I2, 29.7%] and diastolic blood pressure  when compared with ACEIs or ARBs monotherapy, but with significantly increased the risk of hyperkalaemia  and kidney injury . Besides, there was no significant difference in the incidence of major cardiovascular events  between the combined therapy and ACEIs or ARBs monotherapy. In conclusion, this meta-analysis demonstrated that aliskiren in combination therapy with ACEs/ARBs could control BP effectively, but is associated with increasing risks of hyperkalaemia and kidney injury, and have no benefit in preventing of major cardiovascular events.The efficacy and safety of aliskiren combination therapy with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in patients with hypertension and cardiovascular disease remains attractive attention. We searched the Cochrane Central Register, the Clinical Trials Registry, EMBASE, MEDLINE and PubMed for relevant literatures up to January 2017. A total of 13 randomized controlled trials (RCTs) with 12222 patients were included in this study, and the combined results indicated that aliskiren in combination therapy with ACEIs or ARBs had remarkable effects in reducing systolic blood pressure (SBP) [weighted mean differences (WMD), -4.20; 95% confidential intervals (CI) -5.44 to -2.97;  Excessive renin-angiotensin-aldosterone system (RAAS) activity is a major underlying cause of many pathological states such as hypertension, heart failure, chronic renal failure and related cardiovascular disorders.  Because However, drugs fail to absolutely block RAAS activity with increasing the concentration of renin because they attenuate the negative feedback effect of Ang II on renin release, and such high renin levels will activate the (pro)renin receptor ((P)RR). Once activated, PRR is able to trigger the catalytic activation of the inflammatory and profibrotic prorenin/PRR/MAP kinase/ ERK 1/2 cascade. Consequently, ERK 1/2 activation results in an overexpression of the genes coding for several mediators of the mesangial cells proliferation and sclerosis, such as the transforming growth factor-β1 (TGF- β1), the plasminogen activator inhibitor-1 (PAI-1), fibronectin and collagen, which lead to the progression of renal damage and cardiovascular disorders along with Ang II generation, which is called “RAAS escape’”. Aliskiren, a direct renin inhibitor (DRI), has no effect on (pro)renin binding to its receptors, but blocks the most critical site of renin activation, which demonstrated as a considerable reduction in plasma rennin activity (PRA), and with PRA decreases significantly, Ang I, Ang II and aldosterone also decrease significantly,  which seIn the past several important large-scale trials of aliskiren therapy had been conducted to evaluate the potential cardiorenal effects on morbidity and mortality. The ALTITUDE trial suggested the addition of aliskiren to standard therapy with renin-angiotensin system blockades in patients with type 2 diabetes had no effect on cardiovascular and renal events, and it may even be harmful.  The ASTRThe previous meta-analysis provided discordant conclusions. Weir et al. and Zheng et al. suggested there was no statistically significant difference in hyperkalaemia between aliskiren combinatiom therapy and ACEIs or ARBs monotherapy in patients with essential hypertension. , 11 WhitConsidering these factors, it was thus necessary to conduct a new and comprehensive analysis including the latest published studies with large sample size.We enrolled 13 studies with 12222 patients in the present analysis evaluated the efficacy and safety of aliskiren in combination therapy with ACEs/ARBs in patients with hypertension and cardiovascular disease, and Figure I2, 29.7%) and DBP reduction  as described in Figure Six trials -19 involI2, 10.6 %). Among ten studies involved in hyperkalaemia, seven studies [Ten studies , 19-24 r studies , 20-24 e studies , 17, 19 I2, 0%). Among eight studies involved in kidney injury, five studies [Eight studies , 22-24 i studies , 22-24 e studies , 17, 19 I2, 0%).Five studies , 22, 23 I2, 10.6 %) and when the ATMOSPHERE study was excluded, there was no effects on the statistical significance. The Egger’s test and Begg’s funnel plot showed no evidence of publication bias for the primary outcomes and secondary outcomes.In our analysis, we performed a sensitivity analysis to seek for the source of heterogeneity. There was a significant effect on the result of the RR and 95% CI , and we have attempted to perform subgroup analysis to study the influence of disease types on the heterogeneity, we found that the heterogeneity would increase in both groups. Therefore we abruptly regard them as a study population in case of data loss and result bias.In analyses of Weir et al. White et al. and Zheng et al. enrolled patients with essential hypertension without cardiovascular disease or renal insufficiency at baseline, which might be representative of a lower-risk population. In contrast, Harel Z et al. included population with a broad range of baseline characteristics including lower-risk populations  and higher-risk populations . In our article, we included 13 trials with a total population of 12222 patients, and the study population consisted of hypertension and cardiovascular diseases (such as HF and coronary disease), as described in Table According to the results of our meta-analysis, aliskiren combination therapy could control BP effectively, but with increasing risks of hyperkalaemia and kidney injury. Compared to ACEIs/ARBs monotherapy, the dual blockade of aliskirien combination therapy cause the more significant decrease in aldosterone due to the more significant blockade of Ang II generation, which should not only account for the superior antihypertension effect, but also the increased incidence of hyperkalemia.Because the incidence of hyperkalaemia and kidney injury may be linked with the susceptible populations (high-risk populations), we stratified patients by their risk of hyperkalaemia and kidney injury into low and high risk groups and conducted subgroup analyses to discuss the effects of susceptible and non-susceptible populations. Aliskiren combination therapy did significantly increase the risk for hyperkalaemia in both groups but aliskiren combination therapy did not significantly increase the risk for kidney injury in low risk group but did significantly increase in high risk group when compared with ACEIs or ARBs. So we should take caution in combining aliskiren with an ACE inhibitor or an ARB, particularly in patients with heart disease, CKD and diabetes mellitus.Aliskiren has been shown to be effective in lowering BP and affect proteinuria, left ventricular mass index and brain natriuretic peptide (BNP) levels in patients with albuminuria, LVH and HF when in combination with ACEs/ARBs, , 28, 29 There are several limitations in our study. We didn’t analyze the effects of dosage, duration of treatment and other antihypertension drugs on the results. Therefore for future study, the role of treatment duration and dosage should be taken into consideration before evaluating clinical outcomes.In conclusion, this meta-analysis revealed that the use of aliskiren add-on therapy could control BP effectively but with increasing risk of hyperkalaemia and kidney injury, and have no benefits in preventing of cardiovascular events among patients with hypertension and cardiovascular disease prescribed conventional therapy with ACEIs or ARBs.We included studies that evaluated the efficacy and safety of aliskiren in combination therapy with ACEs/ARBs in patients with hypertension and heart failure (with a history of hypertension). In these articles, hyperkalaemia was defined as a serum potassium level of > 5.5 mmol/L, and 8 out of 13 studies reported this outcome related to “a serum Creatinine concentration > 2,0 mg/dl”, the span of study duration in the 8 studies is very large (varying from 8 weeks to 36 weeks), according to the KIDGO Clinical practice guideline, “a serum Creatinine concentration > 2,0 mg/dl” cannot defined as Acute Kidney Diease (AKD), Chronic Kidney Diease (CKD) or Acute Kidney Injury (AKI), so kidney injury was abruptly defined as serum creatinine concentration > 176.8 umol/L or 2.0 mg/dL, and major cardiovascular events consisted of acute myocardial infarction (AMI), stroke, resuscitated cardiac arrest, death from cardiovascular cause, and hospitalization for HF. The primary outcome was the antihypertensive effects, and the secondary outcomes were the risks of hyperkalaemia, kidney injury and major cardiovascular events.We searched the Cochrane Central Register, the Clinical Trials Registry, EMBASE, MEDLINE and PubMed for relevant literatures to Juanary 2017. Keywords include aliskiren or renin inhibitor or RAAS, hypertension, randomized controlled trial or RCT. Besides we reviewed the related research references.The inclusion criteria were as follows: (a) adults with hypertension and cardiovascular disease, (b) the study design should be a RCT, (c) the study described the efficacy and safety of aliskiren combination with either ACEIs or ARBs relative to an ACEI or ARB monotherapy that provided exact value on BP reduction, or the incidence of hyperkalaemia, kidney injury or cardiovascular outcomes, (d) complete data available to calculate relative ratio (RR) or weighted difference (WMD) with 95% confidence interval (CI), and (e) all dosing regimens of aliskiren, ACEIs or ARBs were considered. Exclusion criteria were as follows: (a) data from the studies could not be extracted and analyzed, (b) duplicate publications, and (c) non-human experimental studies.Three investigators  independently performed the study selection. All the disagreements were resolved by discussion. We extracted the following data from each article: first author or study group name, year of publication, number of patients, study duration, the proportion of diabetes, the Mean and standard deviation (SD) value in systolic blood pressure (SBP) and diastolic blood pressure (DBP) reduction, the occurrence rate of hyperkalaemia, kidney injury or major cardiovascular outcomes.The risk of bias assessment tool by the Cochrane Collaboration was applied specifying the following bias domains: selection, performance, attrition, reporting bias and a judgment of low risk, unclear risk, or high risk was provided for each domain. I2 tests. A random-effect model was used when Q-test exhibits a P < 0.05 or I2 test shows > 50%; otherwise, the fixed-effect model was selected. We performed subgroup analyses to assess for clinical heterogeneity stemming from the disease states, and we stratified patients by their risk of hyperkalemia and kidney injury into low and high risk groups, low risk was defined as patient without CKD, CAD, HF or diabetes mellitus. Inversely in high risk. Sensitivity analyses were conducted in the meta-analysis to examine the influence of an individual study. Publication bias was assessed by constructing a funnel plot and using Egger’s and Begg’s tests. A significant two-way P value for comparison was defined as P < 0.05.Statistical analysis was performed by Review Manager (version 5.3) and STATA statistical software (version 12.0). The adjusted estimated effects expressed as WMD or RR with 95% CI were calculated for continuous and dichotomous data, respectively, and summarized by Forest plots. Heterogeneity among studies was estimated by Cochrane’s Q-statistic and


