Puumala orthohantavirus causes hemorrhagic fever with renal syndrome (HFRS) characterized by acute kidney injury (AKI), an abrupt decrease in renal function. Creatinine is routinely used to detect and quantify AKI; however, early AKI may not be reflected in increased creatinine levels. Therefore, kidney injury markers that can predict AKI are needed. The potential of the kidney injury markers urea, cystatin C, α1-microglobulin (A1M) and neutrophil gelatinase-associated lipocalin (NGAL) to detect early AKI during HFRS was studied by quantifying the levels of these markers in consecutively obtained plasma (P) and urine samples (U) for 44 HFRS patients. P-cystatin C and U-A1M levels were significantly increased during early HFRS compared to follow-up. In a receiver operating characteristic (ROC) curve analysis, P-cystatin C, U-A1M and P-urea predicted severe AKI with area under the curve 0.72, 0.73 and 0.71, respectively, whereas the traditional kidney injury biomarkers creatinine and U-albumin did not predict AKI. Nearly half of the HFRS patients (41%) fulfilled the criteria for shrunken pore syndrome, which was associated with the level of inflammation as measured by P-CRP. P-cystatin C and U-A1M are more sensitive and earlier markers compared to creatinine in predicting kidney injury during HFRS. Orthohantaviruses (henceforth termed hantaviruses) can cause the viral hemorrhagic fever diseases: hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome ,2. TheseAKI is stratified into the severity stages 1, 2 and 3 based on the guidelines recommended by KDIGO 2012  using primarily plasma creatinine levels . UnfortuAnother kidney disorder, the shrunken pore syndrome (SPS) describes the impairment of glomerular filtration of molecular sizes between 12–29 kDa ,28. SPS Hence, the main aims of our study were to determine which kidney injury markers increased during early HFRS, to identify which of them could predict severe AKI in HFRS patients, and to provide a descriptive study to determine whether SPS could be present during HFRS. For all 44 patients, demography, hospital care characteristics and laboratory values are shown in The levels of study  and conventional  kidney injury markers in patient plasma and urine were quantified and the kinetics visualized in cystatin c was significantly lower than eGFRcreatinine in the first week following HFRS onset (0–4 and 5–7 DPDO). Furthermore, eGFRcystatin c decreases significantly in the earliest time point (0–4 DPDO) compared to follow-up (<90 DPDO)  calculated using P-cystatin C is lower compared to eGFR calculated using creatinine, the eGFR was quantified and the kinetics for both eGFR compared in 90 DPDO) , reflect5–7 DPDO . A potential confounder is corticosteroid treatment since it can increase cystatin C levels without presence of renal function impairment . To studTo determine whether the study and conventional kidney injury markers are increased in patients with severe AKI (stage 2 or 3) compared to HFRS patients that did not fulfil these criteria, the levels of kidney injury markers were stratified into different time groups and compared between the two groups within each time group . AKI strTo investigate whether the studied kidney injury markers, P-cystatin C, U-A1M and U-NGAL, associate significantly with the traditional kidney injury markers P-creatinine and P-urea, all plasma and urine samples for all patients obtained during HFRS (≤30 DPDO) were analyzed using the GEE method and adjusted for sex and age . P-cystaThe ability of the studied kidney injury markers  vs. traditional kidney injury markers  to predict severe AKI and the following cut-off level were determined using a ROC curve analysis . In ordeTo determine whether there is a pathophysiological association between SPS and disease outcome, the maximum levels of the kidney injury markers, P-cystatin C, P-urea, P-creatinine, U-A1M and U-NGAL, and CRP, a marker of inflammation, were analyzed for significant differences between patients who fulfilled SPS criteria at any time point during HFRS vs. those who did not. None of the studied kidney damage markers were increased in patients who fulfilled SPS criteria during HFRS , nor didcystatin C decreased significantly compared to eGFRcreatinine during early HFRS. We also show that nearly half (41%) of the patients fulfilled criteria for SPS during HFRS. To the best of our knowledge, this is the first time SPS has been studied in a cohort of infectious disease patients.AKI is a common feature during HFRS , and in According to the KDIGO 2012 guidelines, AKI severity is defined primarily by increased levels of creatinine in patient plasma . HoweverThe levels of U-NGAL in the present study were increased in HFRS patients with severe AKI compared to HFRS patients with no severe AKI, but U-NGAL levels did not increase during early HFRS. Furthermore, U-NGAL did not predict severe AKI in the present study. A previous study reports data on HFRS caused by PUUV where the peak level of U-NGAL associated significantly with the peak level of creatinine, indicating a pathophysiological association . Even thNearly half 41%) of the HFRS patients fulfilled the criteria for SPS, and the levels of CRP, a marker of inflammation, were increased; however, these patients did not have increased kidney damage marker levels. In several previous studies, SPS has been shown to be associated with increased mortality and morbidity . SPS is % of the In conclusion, we show that P-urea, P-cystatin C and U-A1M predicts future severe AKI during HFRS. In addition, P-cystatin C and U-A1M levels increase significantly during early time points compared to follow-up, which P-creatinine did not. We therefore highlight the potential of P-cystatin C and U-A1M as early and sensitive markers of kidney injury during HFRS and likely also for other diseases.In total, 44 patients were enrolled in this study after being diagnosed with PUUV infection during 2008–2014 at the Infectious Disease Clinic, Umeå University hospital. The diagnosis of PUUV infection was verified by the patient having typical clinical manifestations of HFRS and presence of immunoglobulin (Ig)G and IgM antibodies towards PUUV detected using an immunofluorescence assay. To be included in the study, the patients had to give oral and written informed consent. Following inclusion, blood and urine samples were collected at different time points during HFRS and ending with a follow-up sample at least 90 DPDO. The peripheral venous blood samples were collected using commercially available vacutainers containing sodium heparin as the anti-coagulant . The vacutainers were centrifuged and plasma aliquoted into different vials immediately stored at −80 °C until use. Urine was collected and frozen at −80 °C for later analyses.Blood and urine samples from patients were analyzed at the accredited Clinical Chemistry Laboratory, University Hospital of Umeå, for levels of P-creatine, P-cystatin-C, P-urea, P-CRP, U-albumin and U-creatinine. The concentration of U-albumin was normalized using urinary creatinine concentration.® 8000 c502 instrument  with particle-enhanced turbidimetric immunoassay reagents . U-A1M was measured using a BN ProSpec instrument  by immune nephelometry with reagents from Siemens. The samples were run in batches of 30–50 samples at a time, and control samples were analyzed prior to analysis of each batch of samples. The same lots of reagents, calibrators and controls were used for both U-NGAL and U-A1M throughout the study. The concentrations of U-NGAL and U-A1M were normalized using urinary creatinine concentration. The levels of U-NGAL and U-A1M were quantified in urine samples from HFRS patients obtained at different time points during HFRS and at follow-up, at the central accredited Clinical Chemistry Laboratory at the Karolinska University hospital. U-NGAL was measured using a CobasThe severity of AKI during HFRS was scored according to KDIGO 2012 guidelines  into no We define the outcome “severe AKI” as the patients who fulfilled AKI stage 2 or 3 at any time during HFRS (≤30 DPDO). −0.329 × (0.993)Age and if P-creatinine > 62 µmol/L: 144 × (Scr/0.7)−1.209 × (0.993)Age. For men, the equations were as follows: P-creatinine < 80 µmol/L: 141 × (Scr/0.9)−0.411 × (0.993)Age and if P-creatinine > 80 µmol/L: 141 × (Scr/0.9)−1.209 × (0.993)Age [The eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration (CDK-EPI) equations based on P-creatinine levels and sex. For women, the equations were as follows: P-creatinine < 62 µmol/L: 144 × (Scr/0.7).993)Age .In order to determine whether patients fulfilled shrunken pore syndrome, eGFR was also calculated using the revised Lund–Malmö (eGFR LM-rev) equations based on P-creatinine levels and sex. For women if P-creatinine < 150 µmol/L: e^((2.5 + (0.0121 × (150 − creatinine))) − (0.0158 × age) + (0.438 × Ln(age))), and if P-creatine ≥ 150 µmol/L e^((2.5 − (0.926 × Ln(creatinine/150))) − (0.0158 × age)+(0.438 × Ln(age))). For men if P-creatinine < 180 µmol/L: e^((2.56 + (0.00968 × (180 − creatinine))) − (0.0158 × age) + (0.438 × Ln(age))) and if P-creatinine ≥ 180 µmol/L e^((2.56 − (0.926 × Ln(creatinine/180))) − (0.0158 × age) + (0.438 × Ln(age))) ,28. −1.069 × (Age)−0.117 − 7 [The eGFR was also calculated using P-cystatin C levels using the Caucasian and Asian pediatric and adult subjects (CAPA) formula: 130 × (cystatin C).117 − 7 . The criteria for Shrunken pore syndrome (SPS) was fulfilled if the ratio between eGFR calculated using cystatin C (CAPA) and creatinine (LM Rev) was below 0.7 ,28.cystatin C differed to eGFRcreatinine within the same time point was determined using the Wilcoxon signed rank test for paired samples.The generalized estimating equation (GEE) method with assumption of exchangeable correlation structure between consecutive observations was used to quantify the estimated mean and standard error of the mean (SEM) for longitudinal changes in the levels of kidney injury markers in plasma , urine , eGFR calculated using either cystatin C or creatinine levels and the ratio of U-A1M to U-albumin. The estimated means within each specified time group  were compared to means at follow-up (at least 90 DPDO). Furthermore, whether eGFRIn order to visualize the difference in levels of kidney damage markers in HFRS patients with severe AKI compared to those who did not have severe AKI, the mean and standard error of the mean were calculated using the GEE method. Since the patients were stratified into two groups, the time points were extended to 0–7; 8–14 and 15–30 DPDO to ensure most patients had samples within the given time points. Whether the levels of kidney damage markers in plasma and urine differed between HFRS patient with severe AKI compared to those who did not have severe AKI was determined using the GEE method.To determine the pathophysiological association between SPS and kidney damage markers, inflammation and whether patients with SPS were older or in increased need of hospital care, the generalized linear model was used. The estimated mean and standard error of the mean were calculated using the generalized linear model for HFRS patients stratified into whether they fulfilled SPS criteria at any time point during HFRS and tested for significant difference. Furthermore, the kinetics of kidney damage markers and marker of inflammation (CRP) were calculated using the GEE model and stratifying the patients into groups of those who fulfilled SPS criteria vs. those who did not. The difference within each time group between the two SPS groups was tested for significance using the GEE model.In order to determine a potential pathophysiological association between the traditional kidney damage markers P-creatinine and P-urea and our studied kidney injury markers P-cystatin-C, U-NGAL and U-A1M was studied using the levels quantified in all plasma and urine samples during HFRS (≤30 DPDO) using the GEE method and adjusting for sex and age.To determine whether the levels of the traditional kidney injury markers P-creatinine, P-urea and U-albumin, and our studied kidney injury markers P-cystatin C, U-A1M and U-NGAL can predict severe AKI, a ROC curve analysis was performed. Only samples obtained from HFRS patients that did not have severe AKI at time point of first sample collection were included in order to enable prediction of AKI. The cut-off value with highest sensitivity and specificity for each kidney damage marker was determined if area under the curve (AUC) was significant. p < 0.05. The statistical analyses were performed using SPSS version 25 .The level of significance was set to The study was approved by the Ethical Committee of Umeå University . All patients were included after oral and written informed consent.


