Receiver Operating Characteristics analysis for HSD was 0.781, 0.804, 0.770, respectively. HSD < 9439.5 μm2 predicted high BP and arterial stiffness . These results suggest that OMA is a sensitive index to predict arterial stiffness in HTN population.We aimed to analyze whether opisthenar microvessel area  angiography) was associated with blood pressure (BP), arterial stiffness and whether OMA can predict arterial stiffness in hypertensive (HTN) patients. Results from 90 participants showed that BP, brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI) were significantly higher but OMA  were significantly reduced in HTN group (n = 36) compared to non-HTN (n = 54). NT, CST, HST and HSD showed negative correlations with baPWV and ABI in all participants, female (n = 47) and male group (n = 43), but the correlation was absent when the participants were divided into HTN and non-HTN. Logistic Regression analysis showed that only baPWV was a significant risk factor for HSD (OR 19.7, 95%CI 4.959–78.733,  The hypertensive population is estimated to be over 10% worldwide, and the numbers are on the rise with the new diagnostic criteria (systolic and diastolic blood pressure > 130/80 mmHg)4. Early diagnosis and management of HTN to reduce vascular dysfunction are of vital importance.Hypertension (HTN) is the main risk factor of fatal cardiovascular diseases due to the comorbidities in vasculature including myocardial infarction, atherosclerosis, cerebral hemorrhage, stroke, diabetes and renal failure6. General consensus is that arterial stiffness of aorta and large conduit arteries are independent risk factors of cardiovascular mortality and morbidity, especially in aged population with HTN. Sustained blood pressure elevation and arterial stiffness increase vascular pulsatility, if left untreated, result in endothelial injury and peripheral arterial diseases. Consequently, reduced blood flow causes distal arterial narrowing or closure of the circulatory lumen, a phenomenon called microvascular rarefaction (MR)8. Concomitant stimulation of sympathetic nervous system, renin-angiotensin- aldosterone system and endothelin system as well as systemic or local inflammation in HTN exacerbate the blood flow reduction through impaired microcirculation and causes vital organ damage9. Accordingly, changes in microcirculation reflects arterial dysfunction, which can be used to predict cardiovascular disease-oriented organ function.Chronic HTN is associated with arterial remodeling and dysfunction—e.g., aortic dissection and aneurysm, arterial calcification and atherosclerosis11. E.g., choriocapillaris flow deficit, measured using OCT, has been associated with high blood pressure and kidney dysfunction in HTN patients12. Furthermore, OCT images have shown that retinal capillary densities were reduced in diabetic and HTN patients14. Conversely, carotid plasticity and stent treatment reversed capillary density15. In line with these findings, retinal capillary remodeling has been shown to correlate with arterial stiffness and kidney dysfunction16. These compelling evidences indicate that OCT angiography is a reliable tool to detect the microcirculation changes and MR for cardiovascular monitoring under various disease conditions. Very recently, high-resolution images of cutaneous vessels are measured with OCT angiography and the vessel densities or diameters are shown to respond well to physiological stimulus (e.g. warm) in both healthy and diseased populations19.Recently, optical coherence tomographic (OCT) angiography is recognized to be a useful tool to visualize the microcirculation non-invasively and analyze the association with various diseasesThe associations between cutaneous microvessels and arterial dysfunction parameters in HTN patients are unidentified. Accordingly, we aimed to investigate whether opisthenar microcirculation was associated with arterial dysfunctions in HTN patients and whether opisthenar microvascular changes to physiological stimuli (cold or warm stimulus) could be a useful index in predicting the pathology in this group of patients. We measured the opisthenar microvessel area (OMA) using OCT angiography and baPWV and ABI with non-invasive automatic device in 90 volunteers with and without HTN to validate the clinical application of this parameter.90 volunteers are recruited from the Physical Examination Center of Yanbian Affiliated Hospital in China Between September 2020 and January 2021. Individuals with medical history of cardiovascular diseases, such as heart failure, stroke, diabetes , kidney diseases and chronic or acute infection were excluded from the study. All individuals are at fasting state on the day of OCT imaging and brachial-ankle pulse wave velocity (baPWV), ankle-brachel index (AMI) measurements and no medication were taken for the previous 24 h. Examiners are divided into HTN  and non-HTN group . 26 HTN participants take nifedipine (30 mg/once/day) regularly. 10 did not take antihypertensive medication before. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Affiliated Hospital of Yanbian University. The informed consent was obtained from all participating subjects.20. Brachial and ankle wristbands were placed in supine position and two consecutive measurements were conducted after relaxed for 5 min. Data processing is followed straight after the second measurement. baPWV and ABI of both left and right values of the second measurement were analyzed when the readings were similar (or third measurement was taken if inconsistent results were recognized).baPWV and ABI were measured using an automated device  as described elsewhere21. Briefly, a high-speed super-luminescent diode  scanned the field of view (4 mm × 4 mm) with 16 μm/pixel resolution. Laser reflectance of the surface of flowing red blood cells depict microvessels under the skin. Longitudinal (x-axis) and cross-sectional area (y axis) were scanned and data were processed for quantitative measurement and vessel density. To obtain 3-dimentional images, 250 A-lines through B scan (x-axis) and 250 B-scan (y-axis) with four repeats forming a cube of approximately 4 mm (x axis) × 4 mm (y axis) × 3.8 mm (z axis) for data processing. The structure, shape and branch of the blood vessels were analyzed in the built-in analysis software (Angiotool).All 90 participants were examined on the back of hand (1 cm from the middle finger bone) under the detecting probe using a non-invasive imaging system , the hand was covered by a medical cold pad  for 45 s and measured the same area after 1 min (the 2nd stage). Rest 30 min for the normalization, the hand was covered by a medical hot pad  for 45 s, took the measurement in the same area. The hand was kept still during the test.p < 0.05 was considered to be statistically significant.SPSS 19.0  statistical software was used for data analysis. The data with the normal distribution was expressed as the mean ± standard deviation (mean ± SD). Non-parametric statistical analysis was used for comparison between groups. The Spearman correlation analysis was used to analyze the correlation of each test parameter, and the receiver operating characteristic curve was used to explore the relationship between the arterial stiffness and OMA. Logistic Regression analysis was used to study the correlations between related risk factors  and HSD, and findings were reported with the beta coefficient (β), SE, OR 95% CI. p < 0.0001). The brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) of both left and right side were significantly higher in HTN (Table p < 0.0001).A total of 90 examiners were divided into normal blood pressure group (Non-HTN) and hypertension group (HTN) according to the day of blood pressure measurement and their HTN history. Individuals with complete data sets were included in the analysis. Age, body mass index, gender, systolic blood pressure, diastolic blood pressure, and mean blood pressure were different between two groups (Table OCT angiographic data of opisthenar microvessel and averaged microvascular area (OMA) from non-HTN and HTN individuals before and after cold and warm-stimulation  were shown in Fig. Next, we examined the correlations between baPWV or ABI and OMA in non-HTN and HTN groups. In all 90 examiners, baPWV and ABI (both left and right) were negatively correlated with OMA-NT, CST, HST Table -All. BetThe examiners were separated into male n = 43) and female (n = 47) groups and OMA and their responses to cold and warm-stimulation were analyzed. As shown in Figs.  and femaSimilar negative correlations were observed between baPWV or ABI and NT, CST, HST in male and female groups Table . In bothFurther separation of male and female groups into non-HTN and HTN, the correlations between OMA and baPWV were absent Tables , 5. Thesp < 0.0001).In HTN group, average age, BMI are higher and more individuals are sedentary, with smoking and drinking habits. Therefore, we went on and analyzed the interactions between HSD and age, BMI, smoking, drinking habits, exercise or baPWV in all individuals. As shown in Table 2 in all 90 examiners, 9485.5 μm2 for male and 7631 μm2 for female. AUC for baPWV, SBP, DBP for all examiners were 0.781, 0.804, 0.770, respectively (p < 0.0001), male group were 0.887, 0.893, 0.869 (p < 0.0001) and female group were 0.710, 0.711, 0.645 , which is important in early prevention of HTN-induced complications. In particular, we found that the area and the density of cutaneous microvasculature (OMA) and their responses to cold and warm stimulus, measured with recently developed OCT angiographic system, were significantly reduced in HTN group. As expected, arterial stiffness parameters (baPWV and ABI) were greater in HTN group and further analysis revealed that OMA at basal (NT), with cold and warm stimuli (CST and HST) were negatively related with baPWV and ABI in all individuals, irrespective of blood pressure group, excluding the effect of gender and suggest the importance of blood pressure in the association with OMA. Logistic Regression analysis confirmed that the differences in response to warm stimulation (HSD) were associated with baPWV, but not with age, BMI, smoking, drinking and sedentary status. In addition, ROC analysis suggest that HSD < 9435.5 μm22. Subcutaneous blood vessels constitute the whole microvascular network structure and the capacity for volume changes is remarkable (from 5 to 60% of cardiac output with warm stimulation23). Using OCT angiography, researchers from Green DJ group demonstrate that it is possible to quantify microvascular anatomic and dynamic flow rate and to make comprehensive assessment of the structure and functions of cutaneous microvasculature25. In addition, the microvascular area and diameters are increased in response to either whole-body warming (30 min of lower limb warming at 40 °C water bath)19 or local warming (30 min at 44 °C)25, further validating the measurement in human. Using similar protocols, we have found that OMA was increased following local cold (0–4 °C) and warm (42 °C) stimulation but the area and density of these parameters were significantly reduced in HTN group. These characteristics were not different between male and female, where responses were similar and OMA was reduced in HTN in both gender groups. Our results provide direct evidence of MR in peripheral cutaneous tissue of HTN patients.Recent development of OCT angiography provides quality analysis of the microcirculation in various tissues, including retinal, cutaneous, cerebral as well as tumor tissues26. Our results provided alternative protocol of assessing MR using OCT angiography, which is convenient and efficient in healthy and HTN population. The dynamic signals indicate that the subcutaneous microvascular blood flow of healthy individual is stable but those from HTN group are disrupted with capillary thinning or compensatory hypertrophy of blood vessels. Although not studied, reduced blood flow and "ischemic" status are liable to the inflammation of target tissue, which deteriorates local blood supply, and inversely exacerbate HTN by increasing the load and reduce the distensability of the arterial walls, a vicious circle between main arteries and the microcirculation, exacerbate vascular injury28. MR and its pathology in HTN has been recognized for more than a few decades and the significance of MR in HTN remains an area of intensive research33, integrated regulations between local and systemic blood supply, ischemia, inflammation and neuronal hormonal regulation warrants further investigation.It is