FTOE relative to the total duration of anesthesia. HyperoxiaFTOE was defined as FTOE ≤ 0.1. Cumulative doses of sedative agents (benzodiazepines and morphine), given up to 24 h preoperatively, correlated with the mean intraoperative FTOE  and were predictive for the % of time of intraoperative hyperoxiaFTOE (β (95% CI) 47.12 ) when adjusted for the patients’ age, type of surgery, preoperative hemoglobin, intraoperative sevoflurane and fentanyl dose, mean intraoperative arterial blood pressure, and end-tidal CO2 by multivariate 0.75 quantile regression. There was no association with 0.5 quantile regression. We observed the suggestive positive association of decreased fractional cerebral tissue oxygen extraction and the use of sedative agents in neonates and infants undergoing surgery.Fractional tissue oxygen extraction (FTOE) by means of cerebral near-infrared spectroscopy (NIRS) provides information about oxygen uptake in the brain. Experimental animal data suggest that sedative agents decrease cerebral oxygen demand. The aim of the present study was to investigate the association between the cerebral FTOE and the use of pre and intraoperative sedative agents in infants aged 1–90 days. Cerebral NIRS was continuously applied during open major non-cardiac surgery in 46 infants. The main outcomes were the mean intraoperative FTOE and the percentage (%) of time of intraoperative hyperoxia Major surgery in neonates and infants has been related to worse neurodevelopmental outcomes . The defPainful stimulation accompanies every perioperative period. Pain itself has been related to poorer long-term outcomes . BenzodiNear-infrared spectroscopy (NIRS) was shown to be a convenient method for monitoring cerebral tissue oxygenation during surgery and intensive care . Along wFactors such as arterial blood pressure, hemoglobin level, arterial blood oxygen saturation ,13,14, aA decreased oxygen uptake with the use of benzodiazepines and opioids was determined in experimental animal studies ,18; howe−1 or hyperbilirubinemia, bronchopulmonary dysplasia, and neurosurgical disease. Patients with malignancy, sepsis, bone or muscle disease, renal or hepatic insufficiency, or a physical status corresponding to the American Society of Anesthesiologists (ASA) classification 5th class were also excluded.Neonates and infants younger than 3 months old undergoing open non-cardiac surgery for congenital anomalies or diseases were eligible for the study. Patients were excluded if they had clinical conditions that significantly affected their cerebral oxygenation values. These were Hb < 80 g·L2) monitoring ) was continuously applied until wound closure. Before the induction of anesthesia, two pediatric cerebral sensors were placed bilateral to the forehead region and rSO2 monitoring was started. Data were captured with a sampling interval of 5 s and recorded every 5 min. Simultaneously, the arterial blood pressure (mean), hemoglobin (Hb), oxygen saturation (SpO2), end tidal (ET) CO2, and ET sevoflurane concentration in percentages (%) were registered /SpO2 [2 and rSO2. The main outcome measures were mean intraoperative FTOE and the duration of hyperoxia by FTOE (hyperoxiaFTOE) during surgery relative to the total duration of anesthesia (% of the time of intraoperative hyperoxiaFTOE).General anesthesia with tracheal intubation using a sevoflurane in air and oxygen mixture (1:1) was used. During anesthesia, cerebral oxygenation (rSOlsewhere ). The ceO2)/SpO2 ,20 for eFTOE was defined as FTOE ≤ 0.1, normoxiaFTOE as FTOE > 0.1 and ≤0.4, and hypoxiaFTOE as FTOE > 0.4 [HyperoxiaOE > 0.4 ,19.−1 were calculated separately for each intravenously (iv) administered sedative agent ) up to 24 h before surgery. In patients given a combination of two or three sedative agents, the individual cumulative doses of diazepam, midazolam, and morphine were added (assuming the ratio 1:1:1), resulting in the cumulative dose of all sedative agents in mg·kg−1 for each patient. Intravenous fentanyl (opioid), oral or rectal forms of benzodiazepines, or morphine were not used preoperatively.Individual cumulative doses in mg·kg2, FTOE, mean arterial pressure, SpO2, ET CO2, ET % sevoflurane. Shapiro–Wilk test was used to assess the normality of distribution of continuous data. Parameters distributed abnormally are presented as median (range), normally distributed parameters are presented as mean and standard deviation (SD), and categorical and binomial variables are presented as number of patients (%). The Mann–Whitney U test was used for the comparison of abnormally distributed continuous variables, the unpaired t test for normally distributed continuous variables, and the chi square test for categorical variables.For each patient, mean values were calculated for intraoperative variables: rSOFTOE with the cumulative doses of preoperative sedative agents and the demographic and clinical variables. As the main outcome variable, % of time of intraoperative hyperoxiaFTOE, was distributed abnormally, a univariate and multivariate 0.5 (median) and 0.75 quantile regression analysis [FTOE, calculating regression coefficients (β) and their 95% confidence intervals (CI); p < 0.05 was considered statistically significant for all the statistical tests. All the statistical analyses were performed using the STATA/IC 15 software .Spearman’s rank correlation was used to assess the associations of FTOE and the % of time of intraoperative hyperoxiaanalysis  was usedThe study was approved by the Kaunas Regional Biomedical Research Ethics Committee , and conducted in accordance with the Helsinki Declaration. Informed written parental consent was obtained before the enrollment of each patient.FTOE during surgery occurred in 69.6% (n = 32) of patients, with a duration of 14.7 (0–100)% (median (range)) of time. HypoxiaFTOE was observed in 6.5% (n = 3) patients, with a duration of 59 (7.7–65)% of time.The cerebral oxygen saturations were measured in 46 patients. The demographic and clinical characteristics of the studied patients are shown in The pattern of administration and the cumulative doses of preoperative sedative agents are shown in FTOE. The cumulative doses of sedative agents moderately correlated with both FTOE . Patient’s age correlated with the % of time of hyperoxiaFTOE , but not with FTOE. There were no other significant correlations.In order to identify potential associations with intraoperative hyperoxia, we correlated the cumulated doses of sedative agents and demographic and clinical variables with the mean intraoperative FTOE values and the % of time of intraoperative hyperoxiaoth FTOE a and theOE  corresponds to a duration of 14.7%. Thus, it means that cumulative doses of preoperatively administered sedative agents are potentially predictive for a prolonged (43.8% and over) but not short duration of intraoperative hyperoxia.During surgery, several other important factors may influence cerebral oxygenation and consequently FTOE. These are arterial blood pressure, intraoperatively administered fentanyl, and ET COrcentile . The aboFTOE (p = 0.264). One of the three patients with intraoperative hypoxiaFTOE had bilateral subependymal hemorrhages during the in-hospital follow-up.The in-hospital outcomes did not differ between patients with and without intraoperative hyperoxiaThe experimental animal data indicate that benzodiazepines and opioids reduce cerebral oxygen uptake ,18. Here2 as markers of reduced oxygen uptake were demonstrated during the simultaneous use of NIRS and EEG for brain function monitoring in term and preterm neonates with different pathological conditions [Recently, Weber and Scoones described increased cerebral NIRS values in ventilated neonates who were given midazolam for sedation , howevernditions , in pretnditions , as wellnditions . As amplnditions . TherefoApart from sedative effects, inhalational anesthetic sevoflurane, which was used during the maintenance of anesthesia in our patients, depending on the administered concentration may affect the cerebral blood flow through the direct effect on cerebral blood vessels or through the effect on the systemic arterial blood pressure, thus affecting the cerebral oxygen supply, cerebral oxygenation, and consequently FTOE . The obs2 pressure in blood (p CO2) and FTOE [2 during neonatal and infantile surgery is highly unreliable due to considerable dilution of exhaled gas with fresh gas. A more precise method would have been measurement of p CO2. Invasive methods, such as the placement of arterial cannulae, allow us to obtain multiple p CO2 measurements. However, arterial cannulae were not present in our patients. For these reasons, ET CO2 included into the model may carry a certain bias.Carbon dioxide is a potent factor of cerebrovascular reactivity and thus oxygen delivery to the brain. Other investigators, though, did not find significant association between partial COand FTOE . ET CO2 FTOE in our study, the in-hospital outcomes did not differ between patients with and without hyperoxiaFTOE. This is in accordance to the observation of SafeBoosC trial, where no major neurological complications nor deaths were associated with cerebral hyperoxia within 72 h after birth [Both cerebral hypoxia and hyperoxia have been related to worse conditions in severely ill neonates and infants ,32. Desper birth .2 and FTOE values may provide us with different and additive information. We based our analysis on FTOE, but not rSO2 values, as there was no correlation between cumulative doses of sedative agents and the mean intraoperative rSO2. The categorization of hyperoxiaFTOE selected by us was based on previous publications in preterm infants or neonates in the immediate transition period after birth. Whether these thresholds are applicable to term infants up to 3 months of age is unknown. However, the cumulative doses of sedative agents correlated not only with the duration of time with FTOE ≤ 0.1, but also with mean intraoperative FTOE, showing that higher cumulative doses of sedative agents were positively associated with less cerebral oxygen extraction. We based our analysis on the % of time (or duration) of intraoperative hyperoxiaFTOE, as this measure more adequately than the mean intraoperative FTOE reflects the intraoperative variability in FTOE values.Although directly, related rSOThe coadministration of benzodiazepines and opioids occurred in almost half of patients given sedative agents. Although these two classes of sedatives have a different pharmacology, it was shown that coadministration results in functional but not pharmacological synergism, which is also not pharmacokinetics-dependent . HoweverFTOE and the preoperative dose of sedative agents should be interpreted with caution.This was an observational trial, describing present clinical practice in a patient cohort of limited size and undergoing surgery. Under these circumstances, the effects of sedative agents interplay with many other significant factors. Although we tried to take these factors into account, our results may not be applicable to all neonates and infants. We also had no possibility of measuring the cerebral oxygenation at baseline before any sedatives were administered, therefore the relationship between the intraoperative hyperoxiaWe observed a suggestive positive association of decreased fractional cerebral tissue oxygen extraction by means of cerebral near-infrared spectroscopy and the use of benzodiazepines and opioids in surgical neonates and infants up until 3 months of age. In order to better understand the magnitude of the effect of sedative agents on infants’ brain tissue oxygenation within the complex clinical scenarios and the potential relationship with outcomes, future clinical trials in larger and more homogenous populations are required. Additionally, using techniques allowing us to directly observe the effects of sedative agents on the electrocortical activity would be helpful in quantifying the effects on the infantile brain.