Background: In the context of recently updated strategies of pressure management, there is a paucity of evidence on the effect of diastolic blood pressure (DBP) level on adverse events among stroke patients. This study aimed to examine the effect of low DBP (<60 mmHg) under different levels of systolic blood pressure (SBP) on the risk of composite events and stroke recurrence among patients with ischemic stroke (IS) or transient ischemic attack (TIA).Material and Methods: This study was conducted in 2,325 patients with IS or TIA. DBP values were categorized into <60, 60–70, 70–80 (reference), 80–90, and ≥90 mmHg in the main sample and were further categorized as <60 and ≥60 mmHg (reference) when patients were stratified according to SBP levels . The outcomes were defined as recurrent stroke and cumulative composite events  at 1 year.Results: During 1 year of follow-up, a total of 95 composite events and 138 stroke recurrences were identified. The patients with low DBP showed a significantly higher risk of composite events , especially the elderly patients (≥60 years); however, this result was not observed for stroke recurrence . With the reduction of the SBP levels, the proportion of patients with low DBP increased , and the risk for composite events persisted.Conclusions: Along with the new target levels of SBP suggested by updated criteria, there is a trend for DBP to be reduced to a harmfully low level, which was associated with an increased risk of composite events among patients with IS or TIA. Stroke is a leading cause of mortality and disability worldwide, considerably contributing to social and economic burden, and hypertension has been widely recognized as one of the most powerful risk factors of stroke –4. BloodPrevious studies mainly focused on the harms of SBP, resulting in more concern of SBP than diastolic BP (DBP) for risk assessment and treatment , 12. FurThe current study aimed to examine the effect of low DBP (defined as <60 mmHg in this study) , 21 undeThe Blood Pressure and Clinical Outcome in Stroke Survivors (BOSS) study is a nationwide, hospital-based, longitudinal cohort study conducted in 61 hospitals in China. The details of the study design, rationale, and baseline characteristics have been previously described . BrieflyThe study was approved by the central institutional review board of Beijing Tiantan Hospital, as well as ethical committees at the 61 participating hospitals, in compliance with the Declaration of Helsinki. All patients or the designated relatives signed the written informed consent form.After admission, each enrolled patient was provided a semiautomatic upper-arm BP monitor . Nurses trained the patients or their accompanying relatives on the use of the device. During hospitalization, BP was measured twice daily by the patients themselves or their relatives, according to the standard measurement method recommended by the American Heart Association . BP dataIn the overall population, DBP values were categorized into 10-mmHg increments: <60, 60–70, 70–80, 80–90, and ≥90 mmHg. We chose the category of 70–80 mmHg as the reference. When patients were further stratified according to SBP categories , the DBP values were categorized as <60 and ≥60 mmHg, with ≥60 mmHg as the reference.Other baseline information, including age, sex, smoking, alcohol drinking, medical history, and medications, was obtained through a nurse-administered standardized questionnaire at the time of admission. History of stroke was defined as previous IS, intracerebral hemorrhage, and subarachnoid hemorrhage confirmed by medical records. History of coronary heart disease was defined as a reported history of myocardial infarction or cardiac surgery or a final diagnosis of myocardial infarction at discharge. History of hypertension was defined as previous hypertension and use of antihypertensive medication. History of diabetes mellitus was defined as self-reported physician-diagnosed diabetes mellitus or use of antidiabetic drugs. History of dyslipidemia was defined as self-reported physician-diagnosed dyslipidemia or use of lipid-lowering agents.The patients were followed up at 3 months through a face-to-face interview and at 12 months via a telephone survey. Patients with nonfatal events were asked to return for a face-to-face follow-up or were visited at home. The clinical outcomes were defined as cumulative composite events and recurrent stroke (ischemic or hemorrhagic) at 1 year.In the current study, composite events were defined as the combination of nonfatal myocardial infarction, nonfatal congestive heart failure, and death of any cause. Death certificates were obtained for deceased participants, and hospital data were abstracted for all vascular events.Stroke recurrence was defined as a new stroke event or rapid worsening of an existing focal neurologic deficit lasting >24 h [an increase in the National Institutes of Health Stroke Scale (NIHSS) score by ≥4 points compared with the baseline NIHSS score], accompanied by new ischemic changes on magnetic resonance imaging or computed tomography of brain  and 95% confidence intervals (CIs) for clinical outcomes. The adjustment variables included age, sex, medical history , and medication at discharge .p-values of 0.05 were considered statistically significant.All analyses were performed with SAS 9.4 . Two-sided Among the 2,608 patients recruited from the BOSS study, 106 (4.06%) patients with incomplete baseline data and 72 (2.76%) and 105 (4.03%) patients who were lost to follow-up at 3 months and 1 year, respectively, were excluded. Finally, a total of 2,325 patients were successfully enrolled for the final analysis. The flowchart of patient selection is presented in During 1 year of follow-up, a total of 95 (4.09%) patients with composite events and 138 (5.94%) patients with stroke recurrence were identified. In this study, we demonstrated that, compared with the medium level of DBP (70–80 mmHg), low DBP (<60 mmHg) was associated with a significantly higher risk of composite events, especially among the elderly (the main population affected by isolated systolic hypertension) –27. HoweAlthough a lower SBP target than that previously recommended (140 mmHg) has been endorsed by SPRINT and the 2017 ACC/AHA guidelines, its benefits have not been widely recognized , 10. In In the elderly, as the main population affected by stroke, isolated systolic hypertension is the most common hemodynamic form of hypertension –27. In oThe main strength of this study was that compared with the pressure measurement at a single time point, the averaged BP value over 3 months of monitoring might be a more reliable indicator of long-term BP control. Our blood pressure measurement is also better correlated with cardiovascular events than other clinic measurements. It was a better prognostic indicator for long-term cardiovascular events and mortality and can identify white coat and masked hypertension. It provided better sensitivity and might be suitable for identifying abnormal blood pressure given its relative ease of use and availability compared with other clinic measurements like ambulatory monitoring.However, our main analysis included the adverse events that occurred within the period of pressure monitoring, which ignored the time sequence of pressure monitoring and adverse events. Therefore, we further performed a sensitivity analysis including only the outcomes from 4 months to 1 year of follow-up. Although lacking statistical power, the event rate showed the same trend as in the main analysis. Besides, because this study included Chinese patients only, it may limit the generalizability of the conclusions to other populations. Additionally, this study was an observational study, and the possibility of residual confounding cannot be fully eliminated, in spite of the multivariable regression analyses for several important potential confounders. Moreover, our study does not have the information about cardiovascular mortality, so we used all-cause mortality instead. Further studies using cardiovascular mortality as the endpoint are needed to verify the findings of this study.In summary, our study demonstrated the correlation between the reduction of SBP levels  and increasing proportion of patients with low DBP, indicating that a strict SBP control targeting 130 and 120 mmHg may be related to an increased likelihood of harmfully low DBP, which can affect the cardiac risk. In other words, care should be taken when considering intensive SBP control in patients with IS or TIA.All datasets generated for this study are included in the article/The studies involving human participants were reviewed and approved by the central institutional review board of Beijing Tiantan Hospital. The patients/participants provided their written informed consent to participate in this study.YW contributed to the conception and design of the study. ZC contributed to manuscript drafting and critical revisions of the manuscript. JM, JX, LD, AC, GY, XM, and HL contributed to the acquisition and analysis of data and AW contributed to statistical analysis.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.