well recognized that MR significantly reduces the tissue blood flow and increases arterial resistance. As a result, MR could be the direct cause and the consequence of BP increment. Importantly, MR is a systemic phenomenon, it provides a window to assess organ or tissue-oriented pathology through “visible” microvascular detection. Indeed, MR has been detected and confirmed in various organs, including retinal and dermal capillary using either invasive retinal angiographic (gold standards), non-invasive intravital capillaroscopy and laser Doppler flowmetry, etc.34, confirming cutaneous MR in essential HTN. In addition, retinal capillary MR measured from OCT angiography was shown to be associated with PWV and BP in HTN35. In addition, laser Doppler Flowmetry showed functional correlations between reduced retinal capillary flow and high arterial stiffness (PWV) in HTN patients36. Since capillaries represent systemic microvascular network, reduced local blood flow due to MR links to respective organ dysfunction in HTN, with PVW an independent factor for HTN-induced organ damage. Of note, Logistic Regression analysis showed that only baPWV was associated with HSD changes, but not the age, BMI, smoking, drinking habit and exercise status, clearly indicating the importance of arterial stiffness on OMA parameter change in HTN. Taken together, our results demonstrate that OMA could be used to predict the pathology of the aorta and large conduit arteries. Early detection of HTN damage is important to both CV risk stratification.The novel information of the current study is that OMA was reduced in HTN and OMA showed significant negative associations with baPWV and ABI in 90 participants and similar associations were observed in male or female groups, excluding gender differences. No correlations were observed in non-HTN or HTN groups because of significant differences in OMA between two groups and no associations could be observed in two clusters. Similar reductions in capillary density from dorsum of the fingers to the forearm in HTN were observed using videomicroscopy/ capillaroscopy2, HSD < 9485.5 μm2 in male and HSD < 7631 μm2 in female groups. High sensitivity was obtained in all examiners and in male group, whereas female group showed less sensitivity, probably due to more diverse individual varieties. Nevertheless, prediction of large arterial dysfunction with microvascular area changes of each individual will be beneficial in preventing unwanted cardiovascular consequences of HTN patients. In conclusion, we have demonstrated that OMA measured from OCT angiography is reduced in HTN, indicating HTN-induced subcutaneous microvascular remodeling. Furthermore, OMA was inversely associated with arterial stiffness indexes (PWV and ABI) and HSD is a useful index to predict arterial stiffness, which is important in early prevention of HTN-induced complications. It should be stated that microcirculation measurement using OCT is not in daily clinical practice for HTN yet. However, this novel technique can be developed to observe regional dynamic blood flow, complimenting MRI or Doppler ultrasound for small vessels38. Our current study using OCT angiography proved the concept of macro- and microvascular remodeling in HTN, therefore, will significantly contribute to future clinical applications to evaluate the comorbidities of HTN patients.Notably, we provided reference values of OMA for predicting high BP and arterial stiffness. We have analyzed HSD and CSD to avoid the bias by individual discrepancies, and we found that HSD showed significant correlations with baPWV, therefore, HSD was analyzed for predictive purposes. Our results found that the cut off values in all HTN patients were HSD < 9439.5 μm


To explore the determinants of incident hypertension, and especially the impact of baseline blood pressure categories, in a representative Swedish population.A 10-year longitudinal study of residents aged 30–74. Blood pressures were measured and categorized according to ESH guidelines with optimal blood pressure < 120/80 mmHg, normal 120–129/80–84 mmHg, and high normal 130–139/85–89 mmHg. Incident hypertension was defined as ongoing treatment or three consecutive blood pressure readings ≥ 140/ ≥ 90 mmHg (one or both) at follow-up, while those with ≥ 140 and/or ≥ 90 mmHg at only one or two visits were labelled as unstable. After excluding subjects with hypertension, ongoing blood pressure lowering medication or a previous CVD event at baseline, 1099 remained for further analyses.p < 0.001), however, not by age.Sixteen (2.6%) subjects with optimal baseline blood pressure had hypertension at follow up. Corresponding numbers for subjects with normal, high normal and unstable blood pressure were 55 (19.4%), 50 (39.1%) and 46 (74.2%), respectively. Compared with subjects in optimal group those in normal, high normal and unstable blood pressure categories had significantly higher risk to develop manifest hypertension with odds ratios OR and (95% CI) of 7.04 (3.89–12.7), 17.1 (8.88–33.0) and 84.2 (37.4–190), respectively, with adjustment for age, BMI and family history for hypertension. The progression to hypertension was also independently predicted by BMI (Subjects with high normal or unstable blood pressure should be identified in clinical practice, evaluated for global hypertension risk and offered personalized advice on lifestyle modification for early prevention of manifest hypertension and cardiovascular disease. Estimates of hypertension conversion rate vary, but earlier studies [prehypertension. Thus, subjects of high normal blood pressure, especially in younger population strata, constitute a highly interesting and still rather poorly studied group.Hypertension is a common condition, strongly associated with cardiovascular mortality and morbidity , 2 and 2 studies  suggest Our study aim was accordingly to study the determinants for incident hypertension among a representative population sample of individuals mainly in their early middle-ages with focus on baseline blood pressure categories.The first visit of this prospective study, including 2816 individuals, was performed 2002–2005 in the two municipalities Vara and Skövde in the south-west of Sweden. All participants were randomly selected from the population census register, 30–74 years old, stratified by gender and five-year age groups with intentional oversampling (threefold) in the age group 30 to < 50 years as compared with those aged 50 years or older. Signed informed consent was obtained from all participants. A follow-up visit including 1327 representative individuals was performed between 2012 and 2014, 9.7 years after base-line with a participation rate of 66%. The same protocol as at baseline visit was used at the follow-up visit. Individuals diagnosed with hypertension or on anti-hypertensive medication at base-line were excluded in this study (n = 198), as were those with a previous CVD event (n = 25), and 5 participants lacking a complete series of blood pressure readings at follow-up, leaving 1099 individuals for the final analyses . New diagnosis of diabetes mellitus was confirmed after two fasting plasma glucose values of ≥ 7.0 mmol/L, or one 2-h plasma glucose value of ≥ 11.1 mmol/L in an oral glucose tolerance test . InsulinThe participants were interviewed by trained nurses concerning medical history and medication. All participants also completed questionnaires concerning psychosocial health, lifestyle, i.e., physical activity and smoking, stress and quality of life. The participants were asked to grade their leisure time physical activity the last year in a validated, four-graded questionnaire: “How physically active are you during your leisure time? (1) Sedentary leisure time: reading, watching television, stamp collecting or other sedentary activity; (2) Light leisure time physical activity: walking, cycling, or similar physical activity at least four hours per week; (3) Moderate leisure time physical activity: running, swimming, tennis, aerobic, heavier gardening, or similar activity during at least 2 h per week; (4) Heavy training or competitive sport in running, skiing, swimming, football, etc., performed regularly and several times a week” .Information on level of education was also collected by the questionnaire and was further categorised as those with ≤ 9 years, 9–12 years, and > 12 years education. A family tree tracking the presence of hypertension among first degree relatives was created. For this study a family history of hypertension was defined as the occurrence among one or both parents and/or among the siblings. Alcohol consumption during the last month was estimated using a technic Time-Line Follow-Back systematically reviewing intake of beer, wine and liquor by frequency and quantities. An algorithm was then used to estimate gram alcohol consumed by time allowing also for the effect of binge drinking . For theAll statistical analyses were performed using the SPSS software package for Windows, version 24.0. Logistic regression was used to investigate association between baseline blood pressure categorical variable and the development of hypertension, with adjustment with continuous age, BMI at baseline and binary family history of hypertension. In addition, baseline blood pressure category was also used as a continuous variable in the regression to test the trend of association. In an extended model we added information on duration of education, type 2 diabetes, level of leisure time physical activity (LTPA), concentration of LDL cholesterol, and alcohol use as covariates.Stratification of analyses for sex revealed no significant sex-differences, and when adjusting for age no significant interactions between sex and each of the other factors included in the multivariable analysis were significant (Data not shown).Characteristics of the baseline population are presented in Table p < 0.001. These results remained practically the same when also duration of education, leisure time of physical activity, type 2 diabetes, LDL-cholesterol and alcohol use were included in the regression (Table p < 0.001), however, the OR’s for the other covariates remained practically the same. Level of physical activity, reported alcohol intake, level of education and concentrations of LDL cholesterol was, however, not predictive of progression to manifest hypertension in corresponding multivariate models (data not shown).Accordingly, normal, high normal and unstable baseline blood pressure were all significantly associated with the development of manifest hypertension compared to optimal blood pressure OR (CI), of 7.04 3.89–12.7), 17.1 (8.88–33.0) and 84.2 (37.4–190), respectively ), and a type 2 error may be at hand. Therefore, we suggest that the clinical implications of heritability should be further studied in the future. Indeed, part of the effects of heritability might be expressed through the impact of baseline blood pressure categories as observed in this study.The blood pressure category in focus here, high normal blood pressure, has in some contexts been labelled prehypertension based on its increased risk of hypertension within near future , 17. ActThe results obtained are in accordance with previous studies and confirm the fact that also a mild blood pressure elevation, already in middle age, constitutes a serious risk factor for future hypertension. CVD-risk grading tools, such as SCORE , are impAmong the strengths of this study are the representative population-based sampling and the comparably high participation rate, that confers a strong generalizability. It should be emphasized that our study population derives from two smaller communities, Vara with about 16,000 residents and Skövde with about 50,000 residents, and thus exposed to a higher prevalence of overweight and obesity as there is a strong gradient along the population density for these conditions as recently published by Hemmingsson et al. . Other dIn conclusion, high normal blood pressure is common in the general population and these individuals run a considerable risk of progression to manifest hypertension already in the middle-ages, as do individuals with one or two blood pressures within the hypertension range. They should be easy to identify among the flow of patients in primary care applying the present findings and proper intervention should be in accordance with general preventive strategies with a focus on diet and starting in young adults. However, controlled clinical trials comprising also cost benefit analyses are called for in this area.