Gallstones and kidney stones are known complications of inflammatory bowel diseases (IBD). Risk factors have been insufficiently studied and explanatory studies date back up to 30 years. It remains unclear, whether improved treatment options also influenced risk factors for these complications.Identifying risk factors for gallstones and kidney stones in IBD patients.Using data from the Swiss Inflammatory Bowel Disease Cohort Study we assessed associations of diseases characteristics with gallstones and kidney stones in univariate and multivariate logistic regression analyses.Out of 2323 IBD patients, 104 (7.8%) Crohn’s disease (CD) and 38 (3.8%) ulcerative colitis (UC) patients were diagnosed with gallstones. Significant risk factors for gallstones were diagnosis of CD, age at diagnosis, disease activity and duration, NSAID intake, extra-intestinal manifestations and intestinal surgery. Kidney stones were described in 61 (4.6%) CD and 30 (3.0%) UC patients. Male gender, disease activity, intestinal surgery, NSAID usage and reduced physical activity were significant risk factors. Hospitalization was associated with gallstones and kidney stones. The presence of gallstones increased the risk for kidney stones .The diagnosis of CD, intestinal surgery, prolonged NSAID use, disease activity and duration and bowel stenosis were significantly associated with cholecystonephrolithiasis in IBD. Inflammatory bowel diseases (IBD) comprise chronic inflammatory diseases of the gastrointestinal tract (GIT), including Crohn’s disease (CD), ulcerative colitis (UC) and indeterminate colitis (IC). The diseases are associated with lifelong morbidity and increased mortality , 2.Frequently, patients suffer from extraintestinal complications of IBD. An increased risk of gallstone disease in CD patients is well established –9. A recRenal involvement is also considered an extraintestinal complication of IBD and typical manifestations include nephrolithiasis, tubulointerstitial nephritis, glomerulonephritis and amyloidosis . Kidney However, patient data for gallstones and kidney stones are limited and studies were insufficiently powered to detect potentially relevant risk factors. In addition, many relevant studies date back up to 50 years , 18. ConThe identification of risk factors for gallstones and nephrolithiasis remains an important task to prevent complications and identify patients who would benefit from potentially protective interventions. We therefore aimed to assess risk factors using data from the Swiss IBD cohort study, a large prospective cohort of well-characterized patients.We provide a comprehensive analysis of risk factors for gallstones and kidney stones, potentially enabling prophylactic interventions.Data were retrieved from the nationwide Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS). The SIBDCS is a multicenter prospective observational population-based study and includes patients with IBD from Switzerland. The study was extended to all regions of Switzerland in 2006 in a multidisciplinary effort by gastroenterologists, pathologists, psychologists and bioinformatics specialists. The cohort study is funded by the Swiss National Science Foundation (SNF). For inclusion in the study, all patients must have a diagnosis established at least 4 months prior to inclusion. Data are prospectively collected once a year and entered into a central database .Epidemiological characteristics: diagnosis of CD or UC, disease duration (years), gender, age at diagnosis and body mass index (BMI), physical activity. 77 patients with indeterminate colitis (IC) were excluded. If not indicated otherwise, patients with CD were considered as a single entity and patients with Crohn’s colitis and Crohn’s ileitis were not distinguished. 2) Disease characteristics: activity index, disease location, extra-intestinal manifestations (EIM), existence of stenosis, fistula, fissure and abscess, intestinal surgery. 3) Selected co-medications: steroids, non-steroidal anti-inflammatory drugs (NSAID).Using the exclusive patient collective of the SIBDCS we evaluated complications in IBD patients and assessed potential associations with specific diseases characteristics. Univariate and multivariate logistic regression analyses were performed, each time with a complication as response. The following possible explanatory variables were considered: 1) To assess disease activity and allow comparison between UC  and CD , disease activity measures were normalized to a value between 0 and 100 and expressed as an activity index. For a diagnosis of gallstones, or kidney stones all appropriate diagnostic modalities including abdominal ultrasound or CT scan, MRI, X-ray or surgical examination upon cholecystectomy would be considered. The cohort design did not permit assessment of exact imaging modalities leading to diagnosis and symptom status at diagnosis.Whenever possible, the disease characteristics immediately preceding the diagnosis of gallstones were used. Patients with missing values in relevant variables were excluded.For a secondary analysis, we performed univariate and multivariate logistic regressions with gallstones or nephrolithiasis as response and specific surgical procedures as explanatory variables. Finally, we tested for a dependency between hospitalization and the existence of gallstones/kidney stones.In order to build a multivariate logistic regression model, we first performed univariate regressions with each factor mentioned in The IBD cohort study has been approved by all ethics committees in Switzerland  All patients signed an informed consent and confirmed their participation in the cohort study at the time of enrollment and gave informed consent for data collection and analysis for research purposes. The current substudy has been evaluated and approved by the scientific board of SIBDCS.For our analysis a group of 2323 IBD patients was considered of whom 1333 (55.4%) suffered from CD and 999 (42.6%) from UC. Basic epidemiological variables and distribution of possible risk factors for complications are presented in Gallstones were reported in 104 patients with CD (7.8%) and 38 patients with UC (3.8%). In the univariate analysis the diagnosis of CD was significantly associated with gallstones. Higher disease activity, long disease duration, existence of stenosis, intestinal surgery and usage of NSAID, as well as epidemiological characteristics like age, were also significantly related to the presence of gallstones .Multivariate logistic regression analysis confirmed the association of seven risk factors with gallstones: diagnosis of CD, age at diagnosis, disease duration, intestinal surgery, EIM, NSAID intake and disease activity . For disWhen patients with CD and UC were considered separately  Tables, Kidney stones were reported in 92 patients, 61 patients with CD (4.6%) and 30 patients with UC (3.0%). According to univariate regression analysis  a diagnoUsing all variables for calculation of a multivariate logistic regression model, five risk factors  remained significant .When patients with CD and UC were considered separately, male gender and disease activity were significant risk factors in both diseases. In CD patients, intestinal surgery and physical activity were additional risk factors; in UC patients NSAID usage was a predictive factor for nephrolithiasis  Tables.Intestinal surgery was performed in 561 patients with CD and 99 UC patients . In CD, After adjustment for risk factors from the multivariate model , right colectomy was a significant risk in CD patients .In CD patients, nephrolithiasis was associated with surgery of the small intestine, subtotal and right colectomy and with colostomy and ileostomy . After aThe occurrence of gallstones and kidney stones were significantly correlated. The presence of gallstones or kidney stones increased the risk for the other complication by an OR of 4.87, 95% CI: 2.8–8.0, p<0.001).Hospitalization was a risk factor for gallstones: 52 out of 148 patients (35.1%) with a hospitalization during the last 12 months vs. 96 out of 2323 patients (4.1%) without a hospitalization had a diagnosis of gallstones  . This efKidney stones were also more prevalent in patients with a previous hospitalization and 36 out of 136 patients (26.5%) with a hospitalization vs. 55 out of 2132 patients (2.5%) without a previous hospitalization had a diagnosis of kidney stones  . This diWe provide a comprehensive analysis of risk factors for gallstones and kidney stones in a large cohort of Swiss IBD patients. Gallstones were associated with diagnosis of CD, age at diagnosis, disease duration and activity, past intestinal surgery, EIM and NSAID intake with strong statistical significance. Kidney stones shared most of these risk factors including disease activity, intestinal surgery and NSAID intake but also showed association with male gender and reduced physical activity.In the literature there is general agreement that CD patients have an increased risk of gallstones –10. Past561 out of 1339 CD patients underwent intestinal surgery and detailed information regarding surgical procedures was available. Ileostomy was associated with a strong risk for gallstones. Most major surgical procedures of the colon and the ileum were also associated