ERC/2012/33.In the original article, there was an error in the ethical clearance number. The correct number for ethical clearance is Materials and Methods, Paragraph 3:A correction has been made to 1c <6.5%), not on treatment for diabetes, no elevated blood pressure, and no past history of kidney disease or snake bite were included. Patients with other known causes of chronic kidney disease (CKD) and those who did not consent were excluded from the study . Studies involving human patients/participants were reviewed and approved by the Research, Ethical Review and Higher degree committee of the faculty of Medicine and Allied Sciences, Rajarata University, Sri Lanka. Patients/participants provided their written informed consent to participate in this study (ERC/2012/33)According to CKDu case definition, an individual identified with an albumin-to-creatinine ratio (ACR) ≥ 30 mg/g urine creatinine during the initial visit and at a follow-up visit, a normal glycosylated hemoglobin (HbA.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Simultaneous pancreas-kidney (SPK) transplantation is a proven option of treatment for patients with type 1 diabetes mellitus (T1DM) and related end-stage renal disease. There is discrepancy between the results of different studies about the impact of prolonged normalization of glucose metabolism achieved by SPK on the course of diabetic complications including severe forms of diabetic neuropathy. The objective of the study was to evaluate the prevalence of cardiovascular autonomic neuropathy (CAN) in patients undergoing SPK transplantation and its evolution 10 years after transplantation.  Prospective study of 81 patients transplanted in a single center from year 2002 to 2015. Autonomic function was assessed using cardiovascular autonomic reflex tests (CARTs). CARTs were made before SPK transplantation and during the follow-up. Evolution of tests after SPK transplantation was evaluated by contrasting hypotheses (paired tests). Multiple testing was adjusted with the Benjamini-Hochberg procedure with a false discovery rate of 10%. 2, and mean duration of diabetes 25.5 ± 6.5 years, received SPK transplantation. Ten years after SPK transplantation, 56 patients re tained the pancreatic graft (42 of them with normofunctioning pancreas and 14 with low doses of insulin therapy). These 42 patients were selected for the autonomic study. Before transplant procedure, all CART results were abnormal. After SPK transplantation, paired test analysis showed an improvement of systolic blood pressure (SBP) response to orthostasis at the 5th year after SPK (p = 0.03), as well as improvement of the Valsalva ratio at the 3rd (p < 0.001) and 5th (p = 0.001) year after SPK. After correcting for the false discovery rate, all the variables of autonomic study reached significance at different time points.  48 males and 33 females, mean age 37.4 ± 5.7 years, mean BMI 24.0 ± 3.4 kg/m Prevalence of CAN in patients who are candidates for SPK transplantation is high and is generally advanced. SPK transplantation improves CAN with improved Valsalva ratio as the most precocious test. Diabetic neuropathy is a common microvascular complication of long-term diabetes mellitus (DM). Its etiopathogenesis is multifactorial, but hyperglycemia seems to be the primary cause: increased accumulation of sorbitol and fructose in the nerves and decreased myoinositol and Na/K ATPase activity. Other mechanisms such as hypoglycemia , immunolDiabetic autonomic neuropathy (DAN) is a poorly studied complication of DM, despite its frequency and the significant negative impact it has on the survival and quality of life of diabetic patients . DAN usuCardiovascular autonomic neuropathy (CAN) is the most frequent autonomic complication in DM. CAN is defined as an alteration of the cardiovascular response to various visceral reflexes and is associated with a significant amount of the morbidity and mortality of diabetes. The literature shows a varying CAN prevalence depending on the criteria used for diagnosis, the population studied, and the time of DM evolution –8: autonCAN usually manifests itself subclinically, characterized by the alteration of cardiovascular reflexes such as resting tachycardia, or clinically, less frequently, and generally manifested as exercise intolerance, orthostatic hypotension, silent myocardial infarction, and intraoperative cardiovascular liability , 9–12. OOn the other hand, pancreas transplantation is a proven option of treatment for patients with T1DM and related end-stage renal disease, who are candidates for kidney transplantation. Three types of whole pancreas transplantation are described: simultaneous pancreas kidney transplantation (SPK), pancreas after kidney transplantation (PAK), and pancreas transplantation alone (PTA) . Before However, the data currently available on the improvement of neuropathy of pancreas-kidney transplant patients is limited, and there are doubts about the chronological evolution after transplantation –19. To tThis report describes the results of clinical examination and autonomic function tests in patients with T1DM before and up to 10 years after successful SPK transplantation.2, and mean duration of diabetes 25.5 ± 6.5 years) who received SPK transplantation, at La Fe University Hospital in Valencia (Spain), between 2002 and 2015.This is a prospective study of 81 patients with T1DM , below 50 years of age, with absence of severe psychiatric or psychological disorders and ability to understand what a pancreas transplantation entails in relation to postoperative collaboration, and complications that may arise in the follow-up of treatment.The inclusion criteria for SPK transplantation were T1DM patients (C − peptide < 0.5 ng/mL), end-stage renal disease , and triglycerides levels were measured by enzymatic and colorimetric techniques .C-peptide serum levels were measured using an electrochemiluminescence immunoassay (Cobas c602).Glycated hemoglobin (HbA1c) was measured using high-performance liquid chromatography (HPLC) (Horiba Tosoh G11).The glomerular filtration rate (GFR) was calculated from serum creatinine levels using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.Finally, estimated low-density lipoprotein cholesterol (LDL-c) was calculated using Friedewald's equation.Neurological evaluation was made before SPK transplantation and during follow-up: after 3, 5, 7, and 10 years. Autonomic function was assessed using CARTs that measure systolic blood pressure (SBP) responses to standing up and HR responses to the Valsalva maneuver and to deep breathing –23. All E/I) or deep breathing ratio assesses HR variability induced by a series of deep breathing cycles. This test is based on the fact that the HR decreases during expiration and increases during inspiration. With the patient at rest and supine for at least 10 minutes, HR is monitored by electrocardiogram (ECG) while the patient performs 6 deep breathing cycles, one breath every 10 seconds. The quotient between the longest R-R during expiration and the shortest R-R during the inspiration phase is performed in 3 of the 6 cycles, with the final result being the average of the 3 determinations. A difference of >15 beats per minute (bpm) are considered normal and <10 bpm is abnormal. The lowest normal value for E/I ratio is variable, and it decreases with age: age 20-24 years, 1.17; 25-29, 1.15; 30-34, 1.13; 35-39, 1.12; 40-44, 1.10; 45-49, 1.08; 50-54, 1.07; 55-59, 1.06; 60-64, 1.04; 65-69, 1.03; and 70-75, 1.02 [Expiration/inspiration  as the 30/15 ratio, and they are calculated jointly. The patient has to remain in the supine position for 3 minutes, during which blood pressure is measured 3 times. Afterwards, the patient has to adopt the standing position quickly (in less than 3 seconds). After that, 2 blood pressure measurements are taken. The difference between the mean of the SBP in decubitus and the average of the SBP in standing position is calculated. Normal response is a fall of SBP of <10 mmHg, borderline is a fall of 10-29 mmHg, and abnormal is a fall of >30 mmHg with symptoms .Neurotester® . All the previous test values were transferred and processed by a computer program synchronized with Neurotester®. The normality values were adjusted according to the patient's age. The result of each test will be as follows: normal, borderline , or pathological. According to the American Diabetes Association (ADA) and the American Academy of Neurology recommendations, at least 2 abnormal HR tests are required for a confirmed diagnosis of CAN [CARTs were performed with s of CAN , 26, 27.Continuous variables were described using mean and interquartile range for baseline and follow-up patient characteristics, and the mean and standard deviation for CARTs. Categorical values were summarized as proportions.t-test was used for comparing results over time within each group for continuous variables. The Pearson test was used for categorical variables. When the available observations were limited, the Fischer exact test was used.With respect to the statistical analysis, a paired two-tailed p < 0.05 for all the tests. Statistical analyses were performed using SPSS Statistics® (version 20). The Benjamini-Hochberg Procedure [The level of significance was rocedure  correctiComité Ético de Investigacion Clínica (CEIC) of La Fe Health Research Institute, Valencia (Spain). This article contains human studies approved by CEIC. Written informed consent was obtained from all patients prior to their inclusion in the study.This study was approved by 2, and a mean duration of diabetes 25.2 ± 6.2 years) who had undergone SPK transplantation and maintained functioning pancreatic and renal grafts during the follow-up. All patients were dialysis- and insulin-free and normoglycemic  at the moment of this study. Baseline and post-SPK follow-up characteristics are included in This study included 42 patients with T1DM , as well as improvement of the Vasalva ratio at the 3rd year (p < 0.001) and the 5th year (p = 0.001)  .th year, and the Vasalva ratio also maintained a significant improvement after the 7th year and after SPK. In addition, the 30 : 15 and E/I ratios showed significant improvement after the 3rd year of the SPK transplantation  compared an intensive therapy group versus conventional therapy, and showed that, although CAN prevalence increased in both groups, the incidence was significantly lower in the intensively treated group  [CAN is a common complication of long-standing diabetes mellitus. Its etiopathogenesis is multifactorial, but hyperglycemia seems to be the primary cause, just as diabetic nephropathy. Several studies have shown that the longer the time of evolution of poorly controlled DM, the greater the complications. Long-term treatment of patients with short-duration of T1DM with intensive insulin therapy achieving normoglycemia leads to a reduced CAN prevalence as well and incidence. In fact, the < 0.018) . Also, i< 0.018) . FurtherAccording to the inclusion criteria, patients undergoing SPK transplantation present terminal diabetic nephropathy that requires dialysis programs prior to transplantation. The pathogenic mechanisms that lead to diabetic nephropathy are the same that may produce diabetic retinopathy and neuropathy. Therefore, these patients would be expected to present retinopathy and diabetic neuropathy. In fact, diabetic neuropathy is very common and severe among candidates for SPK transplantation .In our study, at baseline, all patients presented abnormal results in all CARTs. Mean time of evolution of T1DM was 25 years, and glycemic control was not optimal, according to ADA recommendations, with an HbA1C mean: 8.1% . TherefoAfter pancreas transplantation, a slight improvement in cardiovascular autonomic function has been demonstrated in previous studies , 19. SomOur prospective 10-year study shows that cardiovascular autonomic function improves significantly after SPK transplantation. CARTs were analyzed individually using aged-stratified levels, as reflected in the Methods section. However, in The patient population was analyzed using descriptive statistics and paired tests. Mean values of the observed variables  for each time period were compared with the preoperative values (baseline).th and 5th year after SPK, respectively. The E/I ratio and the 30 : 15 ratio did not reach significance for paired patient samples.Paired patient sample analysis showed that the Valsalva ratio and SBP response to orthostasis improved statistically at the 3E/I ratio, as statistically significant differences were already found 3 years after SPK. However, these differences were maintained until 10 years after SPK only in the Valsalva ratio, and the SBP-response to orthostasis only reached statistical significance 5 years and 7 years post-SPK.To reduce the chances of false discoveries in this multiple testing, the Benjamini-Hochberg correction  was applIn the early stages, CAN may be completely asymptomatic and is detected only by a decrease in HR variability, subsequently leading to a clinical form characterized by resting tachycardia and exercise intolerance. In the most severe cases, it is accompanied by orthostatic hypotension , 26. SPBd-4th and 5th-6th year after SPK. This could be the reason why SBP-response to orthostasis does not reach statistical significance 3 years after transplantation.Regarding the sample size, in the basal period the interquartile range is lower than in the later periods, probably due to a larger sample size. However, attending SPS response to orthostasis, the interquartile range is higher in the basal period than in the 3rth-8th and 9th-10th periods are not enough to draw a conclusion; hence, the great dispersion of the data is obtained.In all tests evaluated, the number of observations made in the 7Additionally, the authors have previously considered the development models for the assessment of the risk of SPK transplantation , in whicAlso, uremia and calcineurin inhibitors (CNI) as causes of neuropathy should be considered. Both diabetes and uremia contribute to the nerve dysfunction seen in uremic diabetic patients. After SPK transplantation, an initial improvement of neuropathy was probably due to the elimination of uremia. Subsequently, an additional improvement of the neuropathy was observed, which could be due to the repair and regeneration of the nerves. This late improvement was not seen in diabetic patients who had only undergone KTA. In our study, all patients underwent SPK transplantation. Uremia levels were high at the moment of SPK but decreased after SPK .CNI produce an abnormal nerve function, specifically reflecting nerve membrane depolarization . For thiDetection of Ischemia in Asymptomatic Diabetic Subjects (DIAD) study showed that a decrease of the Valsalva ratio was associated with silent myocardial ischemia [On the other hand, a meta-analysis of 15 longitudinal studies showed an association between CAN and increased mortality . This riischemia . Also, Cischemia .Consequently, CAN is considered an independent risk factor for mortality  and the CAN treatment is generally focused on alleviating symptoms . But nevThis study has two main limitations. The first one is the limited sample size. If the sample size was larger, statistically significant results would probably be achieved in all evaluated periods. Despite this, the differences in CART results were enough to achieve statistical significance with nonparametric tests in some time periods. The second one is that, in our study, we did not follow a control group of diabetic patients not treated with SPK transplantation such as diabetic patients treated only with insulin therapy or diabetic patients undergoing KTA. With a control group of diabetic patients treated only with KTA, the effect of uremia on neuropathy could have been evaluated.In conclusion, the prevalence of cardiovascular autonomic neuropathy in candidates for SPK transplantation is high and is generally advanced. Successful SPK transplantation normalizes blood glucose, glycosylated hemoglobin, and uremic levels, and improves CAN. Valsalva ratio is the most precocious test. Studies with a larger sample size would be required to confirm our data.


Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes.The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads toImprovement of fetal growth;• No changes of maternal blood pressure or markers of preeclampsia;• Amelioration of HFD-induced glucose intolerance in adult offspring;• No changes in blood pressure development of the offspring on normal chow or high salt-diet;• Potentiation of blood pressure elevation of the offspring on HFD.• The online version of this article (10.1007/s00109-020-01949-0) contains supplementary material, which is available to authorized users. Gestational hypertension is one of the most common pregnancy complications and leads to 20–25% of prenatal mortality in Europe . PreeclaThe mechanisms of the pathology of preeclampsia remain unclear and there is currently no effective treatment available. Several studies have examined the possibility of prophylactic use of low-dose aspirin, while it appears to be inefficient in patients already developing preeclampsia . In addiNitric oxide (NO) donors have been shown to improve blood flow in the fetoplacental circulation of pregnancies affected by mild preeclampsia . PentaerDahl sat sensitive rats (DSSR) are considered a genetic model of salt hypertension . Renal iDSSR were from Charles River Laboratories . PETN-lactose (18% PETN with 82% D-lactose monohydrate) was added into normal chow  at a concentration of 5.5 g/kg (≈ 1 g PETN /kg chow) . F0 pareSystolic blood pressure, diastolic blood pressure, and mean blood pressure were measured noninvasively in conscious animals by a computerized system  with a volume-pressure recording sensor and an occlusion tail-cuff. Rats were placed in individual holders. The occlusion cuff and the volume-pressure recording cuff were placed close to the base of the tail. After an adaptation period of 30 min on a 37 °C warm pad, 10 preliminary measurements were performed before actual measurement. Rats were trained for restraint for 3 consecutive days prior to the actual measurement. Results are presented as the mean of at least 15 recordings on each occasion taken. The measurements were performed at the same time of a day from 2 to 4 pm by the same investigator as done in our previous studies .2/5% CO2. The mesenteric arteries were cut into rings with 2–3 mm long and then suspended in the chambers of a Mulvany–Halpern wire myograph system . Isometric force was recorded by a PowerLab 4SP system . The preparations were equilibrated for 30 min at the optimal resting tensions of 2.5 mN. The viability of the endothelium was tested by the relaxation response to a single dose of acetylcholine (10−4 M) after obtaining a reference contraction to 60 mM potassium chloride (KCl) twice prior to the actual experiment. For actual experiment, preparations were incubated for 30 min with or without different inhibitors . The preparations were then pre-contracted by exposing to increasing concentrations of phenylephrine . Endothelium-dependent relaxation was examined by exposure to increasing concentrations of acetylcholine (10−9 to 10−4 M). Change in tension is expressed as percentages of the PE contraction, which was adjusted to give ∼ 80% contraction of the reference KCl contraction. For calculation of the effect of drugs, area above relaxation curve (AARC) was measured in different dose-dependent curve of the preparation with the inhibitors. The difference between AARC (ΔAARC) was calculated to determine the contribution of different endothelium-dependent relaxation factors. NO-dependent relaxation was measured by the ΔAARC of control and LNNA curve. Prostaglandin (PG)-mediated relaxation was measured by the ΔAARC of control and indomethacin curve. Contribution of endothelium-dependent hyperpolarization factor (EDHF) was measured by the ΔAARC of LNNA + indomethacin and LNNA + Indo + KCl curve. The percentage contribution was calculated by referencing to the AARC of relaxation without inhibitors [Second order mesenteric arteries were dissected free of adherent connective tissues and placed in cold modified Krebs-Ringer bicarbonate buffer under continuous aeration with 95% Ohibitors .Taq Ready-Mix™ (Sigma-Aldrich) on an iCycler real-time PCR detection system (Bio-Rad). Quantification was achieved by the difference in quantification cycles (ΔΔCt) values that were normalized with RNA polymerase II as a reference control. Specificity of the qPCR primers were checked by melting curve analysis or gel electrophoresis of the qPCR product. The sequence of the primers used is listed in supplementary Table STotal RNA of rat thoracic aortae and mesenteric arteries were isolated using peqGOLD TriFast™ (PEQLAB) and cDNA was reverse transcribed using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems) according to previous publication . QPCR waT), while closed chromatin regions were protected from the MNase digestion resulting in minimal delays in CT value, compared with that of undigested templates. The sequence of the primers used is listed in supplementary Table SChromatin accessibility was studied using the micrococcal nuclease  digestion method. Thoracic aortae were homogenized and MNase digested for 1 h at 37 °C. The genomic DNA was then isolated and collected using ChIP DNA purification kit (Active Motif). Quantitative PCR was performed using 5 ng DNA samples as template. In general, open chromatin regions were more susceptible to MNase digestion resulting in a greater delay of quantification cycle (Cv/v) protease inhibitor cocktail and chromatin fragments of 500–1000 base pair was obtained by sonication. The lysate was incubated with either 1.5-μg-specific primary antibody or IgG at 4 °C overnight with rotation. Pierce™ Protein A agarose beads (Thermo Fisher Scientific) were added to the lysates and incubated for another hour. After washing for four times, the chromatin fragments were eluted into a TE buffer containing proteinase K. Quantitative PCR was performed using 10% volume of the DNA samples and quantified by using the Ct values for normalization against the input control, for which 1% of the DNA samples were used for qPCR [Thoracic aortae were cross-linked in 1.5% formaldehyde (in PBS) at room temperature for 15 min. After adding glycine to a final concentration of 125 mM, aorta samples were homogenized in Pierce™ IP lysis buffer (Thermo Fisher Scientific) containing 1% (for qPCR . H3K9 (Av/v) protease inhibitor cocktail) and 100-μl serum were added as samples. Samples and standard were then covered and incubated at room temperature for 90 min with gentle shaking. After washing twice, biotinylated antibodies were added and incubated at room temperature for another 60 min. After washing for three times, HRP-Avidin was added and incubated for 30 min at room temperature with gentle shaking. After washing for five times, color reagent was added in dark with gentle shaking. After 30 min of incubation, stop solution was added and the absorption was read at 450 nm immediately with Sunrise™ microplate reader (Tecan Group) and analyzed by Magellan™ software (Tecan Group).Rat soluble fms-like tyrosine kinase-1  and placenta growth factor  were tested in placenta and serum with enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instruction (Mybiosource). In brief, 1-mg protein of rat placenta (homogenized in Pierce™ IP lysis buffer containing 1% (Glucose tolerance test (GTT) was performed in rats after 6-h fasting at the age of 16 weeks or after overnight fasting at the age of 30 weeks. After measuring basal blood glucose levels, each rat was injected with glucose (2 g per kg body weight) intraperitoneally (i.p.). Blood glucose levels were measured 15, 30, 60, 90, and 120 min after glucose injection. Blood glucose was measured by needle puncture in the tail vein with a glucometer (Contour® XT) in conscious unrestrained rats.Insulin tolerance test (ITT) was performed in rats after 6-h fasting at 16 weeks or after 16-h overnight fasting at 30 weeks. After measuring basal blood glucose levels, each rat was injected with 0.5 U per kg body weight of insulin intraperitoneally (i.p.). Blood glucose levels were measured 15, 30, 60, 90, and 120 min after insulin injection. Blood glucose was measured by needle puncture in the tail vein with a glucometer (Contour® XT) in conscious unrestrained rats.t test or two-way ANOVA were used for comparison between groups. P values < 0.05 were considered significant. GraphPad Prism  was used to generate graphs and statistical analysis.Results were expressed as mean ± SEM (standard error of the mean). If otherwise stated in the figure legends, Student’s At day 20 of pregnancy, the mass of PETN pups (5.79 ± 0.07 g) was significantly higher than control pups 4.38 ± 0.15 g), while there was no significant difference in the mass of placenta. Thus, the resulting fetus/placenta mass ratio was also significantly increased in the PETN group compared with that of control  an improvement of fetal growth; (ii) no changes of maternal blood pressure or markers of preeclampsia; (iii) amelioration of HFD-induced glucose intolerance in adult offspring; (iv) no changes in blood pressure development of the offspring on normal chow or high salt-diet; and (v) potentiation of blood pressure elevation in offspring on HFD.DSSR is reported to have intrauterine growth restriction and a significantly reduced pup weight compared with normal Sprague-Dawley rat , 23. OurSeveral recent studies have shown that DSSR exhibit diet-induced blood pressure increase independent of salt intake –28. HFD Maternal PETN treatment improves glucose metabolism in DSSR, as well as reduces the weight of adipose tissue. These data further support that maternal PETN treatment can improve the metabolic phenotype of the preeclamptic offspring, probably through the prevention of early epigenetic disruptions, and result in a reduced risk of metabolic diseases later in adulthood , 10. We Recent findings suggest the potential involvement of epigenetic mechanisms in the progression of endothelial dysfunction in metabolic diseases , 38. A cOn the other hand, HFD feeding significantly reduces EDHF in DSSR with maternal PETN treatment but not in control DSSR. EDHF is the NO-/PG-independent component of endothelium-dependent relaxation that is prominent in the microcirculation as well as mesenteric arteries , 45. TheIn this study, maternal PETN treatment shows a significant improvement in fetus growth and moderate effect in blood pressure control in DSSR offspring. In contrast to our previous studies , we notiIn conclusion, maternal PETN treatment shows improved fetal growth in a rat model of superimposed preeclampsia and had no effects on blood pressure development in offspring on normal chow or high-salt diet. In HFD-fed offspring, maternal PETN treatment was beneficial to glucose metabolism without significant effects on bodyweight gain. However, maternal PETN treatment exacerbated blood pressure elevation in HFD-fed offspring. Epigenetic changes in vasculature modulated by HFD and maternal PETN treatment contributed to the improvement of PG-dependent vascular relaxation and blunted EDHF-mediated vascular relaxation in DSSR. In this model, maternal PETN treatment leads to a plasticity of the offspring phenotype which can be affected by HFD in both beneficial and detrimental directions. Based on the above findings, it is proposed that maternal PETN treatment in DSSR may represent a novel potential treatment for preeclampsia which benefits both the mother and offspring, as evidenced by an improvement of fetal growth and amelioration of glucose intolerance of the offspring in adult age. However, the offspring should avoid high-fat diets in later life because of the potentially higher risk of blood pressure elevation in response to high-fat diet.ESM 1(PDF 482 kb)