Almost 50% of the adults in the United States have hypertension. Although clinical trials indicate that home blood pressure monitoring can be effective in managing hypertension, the reported results might not materialize in practice because of patient adherence problems.The aims of this study are to characterize the adherence of Medicaid patients with hypertension to daily telemonitoring, identify the impacts of adherence reminder calls, and investigate associations with blood pressure control.This study targeted Medicaid patients with hypertension from the state of Texas. A total of 180 days of blood pressure and pulse data in 2016-2018 from a telemonitoring company were analyzed for mean transmission rate and mean blood pressure change. The first 30 days of data were excluded because of startup effects. The protocols required the patients to transmit readings by a specified time daily. Patients not transmitting their readings received an adherence reminder call to troubleshoot problems and encourage transmission. The patients were classified into adherent and nonadherent cohorts; adherent patients were those who transmitted data on at least 80% of the days.P<.001 and P=.004), respectively, for the adherent cohort during the study period, whereas only the systolic blood pressure value improved by an average of 1.6 mm Hg (P=.02) for the nonadherent cohort.The mean patient age was 73.2 (SD 11.7) years. Of the 823 patients, 536 (65.1%) were women, and 660 (80.2%) were urban residents. The adherent cohort  had mean transmission rates of 74.9% before the adherence reminder call and 91.3% after the call, whereas the nonadherent cohort  had mean transmission rates of 39% and 58% before and after the call, respectively. From month 1 to month 5, the transmission rates dropped by 1.9% and 10.2% for the adherent and nonadherent cohorts, respectively. The systolic and diastolic blood pressure values improved by an average of 2.2 and 0.7 mm Hg (Although we found that patients can achieve high levels of adherence, many experience adherence problems. Although adherence reminder calls help, they may not be sufficient. Telemonitoring lowered blood pressure, as has been observed in clinical trials. Furthermore, blood pressure control was positively associated with adherence. Hypertension affects nearly half of the adults in the United States, costs approximately US $131 billion annually, and is a major risk factor for cardiovascular disease and stroke . NonetheHome blood pressure monitoring is an emerging strategy to help control hypertension, with many medical organizations recommending its use in diagnosis, distinguishing between blood pressure phenotypes, and ongoing hypertension management . SeveralAlthough clinical trials are the gold standard, the reported results may not materialize in practice. Physicians have concerns about instrumentation quality, patient skills in taking readings, regular recording and transmission of results, and adherence to a regimen of routine measurement . The 201The aims of this study are to (1) investigate how well Texas Medicaid patients adhere to daily blood pressure and pulse rate monitoring when supported by a daily telemonitoring services company, (2) determine whether an adherence reminder call intervention improves the daily transmission rate, and (3) investigate any association between daily adherence and blood pressure control.We note that insurance coverage is a requisite for daily telemonitoring. Medicare began paying for home monitoring in November 2018 , and TexIn this study, a telemonitoring company provided historical telemonitoring data (from January 2016 to December 2018) for Medicaid clients with hypertension in the state of Texas. The monitoring protocol  requiredThe telemonitoring company provided historical telemonitoring data for Texas Medicaid clients using their service. Only clients with 180 days or more of home telemonitoring were included in this study. The first 30 days were regarded as a startup period during which the patients learned to use the equipment to measure their vital signs. Data from the first 30 days were excluded from this study; thus, the study period was 150 days (months 1-5).The number of transmissions before and after the adherence reminder calls was recorded each day, as was the number of adherence reminder calls made. We included all attempted adherence reminder calls, even those that the patients did not answer, because, in these cases, voice mail was left whenever possible. Daily systolic and diastolic blood pressure values were also collected to investigate improvements in blood pressure values during the study period. The mean systolic and diastolic blood pressure values at month 5 for each patient were calculated and compared with those at month 1. If the blood pressure values of the patient were missing for the entire month, that patient was excluded from this analysis.The patients were separated into adherent and nonadherent cohorts; adherent patients were those who transmitted blood pressure and pulse values on at least 120 of the 150 days .This study was approved by the institutional review board of Texas A&M University.t tests for continuous variables. In addition, z tests for the equity of the two proportions were performed to examine whether the rates of transmission differed by population subgroups. Paired t tests were performed to analyze the changes in blood pressure values at month 5 by comparing them with those at month 1 for each subgroup. Independent t tests were used to compare the changes in blood pressure values between the population subgroups. Analyses were conducted using SAS version 9.4 (SAS Institute).To determine whether the patient baseline characteristics differed by population subgroups, we used chi-square tests for categorical variables and two-tailed The data of 2093 clients enrolled in hypertension telemonitoring were provided. Of the 2093 patients, 1325 (63.31%) transmitted data at least once, and 823 (39.32%) transmitted data throughout a continuous 180-day period. P<.001).Most of the participants  were from McAllen in south Texas near the Mexican border, and most of them  resided in urban areas. Of the 823 participants, 731 (88.8%), 725 (88.1%), and 724 (88%) participants had acceptable systolic blood pressure, diastolic blood pressure, and pulse ranges of 90-160 mm Hg, 60-90 mm Hg, and 60-120 bpm, respectively, which were defined by their primary care physician. The remaining 92 (11.2%), 98 (11.9%), and 99 (12%) participants had customized acceptable values above or below these ranges . P<.001). The mean transmission rates for the first month were 61.6% and 79.1% before and after the call, respectively. These values declined until the fifth month when they reached 56.2% and 73.7% before and after the call, respectively. As indicated by the orange area in P<.001). After the adherence reminder call, these values increased to 91.3% and 58% (P<.001), respectively.These aggregate findings mask large differences between the adherent and nonadherent cohorts . The adhP<.001).The mean transmission rates for the first month were 75.6% before the adherence reminder call and 91.7% after the call for the adherent cohort and 42.6% and 61.9% before and after the call, respectively, for the nonadherent cohort. These values fluctuated and declined until the fifth month when they reached 73% and 89.9% before and after the call, respectively, for the adherent cohort and 33.3% and 51.7% before and after the call, respectively, for the nonadherent cohort. On average, an additional 16.5% and 19% transmissions were received after an adherence reminder call from the adherent and nonadherent cohorts, respectively (P<.001). We noted that, on average, 8.4% of the nonadherent participants who did not transmit data by the specified time failed to receive an adherence reminder call. This value increased to 10.3% in the fifth month of monitoring. In contrast, only 1.02% of the adherent cohort who did not transmit data failed to receive an adherence reminder call.The percentage of participants not transmitting after an adherence reminder call was, on average, 7.6% for the adherent cohort and 33.6% for the nonadherent cohort. These values increased from 6.8% in the first month to 9.4% in the fifth month for the adherent cohort and from 28.3% in the first month to 38.1% in the fifth month for the nonadherent cohort  was found to be 60.9% (SD 26%) for the adherent cohort and 53.9% (SD 24.9%) for the nonadherent cohort. The percentage in range increased for both cohorts over the 5-month period, indicating that telemonitoring was effective, from 59.2% in month 1 to 62.3% in month 5 for the adherent cohort and 49.8% in month 1 to 56.7% in month 5 for the nonadherent cohort.transmission events. Frequency analysis indicated an association between the transmission events observed on consecutive days. This is explored in the following sections. The percentages are listed in Finally, the data indicated that the transmission results for 2 consecutive days were related. Note that for any given day, there were three possible outcomes: the patient did not transmit, the patient transmitted an out-of-range reading  or the patient transmitted an in-range reading. We refer to these as Adherence on the day after a missed transmission was far below the overall average for both adherent (67.1% vs an average of 91.3%) and nonadherent (38.3% vs an average of 58%) cohorts. Furthermore, the transmissions that were received the day after a missed transmission were less likely to be in range than the average for both cohorts. For