with gallstones while other smaller procedures (stricturoplasty) were not. Past work demonstrated length of the resected small intestine [In contrast to CD, less information for UC and gallstone is available. While a recent meta-analysis concluded that the risk of gallstones for UC was not significantly elevated , a few single studies demonstrated an increased risk for gallstones in UC , 20 withSeveral mechanisms explaining an increased risk for gallstones in IBD have been proposed: i) Bile acid malabsorption in enterohepatic circulation after ileal disease or resection would lead to cholesterol supersaturated bile , 23. HowOxalobacter fromigenes was associated with hyperoxaluria and kidney stones in IBD patients [Nephrolithiasis results from urine supersaturation of some components including oxalate or urate. Therefore, low urine volume, low urine pH (resulting in urate precipitation), low urine citrate or magnesium concentration (which can act as inhibitors of stone formation) and high urine oxalate levels increase the risk for kidney stones . Variouspatients .Risk factors for kidney stones in the general population include: male gender, high BMI, diabetes mellitus, gout and low socioeconomic status . HoweverIn our study, intestinal surgery increases the incidence for kidney stones. We provide an estimated risk of various surgical procedures with the highest risk attributable to ileo/ileo-caecal resection in CD . In KnudNSAID as a standard medication for symptomatic kidney stones  have notOur finding of lack of physical activity as a risk factor regarding kidney stones is interesting since a sedentary life style has also been described as a risk factor in some  but not Our data show an overlap of the risk of gallstones and kidney stones. This is in line with data from large epidemiological studies. In multivariate analyses accounting for risk factors such as age, diet and BMI an OR for kidney stones of patients with gallstones was 1.61–1.85 and vice versa the risk of gallstones in patients with a history of kidney stones was 1.17–1.51 .Current guidelines do not recommend specific preventive measures regarding nephrolithiasis or gallstones. However, identification of high-risk patients for gallstones and kidney stones seems to be important in prevention. Strategies to lower the risk of kidney stones include a low oxalate diet, substitution of medium chain fatty acids and an increase in fluid intake . PatientStrengths of our study include the large number of patients and the high level of detailed information available for each patient allowing for testing and controlling several potential risk factors for all complications. Important limitations of our study include: i) We did not systematically test all individuals included in the SWISS IBD cohort for gallstones or kidney stones by ultrasound screening. This represents considerable bias, as several clinically silent cases would have been missed and the frequency of gallstones and kidney stones in our cohort is lower than in other IBD cohorts. ii) Because of a lack of a control group of individuals without IBD the absolute risk for gallstones and kidney stones attributable to IBD remains unknown. iii) Our study is not strictly population based. The Swiss IBD cohort study collects data from patients followed in private practice as well as in large hospitals; however, tertiary care centres are slightly over-represented, potentially affecting our conclusions. iv) Complications and symptoms of gallstones and kidney stones were not recorded in our database. Therefore, we cannot distinguish between incidental observations and relevant conditions for both diseases.In conclusion, our study identifies and confirms specific risk factors in IBD patients for gallstones and kidney stones. Most of these parameters are related to severe disease of long duration as well as intestinal surgery. Our study thus points out characteristics of high-risk patients, which might benefit from preventive strategies.S1 STROBE Checklist(DOC)Click here for additional data file.S1 TableCD: Crohn`s disease; EIM: Extraintestinal manifestation; CDAI: Crohn`s disease activity index.(DOCX)Click here for additional data file.S2 TableUC: Ulcerative colitis; NSAID: Non-steroidal anti-inflammatory drugs; MTWAI: Modified truelove and witts activity index.(DOCX)Click here for additional data file.S3 TableCD: Crohn`s disease; CDAI: Crohn`s disease activity index.(DOCX)Click here for additional data file.S4 TableUC: Ulcerative colitis; NSAID: Non-steroidal anti-inflammatory drugs; MTWAI: Modified truelove and witts activity index.(DOCX)Click here for additional data file.S5 TableOR: 12.63 ; Subgroup analysis; CD patients: OR 9.85 ; UC patients: OR 19.42 .(DOCX)Click here for additional data file.S6 TableOR: 13.90 . Subgroup analysis; CD patients: OR 13.40 ; UC patients: OR 13.96 (DOCX)Click here for additional data file.


P > 0.05). Vessel density in each subregion did not change either. If only enrolled eyes with IOP rise ≥10 mmHg, similar results were obtained in condition of IOP increase by 15.0 ± 3.6 mmHg. To conclude, eyes with an acute IOP elevation by 10 or 15 mmHg for two hours, while the blood pressure remained constant, the vessel density in both ONH and macula region examined by OCTA did not show significant changes. The observations fit with an IOP-related autoregulation in retinal blood flow for a moderate elevation of IOP.To investigate changes in retinal vessel density in optic nerve head (ONH) and macula after acute intraocular pressure (IOP) elevation, we conducted a prospective observational study. Eyes with IOP rise ≥5 mmHg after 2-hour dark room prone provocative test (DRPPT) were included. Vasculature of ONH and macula was examined by optical coherence tomography angiography (OCTA) at baseline and after DRPPT. Among the 65 eyes of 42 individuals, 40 eyes with qualified images were enrolled. Mean IOP rise was 9.6 ± 4.2 mmHg (5.0–23.3 mmHg) after DRPPT. Retinal vessel density did not differ after IOP rise for either the papillary region  or the macula region  ( Correspondingly, marked elevation of IOP to suprasystolic levels leads to a stop of retinal blood circulation and a temporary central retinal artery occlusion. Investigations revealed that a moderate elevation in IOP or moderate changes in blood pressure did not markedly affect the retinal blood circulation, a phenomenon which was called retinal autoregulation9. Studies suggested that the retinal autoregulation may be impeded in open-angle glaucoma fitting with the notion of a vascular element in the pathogenesis of glaucomatous optic neuropathy14.The blood perfusion of the optic nerve head (ONH) and retina depends on the local arterial blood pressure and the intraocular pressure (IOP) as counter-pressure against the arterial blood pressure. Subsequently, the mean ocular perfusion pressure has been defined as the difference of 2/3 of the mean blood pressure minus IOP, with mean blood pressure calculated as diastolic blood pressure +1/3 of the blood pressure amplitude 18. All these techniques had disadvantages such as limitations in spatial resolution, relatively low validity, or only indirectly assessing parameters of blood flow, to mention a few. Split-spectrum amplitude-decorrelation angiography (SSADA) associated with optical coherence tomography angiography (OCTA) is a new method that can visualize the vascular networks in separate layers of the retina in the macular region and in the ONH21. Recent studies confirmed a high intra-visit repeatability and inter-visit reproducibility of the measurements taken with OCTA, a high spatial resolution of the images, and the possibility of the OCTA technique to assess for the first time the retinal blood circulation system at different levels of the retina and ONH22. In view of these new technical possibilities, we conducted the present study to re-assess the relationship between the blood circulation in the retina and optic nerve in eyes at a normal IOP and at an elevated level of IOP. In contrast to previous investigations in which artificial means, such as a suction cup, were applied to increase the IOP, we used the physiological model of IOP elevation by performing a dark room provocative test25.In the previous investigations, the retinal blood perfusion was examined applying techniques such as fluorescein angiography, confocal scanning laser ophthalmoscopic angiography with fluorescein dye, color Doppler imaging, Canon laser blood flowmetry, scanning laser Doppler flowmetry, and retinal photographic oximetryThe prospective comparative study included all individuals who routinely and consecutively underwent a dark room prone provocative test (DRPPT) from November 2015 through January 2016 and who showed an elevation in IOP of more than 5 mmHg during the DRPPT. The Ethical Review Committee of the Beijing Tongren Hospital approved the study and confirmed its adherence to the provisions of the Declaration of Helsinki for research involving human subjects. Informed consent was obtained from each participant after providing an explanation of the nature and possible consequences of the study. Exclusion criteria were an age <18 years, any optic nerve disease including glaucomatous optic neuropathy, any eye disease that might affect the quality of fundus images, and difficulties in fixation.24. Shortly before the test and at one and two hours after the start of the test, IOP was measured by noncontact tonometry . All tonometric measurements were performed three times, and the mean value of the three measurements was used for further statistical analysis. Before the start of the DRPPT and within 5 minutes after the end of the test, the vasculature of ONH and macula was visualized by OCTA. We used the RTVue XR Avanti device  with the Angio Retina mode (3 × 3 mm2) and the Angio Disc (4.5 × 4.5 mm2) mode. Ocular biometry  was additionally carried out after the DRPPT.The DRPPT has routinely been performed in the Beijing Tongren Hospital for the examination of individuals suspected for acute primary angle closure, which was defined as patients with narrow but not occluded anterior angles but otherwise normal. The details of the test were described previouslyCriteria for inclusion into the study were an IOP rise during the DRPPT of ≥5 mmHg and the availability of OCT angiographic images of