Phosphate increased by day 1 (1.1(0.9–1.2) to 1.3(1.1–1.4) mmol/L, p <0.001) but declined to 0.8(0.8–1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age , BMI , systolic BP , diastolic BP  and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m Mineral and bone disorder (MBD) is a life-limiting complication in patients with Chronic Kidney Disease (CKD). The three component alterations that characterize MBD include disturbances in mineral metabolism, osteodystrophy and extraskeletal calcification. Abnormalities in mineral metabolism in CKD include the development hyperphosphataemia, elevations in the phosphatonins fibroblast growth factor (FGF)-23 and parathyroid hormone (PTH), reduced circulating active 1,25-dihydroxyvitamin D and hypo- or hypercalcaemia . In factSkeletal disorders in CKD are characterised by alterations of bone morphology and turnover that result in an increased fracture risk and may contribute to extraskeletal calcification . NotablyKidney donation represents an excellent model for studying the effects of a decrease in GFR on MBD, since it allows interrogation of the effect of an acute and isolated GFR reduction of 50% in the absence of significant systemic disease , 12 FurtWe conducted a prospective, controlled study of living kidney donors and healthy controls to elucidate the effects of an acute decrement in GFR on biochemical markers of mineral metabolism, haemodynamic parameters and skeletal health.Kidney donAtion on bone and mineRal MetAbolism) study was a single-center matched prospective cohort study that enrolled patients between May 2012 and March 2014 at Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust (CUH), United Kingdom. All kidney transplants were carried out in the UK National Health Service. The National Health Service is free at the point of care. Donors did not receive any payments. The KARMA study design is illustrated in The KARMA  assessment by DEXA scanning at baseline and after 12 months. Bone density was determined by DEXA scanning on all kidney donor patients at baseline and 12 months. BMD assessment was not carried out in the control group.Blood and urine samples in the immediate post transplant period (day 1 to day 3 after transplantation) were taken as early morning samples to ensure standardization. Biochemical analysis was conducted at Addenbrooke’s Hospital clinical laboratory and Cambridge Core Biochemical Assay Laboratory (CBAL). Creatinine, calcium, inorganic phosphate, albumin & alkaline phosphatase were analysed on the Siemens Advia 2400 autoanalyser. PTH [normal range 14–72 ng/l] was analysed using the ADVIA® Centaur XP Immunoassay system for intact PTH (1–84) The eGFR was computed using the four-variable Modification of Diet in Renal Disease equation. Serum FGF-23 levels were analyzed using an ELISA kit detecting the FGF-23 c-terminal . This assay detects both the intact molecule and large carboxyl terminal fragments of human FGF-23. Serum α-Klotho levels were analyzed . 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D were analysed by automated chemiluminescent immunoassay on the Diasorin Liaison XL autoanalyser.The study protocol was approved by the NRES Committee East of England–Cambridge EAST (REC reference 10/H0304/74). All participants provided written informed consent. None of the transplant donors were from a vulnerable population and all donors provided written informed consent that was freely given.Prospective kidney donors were seen on multiple occasions on separate dates in the outpatient clinic during the screening process and interviewed by a member of the transplant team and a transplant coordinator. Information about donation was provided in written and verbal form, with a full description of the procedure, the potential risks and complications and the nature and duration of the recovery period. Prospective donors were afforded as much time as required to come to a decision. All donors were living donors and were registered as organ donors. No organs were obtained from deceased donors. Kidney donation for transplantation followed a standard local protocol. Nephrectomy was performed by a laparoscopic technique. Donors received enoxaparin 40mg before surgery, flucloxacillin 1 gram and 100ml 20% mannitol intravenously intra-operatively, ibuprofen 200mg three times daily and paracetamol 1 gram 6 hourly as required in the post-operative period, and intravenous fluid as 0.9% Saline as required. Donors remained nil by mouth on the day of donation, but were allowed an oral diet from day 1 after donation. The majority of transplant donors were discharged from hospital on the second or third post-operative day.Data are presented as mean ± SD, median (IQR) according to their distribution. Counts are presented as frequencies (%). Between-group comparisons were performed using independent samples T tests or Mann Whitney U-tests as appropriate. Within-subject comparisons were made using repeated measures ANOVA, or chi-squared for categorical variables. Parameter estimate, standard error, and 95% confidence interval (CI) were calculated for each variable. P<0.05 was considered statistically significant. All analyses were conducted using STATA (version 14).We enrolled 34 kidney donors and 34 controls between 2012 and 2016 at Addenbrooke’s Hospital, Cambridge.2, p = 0.59), systolic and diastolic clinic blood pressure  between donors and controls. PWV was also not statistically different between the donor and control groups at baseline (7.2 (6.8–7.8) vs 6.6 (6.0–7.7) ms, p = 0.25). Baseline eGFR was similar between donors and controls . Biochemical and hematologic parameters between groups, including phosphate (p = 0.97), PTH (p = 0.74) and hemoglobin (p = 0.19), were not statistically different. Donor patients had marginally higher albumin (41.0 (39–42) vs 39.0 (37–42) mg/l, p = 0.02) levels than control patients.Clinical and biochemical parameters between the donor and control populations were similar at baseline . A simil2 (p<0.001) on post-operative day 1  by post-operative days 1 and remained low by post-operative day 3. Serum phosphate concentrations showed an increase from 1.1 (1.0–1.2) to 1.3 (1.1–1.4) mmol/L (p<0.001) by day 1 before declining sharply below baseline by day 2 (0.9 (0.8–1.0) p<0.001) and 3 (0.8 (0.8–0.9), p<0.001). The acuOn mid-term follow-up, we found that albumin-corrected calcium concentrations t did not differ at 6 weeks or 12 months after donation . Phospha3) concentration decreased significantly by day 1  RU/ml) to day 1 (51.1 (39.2–72.4) RU/ml, p = 0.97), day 2 (36.1 (31.1–53.1) RU/ml, p = 0.57) or day 3 (32.9 (28.5–45.5) RU/ml, p = 0.75) after kidney donation ; Fig 2G.donation .On mid-term follow-up, we found no change in FGF-23 levels at 6 weeks (48.0 (17.0–72.0) RU/ml, p = 0.379) or 12 months (57.0 (30.0–83.0), p = 0.616) after kidney donation. α-Klotho levels remained low after 6 weeks (701.6 (548.6–874.0), p = 0.02) and 1 year (721.4 (562.5–956.5), p = 0.04) following kidney donation. Active vitamin D levels remained at months (p<0.001) and at 12 months (p = 0.016) following kidney donation . There wNo difference in BMD  was observed after 12 months compared to baseline at either the lumbar spine (L1 (p = 0.295), L2 (p = 0.717), L3 (p = 0.466) and L4 (p = 0.943)), femoral neck (p = 0.402), shaft (p = 0.510) or total hip region BMD (p = 0.436) .Kidney donation results in a predictable and marked decline in kidney function with incomplete recovery. We report the acute and medium-term changes in bone mineral metabolism after kidney donation compared to a well matched control population. Our data demonstrate that disturbances in mineral metabolism occur acutely following kidney donation and are detectable from the first post-operative day.fePO4). It is therefore likely that the acute loss in GFR results in an initial reduction in phosphate excretion and hyperphosphataemia, which is (over) corrected by a phosphaturic response. Despite these observations, it is notable that we identified no detectable change in the phosphaturic factors PTH and FGF23 over the corresponding period. The driver for the increase in fePO4 is not known.Unilateral nephrectomy resulted in a mean decline in eGFR of 38% after 24 hours, and eGFR remained 20% below baseline after 12 months. We found an acute elevation in serum phosphate (day 1), followed by an immediate and profound decline in phosphate to significantly lower than baseline by day 2. This was associated with an increase in fractional excretion of phosphate  are usually not observed until the GFR declines to < 40mL/min in CKD patients . HoweverWe observed numerical but non-significant increases in PTH after 6 weeks, but PTH was no different between donors and controls after 12 months. In contrast, Kasiske et al. observed significant elevations in PTH after 6 months (for which we do not have a corresponding time point) and 36 months . The absIn contrast to phosphate, we did not record any similarly biphasic changes in any other measured parameters over the first 72 hours. We also did not identify any change in bone density within the follow-up period . HoweverWe found that Klotho levels fell acutely by day 1 post-operatively and remained lower than baseline by 12 months following kidney donation. Klotho is produced predominantly by the kidney, which is thought to be the major source of circulating Klotho , 23 CircThe strengths of the present study is the inclusion of a well-matched control group to comprehensively assess the acute changes in markers of bone and mineral metabolism. Participants were representative of the typical living kidney donor in the United Kingdom, and no participants were lost to follow-up. The results of the present study should be cautiously interpreted in light of its limitations. We recognize several limitations that include a relatively modest sample size and, to date, short follow-up. In the present study, given that the FGF23 assay used detects both the intact and c-terminal FGF23 fragments, we are unable to infer changes in the levels of the intact (active) or cleaved (inactive) FGF23 fragments. Additionally, due to current limitations in the availability of robust assays for assessing circulating Klotho levels, assessment of Klotho levels must be cautiously interpreted. To give an example of the magnitude of discrepancy between various assays, in one published study comparing a time-resolved fluorescence immunoassay  with an ELISA based assay , no correlation was found between the assays .In summary, we identify biphasic acute changes in phosphate, and acute reductions in circulating klotho, 1,25-dihydroxyvitamin D and calcium. Larger studies with longer follow-up are required to establish the association between these changes and long term outcomes. Further physiological studies are required to establish the basis for the acute changes observed here.S1 File(DOCX)Click here for additional data file.S1 Data(DTA)Click here for additional data file.S2 Data(DTA)Click here for additional data file.S3 Data(DTA)Click here for additional data file.