Since blood pressure tends to be unstable during induction of anesthesia in patients undergoing cardiovascular surgery, an artery catheter is often inserted before induction to continuously monitor arterial pressure during induction of anesthesia. ClearSight System™ enables noninvasive continuous measurement of beat-to-beat arterial pressure via a single finger cuff without pain using photoplethysmographic technology. If ClearSight System™ can replace intra-arterial pressure measurement, blood pressure could be easily and noninvasively assessed. However, the validity of ClearSight System™ during induction of anesthesia in patients undergoing cardiovascular surgery has not been evaluated. The aim of this study was to compare blood pressure measured by ClearSight System™ with intra-arterial pressure during induction of anesthesia for cardiovascular surgery.This study was registered retrospectively. Data during induction of anesthesia for elective cardiovascular surgery were obtained for patients in whom noninvasive arterial pressure was measured by ClearSight System™ (APcs) and invasive radial arterial pressure (APrad) was measured simultaneously. According to the widely used criteria formulated by international standards from the Association for the Advancement of Medical Instrumentation, the acceptable bias and precision for arterial pressure measurements were fixed at < 5 mmHg and 8 mmHg, respectively.Data for 18 patients were analyzed. For 3068 analyzed paired measurements, values of APcs vs APrad bias (precision) were 13.2 (17.5), − 9.1 (7.3) and − 3.9 (7.8) mmHg for systolic, diastolic, and mean arterial pressures, respectively.Mean arterial pressure measured by ClearSight System™ could be considered as an alternative for mean radial arterial pressure during induction of anesthesia for elective cardiovascular surgery. Since blood pressure tends to be unstable during induction of anesthesia in patients undergoing cardiovascular surgery, an artery catheter is often inserted before induction to continuously monitor arterial pressure during induction of anesthesia. The success rate of the first attempt at arterial cannulation using palpation has been reported to be less than 50% and sometimes cannulation still fails despite the use of ultrasound . TherefoClearSight System™  enables noninvasive continuous measurement of beat-to-beat arterial pressure via a single finger cuff without pain using photoplethysmographic technology. If ClearSight System™ can replace intra-arterial pressure measurement, blood pressure could be continuously, easily, and noninvasively assessed. Previous studies have shown that this device is reliable in pregnant women , childreThis retrospective observational study was approved by the medical ethics committee of Wakayama Medical University prior to its initiation (reference number 1919). The study was conducted at Wakayama Medical University Hospital.In this retrospective analysis, data were collected from all patients in whom noninvasive arterial pressure was measured by ClearSight System™ (APcs) and invasive radial arterial pressure (APrad) was measured simultaneously during induction of anesthesia for elective cardiovascular surgery between November 2016 and November 2017 at Wakayama Medical University Hospital. The use of ClearSight System™ depended on the anesthesiologists in charge. Paired values of systolic, diastolic, and mean arterial pressures obtained by both methods were recorded at the rate of 1 sample every 3 s in the institution’s Anesthesia Information Management System . Data from 5 min before tracheal intubation to 5 min after tracheal intubation based on anesthetic records were analyzed.In our hospital, the induction of cardiovascular anesthesia has been standardized. Two anesthesiologists are generally involved in one case: one anesthesiologist for managing the anesthesia, and other for recording. Before induction of anesthesia, an catheter is inserted into right radial artery in the most of patients to continuously measure blood pressure. Then anesthesia is induced by target-controlled infusion of propofol (1.5–3.0 μg/ml), remifentanil (0.1–0.3 μg/kg/min), and rocuronium (0.6–1.0 mg/kg). The doses of anesthetics depend on the decision of the anesthesiologist in charge. When blood pressure decreases during the induction, ephedrine (4 mg or 8 mg) or phenylephrine (0.1 mg or 0.2 mg) is intravenously administered according to the decision of the anesthesiologist in charge.There is no established knowledge of how many patients should be included and how many measurements should be analyzed for each when performing a repeated measurement. In most of the studies using Bland-Altman analysis, the sample size was not examined. In this study, we collected over 3000 pairs of data based on similar previous studies in which radial arterial pressure was compared with blood pressure measured by ClearSight System™ , 8.Data considered to be artifacts were excluded based on ClearSight auto-calibration, radial artery artifacts, and ClearSight artifacts. Auto-calibration is performed at least once every 70 heartbeats to keep the finger arteries open and of constant diameter. In addition, auto-calibration is performed when the measurement of blood pressure is temporarily interrupted for two or more beats. When auto-calibration is performed, systolic, diastolic and mean blood pressures become the same values, and the values increase step by step. Therefore, it is possible to discriminate such data as artifacts. Radial artery artifacts, which result from blood sampling and flushing, could be discriminated since systolic and diastolic pressures become the same values. ClearSight artifacts, which occur due to external pressure to the ClearSight cuff, can be recognized as extreme outliers.Data are expressed as means (SD) or medians (interquartile range) as appropriate. For whole repeated paired measurements from all patients, correlations between APrad and APcs were determined by a linear regression. In addition, Bland-Altman analysis was used to study agreement between APrad and APcs. In this analysis, bias and precision were defined as the mean difference between APrad and APcs and as the SD of bias, respectively. In addition, limits of agreement (LOA) were calculated as bias ±2SD of bias. According to the widely used criteria formulated by international standards from the Association for the Advancement of Medical Instrumentation (AAMI), the acceptable bias and precision for arterial pressure measurements were fixed at < 5 mmHg and 8 mmHg, respectively .For each patient, the SDs of averages of APrad and APcs (“within-subject variability”) were calculated to quantify the ranges of different pressures. The SDs of differences between APrad and APcs (“within-subject precision”) were also calculated to quantify tracking for systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP). In addition, correlations between APrad and APcs were determined by linear regression.P-value of 0.05 was considered statistically significant. All analyses were performed using JMPⓇ statistical software .A two-sided Data for 18 patients were obtained in this study. The characteristics of the patients are shown in Table Figure In this study, Pearson’s correlation coefficients showed that SAP, DAP and MAP measured by ClearSight System™ were significantly correlated with radial arterial pressure. Bland-Altman analysis showed that ClearSight System™ had acceptable bias and precision in MAP but not in SAP and DAP for radial arterial pressure measurements. Our results suggest that changes in SAP, DAP and MAP measured by ClearSight System™ reflect those in radial arterial pressure and that MAP measured by ClearSight System™ is interchangeable with radial arterial pressure during induction of anesthesia for elective cardiovascular surgery.Our study showed that MAP measured by ClearSight System™ statistically matched the AAMI criteria. On the other hand, neither SAP nor DAP matched the criteria. A previous study also showed that MAP, but not SAP and DAP, could be considered as an alternative for radial artery blood pressure during carotid endarterectomy, based on AAMI criteria . In geneThe aim of managing hemodynamics is to maintain adequate organ perfusion. MAP is widely used as an index for optimal blood pressure, and it reflects driving pressure at the organ level . MAP is The limitation of this study would result from a retrospective nature. The quality of data in a prospective study are generally higher than that in a retrospective study. When APcs is compared to APrad, the advantage of a prospective study is that study conditions including patient’s bias, data collection period, and exclusion of data influenced by artifacts can be controlled. In this study, we decided to analyzed preserved data for the following reasons. First, when we reviewed our preserved data from 18 patients before data analysis, the characteristics of patients were similar to those in previous prospective studies. The exclusion criteria in previous studies included peripheral arterial disease, preoperative atrial fibrillation, and obesity (> BMI 30) , 15, 16,MAP measured by ClearSight System™ could be considered as an alternative for mean radial arterial pressure during induction of anesthesia for elective cardiovascular surgery. SAP and DAP may be useful for inferring changes in systolic and diastolic radial arterial pressures.