sufficient quality. Insufficient quality of the OCT angiographic images was defined by a signal strength index lower than 50 or by an obvious offset deviation Fig. . The exa2) were composed of the measurement at the ONH layer and measurement at the radial peripapillary capillary (RPC) layer, which extended from the inner limiting membrane to 150 μm below the inner limiting membrane, and from the upper boundary of the inner limiting membrane to the lower boundary of the nerve fiber layer, respectively. The measurement of capillary density in the macula region (3 × 3 mm2) were composed of the density at the superficial retinal layer, the deep retinal layer, and the outer retinal layer, which extended from approximately 3 μm below the inner limiting membrane to 15 μm below the inner plexiform layer, from 15 μm below the inner plexiform layer to 70 μm below the inner plexiform layer, and from 70 μm below the inner plexiform layer to 30 μm below the retina pigment epithelium layer, respectively19. The optic disc region was divided into an intrapapillary region and six peripapillary regions, while the macula region was divided into a fovea region and four parafoveal areas .P-values were based on 2-sided tests and considered statistically significant if less than 0.05.Statistical analysis was performed using a statistical software package . Measurements obtained before and after the DRPPT were compared with each other using the paired Student t test. All measurements were described as mean ± standard error. All The study included 65 eyes of 42 individuals suspect for occludable angles with otherwise normal eyes, who showed an IOP rise ≥5 mmHg after the dark room prone provocative test (DRPPT). There were 32 women and 10 men included with age of 56.4 ± 9.2 years (range: 41 to 76 years). The IOP increased from 17.3 ± 3.5 mmHg to 26.9 ± 6.4 mmHg, with the mean rise of 9.7 ± 5.4 mmHg.After excluding the OCTA images with insufficient quality defined by a signal strength index lower than 50 (6 eyes) and those with obvious offset deviations (9 eyes), a total of 40 eyes of 29 individuals (21 women) were included in the final analysis. The mean age was 55.2 ± 7.2 years (range: 42–69 years) and mean axial length was 22.9 ± 1.1 mm (range: 21.2–25.5 mm). The mean anterior chamber depth was 2.1 ± 0.3 mm (range: 1.5–2.8) and mean lens thickness was 4.7 ± 0.3 mm (range: 3.9–5.3 mm). The IOP increased from 17.2 ± 2.9 mmHg (range: 10–26 mmHg) at baseline to 26.4 ± 5.6 mmHg (range: 19–49 mmHg) at the end of DRPPT, with a mean rise of 9.6 ± 4.2 mmHg (range: 5.0–23.3 mmHg).P = 0.14) or at the RPC layer   , vessel density in the papillary area and the macula area did not change significantly during the test period  for a duration of two hours. The findings support the notion of an autoregulation of the blood flow in the ONH and in the macula during a rise in IOP ranging between 10 mmHg and 26 mmHg for a period of two hours. To our knowledge, this is the first time that the autoregulation was observed in human retinal microcirculation in condition of natural IOP elevation.29. Riva CE and colleagues found that the blood flow in the optic nerve region remained constant down to a perfusion pressure of approximately 22 mmHg by suction cup3. In a recent study by Schmidl and colleagues, the authors observed a wide inter-individual variability of the response of the ONH blood flow to a change in ocular perfusion pressure in healthy subjects and identified a subgroup of individuals with abnormal autoregulation of the ONH blood flow6. In an investigation by Boltz and coworkers, the regulation of the ONH blood flow using laser Doppler flowmetry was examined during a separate increase in IOP by the suction method and increase in arterial pressure by an isometric exercise26. During the handgrip-induced increase in ocular perfusion pressure by approximately 15 mmHg ONH blood flow did not change, indicating that the blood flow of the ONH vasculature reduced potentially by vasoconstriction. Conway and coworkers assessed the blood flow responses before and after application of a microkeratome for refractive corneal surgery27. After elevating the IOP to a level of higher than 85 mmHg for 90 seconds in 10 eyes, no difference in ocular-perfusion measurements were detected by color Doppler imaging and the Heidelberg retinal flowmeter between the baseline measurements and the readings obtained shortly after the IOP elevation. It was appropriate for quantitative defining the blood flow in larger vessels with Doppler technique, but not accurate in the capillaries. Comparing with OCTA, the laser Doppler flowmetry, and the laser speckle flowgraphy can only observe within a limited area of the retina, and the inter-visit variability was reported to be not ideal, with 12.8% and 6.6% to 21.2%, for the laser speckle flowgraphy and for the laser Doppler flowmetry, respectively31.The results obtained in our study were consistent with the findings that the autoregulation of the blood flow reported in previous studies on retinal autoregulation mainly based on the techniques of the laser Doppler flowmetry32. Zéboulon and colleagues observed the retinal vessel density one month after surgically induced IOP lowering of 44.2 ± 4.8% in 21 eyes out of 21 glaucoma patients however didn’t find distinct changes comparing with baseline parameters33. Shin JW found an improvement in peripapillary retinal microcirculation in glaucoma patients 3 months after trabeculectomy. The difference in the results may perhaps be associated with the level of the IOP change, the methods of IOP decrease, age of patients, and the level of glaucomatous damage. It will be interesting to compare the microvascular changes between glaucoma patients and normal in the same study settings, thus to furtherly investigate the vascular factors of glaucoma pathogenesis34.Recently there were several studies showing the vessel density change after IOP decrease quantified by OCTA. Holló G found that the peripapillary angioflow density increased at 2 to 4 weeks after medical reduction of IOP of more than 50% in 6 eyes of 4 glaucoma patients38. Using OCT based microangiography, Zhi and colleagues examined the retinal capillary filling in rats with an acutely elevated IOP35. They observed that the retinal blood flow diminished linearly with increasing IOP when the increase in IOP was 30 mmHg to 100 mmHg. Wang et al. found that the ONH blood flow remained at a constant level within a range of ocular perfusion pressure of 41 mm Hg and above, with IOP elevation by laser treatment to the trabecular meshwork in monkeys36. Shibata et al. showed that ONH blood flow in l-2-aminoadipic acid injected rabbit eyes was significantly decreased with a reduction of OPP during IOP elevation to 50 and 70 mm Hg37.Animal studies have also focused on the blood flow regulation in normal and experimental glaucoma39. With the unique pattern and distribution of the vessels, RPC were thought to be vulnerable to the increase in IOP comparing with other retinal capillaries, thus possibly be involved in the pathogenesis of glaucoma41. According to our study, the blood flow remained unchanged in the RPC layer after moderate IOP rise in 2 hours, showing similar regulation resisting pressure with other layers in the retina. It is speculated that the potential link between the RPC and glaucoma does not necessarily lie in its susceptibility to the IOP.The RPC is a superficial layer of capillaries with relative constant caliber, paralleling with the retinal nerve fiber layer in the peripapillary region. One of its functions is likely to play a role in supplying nutrition to the retinal ganglion cells25.The mostly unchanged blood flow in the macular region of the retina and in the ONH region at different IOP levels contrasts with a IOP rise related morphological changes in the choroid and the ONH. Previous studies revealed that eyes with an IOP rise in the DRPPT showed a IOP-rise dependent thinning of the choroid, a thinning of the neuroretinal rim, in particular at the temporal border of the optic disc, a centrifugal shift of the retinal pigment epithelium on parapapillary Bruch’s membrane, and a condensation of the tissue covering the lamina cribrosa at the bottom of the optic cup22. Fifth, since an abnormal autoregulation of retinal blood flow in open angle glaucoma was suggested in several studies14, it is important to compare the present results with glaucoma patients. Further work should be applied. A strength of our study is the application of OCTA as a new technique, the use of a physiological model of elevation of IOP, and the assessment of the blood flow in the macular region in addition to the blood flow characteristics in the ONH region.Limitations of our study should be discussed. First, arterial blood pressure was not measured in the specific 42 participants of our study. However, another group of 55 randomly-selected patients with similar settings showed that with acute IOP rise after the 2-hour-DRPPT, both the systolic and the diastolic blood pressure didn’t change from baseline of the test. Second, our study included only a selected group of individuals who were at risk for a rise in IOP provoked by the dark room test. It has remained open, whether the results of our study can be generalized to any individual. Third, absence of prove is no prove of absence, so that potential differences between the measurements might have become statistically significant if the number of study participants had been increased. The differences between the measurements taken at baseline of the DRPPT and at the end of the test were however usually less 1% of the mean, and for the comparison of 12 parameters, measurements obtained at baseline of the test were higher than the measurements taken at the end of the DRPPT, and for the comparison of 15 parameters, the readings taken at the end of the test were higher than the measurements obtained at the start of the DRPPT (Tables In conclusion, healthy eyes with an acute and physiologic IOP elevation of 10 mmHg or 15 mmHg for two hours did not show significant changes in the capillary vessel density both of the ONH and macula as examined by OCTA, supporting the notion of an IOP-related autoregulation of the blood circulation system of the ONH and retina for a moderate elevation of IOP for a period of 2 hours.