Among patients with Chagas disease, men have a higher risk of worse pathological symptoms than women. We aimed to explore the role of the Y chromosome in men diagnosed with Chagas disease and assess the relationship between their ancestry and disease status.  In this comparative study, we analyzed 150 men with unrelated non-chagasic disease (nCD) and 150 men with unrelated chagasic disease (CD). We assessed the serological diagnosis of Chagas disease, biochemical parameters, thoracic X-rays, electrocardiogram, and transthoracic echocardiography and determined the haplogroup by analyzing a set of 17 microsatellites from the Y chromosome. We examined the associations between common Y chromosome haplogroups and the clinical parameters of risk by logistic regression. For all patients, the most common haplogroups were R1b (43%), G2a (9%), and E1b1b (9%). The R1b and G2a haplogroup was more frequent in men with nCD and CD, respectively. As expected, we observed a high proportion of symptomatic patients in the CD group independent of the haplogroups. Men from both groups classified as having the R1b haplogroup showed less clinical evidence of disease. Multivariate analysis showed that CD patients without R1b were about five times more likely to have a cardio-thorax index >0.5% . Men without the R1b haplogroup were 2.5 times more likely to show EcoCG alterations .  Our results provided evidence that the R1b haplogroup may have a potential protective cardiovascular effect for its carriers. Trypanosome cruzi (T. cruzi). This disease affects millions of people in South and Central AmericaT. cruzi antibodies. This stage is also characterized by a large difference in clinical indicators from those associated with an asymptomatic phenotype, such as severe cardiac and gastrointestinal damage,,,Chagas disease (CD) is a parasitic infection caused by the protozoa Currently, many uncertainties exist regarding the pathophysiological mechanisms involved in CCC development and it is not known why certain patients from endemic areas survive without symptoms, while others develop severe arrhythmia or suffer sudden death at a certain point in their livesSeveral studies in the general population reported relationships between polymorphisms of a single nucleotide in the male-specific region of the Y chromosome (MSY) and blood pressure, total plasma level of cholesterol, low density lipoprotein cholesterol, and male parent history of myocardial arrest and coronary diseasesT. cruzi and to establish a possible relationship between haplogroups of the Y chromosome and the clinical cardiovascular characteristics of CD.The aim of this study was to analyze the frequency of haplogroups of the Y chromosome in a sample of patients infected with In this case-control study, 300 unrelated men who consecutively attended the Hypertension Department of the Córdoba Hospital in the city of Córdoba, Argentina were randomly selected. Every patient completed a form on their family medical histories of cardiovascular disease, and other current diseases. A physical assessment was carried out according to the ethical rules (Helsinki-Armonization) and informed consent was acquired from the patients before admission. The study was approved by the Institution Ethics Committee (RePIS 2517). Patients with the following characteristics were excluded: minor patients (under the age of 21), secondary hypertension, diabetes mellitus, active malign neoplastic conditions, drug or alcohol abuse, previous bone marrow allogeneic transplant, whole blood transfusion with no reduction in white blood cells within 120 days of the blood test, patients on treatment regimens with corticoids, immunosuppressors and/or chronic non-steroidal anti-inflammatory drugs. ,,After the physical assessment was performed, a 12-lead electrocardiogram (ECG) at rest was carried out (Fukuda Denshi FX 7402 Cardimax) at the Cardiology and Radiology Department of the Hospital of Córdoba, a transthoracic echocardiography (TTE) in M-mode, 2D, color, with pulsed and continuous-wave Doppler, and multifrequency transducer , and a thoracic X-ray (XR) (Siemens 1000 A-Polidoros IT). Results of the TTE, ECG, and thoracic XR were reported by professional practitionersTeichholz method and as per international regulationsSystolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using a standard mercury blood pressure gauge. SBP>140 mmHg, DBP>90 mmHg, or both were considered as thresholds for the diagnosis of hypertension as per the criteria of the WHO and International Society of Hypertension. The cardiothoracic index (CTI) was analyzed using conventional methods, and enlarged heart was defined as CTI>0.5%Individuals analyzed were divided into two groups, with CD (CD group) and without CD (nCD group), according to the serological tests. Subsequently, patients were classified according to the clinical and biochemical tests and non-invasive studies as mildly symptomatic or asymptomatic patients without cardiac symptoms, and with normal ECG and TTE with some risk factors . The other group included symptomatic or cardiomyopathic patients with different clinical severity conditions who showed one or more of the following characteristics: different conductance alterations (such as complete right bundle branch block), left ventricular hypertrophy, repolarisation disorders and/or complex ventricular arrhythmia, structural cardiomyopathy abnormalities determined by TTE (such as cavity dilations and ventricular dysfunction [diminished ejection fraction]), and cardiomegaly (different heart enlargements) as determined by chest radiography,Deoxyribonucleic acid (DNA) was extracted from a blood sample mixed with EDTA  and quantified using conventional methodsThe statistical analysis was performed using Infostat/P2018 (Argentina). It was established for a random sample of 300 patients as the sample size, with a security coefficient of 95% for a Type I probability error  of 0.05, with the fact that between 12 and 13 male patients attended the hypertension consulting room of the Córdoba Hospital each week being taken into account.Data were examined for normality using the Kolmogorov-Smirnov test. The data that did not achieve normality were analyzed using nonparametric methods. Continuous variables were presented as mean values and standard deviations, while categorical and qualitative variables were presented as frequencies (percentages). Comparisons between the continuous variables  were performed using the Student’s t-test for independent samples. Categorical variables were analyzed using the chi-square test or Fisher’s exact test. The relationships between the Y chromosome haplogroups and the clinical parameters for CCC were evaluated using logistic regression, and the corresponding odds ratios (ORs) and 95% confidence intervals (CIs) were determined and used as the response variables of the affected population. For the multivariate analysis, covariates of the presence/absence of a haplogroup and presence/absence of CD were age, cholesterol level, and plasma lipoprotein level. For all the analyses, the significance level was set at 0.05.Chagas was 0.88 in the CD group, while it was 0.69 in the nCD group, which indicates that both groups had a high level of genetic diversity in the Y chromosome. Haplotype diversity (Hd) showed an index of 0.785 for the total population; in particular, HdT. cruzi or not as covariables. The multivariate analysis (Data were analyzed using logistic regression to estimate the probabilities of symptomatic CD condition related to haplogroups of Y chromosome using symptomatic patient ratio as the response variable, and if the patients carried the R1b haplogroup or not and if they were infected with analysis  showed tanalysis .T. cruzi develop cardiomyopathy suggests the presence of a set of pathophysiological events that lead to the clinical manifestations of chagasic cardiomyopathyThe fact that 20-30% of individuals infected with ,,In this study, we observed a high level of haplogroup diversity within the population, with the predominance of the haplogroups R1b and G2a. The former was more frequent in non-CD patients, while the latter was predominant in CD patients. To the best of our knowledge, this is the first study to demonstrate such a difference. Previous studies carried out in the Argentinean Mennonites community and the global population showed no difference in the frequency of Y chromosome haplogroupsUTY was reduced in blood samples from men with haplogroup I1 when compared with those with other haplogroupsThree of them were related to haplogroup I and participated in immunologic processes: UTY/UTX, PRKY/PRKX, and DM5D/KDM5CThe present work was limited to a population consisting of middle-aged men, most of whom were undergoing pharmacological treatment, which may have potentially affected the phenotypic characteristics. Therefore, it may be difficult to generalize these findings to a wider healthy male population. It should be noted that due to the relatively low quantity of informative Y-SNP in the matrix Affymetrix 6.0, the study was limited only to the phylogenetic analysis of the main haplogroups. Further studies of the whole spectrum of the Y chromosome variations will be necessary to determine the possible role of the Y chromosome sequence in different human phenotypes.T. cruzishowed worse heart disease diagnoses than patients without infection. We observed that the Y chromosome may have significant effects on men’s cardiac health and may be considered to be a new risk factor to explain the different stages of CCC. Further studies should be carried out using a broader range of phenotypes to fully understand the biological bases of human health, men’s health, and CDOn clinical assessment, we found that patients infected with