Hypertension is a prevalent and costly burden in the United States. Clinical pharmacists within care teams provide effective management of hypertension, as does home blood pressure monitoring; however, concerns about data quality and latency are widespread. One approach to close the gap between clinical pharmacist intervention and home blood pressure monitoring is the use of mobile health  technology.We sought to investigate the feasibility, acceptability, and preliminary effectiveness of BPTrack, a clinical pharmacist-led intervention that incorporates patient- and clinician-facing apps to make electronically collected, patient-generated data available to providers in real time for hypertension management. The patient app also included customizable daily medication reminders and educational messages. Additionally, this study sought to understand barriers to adoption and areas for improvement identified by key stakeholders, so more widespread use of such interventions may be achieved.We conducted a mixed methods pilot study of BPTrack, to improve blood pressure control in patients with uncontrolled hypertension through a 12-week pre-post intervention. All patients were recruited from a primary care setting where they worked with a clinical pharmacist for hypertension management. Participants completed a baseline visit, then spent 12 weeks utilizing BPTrack before returning to the clinic for follow-up. Collected data from patient participants included surveys pre- and postintervention, clinical measures , utilization of the BPTrack app, interviews at follow-up, and chart review. We also conducted interviews with key stakeholders.P=.02) and diastolic blood pressure . On average, patients uploaded at least one blood pressure measurement on 75% (SD 25%) of study days. No improvements in medication adherence were noted. Interview data revealed areas of improvement and refinement for the patient experience. Furthermore, stakeholders require integration into the electronic health record and a modified clinical workflow for BPTrack to be truly useful; however, both patients and stakeholders perceived benefits of BPTrack when used within the context of a clinical relationship.A total of 15 patient participants were included (13 remained through follow-up for an 86.7% retention rate) in a single group, pre-post assessment pilot study. Data supported the hypothesis that BPTrack was feasible and acceptable for use by patient and provider participants and was effective at reducing patient blood pressure. At the 12-week follow-up, patients exhibited significant reductions in both systolic blood pressure (baseline mean 137.3 mm Hg, SD 11.1 mm Hg; follow-up mean 131.0 mm Hg, SD 9.9 mm Hg; Results demonstrate that a pharmacist-led mHealth intervention promoting home blood pressure monitoring and clinical pharmacist management of hypertension can be effective at reducing blood pressure in primary care patients with uncontrolled hypertension. Our data also support the feasibility and acceptability of these types of interventions for patients and providers.ClinicalTrials.gov NCT02898584; https://clinicaltrials.gov/ct2/show/NCT02898584RR2-10.2196/resprot.8059 Hypertension is a prevalent and costly burden in the United States, affecting about 116.4 million adults ≥20 years of age, and resulting in approximately $55.9 billion in estimated annual direct and indirect costs from 2014-2015. Poor rates of control exacerbate these concerns; of those affected, only about 50% of people achieve blood pressure control, and another 20% remain unaware of their condition , making Clinical pharmacists, who assist patients in managing chronic conditions in primary care clinics ,5, proviThe current mHealth landscape is limited by applications that do not support bidirectional patient-provider communication or automatic transmission of electronic data from home blood pressure monitors in real-time. However, a bidirectional intervention that allows for the immediate upload of electronic data has the potential to increase the number of hypertensive patients a clinical pharmacist could assist, as well as improve the quality of blood pressure management for patients.The goal of this study was to investigate the feasibility, acceptability, and preliminary effectiveness of BPTrack, a clinical pharmacist-led intervention that makes electronically collected data available to the pharmacist in real-time for hypertension management. The bidirectional intervention supports both home blood pressure monitoring and medication adherence for patients with uncontrolled hypertension. The study also aimed to understand barriers to adoption and areas for improvement identified by key stakeholders so that more widespread use of such interventions may be achieved, and further research can occur.The BPTrack study protocol has been described elsewhere ; howeverWe conducted a one-group design, pre-post pilot study of BPTrack, a clinical pharmacist-led mHealth intervention, intending to improve blood pressure control in patients with uncontrolled hypertension through a 12-week pre-post intervention. All patients were recruited from a primary care setting where they received treatment from a clinical pharmacist at the recruiting clinic site for hypertension management. Participants completed a baseline visit at the recruiting clinic, then spent 12 weeks utilizing the intervention at home before returning for a follow-up visit.Patient participants were recruited from a Family Medicine clinic associated with a large Midwestern academic medical center. The clinic site serves a majority blue-collar, underserved African American and Hispanic population, and hypertension is a commonly treated chronic disease at the site. Recruitment occurred through two primary procedures: recruitment flyers distributed by clinic staff to potential patient participants and targeted recruitment letters. Further details of these recruitment methods are described elsewhere . All patStakeholder participants were recruited through the purposive sampling of individuals affiliated with the BPTrack program or health care providers for enrolled patients. Solicitation letters or emails were sent to medical assistants, physicians, a nurse, and the current and former director of the Family Medicine clinic site, as well as the study pharmacist who managed blood pressure care for patient-participants during the study.All potential patient participants were screened for eligibility through a phone interview. Once deemed eligible, candidates were scheduled for the baseline visit, where written informed consent was obtained by research staff and baseline data collection commenced.To be eligible for participation, patients had to be English speakers, ≥18 years of age, possess a smartphone compatible with the mobile intervention, have a diagnosis and history of uncontrolled hypertension (systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg with repeated measurements), under the care of a primary care physician at the recruiting clinic, and taking at least one antihypertensive medication.Exclusion criteria included age >65 years or previously established with a cardiologist or clinical pharmacist for hypertension management. Exclusions also applied to those who were pregnant, had existing medical conditions that would make blood pressure control difficult or required frequent hospitalization. Disqualifying conditions included resistant hypertension, steroid-dependent asthma or emphysema, cirrhosis or hepatic failure, stage C or D chronic heart failure, stage IV or V chronic kidney disease, and terminal cancer or ongoing chemotherapeutic or radiation therapy. Patients were also excluded if they had other serious medical conditions that would inhibit their ability to self-monitor their blood pressure, such as stroke or dementia.The BPTrack intervention consisted of two different mobile applications, one for the patient participant and one for the clinical pharmacist, developed by Tactio Health Group and customized from their TactioRPM Platform. BPTrack was the fully automated patient-facing smartphone app for iOS and Android, and BPTrack Pharm was the mobile application for iPad used by the clinical pharmacist. Together, these applications allowed real-time electronic home blood pressure monitoring and medication adherence tracking so that the clinical pharmacist had access to reliable and timely data. As the apps are not publicly available, participants were granted access by study staff after trial enrollment. The apps were provided free to users for use during the trial. Both applications have been described previously .Patients were asked to measure their blood pressure using the provided blood pressure cuff and sync or manually enter the readings into the app. A written manual provided instructions on how to prepare for and properly obtain blood pressure measurements. Patients were encouraged in the written manual and as part of onboarding to reach out to study staff using the study hotline with any questions, comments, or to report any adverse events. The study manual also included safety instructions related to symptoms or repeat measurements indicating hypotensive or hypertensive emergencies.The clinician-facing app provided the pharmacist with a dashboard view of all enrolled patients and a summary of their recent blood pressure readings, as well as individual page views for each patient, with full access to patient-generated blood pressure data. The clinical pharmacist was instructed to use their best clinical judgment in the interpretation of the BPTrack Pharm data and the appropriate clinical follow-up.Data were collected in a variety of ways to determine the feasibility and acceptability of this mHealth intervention. Data collection methods are described elsewhere  and summPatients completed investigator-developed surveys at baseline and 12 weeks. The baseline survey collected demographics, health status, hypertension history, self-reported medication adherence and use, and other characteristics. The 12-week follow-up survey also collected self-reported medication adherence and use, as well as perceptions of feasibility, acceptability, and effectiveness of the BPTrack intervention. The baseline and 12-week follow-up survey both took approximately 10 to 15 minutes to complete.Blood pressure and medication adherence, as measured by pill counts, were assessed by research staff in the clinic at baseline and 12 weeks. Blood pressure measurements were gathered using manual blood pressure cuffs by trained research staff. Staff also educated patients on best practices for measuring blood pressure, including sitting upright with feet flat on the ground, keeping the measuring arm at heart height, and not having moved for 5 minutes.Patient utilization of the BPTrack app was documented in a variety of ways. Home blood pressure readings were extracted from the BPTrack Secured Cloud and analyzed for blood pressure trends, as well as compliance with self-monitoring protocols. As previously described, patients were asked to take their blood pressure three times per sitting, twice a day. Any text logs sent from within the app from the participants to the pharmacist were extracted as well.To more fully understand patient participant perceptions of the BPTrack program, we conducted semistructured interviews at the 12-week follow-up. Semistructured interviews lasted 2-32 minutes.We conducted a chart review to abstract data to document patients’ health care utilization during the study period. Data abstracted from patient charts included the visit date, diagnoses, type  and reason for the visit, location, whether the visit was with the pharmacist or another provider, medication changes, and blood pressure measurements taken during the encounter.Finally, we invited key stakeholders  to participate in semistructured interviews. These interviews focused on hypertension management, the use of mHealth for hypertension management, how BPTrack was (or could be) used within the clinic, perceived effects of BPTrack, barriers to BPTrack use and implementation, and suggestions for improvement of the program.t tests. The effect of clinical pharmacist contact, other health care utilization, and app utilization with changes in blood pressure levels were assessed using Pearson correlations. Available patient characteristics were assessed regardless of study completion; however, only participants who completed the study were included in the analysis of pre- and postmeasures.Descriptive statistics were compiled for patient characteristics, perceptions of BPTrack, self-reported medication adherence, blood pressure, pill counts, and app and health care