Blood pressure variability (BPV) is associated with the development and progression of severe target organ damage (TOD). This study aims to evaluate the protective effect of paeoniflorin enriched extract from Radix Paeoniae Alba (PG) on BPV and TOD in spontaneously hypertensive rats (SHR). All SHR were orally treated with distilled water, metoprolol , and PG  for a single time or daily for 7 weeks. The 24-hour dynamic blood pressure was monitored and then calculated BPV including long- and short-term systolic blood pressure variability (SBPV), diastolic blood pressure variability (DBPV), mean blood pressure variability (MBPV), and heart rate variability (HRV) as well as the 24-hour-SBP, 24-hour-DBP, and 24-hour-MBP. The protective effects of PG on TOD were observed by histopathologic and biochemical detection. The results indicated that long- and short-term SBPV, DBPV, MBPV, and HRV as well as 24-hour-SBP, 24-hour-DBP, and 24-hour-MBP showed no significant changes after single-dose administration of PG and significantly decreased after administration with PG for 7 weeks. PG could also markedly improve the damage of aorta, heart, kidney, and brain. This study suggested that PG could notably reduce BPV, stabilize blood pressure, and mitigate TOD in SHR. Hypertension is one of the most popular risk factors affecting cardiovascular disease. Blood pressure (BP) sustaining high systolic pressure ≥140 mmHg or diastolic pressure ≥90 mmHg may be defined as hypertension . About 2BPV is associated with the development and progression of severe target organ lesion of the brain, heart, kidney, and vessels, together with increased risk of cardiovascular disease and increased mortality. Thus, the treatment of hypertension should aim not only at decreasing BP but also at reducing BPV . In receRadix Paeoniae Alba (RPA), with paeoniflorin as principal bioactive component, is a traditional Chinese medicine that lowers blood pressure and exhibits anti-inflammatory and antioxidative properties, among others . An incrIn our previous study, we evaluated the potential of paeoniflorin enriched extract from Radix Paeoniae Alba (PG) as an antihypertensive agent in spontaneous hypertensive rats (SHR) , 16. We Male spontaneously hypertensive rats (SHR) (forty-eight weeks old) were all purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., and the licenses numbers of experimental animal were SCXK (Jing) 2012-0001. All procedures were performed according to protocols following the guidelines for the Use and Care of Laboratory Animals published by the Zhejiang province (2009).Paeoniflorin enriched extract from Radix Paeoniae Alba (PG) was obtained from Zelang Medical Technology Co.  and the purity was 53% detected by HPLC analysis . Metoproμm membrane filter before put into the system. The Agilent HPLC1200  was used to determinate the content of paeoniflorin in extracts by C18 column (250 mm × 4.5 mm). The mobile phases were composed of acetic acid and phosphoric acid solution , and solvent flow rate was 1 ml/min at column temperature of 25°C. The injection volume was 5 μl. The photodiode array detector was set at 230 nm with a total runtime of 20 min. The HPLC chromatogram of extracts was showed in Paeoniflorin enriched extract from Radix Paeoniae Alba (PG) was analyzed with HPLC-DAD. The analysis could simply describe that PG sample was diluted with methanol and filtered through a 0.22 Postoperative recovery for one week, selecting three successful surgical SHR, randomly was used for the experiment, based on 24 h dynamic blood pressure (data were not shown). Rats were sequentially given water , metoprolol , and PG  every 24 hours according to body weight.After administration, implantable telemetry technology  collected 24-hour blood pressure (BP) immediately, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MBP). Long-term BPV  was defined as dividing 24-hour BP into 48 sections, each section for 30 min, and calculated the standard deviation of 48 average values, and the short-term BPV  was defined as the average values of the 48 sections. The long- and short-term heart variability (HRV) were calculated with the same way the long- and short -term BPV, respectively.The operation was carried out following the procedures presented in literature , 18. FirSHR were randomly assigned to four groups of eight rats each following as model group (MG), metoprolol positive group , PG high dose group , and PG low dose group , based on SBP (data were not shown). Model group was given water, while others were given corresponding drugs according to body weight daily for seven weeks.With postoperative recovery for 24 hours, level-headed sober animals dynamic blood pressure analysis system  recorded 24-hour BP, including SBP, DBP, and MBP. The computing method of long- and short-term SBPV, MBPV, DBPV, and HRV was the same to former part.The operation was carried out following the procedure presented in literature . FirstlyAfter administration for six weeks, SHR were fasted overnight; then 1.25 ml blood was obtained from ophthalmic venous plexus. Blood were water-bathed for 2 hours at 37°C and centrifuged at 3500 rpm for 10 min. The serum was separated to detect the biochemical indexes of BUN, Cr, and UA by TBA-40FR automatic clinical chemistry analyzer .μm thickness  and stained by hematoxylin-and-eosin (H&E). In addition, the specimens of aorta, heart, and kidney were also used for Masson's trichrome staining. For immunohistochemistry (IHC), Mouse and Rabbit Specific HRP/DAB (ABC) Detection IHC kit was used for the development of reaction of eNOS in aorta, as well as COX-2 in heart and kidney, and tissues were counterstained with hematoxylin. Histopathology observation was used with biological microscope B5-223IEP (Germany).Meanwhile, aorta, heart, kidney, and brain were put into 4% formalin for fixation. Then, the organs were cut into applicable slice and went through washing and dehydration and embedded to make of tissue wax chunks . All the specimens were cut into 4 t-test. When compared with the model group before treatment, the data were subjected to paired-sample t-tests. When compared with the same period of the model group, the data were subjected to independent-sample t-tests. P value of <0.05 was considered statistically significant. All analyses were performed by using an updated version of SPSS 15.0 software.All data were expressed as the mean ± standard deviation and subjected to P < 0.05 and 0.01), and PG 90 mg/kg exhibited significant influence on SBP at the time of 0.5 h (P < 0.05) . As a result, metoprolol 20 mg/kg could decrease SBP, DBP, and MBP at the time of 0.5, 1, and 2 h, compared with the model group before treatment , while PG had no visible influence on long- and short-term of SBPV, DBPV, MBPV, and HRV , and PG 30 mg/kg could also remarkably decrease 24-hour total SBP and MBP (P < 0.05), compared with the model group  were provided with the high stability of BP obviously Figures . The dat Figures .P < 0.01), as well as the short-term blood pressure variability of SBPV, DBPV, and MBPV    . However < 0.01)  and lumi < 0.01) . Moreove < 0.01) . And wit < 0.01) . Of noteIn this section, we examined the protective effect of PG on brain injury with H&E staining. In the model control group, the cortical cells arranged in disorder and decreased . The corHypertension is a disease characterized by high arterial pressure. Sustained high blood pressure leads to cerebral embolism, cardiac failure, renal failure, and other complications. TOD is caused not only by hypertension but also by BPV, which is independent of low mean systolic blood pressure , 20. Theβ-blockers on blood pressure fluctuation remains inconclusive. Beta-blockers might increase in enhanced BPV [β-blockers; high selectivity in β-blockers exerts no such effect [In the early stage of our research, PG exhibited a definite antihypertensive effect on SHR through liver protection activity and improvement of endothelial function by regulating serum NO and endothelin (ET) levels. However, the effect of PG on blood pressure fluctuation has not been evaluated. On the basis of the previous research, single-dose and long-term administration of PG were conducted to investigate its effect on BPV in SHR in this study. The experimental results showed that single-dose administration of PG, unlike metoprolol, significantly reduced blood pressure in rats initially, without aggravating long- and short-term BPV. Long-term administration