P = 0.04). Heart rate increased during both intraduodenal glucose and lipid infusions (P < 0.001 each), and the increment was greater in response to intraduodenal fat than glucose (P = 0.004). In patients with T2DM, intraduodenal fat induced a greater increase in heart rate, associated with a diminished reduction in blood pressure, when compared with isocaloric glucose. The macronutrient composition of meals may be an important consideration in T2DM patients with symptomatic postprandial hypotension.The interaction of nutrients with the small intestine modulates postprandial cardiovascular function. Rapid small intestinal nutrient delivery may reduce blood pressure markedly, particularly in patients with type 2 diabetes (T2DM). Postprandial hypotension occurs in ~30% of patients with longstanding T2DM, but there is little information about the cardiovascular effects of different macronutrients. We compared the blood pressure and heart rate responses to standardized intraduodenal glucose and fat infusions in T2DM. Two parallel groups, including 26 T2DM patients who received intraduodenal glucose infusion and 14 T2DM patients who received intraduodenal fat, both at 2 kcal/min over 120 min, were compared retrospectively. Blood pressure and heart rate were measured at regular intervals. Systolic blood pressure was stable initially and increased slightly thereafter in both groups, without any difference between them. Diastolic blood pressure decreased in response to intraduodenal glucose, but remained unchanged in response to lipid, with a significant difference between the two infusions ( Exposure of the small intestine to ingested nutrients is associated with a substantial increase in splanchnic blood flow and a decrease in peripheral blood volume, which may lead to a reduction in blood pressure and, in some cases, postprandial hypotension  . The latIn the current study, we compared the blood pressure and heart rate responses to intraduodenal glucose and fat infusions at a rate of 2 kcal/min in patients with T2DM.Forty participants with type 2 diabetes managed by diet or metformin monotherapy  were recruited from the community by advertisement for studies evaluating nutritional and/or pharmacological therapies for diabetes in our center. Twenty-six participants received an intraduodenal glucose infusion , 8 and 1t = 0 min, either glucose or lipid  was infused at 2 kcal/min over 120 min (t = 0–120 min) while the participant was lying supine. Systolic and diastolic blood pressure and heart rate were measured regularly  from 60 min before starting infusion using an automatic sphygmomanometer . Mean blood pressure and heart rate every 15 min were reported. Data on heart rate during intraduodenal lipid infusion were only available for nine patients only due to technique issues. Baseline blood pressure and heart rate were calculated as an average of the measurements obtained 15 min prior to intraduodenal infusion.Blood pressure and heart rate were evaluated on a single study visit. All participants refrained from strenuous physical activity for 24 h before the study. After a standardized evening meal  at ~1,900 h and an overnight fast, participants attended the laboratory at 0800 h. A multi-lumen silicone catheter  was inserted transnasally and allowed to pass into the duodenum by peristalsis, as described . An infut-tests after confirming their normality of distribution, with the exception that the proportions of gender and use of antihypertensive medication were compared using Fisher's exact test. Blood pressure and heart rate responses to intraduodenal infusions were evaluated using two-way repeated measures ANOVA, with treatment and time as factors. Post hoc comparisons, adjusted for multiple comparisons by Bonferroni's correction, were performed if ANOVAs revealed significant interactions. Analyses were performed using Prism 8.0 . P-value less than 0.05 was considered statistically significant. Data are expressed as means ± SEM.Demographic data in the two groups were compared using unpaired Student's P < 0.001 during glucose, and P = 0.14 during lipid, infusion), without significant difference between them (P < 0.001), but remained unchanged during lipid infusion (time effect: P = 0.61), such that the reduction in diastolic blood pressure was greater in response to intraduodenal glucose than lipid (treatment effect: P = 0.04) (P < 0.001 for each). The increment in heart rate was greater in response to intraduodenal lipid than glucose ]  . Heart rr each)] .In patients with relatively well-controlled, uncomplicated T2DM, we observed a reduction in diastolic blood pressure in response to intraduodenal glucose infusion at a rate of 2 kcal/min, but not to an isocaloric fat infusion, probably due to its greater effect to increase heart rate. These observations suggest that the macronutrient composition of a meal may have a major impact on postprandial cardiovascular function in T2DM.In contrast to previous observations made in healthy older participants during intraduodenal infusion of glucose and fat at a higher rate  , there wThe mechanisms underlying the differences in the blood pressure and heart rate responses to intraduodenal glucose and lipid remain to be defined, but are unlikely to be related to peripheral glucose and insulin levels . We haveIn interpreting our findings, several limitations should be noted. First, our model of infusing either glucose or fat directly into the duodenum is, by definition, non-physiological, and does not allow us to evaluate the contribution of gastric factors to the regulation of postprandial blood pressure and heart rate. However, it is ideal to differentiate the blood pressure and heart rate changes mediated by the small intestine in response to glucose and fat, by standardizing the delivery of nutrients into the small intestine. Bypassing the stomach eliminated the potential influence of gastric emptying on the postprandial blood pressure and heart rate responses . MoreoveIn summary, when administered at identical energy loads, fat increases heart rate more than glucose, associated with a diminished reduction in blood pressure, in patients with relatively well-controlled, uncomplicated T2DM. These observations highlight the distinct impact of different nutrients on postprandial cardiovascular function and suggest that the macronutrient composition of meals may be an important consideration in T2DM patients with symptomatic postprandial hypotension.tongzhi.wu@adelaide.edu.au.The datasets presented in this article are not readily available because the dataset cannot be publicly due to the restrictions from the ethics committee. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Royal Adelaide Hospital Human Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.CX and XW were involved in conception, design and coordination of the study, subject recruitment, data collection and interpretation, statistical analysis, and writing of the manuscript. ZS, KJ, MH, TL, CR, and TW were all involved in conception, design, and data interpretation. All authors critically reviewed the manuscript and have read and approved the publication of this final version of the manuscript. All authors contributed to the article and approved the submitted version.KJ has received research funding from Sanofi and AstraZeneca and drug supplies from Merck Sharp & Dohme. MH has participated in the advisory boards and/or symposia for Novo Nordisk, Sanofi, Novartis, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, and AstraZeneca and has received honoraria for this activity. CR has received research funding from AstraZeneca, Merck Sharp & Dohme, Eli Lilly, Novartis, and Sanofi. TW has received travel support from Novartis and research funding from Novartis and AstraZeneca. TL has received research funding from Novartis. The remaining 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.