the adherent cohort, 37.8% of the missed transmissions were followed by in-range transmissions, indicating that 56.3% (100 × [37.8 / 67.1]) of the transmissions received the day after a missed transmission were in range, whereas for the nonadherent cohort, 19.8% of the missed transmissions were followed by in-range transmissions, indicating that 51.6% (100 × [19.8 / 38.3]) of the transmissions received the day after a missed transmission were in range.Adherence and in-range transmission after out-of-range transmission also showed similar patterns across the 2 cohorts. For the adherent cohort, out-of-range transmissions were followed by 41.6% of out-of-range transmissions, 52.7% of in-range transmissions, and only 5.6% of no transmissions the next day. For the nonadherent cohort, out-of-range transmissions were followed by 34.8% of out-of-range transmissions, 36.3% of in-range transmissions, and 28.9% of no transmissions the next day. Thus, adherence after an out-of-range day was greater than the overall average (94.6% vs an average of 91.3% for the adherent cohort and 71.1% vs an average of 58% for the nonadherent cohort). Furthermore, the transmissions that were received after an out-of-range transmission were less likely to be in range than the overall average (55.7%—100 × [52.7 / 94.6]—vs an average of 60.9% for the adherent cohort and 51%—100 × [36.3 / 71.1]—vs an average of 53.8% for the nonadherent cohort). It is worth noting that when an adherent patient transmitted an out-of-range reading, the next in-range transmission occurred within 2-3 days on average, that is, it took 2-3 days to resolve whatever problem was causing the out-of-range reading and for the patient to regain blood pressure and pulse rate control. However, when a nonadherent patient transmitted an out-of-range reading, the next in-range transmission did not occur for 5-6 days on average, indicating that nonadherent patients were likely to experience elevated levels of blood pressure or pulse rate over a longer period.Finally, adherence and in-range transmission after an in-range transmission also had similar patterns across the 2 cohorts, with better adherence and more in-range transmissions on the following day. For the adherent cohort, in-range transmissions were followed by 61.7% of in-range transmissions, 32% of out-of-range transmissions, and only 6.3% of no transmissions the next day. For the nonadherent cohort, in-range transmissions were followed by 42.5% of in-range transmissions, 28% of out-of-range transmissions, and 29.6% of no transmissions the next day. Thus, adherence after an in-range day was greater than the overall average (93.7% vs an average of 91.3% for the adherent cohort and 70.5% vs an average of 58% for the nonadherent cohort). Furthermore, the transmissions that were received after an in-range transmission were more likely to be in-range again the next day than the overall average (65.8%—100 × [61.7 / 93.7]—vs an average of 60.9% for the adherent cohort and 60.3%—100 × [42.5 / 70.5]—vs an average of 53.8% for the nonadherent cohort).P<.001) over 5 months, whereas those of the nonadherent cohort improved by an average of 1.6 mm Hg .Overall, we found that the systolic blood pressure values of the adherent cohort improved by an average of 2.2 mm Hg  over 5 months, whereas that of the nonadherent patients  improved by an average of 10.6 mm Hg over 5 months, which was not significantly different (P=.11). The diastolic blood pressure of the adherent patients improved by an average of 0.7 mm Hg (P=.004) over 5 months, whereas the improvement over 5 months was not significant for nonadherent patients  improved by an average of 14.8 mm Hg (P=.02) over 5 months, whereas that of the nonadherent patients  improved over 5 months by an average of 9.7 mm Hg (P=.03).Of the 21 patients with an average systolic and diastolic blood pressure reading of more than 140 and 90 mm Hg for the first month, we found that the diastolic blood pressure of adherent patients  improved by an average of 11.0 mm Hg  are possible for most patients  when telemonitoring is accompanied by adherence reminder calls. For these patients, adherence levels seemed to decline slightly over the 5-month period.Furthermore, many Medicaid patients are likely to have trouble with daily adherence . For these patients, adherence reminder calls can be helpful, but many daily transmissions will still be missed (approximately 13 days per patient per month in this study). Such patients can likely be identified within the first month of monitoring (not including the startup period), when their adherence rates without the adherence reminder call fall well below 50% (42.6% in this study). Indeed, 75% (260/348) of the patients in the nonadherent cohort in this study were not adherent in the first month of monitoring. For these patients, adherence rates can be expected to degrade significantly over time (by approximately 16% over 5 months in this study). Of the 823 patients, the 475 (57.7%) adherent patients and the 348 (42.3%) nonadherent patients together generated the need for approximately 350 adherence reminder calls per day, a significant workload. Regardless of the case, patients with adherence problems clearly need more than an adherence reminder call. Indeed, interventions that delve into health behaviors will likely be necessary (but perhaps not sufficient) to bring adherence levels up to 80% and beyond. The data suggest that such interventions should be targeted to weekends and to days after missed transmissions when the likelihood of poor adherence is higher.Just as additional support for better adherence to daily monitoring is necessary, follow-up on an abnormal clinical condition is also important. A potential benefit of daily monitoring is that health care providers may recognize and address emerging problems before they become urgent. When readings are not transmitted, this opportunity may be lost. If we assume that the percentage of out-of-range transmissions can be applied to the days when data were not transmitted, we can estimate the number of missed transmissions that would have been out of range. Over 150 days of monitoring, this estimate turned out to be 5.1 days ([1 – 0.913] × [0.391] × 150) per patient for the adherent cohort and 29.0 days ([1 – 0.580] × [0.461] × 150) per patient for the nonadherent cohort. This represents a total of 12,528 days (29.04 × 348 + [5.10 × 475]) of unmet needs for 823 patients over 150 days of monitoring (approximately 15 days per patient). In other words, 10.2%  of the required follow-up was missed because of lack of adherence .P=.049). The mean diastolic blood pressure value of the adherent cohort declined significantly during the study period, but the decline was not significant for the nonadherent patients. These results are consistent with those of clinical trials in the literature. In 18 clinical trials of home telemonitoring, the average improvement in systolic and diastolic blood pressure values was 12.1 and 6.3 mm Hg within 6 months [On a positive note, it is encouraging that 58.9% (280/475) of the adherent patients and 54.9% (168/306) of the nonadherent patients experienced an improvement in systolic blood pressure values, and 52.2% (248/475) of the adherent patients and 51.6% (158/306) of the nonadherent patients experienced an improvement in diastolic blood pressure values. The mean systolic blood pressure values of both cohorts improved significantly during the study period, and these improvements were significantly higher in the adherent cohort (6 months -34. Of tFinally, it is important to appreciate that achieving improved adherence requires considerable effort. Patients must be trained in the correct procedures to monitor their blood pressure and pulse; staff members must monitor daily transmissions and contact patients to encourage participation and to resolve technical issues; and, as noted, additional interventions will be needed for many patients. Texas Medicaid payment levels may have been adequate for this level of intervention, but it is not clear whether Medicare or private insurers will reimburse this level of effort in the future. Clearly, the case for reimbursement would be compelling if hypertension telemonitoring could be shown to help avoid even a small number of hospitalizations for stroke and heart disease, which can be extremely expensive.This study included some limitations. It only examined Texas Medicaid clients. It is not clear whether these findings are generalizable to Medicare, privately insured, or uninsured patients with hypertension. It is also unclear whether these findings are generalizable to people with other chronic conditions who would benefit from ongoing monitoring. This study was limited to patients who were referred to the monitoring program. The analysis would be strengthened if there were a control group to more rigorously examine adherence and the impact of the intervention. Finally, the monitoring protocol required the data to be transmitted on a daily basis, which was more frequent than the general home blood pressure monitoring guidelines . ExcessiAdherence reminder calls helped most patients with hypertension to achieve higher levels of adherence to blood pressure and pulse monitoring. Telemonitoring improved blood pressure control, similar to the improvement observed in clinical trials. Furthermore, more adherent patients achieved higher levels of blood pressure control. However, the study suggests that additional adherence interventions and support are needed for many patients to achieve high levels of adherence.