utilization. Categorical data were displayed as frequencies and percentages, and chi-square tests were used for comparison. Systolic and diastolic blood pressures were expressed as mean (SD), and pre- and postintervention blood pressure means were compared using 2-tailed paired-samples Qualitative thematic analysis of patient and stakeholder interviews was performed . We usedWe enrolled 16 patients in the BPTrack pilot study; however, one patient was immediately withdrawn after informed consent, but before collecting study measures, as the home blood pressure cuff did not fit the patient’s arm properly. Improper fit of the blood pressure cuff would have led to inaccurate home blood pressure readings. The remaining 15 patients had a mean age of 52.2 years (SD 6.0), and were predominantly male , married , employed , and had a high school or less education , an annual household income <$50,000 , and private insurance . On average, participants had been living with hypertension for 12.1 years (SD 11.2), and the majority were on two antihypertensive medications . See Across multiple sources of data, we found the use of BPTrack to be feasible within a primary care clinic.The BPTrack protocol asked participants to measure their blood pressure two times per day, with three measurements at each sitting, for a total of 6 daily measurements. All participants were given at least 12 weeks (84 days) between their initial and follow-up visits to upload data, and most uploaded well into the 12th week of the study period. Because not all follow-up visits occurred on day 84, participants had varying numbers of days in the study and were encouraged to continue to measure their blood pressure until the end-of-study visit. Use of BPTrack varied widely across the 13 participants who completed the study; the majority of people (n=11) uploaded at least one blood pressure measurement on 60 or more days, ranging between 13 and 93 days across participants . The aveThe number of measurements uploaded per day by any given person ranged between 1 and 12, with the average being 4.6 (SD 1.5). The most common number of measurements were 3  and 6 . In terms of adherence to the monitoring protocol, we examined total compliance (6 measurements per day) as well as partial compliance (1-5 measurements per day) for all 13 completers. The number of days of total compliance for each participant ranged from 0 to 75, and the number of days where participants logged at least one reading ranged from 13 to 93 days. On average, participants uploaded at least one measurement on 75% (SD 25%) of study days. Also, on average, participants were fully compliant 40.1% (SD 28%) of the days between baseline and follow-up.Findings from patient surveys consistently showed that the use of BPTrack was feasible. The majority of participants agreed or strongly agreed that the program was easy to use , that learning to use BPTrack was easy , and that they tried to use BPTrack every day . Moreover, most patients did not find it challenging to incorporate the information from the application into their blood pressure management , and most patients did not find the integration of the blood pressure monitor and their cell phone to be confusing . Only 1 participant  indicated that using BPTrack took up too much of their time.Findings from our semistructured patient interviews confirmed that patients viewed BPTrack overall as feasible for use within a clinical relationship. Generally, patients were able to utilize the BPTrack functions as designed, reporting, “I had no problems with the program” and “I just liked that it kept me informed. I could just open it up and look at it.”Although patients saw BPTrack as a whole as feasible for use within primary care, two themes arose related to improving app function and adherence challenges. Patients recommended changes to the blood pressure cuffs, sync, and message functions to improve ease of use. While many patients reported that the blood pressure cuffs “worked well” and were “very sturdy,” one patient requested a larger cuff size and stated that the cuff tended to overinflate. Additional concerns expressed by multiple patients included trouble syncing or pairing their blood pressure cuff:The… phone would unsync from the blood pressure. (Um-hm) And it would take several tries. Even though it said it paired, it did not pair. […] So I tried, you know, 5, 6, 7 times.A few patients requested improvements to messaging. One suggestion was to allow custom messages:Um, I had my own way of managing all that, you know. ‘Cause I have other things I like to remind myself of, and… to have yet another… set a notifications. And I turned it off. I, uh… I know you can’t do it in the app, but I can have, on Android I, you can, you know, force the notifications to stop. (Right) And I did. (Okay) So I, I turned ‘em all off.Another patient pointed out that direct communication from the application to the medical record would be beneficial:I’m not a reporting type person. So… it would be better for my health care, if…. It all just went straight to the medical record, and my doctor could just pull up my blood pressure reading.Finally, several participants noted they had trouble adhering to the blood pressure monitoring protocol, which is not surprising given the BPTrack utilization statistics reported above. One concern was simply remembering to take blood pressure:… sometimes it was… it was easy to, to forget to do it in the morning.I did have to keep the monitor, like on a table, so that I would remember to do it, (Right) on a regular basis. I didn’t, if I didn’t see it, I wouldn’t think about it, so.Patients also expressed concerns about keeping the routine for the long term:I don’t know that I could take my blood pressure 3 times… every morning, and 3 times every night, for the rest of my life…”It was kinda hard for me to sit down and take my blood pressure at 2 different times. But, so I did it all, l generally at the same time most days.Despite our best efforts to recruit multiple stakeholders for semistructured interviews after the BPTrack pilot was complete, we only enrolled 1 pharmacist and 1 primary care physician. The stakeholders’ recognized the potential advantages of the BPTrack program. In particular, the physician indicated that “we have so many resources” and that BPTrack could “be part of the clinic workflow” with some minor adjustments. The physician even noted that something like BPTrack could “open up time for other stuff. I mean, we spend a lot of time… follow-ups, nurse visits for [blood pressure checks].” However, despite the feasibility and benefit of integrating BPTrack into routine practice, the stakeholders also indicated a few notable reservations, including the accuracy of readings, patient adherence, and a desire for data to transfer directly from BPTrack into the electronic health record (EHR).In many ways, the physician’s and pharmacist’s perceptions of feasibility were similar. The physician explained, “I think it’s good to have, but I think we’re gonna see that it’s not… for everybody.” The physician indicated that better clinical decisions could be made when an accurate home blood pressure logs were available, either through a program such as BPTrack, or otherwise. Similarly, the pharmacist pointed out the utility of collecting the patient log in a mobile device: “It’s a very portable record because they almost always have their phone […] and they could share it with whoever they’re seeing.” However, they both raised concerns about accuracy. The physician pointed out the importance of using the cuff correctly: “Make sure the blood pressure cuff is… they’re doing it right at home.” Moreover, the pharmacist also noted concern with home blood pressure monitors in general: “I wish that they were more accurate; more consistent.”Ensuring ease of use and minimal burden are critical to improving adherence. Regarding the application specifically, the physician explained:It has to be very simplistic, especially for our older patients. So, I worry that if they have to type in their readings, that they’re gonna put… you know, wrong numbers.The physician and pharmacist echoed patients’ concerns about the long-term sustainability of frequent monitoring. In terms of the desired frequency of home blood pressure testing, the physician and pharmacist suggested monitoring three times per week. The physician explained the potential burden of maintaining the twice-daily regimen long-term and suggested that “Ideally, 3 times a week… All at the same time [of day],” was more maintainable and useful. “I think… like anything else it… when it starts, the patient might be very… motivated […] maybe at the beginning it’s really exciting, but after time people just… not really interested in using it.Similarly, the pharmacist said: “I think once a day is awesome… if that’s asking too much, I think 3 days a week is usually sufficient.”Finally, a concern was noted that the data from the application did not go directly into the EHR. The provider had to manually enter blood pressures and calculate averages, which was less than ideal. The pharmacist recommended:I would love to be able to do that functionality, you know, just import that and have it… average them out for me.The pharmacist went on to add:The parts that we still need to work on are… getting that data into [the EHR]… Relying on a provider to log into a secondary system… long term is going to be very difficult.Lowering the provider-side burden of managing the data will be necessary, mainly through integration with the EHR.Patients self-reported a high degree of acceptability towards the BPTrack program with the majority indicating that they are satisfied with the program , the program was easy to learn  and use , and would like to continue using the program . Fully 100% (13/13) of participants who completed the follow-up assessment indicated that they liked being able to keep track of their blood pressures visually, they liked knowing someone was watching over their blood pressure in between clinic visits and would recommend BPTrack to others. Lending support for our pharmacist-led approach, only 23.1% (3/13) of participants agreed or strongly agreed that they would prefer that their doctor oversee their blood pressure. Only 7.7% (1/13) agreed that they had concerns about the privacy of their data.Findings from our semistructured patient interviews confirmed that patients viewed BPTrack as acceptable for use within a clinical relationship. Thematic analysis revealed that participants were pleased with the program:It was good. I enjoyed bein’ able to see… day to day what my blood pressure was and… you know, seein’ how I was improving, as I was takin’ the medication and stuff.Another patient appreciated the convenience of checking blood pressure outside of a clinic:Uh, the thing that I liked the most about the program was that it was in an environment that wasn’t at a doctor’s office… I could,… check my blood pressure in a usual state, either work, or home, or whatever. And I think that it gave a more accurate representation of what my blood pressure was like than to do it at a doctor’s office where I’m always… uh, stressed out.Patients indicated they would continue to use the application if offered: “Uh, just that I, I would, if it was offered, you know, full time, I would, I would sign up for it.” Participants reported positive feedback regarding timeline and personalized blood pressure feedback:It was… interesting. And… very informative, I thought, because I’m new to high blood pressure. And… um… it was neat to see the trends.So without this app, I wouldn’t know… what my blood pressure was yesterday or the day before that…A patient participant appreciated the timeliness of the information: “Before I… usually didn’t see my blood pressure till uh… the next, uh, visit, uh, to my doctor.” Participants also commonly reported the reassurance of having a health care professional monitor their incoming data:And so I really… liked that part of it, where… it kept it recorded for me. And it was nice to know that it was… being read by a professional. You know, somebody that could help me if it did go out a whack.Because of the increased monitoring by a health care professional, several participants reported that they had a more positive view of their medication regimen:I just feel like I’m … uh, having, taking my medication based more on… on real blood pressure readings than a one or two-time visit to the doctor.Despite positive views on the BPTrack program, participants noted a few areas for improvement. In particular, the daily medication reminders, as implemented, were not well-liked by all. Some complaints concerned the frequency of