Reverse triggering (RT) is a dyssynchrony defined by a respiratory muscle contraction following a passive mechanical insufflation. It is potentially harmful for the lung and the diaphragm, but its detection is challenging. Magnitude of effort generated by RT is currently unknown. Our objective was to validate supervised methods for automatic detection of RT using only airway pressure (Paw) and flow. A secondary objective was to describe the magnitude of the efforts generated during RT.We developed algorithms for detection of RT using Paw and flow waveforms. Experts having Paw, flow and esophageal pressure (Pes) assessed automatic detection accuracy by comparison against visual assessment. Muscular pressure (Pmus) was measured from Pes during RT, triggered breaths and ineffective efforts.20, with a median of 8.7 cmH20. RT with breath stacking had the highest levels of Pmus, and RTs with no breath stacking were of similar magnitude than pressure support breaths.Tracings from 20 hypoxemic patients were used . RT was present in 24% of the breaths ranging from 0  to 93.3%. Automatic detection accuracy was 95.5%: sensitivity 83.1%, specificity 99.4%, positive predictive value 97.6%, negative predictive value 95.0% and kappa index of 0.87. Pmus of RT ranged from 1.3 to 36.8 cmH2O with important variability between and within patients.An automated detection tool using airway pressure and flow can diagnose reverse triggering with excellent accuracy. RT generates a median Pmus of 9 cmHBEARDS, NCT03447288.The online version contains supplementary material available at 10.1186/s13054-020-03387-3. Patient–ventilator dyssynchrony is often associated with poor patient-centered outcomes such as duration of mechanical ventilation or mortality –4. The chttps://bettercare.es/); this platform was used as a starting point for the current algorithm. In a pre-validation phase, we created, developed and tested algorithms for RT based on airway pressure (Paw) and flow  starting more than 0.1 s after the start of a machine-triggered insufflation  during the late expiration phase of a patient-triggered breath and not able to trigger a breath defined an Several methods of digital signal processing and supervised machine learning have been combined to detect RT events from flow and Paw waveforms depending on the mode of mechanical ventilation and the phase of the respiratory cycle where the event occurred. These methods intended to account for the different ways RT impacts on either or  both waveforms. For instance, during constant flow, the impact during inspiration will be mainly on Paw, while during pressure controlled ventilation the impact will be both on Paw and on flow. In both situations there may also be an impact on expiratory flow. The signals were smoothed to avoid artifactual detections. The mechanism that initiated the respiratory cycle was automatically detected . The strategies implemented are summarized in Fig. A training set was based on 20 to 40 minutes long tracings displaying visually detectable RT; these tracings mostly came from a previous study for 9 recordings  and 3 from the BEARDS study. The final validation dataset was only based on recordings from the BEARDS study (and with no patient used in the training dataset). It comprised 20 tracings from 20 different patients among the first 109 patients enrolled in the BEARDS study and the 1087 tracings available: 4 tracings without visible RT, 4 with a low visible rate of RT, 4 with a moderate rate of RT, 4 with a high rate of RT and 4 on PSV. All patients met the criteria for moderate or severe hypoxemic respiratory failure (PaO2/FiO2 < 200 mmHg and deep sedation at inclusion) with unilateral injury or ARDS. Ventilator waveforms and esophageal pressure were synchronously recorded over the first 7 days of mechanical ventilation. We selected 20 patients in order to represent a full spectrum of RT occurrence. A semiquantitative analysis allowed to classify the tracings available (in volume or pressure assist-control mode) according to the estimated frequency of RT: (1) no visible RT; (2) low rate of detectable RT: less than 4 RTs per minute; (3) moderate rate of RT: between 4 and 10 RTs per minute; (4) high rate of RTs: more than 10 RTs per minute. We discarded tracings with technical issues  and randomly selected 4 tracings in each category for the validation. For the 4 tracings with no RT, we purposely selected recordings collected when the patient was receiving neuromuscular blocking agents. Additionally, we randomly selected 4 tracings from the 246 recordings collected while patients were ventilated in pressure support ventilation (PSV). Tracings collected during paralysis or PSV acted as a control to ensure that the algorithm would not have false positives: RT should not occur in these situations because there is either no diaphragm contraction  or because the patient triggers all the breaths and there is no passive insufflation (PSV).Two researchers (TPh and TPi) visually reviewed 10 min of each of these 20 selected tracings and categorized each breath according to the type of trigger (machine vs patient), the presence or absence of RT and the presence or absence of a stacked breath  using Paw, flow and Pes. This assessment was used as the gold standard for breaths classification.Independently, and without the Pes signal, the same breaths were analyzed by the automatic detection software. The results of the visual and automatic detections were merged on a spreadsheet to review agreement and discrepancies breath by breath. All discrepancies were reviewed by a third researcher (RC) blinded to the results obtained with visual or automatic detection. This step confirmed or infirmed the discrepancies.One important question regarding the potential risk of RT (for the lung or diaphragm) relates to the amplitude of efforts generated by RT. Therefore, we calculated the muscular pressure (Pmus) of each breath to estimate the range of effort generated during RT and compare it to the Pmus generated during pressure support ventilation . We aimeAgreement between researchers and automatic detection for the diagnosis of RT was determined with the Kappa statistic , 26. TruSample size calculation: Our primary objective was to validate the automatic detection versus visual assessment of RT aiming at a Kappa above 0.8 that can be considered an almost perfect agreement. To obtain a kappa of 0.85 with a 95% confidence interval  and assuming a rate of RT of 20% with an alpha risk of 0.05, 4655 breaths were estimated to be necessary . Using 2The 109 patients included in the BEARDS study had a median [IQR] of 12  tracings collected and 58 (53%) of the patients had at least one of their tracings displaying reverse triggering. Tracings from 20 of these patients were randomly selected for the validation . The main characteristics of these patients are presented in Table 2O) frequently not strong enough to induce a visible deformation on Paw or Flow; this patient had been sedated and had no sign of wakefulness.A total of 4509 breaths from the 20 recordings were assessed, and 1073 (24%) were considered as RT as per gold standard ; almost all RTs (N = 1070) occurred during controlled ventilation and only 3 following auto-triggered breaths in PSV. Among patients in assisted-control mode presenting at least one RT, the rate of RT ranged from 14.8% to 93.3%. The confusion matrix between visual assessment and the automatic detection is shown in Table 20, ranging from 1.3 to 36.8 cmH20. Between- and within-patient variability in RT effort was considerable with median values ranging from 4.2 to 33.0 cm H2O and within-patient coefficient of variabilities ranging from 5 to 106% .To evaluate the range of efforts generated by RT together with its variability, the muscular pressure (Pmus) was calculated for each breath in 1047 breaths with RT during assist-control ventilation  and was compared to 715 breaths from 4 tracings during pressure support ventilation including 33 expiratory ineffective efforts occurring within triggered breaths. RT efforts were separated into those inducing breath stacking (n = 206) and those without breath stacking (n = 841). The results are presented in Fig. 2O with important variability between and within patients ranging from 1 to 36 cmH2O.We showed that an automated machine learning detection using only airway pressure and flow tracings was able to diagnose reverse triggering with a high specificity, positive and negative predictive values resulting in an excellent accuracy. Despite some false negatives, sensitivity remained very good and specificity was strong. In this selected set of tracings, RT was present in 23% of the breaths and generated a median muscle pressure of 9 cmHRT is a phenomenon that has been described recently and is very likely underdiagnosed at the bedside , 30. VisA major asset of the technique is the possibility to quantify RT continuously with no additional catheter or invasive device. Paw and Flow are readily available on all ventilators, and the system can communicate and capture data from all ventilators for online analysis or subsequent review. Continuous assessment of RT is relevant to identify the changes along the patients’ course of mechanical ventilation and to quantify clusters of dyssynchrony that might have an impact on the outcome. It would also allow to obtain reliable epidemiologic data and to examine relationship between RT and treatments or relationship with other biological phenomena in a continuous manner. A few other studies have previously evaluated the accuracy of automatic detections of some types of dyssynchronies –34 but oThis is the first study providing a quantification of the muscular efforts exerted during different forms of RT and compared to triggered breaths and ineffective efforts. We identified a broad range of efforts from almost negligible to huge contractions showing considerable between- and within-patient variability. Their impact on lung and diaphragm may therefore vary considerably. Physiological –38 and eOur main goal was to evaluate the accuracy of the automatic detection on different types of tracings in terms of modes and patient’s effort, and we assessed a large number of breaths but in a relatively limited number of patients. Our tracing selection included RT rates ranging from 0 to 93.3% representing a broad spectrum of clinical situations. We evaluated pressure control, volume control and pressure support ventilation, which are the most frequently used modes worldwide , 42. We An algorithm for automatic detection for reverse triggering showed excellent performances with usual modes of MV. This monitoring tool allows accurate continuous assessment and diagnosis of RT which is the first step to better understand this phenomenon underlying physiologic mechanism, assess its impact and ultimately propose treatment to prevent clinical complications.Additional file 1. Online Supplement.