Cerebrovascular disease, in particular stroke, is a major public health challenge. An important biomarker is cerebral hemodynamics. To measure and quantify cerebral hemodynamics, however, only invasive, potentially harmful or time-to-treatment prolonging methods are available.We present a simulation-based approach which allows calculation of cerebral hemodynamics based on the patient-individual vessel configuration derived from structural vessel imaging. For this, we implemented a framework allowing segmentation and annotation of brain vessels from structural imaging followed by 0-dimensional lumped simulation modeling of cerebral hemodynamics. For annotation, a 3D-graphical user interface was implemented. For 0D-simulation, we used a modified nodal analysis, which was adapted for easy implementation by code. The simulation enables identification of areas vulnerable to stroke and simulation of changes due to different systemic blood pressures. Moreover, sensitivity analysis was implemented allowing the live simulation of changes to simulate procedures and disease progression. Beyond presentation of the framework, we demonstrated in an exploratory analysis in 67 patients that the simulation has a high specificity and low-to-moderate sensitivity to detect perfusion changes in classic perfusion imaging.The presented precision medicine approach using novel biomarkers has the potential to make the application of harmful and complex perfusion methods obsolete. Cerebrovascular disease, and in particular stroke, is a major public health challenge. It is a leading cause of death and disability . While tAn alternative approach to derive biomarkers for precision medicine is the transformation of routinely acquired data by mechanistic simulations . These sThus, the novel idea presented in this work is a software framework to transform routine structural vessel imaging data as an input to a mechanistic simulation of individual hemodynamics for a given patient. The unique vessel configuration of each patient can be used to simulate hemodynamics to potentially identify areas that are vulnerable in case of stenosis and occlusion. Several use cases can be envisioned for such a framework. It could allow assessment of stroke risk, pre-operative simulation of interventional success like thrombectomy in acute stroke, preventive or therapeutic endarterectomy and stenting of brain-supplying vessels, respectively. Another highly interesting, if rather rare case is the simulation of the outcome of extracranial–intracranial (EC–IC) bypass surgery, e.g., in Moya-Moya disease. Here, there is a special need to predict the success of the surgery . Lastly,Thus, the objective of the presented work was to provide a framework allowing the incorporation of individual structural vessel data to simulate areas of higher hemodynamic vulnerability as a disease biomarker. For this purpose, we developed a pipeline consisting of the following sequential steps: (1) segmentation of vessel information from structural data, in our case from time-of-flight (TOF) magnetic resonance imaging (MRI). (2) Annotation of the vessel tree with an easy-to-use graphical user interface (GUI). And (3) simulation where results can be inspected, and different blood pressure scenarios can be simulated by the user.The simulation was implemented as a steady-state zero-dimensional lumped model of the Circle of Willis (CoW) and major brain artery circulation. We included individual vessel resistances by 1-dimensional calculation using the individual length and the width of the arteries from patient structural vessel imaging. Hemodynamic measures were calculated using an adapted version of the modified nodal analysis (MNA)  coined AWe developed a novel framework for enabling processing of routine imaging (DICOM) into a simulation tool that provides additional information about the state of the hemodynamics of an individual patient.A structural DICOM TOF-image Fig. a is procThis image is then skeletonized Fig. c.The vessel skeleton is imported in our annotation tool, in which the vessel tree is displayed in a 3-dimensional fashion andVessel annotation is performed Fig. d and e.The annotated vasculature is then transferred to the simulation tool Fig. f.Figure The annotation tool is made up of two main components. The segment annotation area, where the vessel segments can be chosen and the 3D view, where the imported vessel tree can be manipulated. We implemented 22 segments of brain-supplying arteries, namely 3 for the carotid artery , 7 for the MCA , 5 for the ACA , 4 for the PCA , as well as the basilar artery, the vertebral artery and the anterior and posterior communicating arteries. There is the option to add bypass vessels or collateral vessels manually, e.g., for planning of interventions or surgical procedures.Next to segment also the following additional labels can be chosen: “pre-occlusion”, “post-occlusion”, and “occlusion” (in case pre- or post-occlusion cannot be determined with certainty). To record occlusion next to the type of vessel is important for the following simulation step, as subsequently the simulation will ignore segments with this flag. A video footage of the annotation process was uploaded to zenodo .The simulation itself consists of a graphical user interface, that is divided functionally in the toolbar Fig. b I., theIn addition, also the intracranial pressure, which is kept constant for our use case at physiological parameters, but can be increased to simulate conditions with increased intracranial pressure, e.g., in hemorrhagic stroke. In the view selector area, in 4B IV., the normal view and the pressure view can be chosen  were included. 68% had previous stroke and 18% had a previous transitory ischemic attack (TIA). The visual analysis revealed a very high specificity and a moderate-to-low sensitivity for the simulation to detect vulnerability defined by visual DSC-rating. Results averaged over both hemispheres for each perfusion territory were (sensitivity/specificity): ACA 0.42/0.94, MCA 0.47/0.98, PCA 0.16/0.94. For detailed results please see Table An example of the sensitivity analysis is shown in Fig. We present the first comprehensive precision medicine pipeline for cerebrovascular disease that is capable to process routine stroke imaging DICOM images for simulation of various boundary conditions to identify brain areas vulnerable for ischemia.Our framework provides annotation of the arterial vasculature derived from neuroimaging followed by zero-dimensional individualized simulation of brain hemodynamics. Implementation was performed by decreasing the computational burden by a modified MNA, the development of an easy-to-use web user interface-frontend for annotation and a java-based cross-platform simulation tool. An exploratory validation analysis comparing our simulation results with DSC perfusion in patients with steno-occlusive disease revealed promising initial results for the simulation-based detection of vulnerable areas. Our results suggest that mechanistic simulation of blood flow derived from routine structural imaging can serve as an individual biomarker for patients with cerebrovascular disease and might be an alternative to complex and potentially harmful perfusion techniques.Stroke is a complex disease with a dynamic progression. The initial infarct area—characterized by rapid neuronal loss—is called the core, which is surrounded by tissue that is slowly surrendering to ischemia but is still salvageable. The latter area is coined the penumbra and defines the therapeutic target in acute stroke management . For theWhile it is true that there is a net profit for patients when treatment is applied within this time window, it is also obvious that many patients do not receive treatment who would benefit from it and at the same time patients receive treatment subjecting them to risk of intervention such as bleeding without its benefit. This is due to the above-mentioned fact that, in reality, several stroke subpopulations exist. Here, precision medicine accounts for the individual features and will improve outcome by personalizing treatment . PrecisiAs suggested by our work, in the case of cerebrovascular disease, we can infer information about hemodynamics from the individual vasculature of a given patient. We successfully built a pipeline that can extract the vessel information by segmentation, allows annotation of the vessels and simulates hemodynamic information which we were able to relate to clinical DSC-perfusion imaging through an exploratory visual comparison of DSC perfusion and simulation results. While these results need gold standard validation, they pave the way for further development of techniques that might make the need for perfusion imaging in cerebrovascular disease obsolete for some patients while still providing the necessary information for precision medicine selection of patients for prevention and treatment. Our results are in line with other recent exploratory validation studies .Given that mechanistic simulations work on a priori assumptions about the biological system and perfusion measurements actually record dynamic information, it is unlikely that the information provided by both systems will always be a complete match. This is also evidenced by the low sensitivity and the high specificity. DSC-MRI is sensitive to very small changes in perfusion, whereas a mechanistic simulation is expected to distinguish between relevant categories. Thus, the simulation was not able to pick up on every change noticed by the readers (low sensitivity), but where the simulation found vulnerabilities they were almost always accompanied by corresponding changes in DSC-MRI (high specificity). While the clinical relevance needs to be validated in further studies, our results suggest, that the information might be intersecting enough to allow treatment-relevant predictions on an individualized patient level, and consequently to avoid harmful imaging procedures. Thus, when the question is for example about a general status, i.e., “is there a general vulnerability in the right MCA area for ischemia”, mechanistic simulations might be able to provide this information instead of direct perfusion measurements. Also, since many variants of the CoW exist, the simulation could allow the identification of patients with high-risk for stroke owing to their individual CoW configuration .Another potentially big advantage of mechanistic simulations is the possibility to simulate interventions. In chronic steno-occlusive disease, like carotid stenosis or Moya-Moya disease, potential lumen reopening interventions or EC–IC bypass surgery can be performed. With our solution as presented in this work, it would be feasible to simulate the reopening of a vessel and thus simulate the post-intervention status.With our framework, it is possible to simulate the response of the vasculature to changes in blood pressure. This can potentially be highly important not only for the determination of areas-at-risk for ischemia, but also to predict the response to interventions and surgery, e.g., blood pressure drops during surgery. This is not possible with perfusion measurements, which can only provide a snap-shot of the status quo. Approximations can be done with acetazolamide challenge measurement , 29, butAs a limitation of our work, our results are exploratory and hypothesis-generating . While oindividualized gold standard values for arterial flow. Other noninvasive methods are either non-gold