of PG could not only significantly reduce the 24 h blood pressure but also decrease BPV . By contrast, metoprolol significantly reduced the 24 h blood pressure; however the trend fluctuated, showing no significant effect on SBPV, DBPV, and MBPV. This effect might be the advantage of using PG as an antihypertensive. The effect of nced BPV , which mVascular cell proliferation, apoptosis, inflammation, fibrosis, and other complex processes change the vascular structure in patients with BPV . The SHREnhanced BPV could trigger a change in pathological cardiac hypertrophy via mechanical stress fluctuation in the cardiomyocytes . That isThe kidneys target organs that not only are prone to hypertension induced injury but also are also involved in exacerbating the development of hypertension. An increase in short-term BPV may be positively correlated with impaired renal function, as determined by microalbuminuria or glomerular filtration rate , 28. GloBPV could also lead to brain damage, including cerebral vascular lesions and histomorphological changes in the brain . CerebroThe current animal models, used to study for hypertension, are mainly hereditary hypertensive animal models (spontaneously hypertensive rats (SHR) , 50, strIn conclusion, abnormal BPV and TOD of heart, brain, kidney, and aorta were observed in SHR of this study, which is consistent with the other researcher reports. And paeoniflorin enriched extract (PG) could reduce BPV, stabilize blood pressure, and reverse the eNOS or COX-2 expression to mitigate target organ damage (TOD) in SHR. These findings provide convincing evidence that PG, with protective effect on BPV and TOD in SHR, can be used to treat hypertension. However, the mechanisms of the increased BPV resulting in TOD were not elucidated in the present study, which may be related to chronic inflammation  and micr


After traumatic brain injury (TBI), the ability of cerebral vessels to appropriately react to changes in arterial blood pressure (pressure reactivity) is impaired, leaving patients vulnerable to cerebral hypo- or hyperperfusion. Although, the traditional pressure reactivity index (PRx) has demonstrated that impaired pressure reactivity is associated with poor patient outcome, PRx is sometimes erratic and may not be reliable in various clinical circumstances. Here, we introduce a more robust transform-based wavelet pressure reactivity index (wPRx) and compare its performance with the widely used traditional PRx across 3 areas: its stability and reliability in time, its ability to give an optimal cerebral perfusion pressure (CPPopt) recommendation, and its relationship with patient outcome.Five hundred and fifteen patients with TBI admitted in Addenbrooke’s Hospital, United Kingdom , with continuous monitoring of arterial blood pressure (ABP) and intracranial pressure (ICP), were retrospectively analyzed to calculate the traditional PRx and a novel wavelet transform-based wPRx. wPRx was calculated by taking the cosine of the wavelet transform phase-shift between ABP and ICP. A time trend of CPPopt was calculated using an automated curve-fitting method that determined the cerebral perfusion pressure (CPP) at which the pressure reactivity (PRx or wPRx) was most efficient .p = 0.002). The 2-hour interval standard deviation of wPRx (0.19 ± 0.07) was smaller than that of PRx . wPRx performed better in distinguishing between mortality and survival . The mean difference between the patients’ CPP and their CPPopt was related to outcome for both calculation methods. There was a good relationship between the 2 CPPopts . CPPopt_wPRx was more stable than CPPopt_PRx .There was a significantly positive relationship between PRx and wPRx (r = 0.73), and wavelet wPRx was more reliable in time  or too much (hyperemia) blood flow following traumatic brain injury (TBI).A physiological mechanism called cerebral autoregulation (CA) exists to maintain stable blood flow even if cerebral perfusion pressure (CPP) is changing, and an assessment of CA as part of bedside neuro-monitoring of patients with TBI could facilitate individualized treatment.A robust method for assessing CA in TBI is not yet available. The traditional measure used, the pressure reactivity index (PRx), provides inherently noisy estimates and may not be reliable in various clinical circumstances.We studied a new method to assess cerebral CA using continuous, real-time assessment of CA from available neuro-monitoring data called transform-based wavelet pressure reactivity index (wPRx).Using data collected from the continuous monitoring of arterial blood pressure (ABP) and intracranial pressure (ICP) from 515 patients with TBI, we compared the performance of wPRx with PRx across 3 areas: its stability/reliability in time, its ability to give an optimal cerebral perfusion pressure (CPPopt) recommendation, and its relationship with patient outcome.We found a significant positive relationship between PRx and wPRx, with wPRx being more stable in time.wPRx performed better in distinguishing different patient outcome groups, while CPPopt calculated using wPRx had lower variance and higher overall yield .In this study, we found wPRx to be more stable in time and yield a more consistent CPPopt recommendation compared to PRx. Importantly, wPRx had a stronger relationship with patient outcome compared to PRx in our study.The clinical utility of wPRx should be explored further in prospective studies of critically injured neurological patients, particularly in circumstances in which reliability of PRx has been questioned, e.g., inpatient after decompressive craniectomy. Traumatic brain injury (TBI) is an important global public health problem as a major cause of traumatic death and disability, especially in young people ,2. ManagOver the past 2 decades, the clinical assessment of CA has transitioned from intermittent testing to continuous monitoring ,6–9. CzoThe clinical utility of PRx in patients with severe TBI has been demonstrated since its development. It can help predict patient outcome; alert the clinician to subtle cerebrovascular impairment or the response to various common clinical interventions ,12; and By contrast, the wavelet transform method, which has been widely applied in the field of geophysics and economics, has been found to be particularly useful for analyzing intermittent, noisy, and nonstationary signals , making In this study, we introduce wavelet transform analysis to assess cerebral pressure reactivity in 515 patients with TBI. The wavelet method was compared with the traditional parameter, PRx, in terms of pragmatic benchmarks: its stability and reliability, its inherent prognostic information, and its ability to estimate CPPopt.The data analyzed in this study consist of 2 groups. One was reviewed and approved by the local ethics committee of Addenbrooke’s Hospital, Cambridge University, United Kingdom (30 REC 97/291), and the other includes anonymized routine clinical data not collected under patient/next of kin consent/assent, in accordance with UK legislation. The Research Governance at Cambridge University Hospitals NHS Trust approved the use of the data for this and other methodological studies since the data have been anonymized, and, in such cases, there was no requirement from NHS Digital for consent to be obtained. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement . We follhttp://www.neurosurg.cam.ac.uk/icmplus) through an A/D converter  or digitally directly from GE Solar monitors. The preanalysis, including artifacts removal, data trend calculation, and all the CA parameters  were calculated through ICM+ software. Artifacts introduced by tracheal suctioning, arterial line flushing, or transducer malfunction were removed manually. Inclusion criteria were all patients with TBI, with availability of ABP and ICP monitoring,. There were no explicit exclusion criteria; however, some of the patients from that time period may have been omitted due to technical/staffing reasons of high-resolution data collection process. Patients were managed according to current institutional TBI guidelines  [This study included a total of 515 patients with TBI who had continuous monitoring of ABP and ICP and were admitted to Addenbrookes’ Hospital, University of Cambridge, UK, between March 23rd, 2003 to December 9th, 2014. ABP was monitored invasively through the radial or femoral artery using a standard pressure monitoring kit . ICP was monitored using an intraparenchymal probe  inserted into the frontal cortex [Time-averaged values of ICP, ABP, and CPP (CPP = ABP − ICP) were calculated using waveform time integration over 10-second intervals. PRx was calculated as a moving Pearson correlation coefficient between 10-second averages of ABP and mean ICP, using a 300-second data window .Wavelet transform phase shift (WTP), the phase difference between ABP and ICP, in the frequency of 0.0067 Hz to 0.05 Hz was calculated through complex wavelet transform, described in n = 33,000).The stability of PRx and wPRx was tested by taking distinct time points. We selected 1 PRx/wPRx point every 10 minutes, then the standard deviation (SD) of these PRx/wPRx points over a period of 1 hour was calculated, i.e., SD of six numbers. The calculation was repeated every 2 hours, thus leaving a 1-hour gap between data segments. Subsequently, a paired comparison of the pulled data of 2-hour interval SD of PRx and wPRx was performed  of a 1-hour period every 3 hours, with a 2-hour gap between data segments. The variance within groups (Vw) and between groups (Vb) of the extracting data were calculated. The total variance (Vt) was calculated as the sum of Vw and Vb (Vw + Vb). The reliability of each parameter (PRx or wPRx) was then calculated as Vb / Vt.To analyze the relationship between PRx/wPRx and patient outcome, the averaged values of each parameter were calculated across the whole monitoring period of each patient. The Glasgow Outcome Scale (GOS) was used to assess patients’ outcome at 6 months, collected by the clinical research nurses in 3 ways: (1) through the hospital record, if the patient died in ward; (2) by patients’ hospital visits to the rehabilitation clinic center after 6-month admission; or (3) by phone interview, answered either by the patient himself/herself or their relatives. The GOS score was scaled into 5 categories: dead, vegetative state , severe disability , moderate disability (the patient is independent but disabled), and good recovery  . For theIn order to test the ability of wPRx to delineate CPPopt, the automatic curve-fitting methodology described in detail by Aries et al  was usedStatistical analyses were performed using the IBM SPSS Statistics (version 21) software. The prespecified analyses were described below:t test was used to analyze the ability of wPRx and PRx in distinguishing different outcome groups . Results were considered significant with p < 0.05. Receiver Operating Characteristic (ROC) curves were used to compare the ability of different CPPopts in distinguishing patient outcome, rendering an area under the ROC curve (AUROC) for each parameter [Cross-relationship between wPRx and PRx was studied using Spearman’s correlation coefficient (r) over the hourly averaged data of all patients . Independent-samples arameter . Bland-Aarameter . The SDsFollowing reviewers’ comments and feedback, more post hoc analyses were added:t test. The difference between wPRx and PRx was also analyzed using average value of the whole monitoring period  through paired sample t test. The association of PRx and/or wPRx with the patient outcome was investigated using the multivariable binary logistic regression model with stepwise (forward) selection of variables. Three different sets of variables were used for the logistic regressions: the first group with input of , the second group with input of , and the third group including both PRx and wPRx.The stability of PRx and wPRx , and the reliability of the 2 parameters  were compared using Wilcoxon n = 75 (17.0%), moderate disability, n = 117 (26.5%), severe disability, n = 142 (32.1%); persistent vegetative state, n = 11 (2.5%); and death, n = 97 (21.9%). The mean recording time per patient after artifact removal was 118.6 hours (range from 1 hour to 536 hours). Time trends of ABP, CPP, PRx, and wPRx are shown in The group of patients included 130 females and 385 males, with their characteristics described in t test of the average value of wPRx and PRx showed significant difference between the 2 parameters . The stability of PRx and wPRx showed a significantly lower 2-hour interval SD with wPRx than with PRx . The reliability analysis of the 2 methods (PRx and wPRx) showed a significantly increased comparison to PRx .The data used for relationship analysis between PRx and wPRx were hour-by-hour average data of all the patients, with 65,443 data points in total. p < 0.001, AUC = 0.613, p < 0.001, AUC = 0.675, p = 0.0002).There was a significant difference in both PRx and wPRx for patients with favorable outcome compared to those with unfavorable outcome . Mean .For the fatal and nonfatal group, PRx and wPRx also showed significant differences between the 2 groups . Mean . The standard deviation of CPPopt_PRx and CPPopt_wPRx across the whole monitoring period was 8.45 ± 2.90 and 7.05 ± 3.78, respectively (p < 0.001).Overall determination of an individual CPPopt across the whole time was possible in 502 patients according to wPRx or PRx. The CPPopt yield was significantly increased by using wPRx  and also between wPRx and age (p = 0.01) in this cohort of 515 patients with TBI. Cerebral pressure reactivity seems to have deteriorated with the increase of age, shown by increased PRx and wPRx. wPRx showed a stronger relationship with ICP  than PRx .There was a significant relationship between PRx and age  demonstrated that each parameter was predictive of outcome; however, when both wPRx and PRx were included in the same model, only wPRx was significant. This indicates that although the 2 are measuring the same phenomenon, wPRx is superior to PRx in terms of prognosis.Fourth, in CPPopt calculation, wPRx makes CPPopt estimation more continuous, which is shown through higher yield than CPPopt according to PRx. Patient outcome correlated similarly with the difference between median CPP and CPPopt_ wPRx as the difference between median CPP and CPPopt_PRx. Mortality was associated with relative hypoperfusion (CPP < CPPopt_wPRx), severe disability with hyperperfusion (CPP > CPPopt_wPRx); favorable outcome was associated with a smaller difference between CPP and CPPopt_wPRx. For the whole cohort of patients with TBI, the asymmetrical “U”-shape curve created by plotting wPRx versus CPP bins  might suThe fifth finding of this research was an age-related deterioration in CA, which indicates that perfusion pressure autoregulation in older patients with TBI no longer performs as efficiently as in younger patients. This relationship was captured by both PRx and wPRx. Normal aging is associated with many well-recognized changes in the cardiovascular system, such as increases in systolic blood pressure, decreases in systemic artery compliance, cardiac baroreceptor sensitivity, and decrease of cortical cerebral blood flow –38. InteThree limitations should be noted:Although this study has a large sample size, it is a retrospective analysis. The data were preprocessed before calculating wPRx, PRx, and CPPopt, with artifacts removed manually. Although, this retrospective analysis confirmed that patients whose median CPP is closer to their determined CPPopt seem to have better clinical outcomes, a prospective validation of these findings is essential, to determine whether CPPopt can be used in prognostic determination or CPP-target guiding treatment to improve patient outcome. Moreover, according to the retrospective study, wPRx showed more stable performance. A randomized controlled trial of CPPopt targeting is essential to suggest which (wPRx or PRx) will be the best technique for pressure reactivity assessment.Although the CPPopt yield was significantly increased by using wPRx, we were only able to estimate CPPopt in around 60% of the monitoring time. Further improvements to the algorithm need to be introduced, as, for example, suggested by Depreitere et al. , in ordeThis study already demonstrated a close relationship between PRx and wPRx; it would be very interesting to compare the wPRx calculations to an autoregulation index derived from an alternative measure of CA  or more direct measures of CA in an animal model.This study introduces a new, wavelet-based method for cerebral pressure reactivity assessment in patients with TBI. Based on these findings, wPRx is stable in time, yields consistent CPPopt recommendation, and, importantly, has a strong relationship with patient outcome.S1 Checklist(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S1 Research Plan(PDF)Click here for additional data file.