P < 0.05). And VBP was good correlated with morning BP  and night BP . The results of mixed linear model analysis showed that patients' visit SBP , morning home SBP  and night home SBP  decreased significantly, after intervention. Both HBP and VBP showed that 18% substitute salt intervention could decrease the blood pressure of hypertensives. Medication led to VBP lower than HBP, but the two still had a good correlation.Aim to compare the home blood pressure monitoring (HBPM) and visit blood pressure monitoring in a clinical phase I single-arm pilot trial. The 18% sodium substitute salt was used in 43 hypertensives for 8 weeks, and visited once a week, while weekly visit blood (VBP) pressure, daily home blood pressure (HBP) and urine test results before and after intervention were collected. 43 hypertensive patients were recruited, 4 were lost. And enrolled 39 patients for analysis. The VBP were lower than morning HBP and night HBP (Trial registration: NCT03226327. Registered 21 July 2017—Retrospectively registered, http://www.clinicaltrials.gov. The World Health Organization recommends that the daily salt intake per person should be less than 5 g per day, while current salt intake is about 12 g or more in many countries, including China4. Therefore, it is imperative to find an effective salt restriction measure. With substitute salt as an effective means to reduce sodium intake, its antihypertensive effect has been widely recognized9. However, the sodium content of substitute salts in previous studies is generally high, mostly around 70%8, and some may be as low as 50% or even 25%10. And substitute salt of different ingredients may have different effects of lowering blood pressure. What’s more, in the case of relatively high sodium intake, some previous salt-restricted studies have also shown that the lower the sodium intake, the lower the blood pressure13. For the first time, this study applied substitute salt with only 18% sodium to patients with hypertension, and observed the effect of blood pressure reduction.As a leading risk factor for cardiovascular diseases22, but there are few comparative studies on two types of blood pressure monitoring in prospective intervention studies.In addition, blood pressure as a key indicator, choosing a superior approach to measure it will be crucial. There are many studies on comparing different types of blood pressure monitoring25. Then, what is the difference between the two kinds of blood pressure monitoring in the intervention studies? And what different blood pressure monitoring will bring to the research results?In the actual intervention studies, taking into account the cost of research and the convenience of implementation, usually, previous intervention studies used visit blood pressure monitoring (VBPM) to observe changes in blood pressure during the study period. In recent years, with the increasing emphasis on the home blood pressure (HBPM) and its popularity, more and more studies have adopted HBPM26.Hypertensive patients under the jurisdiction of a hospital in Chongqing Municipality, China, from May to July 2018. This study was designed as a Phase I clinical trial involving no less than 30 patients in accordance with international practiceInclusion criteria: (1) aged ≥ 50 and ≤ 75 years; (2) not had plans to move out of the community in the next three months; (3) not cooking at home less than 3 times or one day during the study; and (4) provided written informed consent before enrollment in the trial. Exclusion criteria: (1) history of acute myocardial infarction or stroke in the past 3 months, history of malignancy or expected lifetime less than 1 year; (2) hypercortisolism or aldosteronism; (3) acute disease, such as upper respiratory infection, fever and diarrhea; (4) salt substitute use in the family; (5) disease or disabilities that could exert potential influence on their adherence to the intervention, including deafness, dementia, as well as severe depression and other mental disorders; (6) family members not willing to use the salt substitute; (7) liver dysfunction; (8) anyone with abnormal serum potassium in family; (9) anyone using potassium-retaining diuretics in family.The Institutional Review Board of Peking University has approved the experiments, including any relevant details (IRB00001052-17110) which means that all experiments were performed in accordance with relevant guidelines and regulations.It’s based on a clinical phase I trial, after patients and their family signed the informed consent forms, subjects completed baseline questionnaires and medical examination. 18% substitute salt instead of traditional salt was used for 8 weeks, and patients measured home blood pressure every day, while visit staff visited once a week to measure the blood pressure of patients and collect the information of antihypertensive drugs use, dosages of sodium-limited formula salts, and adverse events, and 24-h urine was collected again at week 8 and sent for examination.In this study, 18% substitute salt of "Man Li Kang" was developed by Chongqing Institute of Biotechnology Co., Ltd. Name: solid compound condiment, standard of execution: Q/SWS 0025 S, food production license number: SC10650012000709, food circulation permit: SP5009051610016538, and the main ingredients include potassium chloride (35%), sodium chloride (18%), calcium chloride (10%). The blood pressure measuring instrument adopt validated automated upper-arm cuff devices that operate through the oscillometric technique . The urine samples were sent to the First Affiliated Hospital of Chongqing Medical University laboratory, and the enzyme was detected by HITACHI R7600.Before the start of the study, visit staff were trained in blood pressure measurement related knowledge, followed by one-on-one blood pressure measurement training for each patient by the visit staff, and a home blood pressure measurement handbook was distributed to the patient.The visit staff measured the patient's blood pressure once a week as a visit blood pressure, requiring three blood pressure measurements to be completed before 10:00 am, interval of about 2 min.While, patients were required to complete 3 blood pressure measurements a time in the morning and evening (from 6 to 9 o'clock am/pm) every day. Besides, during the weekly visit, the visit staff will confirm with the patients whether the blood pressure measurement method is correct or not. And the blood pressure measurement results will be automatically uploaded to the terminal management system in real time through the devices.27.Each time, 3 blood pressure measurements were collected, and the last 2 averages were included in the analysis. And home blood pressure was converted to weekly blood pressure according to the European Hypertension League guidelines28. Quantitative normal distribution data was described by mean and standard deviation, and paired T test was used for comparing the difference before and after intervention. Qualitative data is described by frequency. Non-positive distribution data are expressed in median and quartiles, and Wilcoxon Signed Rank Test was used. Analysis of variance for comparing visit blood pressure and home blood pressure, Least-Significant Difference (LSD) for comparison between tow samples, and Pearson correlation analysis for analysis of blood pressure correlation. The linear mixed models were used to analyze the change of the blood pressure. P values less than 0.05 were considered statistically significant.Statistical analysis was carried out using SPSS 22.0 . Visit blood pressure data is complete. And a total of 1953 pieces of complete home blood pressure measurements data were collected in the morning, the missing rate was 9.45%, and 1871 in the evening, with a missing rate of 14.33%. And the missing data of home blood pressure was filled by multiple imputationIn the study, we screened 69 patients, 26 of whom were excluded because they did not meet the exclusion criteria (excluding criteria 2 and 6), and eventually included 43 patients, 4 lost because of the intolerability of the taste from the substitute salt.Analyze by per protocol (PP), and incorporated 39 patients, including 20 males and 19 females, aged 67.1 ± 7.9 years old, BMI (Body Mass Index) was 26.6 ± 3.6. Among them, 5 patients currently have the habit of drinking, and drink ≤ 7 times a week, with an average alcohol consumption of ≤ 100 ml each time. The average age of hypertension was 11.0 ± 6.3 years. Blood pressure and medication at baseline are shown in Table P = 0.220). After intervention, the urine potassium value increased to 61.01 ± 17.26 mmol/L compared with baseline 52.22 ± 19.30 mmol/L, , which increased by 8.79 mmol/L (95% CI:1.41 ~ 16.16). The ratio of sodium to potassium was 2.39 , which was lower than baseline 3.05  (P < 0.001). Among them, the number of patients whose daily NaCl intake < 6 g increased from 8 (20.5%) to 28 (71.8%) at baseline . The 24-h urine microalbumin increased from baseline, P < 0.001  with no significant difference . The SBP  and DBP  of VBP were lower than morning HBP and night HBP.Analysis showed that the difference between the three kinds of blood pressure was statistically significant  and night BP .Correlation analysis showed that visit BP was good correlated with morning BP , morning home SBP  and night home SBP  decreased significantly, after intervention. Besides, visit DBP  and night home DBP  decreased significantly, but the decrease in morning home DBP was not statistically significant. And weekly blood pressure changes are shown in Tables The results of mixed linear model analysis showed that patients' visit SBP 32 found that the substitution of 35–55% potassium and magnesium for sodium ions in traditional salt did not cause excessive poisoning of potassium and magnesium ions. As early as the 1990s, domestic animal toxicity experiments found that LD50 in low-sodium group was higher than that in salt group, indicating that low sodium salt was less toxic than that in salt group, and had no accumulation effect in animals33. It can be seen that the traditional substitute salt is relatively safe. The substitute salt used in this study is different from the traditional ones due to its sodium and potassium content. From the baseline urine test results, the intake of sodium chloride is about 9 g. We assume that the patient's sodium intake is all from the salt, for ordinary substitute salts containing about 70% sodium chloride, and the daily per capita intake of sodium chloride could be reduced by about 2.7 g. However, the use of substitute salt with only 18% NaCl in this study reduced the daily per capita intake of NaCl by about 7.4 g. Therefore, a substantial reduction of sodium is likely to lead to hypertension patients, especially salt-sensitive patients taking antihypertensive drugs at the same time appear to reduce blood pressure too quickly and some symptoms similar to hypotension. In this intervention, there were individual patients with fatigue, dizziness and other symptoms may be related to this. In addition, the results of this study showed that the patient's 24-h urinary microalbumin was significantly higher than before intervention. 