standards themselves, like MRI flow measurement methods, and/or cannot access the complete vasculature, like Doppler-sonography. Intra-operative direct vessel flow measurements recorded during EC–IC bypass surgery might be an option for gold standard measurements—which we will explore in the future—but were not available for the current study. Second, we would like to point out that all relevant pre-processing steps in the pipeline—segmentation, skeletonization, and annotation—were done manually in the pipeline. With the advent of powerful machine learning segmentation methods in recent years, it is very likely that these steps can be automated with sufficient performance. For segmentation, our group has just recently presented deep learning methods to segment the vasculature from structural scans with very high accuracy [Our work has other limitations. First, the simulation values were not compared to a gold standard. However, it is very difficult to derive accuracy , 34. TheWe present the first precision medicine pipeline for cerebrovascular disease that allows annotation of the arterial vasculature derived from structural vessel imaging followed by personalized simulation of brain hemodynamics. This enables further development of precision medicine in stroke using novel biomarkers and might make the application of harmful and complex perfusion methods obsolete for certain use cases.The datasets presented in this article are not readily available because data protection laws prohibit sharing the imaging data used in this study at the current time point. Requests to access the datasets should be directed to ethikkommission@charite.de.Sixty-seven patients with steno-occlusive disease from an imaging study of cerebral perfusion in stroke patients  wereThe framework pipeline consists of these chronological steps: (a) segmentation, (b) skeletonization, (c) annotation, and (d) simulation. In the following, each of the steps is described in detail.Structural MRI imaging consisted of time-of-flight (TOF)-MR images. To save time, all images were first pre-segmented using a high-performing published neural net segmentation model . The preThe segmentations were skeletonized using the DtfSkeletonization module (DtfSkeletonization—MeVisLab documentation) of MeVisLab (website: MeVisLab) . Here, aThe annotation module was developed and coded from scratch by the in-house development team.Within the annotation framework, the transferred skeleton volume is transformed into a Java-based tree structure—the so-called skeleton graph—representing the skeleton as a set of edges containing all necessary geometric information for 3D rendering, and a set of junction vertices. This tree structure is loaded via a RESTful service interface in JSON format into a JavaScript-based web frontend where it is rendered by using the Three.js library as a rotatable and zoomable 3D view.Within the 3D view, it is possible to select edges and tag them with an item from a list of vessels (artery) descriptors and their anatomic location  interactively. The triple consisting of an edge, a tagged vessel item, and an anatomic location is defined as an annotation. A set of made annotations can be saved in the backend via a RESTful service interface within an appropriate Java presentation. In the final step, based on a skeleton graph and a belonging annotation set, a simulation model serving as the input for our simulation component can be created once the annotation is finished.Within our framework, it is possible to annotate 3rd order branches . For exemplary patients in our study, annotations were performed until 2nd order branches , since higher order vessels are unlikely to play a crucial role in steno-occlusive disease.The simulation was developed and coded from scratch in-house. Our model describes the cerebral vascular tree by a planar graph, which is given in Fig. Edges in the graph represent blood vessels, while nodes represent either supply areas, blood sources or junctions between nodes. Supply areas are marked with square-shaped nodes, initial (round) nodes are blood sources and the rest of the (round) nodes are junctions. The arrows of the edges indicate the flow directions to the supply areas or away from source nodes. The blood flow into the supply areas is provided by the outgoing segments  of the circle of Willis.L, with radius r, blood dynamic viscosity μ for a volumetric flow rate Q is determined according to Hagen–Poiseuille equation:The cerebral vessel tree retains an overall Reynolds number allowing to describe the cerebral blood flow in terms of a Newtonian fluid. The arteries are modeled as perfect cylinders and the decrease in blood pressure Hagen–Poiseuille equation is equivalent to Ohm’s law. Therefore, the resistance of an arterial vessel can be defined as:In the presented use case, the vessel diameter is not homogeneous across the whole vessel segment and consequently Eq. n−1 = the number of voxels in the segment. To account for the fact that an antiderivative can only be determined for segments that can be constantly differentiated, we need to approximate the condition of continuity. For this purpose, the radius In practice, discrete application is used, as a segment is defined by a diameters-vector of length According to the mass flow law, the amount of blood entering a node must equal the amount of blood that leaves a node   that incOur network consists of three types of nodes and two types of edges. The primary type of node is one that connects different vessels with each other . The second type of node is a source that provides the system with blood. The third type of node is a supply area, whose resistance depends on the incident pressure and the auto-regulation process described in the next section see Fig. . The typThe simulated vessel network encompasses the circle of Willis and the larger arterial segments of 1st and 2nd order of the three major brain arteries: anterior-, medial- and posterior cerebral artery . Those are the vasculature segments that are (a) accessible for interventions such as surgery or thrombectomy and (b) their anatomical architecture can be derived from medical imaging. The vascular downstream regions after the above segments including the 3rd order segments represent a network of small arteries, finer small arterioles and the capillary bed that can change their radii in order to decrease or increase the blood supply. This process is called auto-regulation and ensures that the blood supply to the brain remains largely constant within certain limits. Most of the vascular network’s resistance originates from these supply areas. Autoregulation was implemented into the simulation framework according to the following equation based on literature values :6\documeIn more detail, the blood flow into the supply areas is provided by the outgoing segments  of the circle of Willis, see Fig. Pin being the system pressure, while Qs,i for i = {1,…,N} being the blood supply demand of supply area i as physical quantity.The model requires a systemic mean arterial pressure (MAP) that drives the flow through the network such that the blood supply to the various supply areas of the brain is constant, while the blood flows and pressures are adjusted accordingly. However, the auto-regulation model is limited to the region between 50 and 150 mmHg. Blood pressure below or above these boundaries indicates a pathological state in which the body cannot maintain the necessary blood pressure to ensure constant blood supply and results in hypoperfusion of the brain tissue. Under these conditions, the simulation indicates that the respective supply areas are not sufficiently supplied with blood. Clinically speaking, these areas are vulnerable to ischemia. In addition to the system pressure a blood flow rate per supply area was provided as N−1 mass flow equations. These mass flow equations can be written in terms of a matrix:The blood supply to the specified brain areas is derived using an adjusted modified nodal analysis (AMNA). The construction of the matrix equations per type of node and edge is detailed in the following. The described system is overdetermined by N equations, where N stands for the number of nodes. The last node is taken as the sink node, with a pressure value of 0. Therefore, the system is described by where the matrix G values for all connected edges and the non-diagonal elements are set to be the negative conductivity value of the corresponding edge—or otherwise 0. An exemplary derivation of a junction node vector is described under Fig. The matrix row vector for a junction node is defined as:The matrix row vector for a source node is defined as:The diagonal element is For the nodes that are directly connected with the source node, the q vector element is then:Figure To model supply areas, the auto-regulation equation is applied Eq. . The matSimilarly to junction nodes, the diagonal element i connected to source s.i.And Figure To summarize, the q-vector has a contribution for a supply area or a source node. If an edge connects a source with a supply area, the corresponding q-vectors will have contributions from both the source and the supply area. Table Here vessel refers to a connection of junction node to junction node, supply refers to a connection of junction node to a supply node and sink refers to a connection of a supply node to sink. The AMNA allows to reduce the size of the solution system by removing known values from the solution vector In order to predict the effects of changes of a certain variable on the system, in this case the radius of a blood vessel, we performed a sensitivity analysis. Sensitivity analysis quantifies this effect by estimating the partial derivative of a system variable such as the blood pressure in this case, with respect to the radius of a given vessel. This is achieved by application of Newton–Raphson method using Taylor series expansion  as folloSimilar Newton steps can be formulated for all relevant system variables and allow to estimate how the system reacts to changes of certain system variables.The simulation interface was implemented as a java application with an integrated graphical user interface (GUI) under the loose-coupling paradigm to ensure that components can be exchanged easily. The key element of the simulation is a 2D projection as a representation of the simulated vessel tree. The interfacé́s main components are the simulation view including areas at risk and pressure view, and the possibility to change blood pressure as a boundary condition.DSC imaging was processed using the pgui software . Four arterial input functions were placed contralateral to the stenosis/occlusion in the M2 vessel area and visually assessed for optimal shape . DeconvoIn 67 patients, we compared simulation and DSC perfusion imaging results. For this purpose, we defined vulnerability for both modalities and determined the detection rate of the simulation to identify vulnerabilities in DSC imaging by sensitivity and specificity.Vulnerability of brain tissue to ischemia was defined in MR-imaging as a visually rated TTP and/or Tmax increase and/or CBF decrease. For the simulation, vulnerability was defined as a perfusion pressure below 50 mmHg, at normal blood pressure or at a mean-arterial-pressure of 70. We assessed the sensitivity/specificity of the simulation results to detect vulnerability as defined by the visual DSC-analysis. Results were recorded for anterior/middle/posterior cerebral artery regions (left/right).