reminders:The reminders were really nice at the beginning. But then… got annoying because, like I already know to take my blood pressure medicine at the same time every day. So the repetitiveness of it just got annoying.Others suggested tailoring reminders and information beyond medication reminders:I don’t know the messages were kinda you know, generic.There’s a lot of little things that might get somebody to adjust their… their medication. But they only, um they only seem to address forgetting.Both the physician and pharmacist indicated their acceptance of incorporating the BPTrack application into practice. The physician appreciated access to blood pressure readings:(It) would be a benefit because… we could do a lot more pharmacotherapy management like that [and] if we can have that information available to us, then it should help us take better control of our patients.In addition, the physician elaborated that extracting home blood pressure readings verbally from patients during office visits was time-consuming and often not representative of actual readings.The pharmacist also appreciated access to readings, commenting that when logs are available, it was appealing to provide the patient with their data: “it’s a very cool, um… system to record blood pressures, so that patients have a record.” However, the pharmacist expressed reservations about timely reporting of elevated readings:I wasn’t checking the app every single day […] I didn’t get enough, I guess, warning or that there was a problem.P=.02) and diastolic blood pressure . Regarding medication adherence, at 12-week follow-up, the effect of BPTrack as measured by the Adherence to Refills and Medications scale was negligible and not significant . During this trial, 3 of our 13 participants had hypertension medications either removed from their treatment plan or had dosages lowered. Changes in systolic and diastolic blood pressure were not significantly associated with app utilization measures. There was a significant correlation between the number of hypertension-related encounters  and the number of encounters with the clinical pharmacist  and change in systolic blood pressure. In both instances, individuals with more encounters saw a greater reduction in their systolic blood pressure. There was no correlation with the number of encounters that were not hypertension-related , nor was there an association with change in diastolic blood pressure and any of the health care utilization measures.At 12 weeks follow-up, patients exhibited significant reductions in both systolic blood pressure , that BPTrack helped them to get their blood pressure under control , and helped them remember to take their medications .Findings from our semistructured patient interviews confirmed that patients perceived BPTrack as useful in a variety of ways. Specifically, patients indicated that BPTrack helped raise their awareness of their hypertension and helped them to make behavior changes, such as eating healthfully, managing medications, and reducing stress.Patients discussed how awareness helped them to consider what they were eating and make adjustments:When I saw the different times of days and, and how that, how it varied across the day, um, you know, which got me thinkin' about what I, maybe what I was eating throughout the day and then the types of food.A specific example was sodium intake:It created an awareness within me to really pay attention to my diet, my salt intake, the types of food and, and become more involved with my overall health.Despite some of the suggestions to go beyond medication reminders, some patients reported the program was helpful for medication management:Helped me remember to take my medication for one thing.Um, just heavy monitored. [The pharmacist] was able to make some adjustments, and we were able to delete some medication and increase some medication and get everything to a nice manageable level.Other patients used the data to recognize the causes of stress by taking readings more frequently than office visits:It’s very telling, I thought. I was able to… uh… distinguish a difference in my blood pressure, uh, based on my stress at work. (Um-hm) You know, when, when my work was more stressful, my blood pressure was definitely hanging out higher area, than it was, uh, when my work was less stressful… I never would have found out if I was taking my blood pressure manually or waited until I came to a doctor to have it taken.Another patient explained being able to act more quickly to reduce stress:It gave me the information [Systolic Blood Pressure] was 140, so I need to relax. It will be better after I get some rest. It kept me alerted as to what I should be doing. As opposed to not knowing at all what the blood pressure was. ‘Cause I felt the same the whole time through. I could never tell if my blood pressure was up or not.The physician and pharmacist both thought that BPTrack would have definite benefits when integrated into routine practice; however, both noted that solutions such as BPTrack cannot stand alone and need to be used in conjunction with standard care. While the physician felt it could be helpful, a concern was over-reliance on BPTrack to manage hypertensive patients:Using this BP method, I worry that they won’t be seen for long periods of time. Or that we’ll… start throwing too many meds without having an adequate follow-up.The physician also explained that regular visits are necessary and help the patient to feel more open to talking:I still think patients should come in and be seen and, even if everything’s fine […] just a regular physical, making sure they’re taking their meds appropriately, that they’re not having any side effects, sometimes these things you won’t, they won’t tell you over the phone.” […] They’ll be more… likely to talk about their side effects or issues that they’re struggling with in person.The pharmacist focused on how the application lent itself to improved patient education:I liked that it graphs the numbers out for them, that it color-codes them. I think it helps patients learn, um, what’s good and what’s not good in terms of blood pressure control.Throughout the 12-week intervention, the 15 participants had 122 points of contact with their primary care clinic or the emergency department . Of these points of contact, one involved a patient who presented to the emergency room experiencing symptoms associated with high blood pressure due to medication nonadherence and was treated accordingly. Most of the points of contact  included a hypertension-related focus . These hypertension-related points of contact were conducted predominantly via phone , with in-person  and email  contacts occurring less frequently. Many of these points of contact are attributed to the increased blood pressure management oversight by our study pharmacist, as 76.0% (73/96) were contacts with our study pharmacist. Moreover, during the 12-week intervention, a total of 20 hypertension medication adjustments were made across our 15 participants (range 0-5 medication changes per participant), 70% (14/20) of which were made by the study pharmacist. Reasons for medication changes included adding or removing medications and dose adjustments.r=0.65, P=.02), number of hypertension-related encounters , and number of encounters resulting in hypertension medication changes  were all positively correlated with a change in systolic blood pressure. Given the high level of collinearity between clinical pharmacists and hypertension-related encounters and med changes as well as the small sample size adjusted analyses were not feasible.The number of contacts with the study pharmacist  systems, namely the EHR, to be truly useful. As noted in several other studies, when systems contain patient data but do not integrate with the EHR, their usability is severely limited due to incompatibility with workflow -25. In aAs noted, the two participating providers suggested several concerns about the long-term feasibility of incorporating BPTrack or similar interventions into routine clinical practice. Our current clinical environment, and existing clinical workflows, are not designed to utilize digital interventions such as these. Most primary care practices in the United States do not have embedded clinical pharmacists, let alone the technological infrastructure needed to support this type of intervention.In addition to reimagining workflow to support the expansion of digital health, well-designed protocols to address the inherent ethical concerns need to be established by health systems. For example, the pharmacist in the present pilot study expressed concerns about response times to concerning blood pressure values and a lack of a consistent alert system embedded in the EHR. Although the data was available to view, the pharmacist was unable to allocate time to review blood pressure values consistently. Integration into the workflow will become increasingly essential as mHealth interventions are scaled up. Also of concern is identifying the correct health care professional to review and respond to incoming patient-generated data. In the present study, we utilized a clinical pharmacist, but perhaps a medical assistant or personnel hired and trained to interact with this type of data specifically would be better suited .Qualitative and quantitative data reveal that patients found BPTrack to be acceptable for use. As noted, participants had high degrees of satisfaction with the program and would like to continue using the program. In particular, participants report that they found it valuable to see their blood pressure data, both daily as it was measured, and as a longitudinal trend. These observations are consistent with constructs such as self-regulation theory (on which this intervention is built) , which sIn addition to general thoughts on the acceptability of BPTrack, participants expressed their sense of satisfaction and safety in knowing their blood pressure measurements were being monitored by a health care professional who could make changes to their medication regimens. For some, this was noted as increasing satisfaction with the actual treatment plan, which may have downstream consequences for medication adherence . For reaAfter 12 weeks, patients exhibited significant reductions in both systolic and diastolic blood pressure, both of which are considered clinically meaningful. Our finding of efficacy in this pilot study is supported by literature demonstrating the benefit of pharmacist-led ,29-32 anDespite improvements in blood pressure and the presence of medication reminders within the BPTrack app, it is particularly interesting to note that our patients exhibited no significant improvements in medication adherence, which contributes to the already mixed literature on the effectiveness of mobile medication reminders -37. Our This study was not without limitations. Given that the BPTrack intervention was available only to participants with smartphones, there are inherent digital-divide concerns. It should be noted though that smartphone adoption is exceedingly high (about 81% of American adults) and increasing; however, smartphone adoption is still lagging among individuals 65+ years of age (53%), with less than a high school education (66%), with annual household incomes <$30,000 (71%), and who live in rural areas (71%) . MoreoveMoreover, the small sample size of both patients and stakeholders limits our findings. Future work should seek to look at longer-term implications, with larger sample sizes of patients and stakeholders, of a digital health intervention embedded within clinical care to determine whether the positive effects might be sustained over time. Finally, as with all packaged interventions, it is not clear which intervention components may have individually, or as a set, contributed to the positive reductions in patient participant blood pressure. Given that pharmacist-led interventions are efficacious -40, we dOur results demonstrate that a pharmacist-led mHealth intervention that promotes home blood pressure monitoring and clinical pharmacist management of hypertension can be effective at reducing systolic and diastolic blood pressure in primary care patients with uncontrolled hypertension. Our data also support the idea that these types of interventions are feasible and acceptable to patients and providers and are effective at improving health outcomes. There is a need for more robust trials of digital health interventions integrated into routine clinical care to more robustly determine potential effectiveness, as well as guided investigations to more fully understand how to implement these types of interventions into clinical practice thoughtfully.