24-h urinary microalbumin (UMA) quantification is the main basis for early clinical diagnosis of nephropathy, 24 h UMA 30 to < 300 mg/24 h is the gold standard for diagnosing early nephropathy34. However, after the intervention in this study, the average 24-h urine microalbumin of patients only increased from 2.0 mg/24 h at baseline to 2.3 mg/24 h. The increase was limited, and it is far from reaching the standard for renal impairment. In addition, during our intervention, a male patient found a kidney-changing stone in the hospital, and his urine microalbumin increased significantly. At the same time, due to the small sample size, the patient may have a greater impact on the overall outcome. Of course, we still cannot rule out that this is related to the use of substitute salt.The study on substitute salt began in the 80s of last century. In 1984, Karppanen et al.37. In our study, the mean of HBP was higher than the VBP, which was contrary to most studies. It can be explained for the following reasons. First of all, although the visit blood pressure and the office blood pressure were measured by the medical staff, the measurement locations were different. Since the VBP was measured at the patient's home, the patient was in a more relaxed environment and the measured blood pressure may be lower. Al-Karkhi et al.37 found that even if hypertensive patients were self-tested at the office, self-test blood pressure was still higher than the self-test blood pressure at home, indicating that the location still has an impact on the patient's blood pressure measurement. What’s more, in the study by Hisao Mori et al.38, among sustained hypertensive patients, the mean HBP was lower than OBP by about 5 mmHg, but among normotensive subjects, the controlled hypertensive patients and the masked hypertensive patients, the HBP was higher than the OBP. And other study had similar results39. And our study was a phase I clinical trial with limited sample size and a high probability of sample bias, which might lead to the majority of patients in our study who were controlled hypertensive patients or had masked hypertension. Last but not least, since most hypertensive patients take antihypertensive drugs immediately after getting up in the morning, most of the patients have already taken antihypertensive drugs when the followers went to the patients' homes to measure blood pressure, resulting in low blood pressure.Previous studies on the comparison between office blood pressure (OBP) and home blood pressure have been conducted, but there was little comparison between the VBP and HBP. Most of the them have shown that the OBP is higher than the HBP40 in adolescents. In addition, the results of Evdokimov et al.41 showed that after the intervention, the VBP (from 160.8 ± 8.8/92.6 ± 7.4 mmHg to 125.9 ± 7.9/77.8 ± 5.0 mmHg) decreased more than the HBP , and our study seems to have this phenomenon, but we don't clear that whether the difference is statistically significant. What’s more, we observed that VBP seems to drop faster than HBP. And VBP showed a significant decrease in the first week of intervention, while HBP dropped in the second and third weeks, and it can be seen that the decline in HBP seems to be more moderate. This may be related to the instability of VBP as a point sample or related to the difference in blood pressure before and after medication.The results of this study show that HBP had a good correlation with VBP, which is similar to the results of Jardim et al.The 18% sodium content of the substitute salt can significantly reduce the patient's VBP and HBP. Although there was a significant difference in the values between VBP and HBP due to the medication, the correlation between them was good, and it does not differ much in the reflection of the intervention effect.


To study whether treatment recommendations based on age and ethnicity according to United Kingdom (UK) clinical guidelines for hypertension translate to blood pressure reductions in current routine clinical care.Observational cohort study.UK primary care, from 1 January 2007 to 31 December 2017.New users of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), calcium channel blockers (CCB), and thiazides.v ≥55) and ethnicity (black v non-black), from baseline to 12, 26, and 52 week follow-up. Secondary analyses included comparisons of new users of CCB with those of thiazides. A negative outcome (herpes zoster) was used to detect residual confounding and a series of positive outcomes (expected drug effects) was used to determine whether the study design could identify expected associations.Change in systolic blood pressure in new users of ACEI/ARB versus CCB, stratified by age  blood pressure measurements per user). For non-black people who did not have diabetes and who were younger than 55, CCB use was associated with a larger reduction in systolic blood pressure of 1.69 mm Hg  relative to ACEI/ARB use at 12 weeks, and a reduction of 0.40 mm Hg (−0.98 to 0.18) in those aged 55 and older. In subgroup analyses using six finer age categories of non-black people who did not have diabetes, CCB use versus ACEI/ARB use was associated with a larger reduction in systolic blood pressure only in people aged 75 and older. Among people who did not have diabetes, systolic blood pressure decreased more with CCB use than with ACEI/ARB use in black people (reduction difference 2.15 mm Hg (−6.17 to 1.87)); the corresponding reduction difference was 0.98 mm Hg (−1.49 to −0.47) in non-black people.Similar reductions in blood pressure were found to be associated with new use of CCB as with new use of ACEI/ARB in non-black people who did not have diabetes, both in those who were aged younger than 55 and those aged 55 and older. For black people without diabetes, CCB new use was associated with numerically greater reductions in blood pressure than ACEI/ARB compared with non-black people without diabetes, but the confidence intervals were overlapping for the two groups. These results suggest that the current UK algorithmic approach to first line antihypertensive treatment might not lead to greater reductions in blood pressure. Specific indications could be considered in treatment recommendations. High blood pressure, or hypertension, affects more than one in four adults globally and is a major modifiable risk factor for morbidity and mortality.In the United Kingdom (UK), National Institute for Health and Care Excellence (NICE) guidelines recommend angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB) as first line treatment for hypertension in people younger than 55, and calcium channel blockers (CCBs) for people without diabetes aged 55 and older, replacing CCB with thiazides for those with drug intolerance.Furthermore, in NICE guidelines, use of CCB or thiazides is recommended as first line treatment for black people of African or Caribbean ethnic origin (referred to in this article as black people to reflect diversity). The same drugs are recommended, after consideration of comorbidities, in international guidelines.Contemporary routine care is characterised by an increasingly older, more ethnically diverse and multi-morbid population. For people initiating hypertension drugs, it is not known whether current age and ethnicity based treatment recommendations translate to greater blood pressure reductions in these settings.The Quality and Outcomes Framework in the UK ensures that blood pressure is regularly measured and recorded in patients’ electronic health records in primary care.We conducted a cohort study using the Clinical Practice Research Database (CPRD-GOLD) linked to Hospital Episodes Statistics. CPRD-GOLD is a nationally representative repository of prospectively collected, anonymised electronic health records from primary care in the UK, which has been extensively validated.We identified new users of hypertension drugs , defined as people who had a prescription for one of these drugs in the study period (1 January 2007 to 31 December 2017), with no previous use of these drugs in the preceding year. People entered the cohort (index date) on the date of the first prescription. People were eligible for inclusion from the latest of the following: study start date (1 January 2007), one year after general practice registration , the date when the general practices’ data recording processes were considered of adequate standard to be included in CPRD-GOLD, or the person’s 18th birthday. People remained in the cohort until the earliest of the following: end of the study period (31 December 2017), last data collection from the general practice, date of leaving the general practice, or death.We sought to study the association between first line drug treatment for hypertension and blood pressure solely in those individuals treated for hypertension. Therefore, we excluded people who initiated any of the study drugs without recorded blood pressure measurements in the year before cohort entry, and those whose blood pressure was at target or lower .Our main analysis looked at the change in systolic blood pressure from baseline at 12 weeks, 26 weeks, and 52 weeks, and repeated this for diastolic blood pressure in a secondary analysis. We included two types of control analyses: a positive outcome control and a negative outcome control.Baseline values of systolic and diastolic blood pressure were taken from CPRD-GOLD, measured on or as close as possible to the index date. Using a priori knowledge about factors that could influence treatment choice or response we defined multiple covariates: age, sex, smoking, alcohol use, body mass index, diabetes, myocardial infarction, stroke, heart failure, arrhythmia, peripheral vascular disease, cancer, depression, and chronic obstructive pulmonary disease. Chronic comorbidities were defined using records from information recorded in both CPRD-GOLD and Hospital Episodes Statistics using all available data. We determined whether each person had ever previously been prescribed statins, antiplatelet agents, proton pump inhibitors, insulin, and loop diuretics. To capture polypharmacy, we measured drug treatment use from multiple British National Formulary chapters in the year before index date. To capture health service use in the year before index date, we determined how often a person visited their general practice. To account for socioeconomic status, we used person level deprivation based on the 2010 English Index Multiple Deprivation scores, separated into five equal groups, using quintiles. We calculated baseline estimated glomerular filtration rate from the most recent creatinine value recorded in CPRD-GOLD within one year before index date using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. This variable was categorised into five groups: no CKD (estimated glomerular filtration rate ≥60), stage 3a (45-59), stage 3b (30-44), stage 4 (15-29), and stage 5 (<15).To retain power in our main analysis, we imputed missing data under the missing-at-random assumption. Data for renal function were approximately 30% missing; our previous work has shown that people without recorded renal function have similar health outcomes to those with normal renal function after adjusting for covariates such as age, diabetes, and vascular disease.Reflecting current NICE guidance,Therefore, among new users of ACEI/ARB or CCB, within each of four