For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond one year. Herein we compare the impact of the ERTs on repeated measurements of glucosylsphingosine . A total of 135 adult patients (77 (57%) female) with GD1, followed from July 2014 to March 2020 and treated with a single ERT , taliglucerase alfa  and velaglucerase alfa ), were included. Disease severity was defined by genotypes (mild: N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous; severe: all other genotypes) and by the severity score index . Lyso-Gb1 testing was performed at Centogene™ on dry blood spot samples collected during routine visits. Patients treated with imiglucerase had higher lyso-Gb1 levels at different time points. A huge variation in lyso-Gb1 levels was noticeable both inter-individually and intra-individually for all three ERTs. A steeper and faster decrease of lyso-Gb1 levels was shown in velaglucerase alfa. Nevertheless, the differences between medications were not very large, and bigger numbers and more pretreatment data are required for more powerful conclusions. Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by partial deficiency of the lysosomal enzyme β-glucocerebrosidase, leading to accumulation of glucocerebroside in tissue macrophages, thereby mainly affecting the spleen, liver, and bone marrow . The disGBA1), but also by different genetic, epigenetic, and environmental factors [Gaucher disease has been traditionally divided into three clinical forms: type 1 (GD1), a chronic, non-neuronopathic form, defined by the absence of central nervous system (CNS) involvement (adult type); type 2 (GD2), an acute and invariably fatal neuronopathic form in infants/toddlers (infantile type); and type 3 (GD3), a sub-acute neuronopathic form (juvenile form) [ factors .In GD1, despite the genotype-phenotype correlations that have been reported and some relationship between a biomarker value and clinical severity that has been noted ,6, we arAt present, there are several formulations of enzyme replacement therapy (ERT), all administered intravenously, usually once every two weeks, and two compounds of oral substrate reduction therapy (SRT) . The magThe biomarkers that have been used until recently included the older and less specific ones such as angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP), serum ferritin, and high-density lipoprotein (HDL), and the newer, more specific, but still imperfect, ones, the chitotriosidase and CCL18. In a search for a more specific and sensitive biomarker, two groups independently identified glucosylsphingosine (lyso-Gb1) as a candidate biomarker, which has been confirmed to be 100% specific and 100% sensitive . The current study was designed to evaluate the impact of the three ERTs commercially available in Israel on lyso-Gb1 levels in patients with GD1 from a single center in Jerusalem according to disease severity and to examine possible differences between the formulations.In this longitudinal observational study, 135 patients  with GD1 were on ERT at the first observation time point over a median period of 51 months (range: 0–322 months) .Most patients (65%) had a milder version of GD1 according to the genotype (c.1226A>G homozygous or c.1604G heterozygous) and SSI . All patients were on the same ERT during the whole study period: most on velaglucerase alfa , 41 (19.2%) on imiglucerase, and 21 (15.6%) on taliglucerase alfa . PatientAssociations of lyso-Gb1 with patient characteristics at the first time point are presented in In all time points, lyso-Gb1 levels were higher for patients treated with imiglucerase than patients treated with velaglucerase alfa and taliglucerase alfa. However, a significant difference between velaglucerase alfa and imiglucerase was found only for the last three time points . The fasDuring the last decade, lyso-Gb1 has emerged as the most sensitive and specific biomarker for GD , outperfIn fact, we have recently confirmed that its reduction following the initiation of ERT precedes the improvement of hematological parameters (platelet counts) and organ volumes , and as such, it is capable of predicting response . While tIn the current study, we chose lyso-Gb1 measurements and compared, for the first time, the performance of the three enzymatic preparations currently commercially available in Israel . The three ERTs are not biosimilar; similarities and dissimilarities between imiglucerase, velaglucerase alfa, and taliglucerase alfa have already been presented . SpecifiIn a head-to-head randomized controlled study of naive GD patients, no patient receiving velaglucerase alfa developed antibodies, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross-reactive with velaglucerase alfa in one patient . The ratHeretofore no efficacy comparison beyond the first 12 months in the high-dose regimen  has beenSince July 2014, the Gaucher Unit at Shaare Zedek Medical Center has begun using lyso-Gb1 as the routine biomarker in all clinic visits. Until March 2020, a total of 3500 measurements  have been tested, of which 1017 were included in this study, i.e., samples of patients who have always been on the same ERT. Untreated patients, children, and those switching from one ERT to another or from ERT to SRT or the other way round were excluded to eliminate confounding factors.The first part of the analysis was a comparison of baseline lyso-Gb1 levels between patients’ groups based on their demographic (sex and age), their treatment , and their disease severity; the second set of statistical analyses was a comparison between the lyso-Gb1 values and overtime of a specific ERT product, adjusted for sex, disease severity and dosage. The association between the duration of therapy and lyso-Gb1 (higher levels among those patients treated for a shorter period) is self-explanatory, as the clearance of the storage glycolipids takes time . Age atA more interesting comparison, which is the primary rationale for the present study, is the lyso-Gb1 levels among the three ERTs. Those who believe that all ERTs are practically the same and even interchangeable may find support in the fact that the differences between the three enzymes were small. On the other hand, those who believe that velaglucerase alfa is somewhat better will appreciate the steeper and faster decreases of the lyso-Gb1 levels in velaglucerase alfa and the finding that the lyso-Gb1 levels at the last follow-up were lowest for velaglucerase alfa.The limitations of the study are related to the retrospective nature of the data, the lack of randomization, possible biases associated with the selection of patients’ population, systematic differences in patient groups, and the low number of patients with pre-treatment (before initiation of ERT) measures of lyso-Gb1. Especially in patients treated with imiglucerase and taliglucerase alfa, only few data of the beginning of treatment were available . In general, the different observation periods might yield imprecise estimates. While 135 subjects with a rare disease is a relatively high number, the uneven number of patients treated with each of the ERTs, the uneven number of patients with pre-treatment measurements, and the length of the follow-up may impact the results. Hence, more significant numbers and multicenter data will certainly lead to more powerful conclusions. As we do not foresee the chance of having a randomized study to answer this question, future studies will also need to rely on retrospective cohort data.All 135 adult patients (age > 18 years) with GD1 seen at the Gaucher Unit, Shaare Zedek Medical Center, from July 2014 till March 2020 who were ever treated with a single ERT were included in the study, and their demographic and clinical characteristics are presented in GBA1 sequencing from DNA extracted from whole blood or dry blood spots (DBS) samples. The definitions of mild versus severe phenotype were determined by genotype (N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous were categorized as “mild”, whereas all other genotypes as “severe”) and by the baseline severity score index (SSI) [Genotyping was done by whole 370S c.12A>G homozTesting of lyso-Gb1 was performed on DBS samples collected during routine visits. Lyso-Gb1 levels were performed at Centogene™ according to the previously described method .To report summary descriptive statistics, we used mean and standard deviation (SD) or median, interquartile range (IQR) for continuous variables, depending on the distribution. Additionally, we report the range of values as minimum and maximum. For nominal data, we report absolute and relative frequencies. Bivariate associations of different characteristics with lyso-Gb1 levels at first observation are reported as descriptive summary measures. Mann–Whitney U-Test and standardized mean difference (SMD) or Spearman rank correlation coefficient (ρ) were used for the association of two continuous variables. To assess differences in lyso-Gb1 over time and between treatments, linear mixed models with a random intercept for individuals were used. Lyso-Gb1 was log-transformed before the analysis to overcome the skewness of values. Models were adjusted for age at first observation, sex, SSI at the time of diagnosis , severity according to genotype (mild or severe), ERT dosage , and time on ERT.Additionally, an interaction term for time on ERT and type of ERT was included. To model the nonlinear relation between time on ERT and outcome, natural cubic splines were used for the time variable with two degrees of freedom. Marginal means of outcome values with 95% confidence intervals (CI) at different time points (time on ERT) and in different subgroups are reported and displayed graphically. Statistical analysis was done using SPSS version 26.0  and R 2. For staIn conclusion, our report adds to the value of lyso-Gb1 as a reliable biomarker for monitoring treated patients with GD1, in this case, with ERT. The statistical models used herein may be adopted in future studies to help physicians, patients, and regulatory agencies comparing the various ERTs with the new therapeutic modalities, such as the existing SRTs  or the


