below 90% (SpO2 time < 90%).All patients underwent a full-night PSG at home. PSG included electroencephalography, electrooculography, surface electromyography, nasal airflow and air temperature, thoracoabdominal movements, pulse oximetry, body position, and snoring sounds. Breathing was recorded with nasal pressure and temperature sensors. Scoring of the electronic raw data was performed manually, following the recommendations of the American Academy of Sleep Medicine . Apnea wt test, and univariate analysis of variance (ANOVA) for continuous variables. Discrimination, the ability of a screening tool to distinguish between patients with and without different outcomes, was estimated from the area under the curve (AUC) obtained by receiver operator characteristic (ROC) curves, which may range from 0.5 (no discrimination) to 1.0 (perfect discrimination) [p < 0.05). A two-tailed p value < 0.05 was considered statistically significant.The statistical analysis was performed by using Statistical Package for Social Studies . Continuous data are presented as means with standard deviations. Categorical variables are presented as frequencies with percentages. Comparisons between groups were performed using Chi-square tests for categorical variables, unpaired Student’s ination) . The AUCination) . Additio2. Based on the AHI, OSA was present in 159 (79.1%) of the patients; 66 (41.5%) with mild OSA, 45 (28.3%) with moderate OSA, and 48 (30.2%) with severe OSA. Male gender, age, BMI, neck circumference, cardiovascular history, hypertension, snoring, and apneas were all significantly higher in the OSA groups than in the no OSA group. A post hoc Bonferroni test showed a statistically significant difference between no OSA and moderate/severe OSA for male gender , age , and BMI . BMI was also significantly different between mild/moderate OSA and severe OSA . Neck circumference , cardiovascular history , and hypertension  all showed a statistically significant difference between no/mild OSA and severe OSA. The ESS did not differ significantly between OSA groups . A total of 54.5%, 75.6%, and 85.4% of the patients in the mild, moderate, and severe OSA group, respectively, were classified as high risk of OSA according to the NoSAS score . A total of 97%, 100%, and 100% in the mild, moderate, and severe OSA group, respectively, were classified as high risk of OSA according to the STOP-Bang questionnaire . Polysomnography results  were all significantly different between the OSA and no OSA groups . Notable is the percentage of patients with positional sleep apnea which was also statistically significant between the groups (p < 0.001). A post hoc Bonferroni test shows that the difference was significant between no OSA and all OSA severity groups (p < 0.001) and mild OSA and severe OSA (p = 0.05).A total of 201 patients met our inclusion criteria; baseline characteristics are mentioned in Table p value > 0.05). The discriminatory ability of the NoSAS score and the STOP-Bang questionnaire was similar in relation to both the AHI and the ODI . When used as categorical variable, the AUC of the NoSAS score ranged from 0.620 to 0.684 (cutoff ≥ 8), the AUC of the STOP-Bang questionnaire ranged from 0.529 to 0.577 (cutoff ≥ 3) .The predictive performance of the different screening instruments as categorical variable is shown in Table p < 0.001; p < 0.001; p = 0.004), moderate to severe OSA (AHI ≥ 15) , ODI ≥ 5 , and ODI ≥ 15 . Gender, BMI, and self-reported history of hypertension proved to be or the strongest predictors for severe OSA (AHI ≥ 30)  and ODI ≥ 30 . The ROC curves of the estimated predictive probability, the NoSAS score, and the STOP-Bang questionnaire with cutoff points AHI ≥ 15 and ODI ≥ 15 are shown in Fig. p value > 0.05).Multivariate logistic regression analyses were performed in order to establish the association between various individual demographic and clinical variables and the presence and degree of OSA categorized by the AHI and the ODI. Gender, age, and BMI proved to be the strongest predictors for any OSA (AHI ≥ 5)


Elevated blood pressure among adolescents has been shown to be associated with future adverse cardiovascular outcomes and early onset diabetes. Most data regarding systolic and diastolic blood pressure trends are based on surveys of selected populations within 10–20-year periods. The goal of this study was to characterize the secular trend of blood pressure given the rising prevalence of adolescent obesity.This nationwide population-based study included 2,785,515 Israeli adolescents  who were medically evaluated and whose weight, height and blood pressure were measured, prior to mandatory military service between 1977 and 2020. The study period was divided into 5-year intervals. Linear regression models were used to describe the P for trend along the time intervals. Analysis of covariance was used to calculate means of blood pressure adjusted for body mass index.2 in males and females, respectively (P for trend  < 0.001 in both sexes). The mean diastolic blood pressure decreased by 3.6 mmHg in males and by 2.9 mmHg in females (P  < 0.001 in both sexes). The mean systolic blood pressure increased by 1.6 mmHg in males and decreased by 1.9 mmHg in females. These trends were also consistent when blood pressure values were adjusted to body mass index.During the study period, the mean body mass index increased by 2.1 and 1.6 kg/mDespite the increase in body mass index over the last four decades, diastolic blood pressure decreased in both sexes while systolic blood pressure increased slightly in males and decreased in females.The online version contains supplementary material available at 10.1186/s12933-021-01433-0. Elevated blood pressure (BP) among the general population is a leading contributor to cardiovascular morbidity and mortality , 2. A nuWeight status is a key determinant of BP in adolescents . ConsistOne year prior to mandatory military service, usually at age 16–19 years, male and female Israeli adolescents are called to regional conscription centers for medical evaluation. The current study comprised adolescents examined during 1977–2020, regardless of their fitness for military service. Orthodox and ultra-orthodox Jewish women are not obligated to serve, and therefore are under-represented [The medical assessment included review of the examinee’s medical history, an interview with a physician, physical examination and further medical tests as appropriate , 21. HeiData regarding years of schooling were obtained from the Ministry of Education and were dichotomized at 11 years (< 11/≥ 11 years) . Data reWe a priori stratified analyses by sex and divided the study period into 5-year time intervals . We calculated the P for trend for all the study variables including SBP, DBP and BMI using linear regression models. We plotted mean SBP, DBP and BMI values for the time intervals.unadjusted) and BMI-adjusted (βBMI-adjusted) models, which reflected the predicted mean change in mmHg per 5-year interval. (ii) We stratified the secular trend of mean SBP and DBP by BMI categories . Additional sensitivity analyses included the following: (1) limiting the study sample to persons with unimpaired health  in order to minimize confounding by coexisting comorbidities. (2) We included only Israeli-born adolescents to reduce health effects related to immigration [Two analytical approaches were taken to address the potential effect of the rise in adolescent BMI throughout the study period , in lighigration . The IBM2 for males and 21.0 (2.9) kg/m2 for females in the earliest time interval, to 22.8 (4.4) kg/m2 and 22.6 (4.4) kg/m2, respectively  were females. The characteristics at assessment are shown separately for males and females in Tables unadjusted = − 0.65 mmHg/5-year, βBMI-adjusted  = − 0.74 mmHg/5-year) in males and 2.9 mmHg  in females. The SBP trend was not consistent between the sexes. In males, we recorded a small increase in mean SBP during the study period, of 1.6 mmHg . In females we observed a decrease of 1.9 mmHg .Mean DBP decreased in both sexes during the study period  and B females , by 5-year time intervals. Figure S2. The secular trends of systolic blood pressure, diastolic blood pressure and BMI among A males  and B females  with unimpaired health, by 5-year time intervals. Figure S3. The secular trends of systolic blood pressure, diastolic blood pressure and BMI among A males  and B females  born in Israel, by 5-year time intervals.