groups defined by age (</≥55) and ethnicity (black/non-black), we estimated the propensity to be prescribed CCB versus ACEI/ARB using a logistic regression model including all the covariates listed above, except for diastolic blood pressure. Then, within each group, we matched one CCB user to one ACEI/ARB user on their propensity score within a caliper of 1%. We used linear mixed models to model change in systolic blood pressure with a random intercept for each person and fixed effects for exposure drug, using splines over time to allow the effects of exposure to vary flexibly over time. The fitted model was used to predict the blood pressure value at each follow-up , so did not require patients to have measurements taken at those particular time points. In this way, the model could accommodate unbalanced data.We used Cox proportional hazards models for the control outcomes within each of the propensity score matched groups defined above. For the gout and ankle swelling outcome models, we observed violation of the proportional hazards assumption. For these outcomes, we also modelled time specific hazard ratios. To reduce the risk of type I error with multiple testing, we defined a priori that we would report 99% confidence intervals.To look more closely at CCB versus ACEI/ARB and thiazide versus CCB in reducing systolic blood pressure according to age in a non-black population that did not have diabetes, we used finer age categories for group specific analyses  and propensity score matched within each age group. We studied reductions in blood pressure associated with thiazide-like diuretics  versus CCB and also older thiazide agents versus CCB.Our main analysis represented an intention-to-treat approach, so we also carried out an as-treated analysis whereby we censored follow-up blood pressure data if participants switched to or added another hypertension drug or discontinued their drug, defined as no repeat prescription within 90 days of previous prescription. This analysis aimed to examine the results for time spent on the drug initiated rather than the duration of follow-up that could include other drugs or no drugs. We carried out a complete case analysis to explore the impact of our multiple imputation approach. Finally, as a post hoc addition, we repeated our main analysis with 95% confidence intervals.No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results.From more than 1 million users of hypertension drugs between 2007 and 2017, we identified 87 440 new users of ACEI/ARB, 67 274 new users of CCB, and 22 040 new users of thiazides . People For each drug comparison, we matched people on propensity score and achieved good balance on all covariates within age and ethnicity groups (appendices 2 and 3). Within the matched group of people with black ethnicity for each drug comparison, there was a 1 mm Hg difference in systolic blood pressure at baseline. A median of four (interquartile range 2-6) blood pressure measurements per person were available during the one year follow-up.In people younger than 55, systolic blood pressure changed from 162.8 mm Hg to 140.7 mm Hg at 12 weeks in new users of CCB, compared with a change from 162.7 mm Hg to 142.2 mm Hg in new users of ACEI/ARB. In relative terms, for people younger than 55, CCB use was associated with a reduction in systolic blood pressure of 1.69 mm Hg  more than ACEI/ARB use . In thosAmong black people, systolic blood pressure changed from 156.0 mm Hg to 140.1 mm Hg at 12 weeks in new users of CCB, compared with a change from 158.4 mm Hg to 144.1 mm Hg in new users of ACEI/ARB. In relative terms, for black people, CCB use was associated with a reduction in systolic blood pressure of 2.15 mm Hg  more than ACEI/ARB use . Among nFor people aged 55 and older, new use of CCB were associated with greater reductions in systolic blood pressure than new use of thiazides at 12 and 26 weeks. However, the reductions observed were similar to those for people younger than 55 years, indicated by overlapping confidence intervals. Similarly, overlapping confidence intervals for blood pressure reductions in each of the ethnicity groups indicated no evidence for a difference for thiazide versus CCB use in black and non-black people . We obseThe incidence of drug specific side effects was as expected for each drug comparison; we found a higher incidence of ankle swelling for new users of CCB than for new users of ACEI/ARB , and a lower incidence of ankle swelling for new users of thiazides than for new users of CCB , 26 weeks change −1.90 mm Hg (−3.03 to −0.77), 52 weeks change −1.86 mm Hg (−3.08 to −0.64); In the whole cohort matched by propensity score, we found that thiazide-like drugs  were of similar effectiveness to CCB in terms of lowering systolic blood pressure, and that CCB were more effective than older thiazide drugs (appendix 8). Our as-treated analysis provided results that were broadly similar to the main analysis. The numerical reduction in blood pressure was greater among black people commencing CCB than those commencing ACEI/ARB , compared with the corresponding numerical reduction observed in non-black people . However, the 99% confidence intervals were overlapping for both groups, indicating no strong evidence for a difference, similar to the main analysis (appendix 9). The complete case analysis found similar results to the main analysis (appendix 10).This propensity score matched cohort study included more than 150 000 people with hypertension in routine primary care in the UK. We found no evidence to support a difference in the blood pressure reductions observed for CCB versus ACEI/ARB among non-black people who did not have diabetes and who were aged above and below 55. In subgroup analyses, however, we found that CCB were associated with larger reductions in blood pressure than ACEI/ARB in people older than 75. Among people who did not have diabetes, our results suggested a numerically greater reduction in systolic blood pressure for CCB versus ACEI/ARB new use among black people compared with non-black people, but the confidence intervals for the reductions overlapped between the two groups indicating no strong evidence for a difference.It is possible that people initiating hypertension drugs other than first line options suggested by current guidance were prescribed them for other indications. Despite good balance on baseline comorbidities in matched cohorts, residual confounding caused by unrecorded heart failure and kidney disease could have attenuated the blood pressure response to treatment. However, we endeavoured to reduce confounding by indication by including only people with hypertension; undertaking our analyses only in people who did not have diabetes; and matching by propensity score on multiple factors, inclusive of heart failure. This last approach achieved highly balanced cohorts for each drug comparison within each group. Furthermore, we used multiple strategies to help detect bias in our matched cohorts; our negative outcome analysis demonstrated no increased risk of herpes zoster in any drug group.Our results related to ethnicity have wide margins of uncertainty, which could have occurred for several reasons. Firstly, we compared changes in blood pressure between black and non-black people, consistent with current UK guidance.Our outcomes relied on measurements of blood pressure at clinics because these measurements are recommended by NICE to monitor hypertension in primary care and to guide treatment decisions, except for patients suspected of white coat hypertension or resistant hypertension, in whom ambulatory or home monitoring is recommended.NICE guidelines recommend ACEI/ARB as the first line treatment for hypertension for those younger than 55.v 40% for age ≥55 in our data), for which CCB might be more effective.Since first including 55 years as the age threshold in NICE guidance (CG18) in 2004, the literature has evolved to capture older populations with subgroup analyses based on older ages (comparison threshold at age 75) or subgroups defined by frailty.International guidelines for hypertension are similar to NICE guidelines in that ethnicity is a major consideration in the choice of a first line hypertension drug, although they do not use the algorithmic approach of UK guidance. Ethnicity based recommendations are supported by strong evidence from the ALLHAT randomised clinical trial, which showed use of thiazides or CCB was more effective than ACEI/ARB at lowering blood pressure in black people.In conclusion, we observed reductions in blood pressure for CCB that were similar in magnitude to those for ACEI/ARB in people aged above and below 55. This finding suggests that some people aged 55 and older who are currently offered CCB, but have indications for renin-angiotensin blockade such as proteinuria, could be missing the therapeutic benefits of ACEI/ARB. We found no evidence that CCB new use was associated with larger reductions in blood pressure than ACEI/ARB new use among black people versus other ethnic groups, although power was limited and uncertainty existed in the estimate. Our results suggest that the algorithm for choice of pharmacotherapy in UK NICE guidance could be simplified. Moving towards a choice of any of the three major hypertension drug classes with suggested compelling indications for their use would align the UK with international guidance, in particular with regard to age.Current NICE recommendations for first line hypertension treatment are based on age, ethnicity, and diabetesExcluding people with diabetes, calcium channel blockers (CCB) are recommended for those aged 55 and older and for people of black African or African-Caribbean family ethnicity (referred to here as black people to reflect diversity); angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) are recommended for non-black people younger than 55Since the current guidance was developed, the medical literature has evolved incrementally with more trials including older populations; meta-analysis of these new data indicate that the effectiveness of first line antihypertensive drugs does not differ by age (</>65); additionally, categorisations of ethnicity to guide clinical decision making have been questionedIt is not known whether recommended drug choices lead to greater reductions in blood pressure in current routine clinical careIn this propensity score matched cohort study excluding people with diabetes, initiation of either CCB or ACEI/ARB for hypertension was associated with similar reductions in blood pressure in people younger than 55 and those aged 55 and older; subgroup analyses indicated that CCB was associated with greater reductions in blood pressure than ACEI/ARB only in those aged 75 and olderReductions in blood pressure appeared to be numerically greater for black people initiating CCB versus ACEI/ARB than those blood pressure reductions in non-black people, but the confidence intervals overlapped between the two groupsThe finding that ACEI/ARB and CCB are associated with similar reductions in blood pressure in those aged above and below 55 suggests that age might not be the best factor to determine drug choice; other characteristics, such as level of urinary protein loss, could favour choice of a specific class of drug