We previously developed a new surgical method, namely, single-port inflatable mediastinoscopy simultaneous laparoscopic-assisted radical esophagectomy. The purpose of this study was to evaluate the effect of carbon dioxide inflation on respiration and circulation using this approach.From April 2018 to October 2020, 105 patients underwent this novel surgical approach. The changes in respiratory and circulatory functions were reported when the mediastinal pressure and pneumoperitoneum pressure were 10 and 12 mmHg, respectively. Data on blood loss, operative time, and postoperative complications were also collected.2 elimination. Postoperative complications included anastomotic fistula (8.6%), pleural effusion that needed to be treated (8.6%), chylothorax (0.9%), pneumonia (7.6%), arrhythmia (3.8%) and postoperative hoarseness (18.2%). There were no cases of perioperative death.104 patients completed the operation successfully, except for 1 patient who was converted to thoracotomy because of intraoperative injury. During the operation, respectively, the heart rate, mean arterial pressure, central venous pressure, peak airway pressure, end-expiratory partial pressure of carbon dioxide and partial pressure of carbon dioxide increased in an admissibility range. The pH and oxygenation index decreased 1 h after inflation, but these values were all within a safe and acceptable range and restored to the baseline level after COWhen the inflation pressure in the mediastinum and abdomen was 10 mmHg and 12 mmHg, respectively, the inflation of carbon dioxide from single-port inflatable mediastinoscopy simultaneous laparoscopic-assisted radical esophagectomy did not cause serious changes in respiratory and circulatory function or increase perioperative complications. Esophageal cancer (EC) is one of the most common malignant tumors in the world, ranking seventh in global morbidity and sixth in mortality . The proThe approaches of MIE are transthoracic and non-transthoracic . Transhiatal esophagectomy (THE) is considered to be less invasive and has fewer pulmonary complications because it avoids thoracotomy . HoweverIn this procedure, we inflated the mediastinum and abdomen to provide a clear field of view for esophagectomy and mediastinal lymph node dissection. This operation, which is a relatively new surgical method, is not performed through the chest or one-lung ventilation and causes less damage to the lungs. Whether simultaneous inflation of the mediastinum and abdomen during surgery has a significant impact on the respiratory and circulatory systems has not been reported. The purpose of this study was to evaluate the perioperative safety of this procedure.From April 2018 to October 2020, patients with esophageal malignant tumors were treated with SPIMSLE in the Fifth Affiliated Hospital of Sun Yat-sen University. The inclusion criteria were as follows: (1) pathologically confirmed malignant tumor and The preoperative T stages were T1b-T3; (2) functional tolerance of major organs and systems for radical surgery; (3) no other cancers; (4) no history of mediastinal surgery; The exclusion criteria were as follows: (1) cervical EC;(2) refusal of surgery.This study was approved by the institutional review committee of our hospital. Written informed consent was obtained from each patient.Preoperative medication included intramuscular injection of atropine 0.01 mg/kg. Anesthesia was induced by intravenous injection of midazolam 0.05 mg/Kg, propofol 2 mg/kg, muscle relaxant cis atracurium 0.15 ~ 0.25 mg/kg and sufentanil citrate 0.1–0.3ug/Kg. Insert 7/7.5-FR single lumen catheter . Do not use bronchial blockers. Mechanical ventilation after intubation . Adjust the respiratory rate and do not use positive end-expiratory pressure. Anesthesia was maintained by continuous intravenous infusion of remifentanil 0.25 g–1.0 g/kg/min, while inhaling air, oxygen and sevoflurane. After operation, the tube was extubated after the recovery of pharynx reflex, inhalation and ventilation. All intubation procedures are performed by experienced anesthesiologists.The patients were ventilated with single-lumen endotracheal intubation under general anesthesia in the supine position; central venous pressure (CVP) was recorded by a central venous catheter in the right subclavian vein; and blood pressure was monitored by an indwelling arterial catheter in the right radial artery. As shown in Fig. 2) gas to create artificial mediastinal emphysema and obtaining a pressure of 10 mmHg. After we methodically tried various pressure gradients, when the mediastinal pressure was 10 mmHg, the operative field was clear, and the operative space was wide. Second, we continued to dissociate the upper and middle thoracic esophagus and dissected the lymph nodes in the thoracic region.The operation in the mediastinal group was performed as follows: first, access was gained through the cervical incision, and the cervical esophagus was freed, establishing a tunnel filled with carbon dioxide , inhaled oxygen concentration (FiO2) and tidal volume (TV) were continuously monitored and recorded during the operation. Arterial blood samples were collected for blood gas analysis at the following time points: 5 min before inflation of the mediastinum and abdomen (baseline); 1 h after inflation; 20 min after CO2 excretion; and 10 min after the operation. These data were collected from anesthetic records. At the same time, the operative duration, amount of bleeding, and A special event during the operation were recorded. Postoperative pathological data, postoperative complications, and postoperative hospital stay information were collected.Heart rate (HR), invasive mean arterial pressure (MAP), central venous pressure (CVP), peak airway pressure (AP), end-expiratory COP < 0.05, the result was considered significant.Continuous data are expressed as the mean ± standard deviation (SD). The classified data are expressed as a percentage. During the operation, taking the pre-inflation data as the reference, the Welch test was used to analyze the numerical difference in each period after inflation. All statistical analyses were conducted using IBM SPSS version 25 . When A total of 105 patients who underwent SPIMSLE from April 2018 to October 2020 were enrolled. The demographic and clinical characteristics of the 105 patients are summarized in Table 2O. The effect of tension pneumothorax on the operation could be avoided by suspending the operation for several minutes, properly reducing tidal volume and enlarging the scope of rupture. The average operative time was 186.7 ± 43.9 min, and the average intraoperative blood loss was 113.4 ± 89.9 ml. The field of view was clear during the operation, and the average number of lymph nodes dissected was 22.5 ± 4.5.There were no deaths within 30 days postoperatively. A total of 104 patients underwent SPIMSLE, and 1 patient underwent thoracotomy because of tracheal membrane injury during mediastinoscopy. Pleural rupture occurred in 5 cases, and the airway pressure increased immediately after pleural rupture, up to 4 cmH2 was inflated into the mediastinum and abdomen synchronously, as shown in Table 2 inflation were taken as the baseline, and there were significant differences in HR, MAP, CVP, Peak AP, ETCO2, PH, oxygenation index  and partial pressure of CO2 (PaCO2) after inflation.During the operation, the hemodynamics and respiratory movement indexes of 104 cases were monitored when COThe variations in hemodynamics after inflation are shown in Fig. 2, OI, PH, and PaCO2 are shown in Fig. 2O during inflation, with a mean increase of 7.4 cmH2O (P < 0.05) 5 min after inflation. The average ETCO2 of 6.2 cmH2O (P < 0.05) increased 5 min after inflation . The OI decreased sharply at 1 h after inflation, with an average decrease of 158.6, gradually returning to close to the baseline value after gas shutdown , stimulate the cardiovascular system, and cause an increase in arterial pressure [In this study, we inflated the mediastinum and abdomen at the same time to provide a clear surgical field of vision Fig. . Our avefunction , 28. Hyppressure . Secondlpressure .Fig. 4In2 was infused into the mediastinum with a mediastinal pressure of 10 mmHg and an intraperitoneal pressure of 12 mmHg. The HR, MAP and CVP increased significantly after inflation, but the values did not fluctuate and were within a safe and acceptable range during the inflation stage and gradually returned to the pre-inflation state after gas closure. No hypoxemia or respiratory inhibition was observed throughout the entire. After CO2 inflation, pH decreased, while PaCO2, peak AP and ETCO2 increased significantly after inflation, but these changes did not last long and returned to the normal level after the removal of CO2. Although PaCO2 increased significantly during the operation, the vital signs of most patients were stable, and there was no significant change in blood lactic acid levels, except for 2 patients who required adjustment in respiratory parameters to correct the elevated PaCO2. Currently, there is no clear definition of the acceptable elevation of PaCO2 in the clinic, so it is necessary to make a comprehensive judgment that also considers the vital signs of the patients. Although the OI decreased after inflation, it was still within a safe and acceptable range. With the deepening of the upper mediastinum and the lower mediastinum during the operation, the space of the operation was narrow, so it was necessary to control the effect of bilateral lung respiration on the mediastinal operation; moreover, the TV was artificially adjusted, so there was a significant difference between the TV at one hour after inflation and the baseline TV value. When dissociating the middle and lower esophagus during the operation, the lower mediastinal retractor should be used to lift the heart. In the study, 5 patients had hypotension or frequent premature ventricular contractions, which led to suspension of the operation. Notably, after waiting for a few minutes, the patients could continue the operation after their vital signs were stable. Therefore, when the mediastinal pressure and pneumoperitoneum pressure are 10 mmHg and 12 mmHg, respectively, this can provide a clear operative field and sufficient operating space, and the operation is safe under standard operation conditions.This study was a retrospective study of 104 patients who successfully completed SPIMSLE. During the operation, COMinimally invasive surgery should be the first choice for patients with EC. Compared with MIE via a transthoracic approach, THE is considered to be less invasive and more tolerable, especially in patients with severe complications , 30. HowIn this study, we successfully completed the operation in 104 patients, there was no perioperative death, and the postoperative pathology confirmed that the R0 resection rate was 100%. The incidence of postoperative anastomotic fistula was similar to that of MIE via the transthoracic approach (5.0 ~ 12%) . CompareWhen the inflation pressures in the mediastinum and abdomen were 10 mmHg and 12 mmHg, respectively, we safely completed surgery without respiratory and circulatory inhibition. In summary, our results show that our single-port inflatable mediastinoscopy with simultaneous laparoscopic radical resection of EC is technically safe and does not increase perioperative complications.