Paid community health workers screened for hypertension in the community, referred cases to the clinic for diagnosis and initial treatment by a physician, and then monitored patients who had well-controlled blood pressure including dispensing maintenance medications prescribed by the physician. Blood pressure control was successful in the majority of such patients. Paid community health workers screened for hypertension in the community, referred cases to the clinic for diagnosis and initial treatment by a physician, and then monitored patients who had well-controlled blood pressure including dispensing maintenance medications prescribed by the physician. Blood pressure control was successful in the majority of such patients. Poor blood pressure control results in tremendous morbidity and mortality in India where the leading cause of death among adults is from coronary heart disease. Despite having little formal education, community health workers (CHWs) are integral to successful public health interventions in India and other low- and middle-income countries that have a shortage of trained health professionals. Training CHWs to screen for and manage chronic hypertension, with support from trained clinicians, offers an excellent opportunity for effecting systemwide change in hypertension-related burden of disease. In this article, we describe the development of a program that trained CHWs between 2014 and 2015 in the tribal region of the Sittilingi Valley in southern India, to identify hypertensive patients in the community, refer them for diagnosis and initial management in a physician-staffed clinic, and provide them with sustained lifestyle interventions and medications over multiple visits. We found that after 2 years, the CHWs had screened 7,176 people over age 18 for hypertension, 1,184 (16.5%) of whom were screened as hypertensive. Of the 1,184 patients screened as hypertensive, 898 (75.8%) had achieved blood pressure control, defined as a systolic blood pressure less than 140 and a diastolic blood pressure less than 90 sustained over 3 consecutive visits. While all of the 24 trained CHWs reported confidence in checking blood pressure with a manual blood pressure cuff, 4 of the 24 CHWs reported occasional difficulty documenting blood pressure values because they were unable to write numbers properly. They compensated by asking other CHWs or members of their community to help with documentation. Our experience and findings suggest that a CHW blood pressure screening system linked to a central clinic can be a promising avenue for improving hypertension control rates in low- and middle-income countries. Over the past decade, there has been a dramatic increase in rates of coronary heart disease (CHD) in the developing world. This trend is expected to continue with a projected increase in rates of CHD in low- and middle-income countries by 6 million deaths over the next 20 years.A shift in disease burden from communicable diseases to noncommunicable diseases, such as hypertension, diabetes, and myocardial infarction, has been documented in both urban and rural regions of India.Two of the major barriers to patients accessing health care in under-resourced regions are the lack of adequate numbers of providers in those regions and the challenge and cost of traveling from remote regions to available health care providers. Community health worker (CHW) systems, which train individuals from within villages to provide first-line care, have been successfully implemented for a variety of public health concerns, including childhood vaccinations, maternal and child health, and tuberculosis and HIV monitoring programs. CHW programs have been discussed as a way to improve the screening, diagnosis, and management of noncommunicable diseases in resource-poor settings.Health workforce shortages and transportation costs are major barriers to patients accessing health care in under-resourced regions.In September 2017, a cluster randomized controlled trial in Argentina showed that a CHW-led multicomponent intervention was superior to usual management of hypertension.The Sittilingi Valley is a remote, tribal region in the southern Indian state of Tamil Nadu with difficult-to-access dirt roads and limited options for public transportation. According to Indian government census data from 2011, the primary occupation of the Sittilingi Valley population is farming, the primary language is Tamil, and less than 10% of the population receives higher than a sixth-grade education.In this article, we describe the development, implementation, and initial achievements of a CHW hypertension program in this area of rural India.In August 2013, the University of California San Francisco (UCSF) and the Tribal Health Initiative (THI) established a partnership to implement and study the effects of adapting an existing CHW program to include hypertension management in the rural under-resourced tribal region served by THI.A “tribal region” in India is a government designation for areas with populations that were historically marginalized and are now officially recognized by the government as neglected.THI is an Indian nonprofit organization founded in 1994 by 2 Indian physicians committed to improving the health of the rural tribal population. It is fully nongovernmental, in the sense that it does not interface directly with any governmental system. When THI was first formed, there was no government clinic in the designated tribal region. Since then, a government clinic has been established 11 km outside the tribal area. However, very few patients seen at the THI clinics and none of the patients enrolled in the hypertension program also seek care at the government clinic. The organization now serves the 12,000 people who live in the 21 villages located in the tribal region of the Sittilingi Valley through their 24-bed tribal hospital and outpatient clinic. Approximately 8 physicians work at the tribal hospital and outpatient clinic.THI also has a CHW program that trains selected women to provide basic medical care in the villages. A CHW is a married woman from each village—aged 30 to 40 years with at least a tenth-grade education—who was chosen by her fellow villagers. Each CHW receives 2 days of training every 2 weeks for 18 months on the basics of sanitation, hygiene, childbirth, nutrition, and methods of communicating this knowledge to the community through stories and songs. A total of 24 CHWs are currently employed by THI and are paid an hourly rate using local standards for competitive wage compensation. Every week, CHWs see patients for 6 hours in their village, providing immunizations for children, prenatal care to pregnant women, and advice, treatment, and follow-up care for adult patients with other medical concerns. Patients with more complex complaints are referred by the CHWs to a THI tribal clinic.In January 2014, THI staff and UCSF faculty developed a curriculum for CHWs that teaches blood pressure measurement, diagnosis, management, and prevention based on the 2014 American Society of Hypertension and International Society of Hypertension (ASH/ISH) guidelines for hypertension management.The goal of the curriculum was to teach CHWs how to incorporate blood pressure measurement, documentation, and referral of hypertensive patients to the central clinic.Over a 7-month period, beginning in March 2014, the 24 CHWs at THI received monthly 3-hour hypertension training sessions led by the head nurse. The CHWs were taught about the physiology of blood pressure, what happens during systole and diastole parts of the cardiac cycle, and why measuring blood pressure is important. The CHWs also received 1 to 2 hours of practical training at the end of each session on the use of the Ashok Nisco-09 electronic arm blood pressure cuffs , which record systolic and diastolic blood pressure and heart rate. They were also taught to record blood pressure and heart rate for each patient in a medical record. After the training was completed, each CHW's level of understanding of the training materials and equipment was evaluated by nurses and physicians observing a CHW's blood pressure measurement technique, checking their ability to record blood pressure numbers accurately, and assessing general understanding of what blood pressure is and why hypertension control is important. Two of the CHWs were found to have knowledge deficits and were required to undergo additional training to reinforce key points. Following completion of the training, the CHWs met monthly with the head nurse for continued mentoring and feedback about the CHW hypertension program.In November 2014, the CHWs began screening all patients over the age of 18 for hypertension during their weekly field clinics in the villages. The screening sites were located at a central setting in the village, usually a school or temple, where villagers would gather and meet with the CHW. The screening process was simple: a person would rest in a chair for 5 minutes with both feet on the ground, after which their blood pressure was measured. Anyone with either a systolic blood pressure greater than 140 or a diastolic blood pressure greater than 90 would receive a second blood pressure check. If the second check also was high, the patient was classified as having screened positive and was sent to the clinic, where he or she was seen by a physician. The physician would recheck the patient's blood pressure and, if it was elevated, the patient would receive a hypertension diagnosis and be enrolled in the hypertension program. From that point, the physician would manage the patient's hypertension in accordance to standard practices, providing lifestyle advice and medications, if warranted.During the first month following the screening event, a visiting nurse would monitor hypertensive patients every week. In the subsequent months, CHWs who had completed their first month of training screened patients for hypertension, recorded blood pressure values in a log, and referred patients for follow up either with the clinic (if screening suggested hypertension) or the CHW  . A visitA visiting nurse would monitor patients' blood pressure measurements every 4 to 6 weeks and provide the CHWs with real-time feedback.A simple algorithm for hypertension management was formulated based on the 2014 ASH/ISH guidelines.In April 2015, the CHWs began to receive teaching during their monthly 2-hour sessions with the head nurse and clinic physician about hypertension management. Specifically, the head nurse and the clinic physician taught the CHWs about goal blood pressure ranges, the 5 classes of blood pressure medication available for patients , potential side effects of the medication, and lifestyle interventions for blood pressure control.The teaching augmented and reinforced the algorithm that CHWs had been trained to follow as to what blood pressure ranges and complaints necessitated immediate referral of patients to the clinic. The CHWs were also taught to refill medications with the same dosages for patients already on medication who were found to be normotensive during the field visits. They were also taught to refer all enrolled patients on medication to the clinic every 6 months for laboratory monitoring of kidney function and electrolytes and refer all enrolled patients not on medication to the clinic every year for routine laboratory monitoring.While the CHWs received this more in-depth teaching monthly until October 2014, they continued to only screen patients for hypertension and send uncontrolled hypertensive patients to the clinic. The CHWs did not start providing any hypertension management interventions during the orientation period.In June 2015, the CHWs began giving lifestyle advice and dispensing medications for chronic conditions to patients with well-controlled blood pressure, based on a decision tree . The lifSupervision of the CHWs began well before the initiation of the hypertension program. Visiting nurses made trips to each village every 2 months, to observe and supervise CHWs providing clinical care and to address illness and treatment management concerns of the villagers that could be taken care of by the CHWs. Additionally, the nurses provided ongoing trainings and educational meetings with CHWs based on deficiencies observed in the field. Once every 6 months, a physician would accompany the visiting nurses to the villages in order to provide additional CHW observation, on-the-ground training, and quality assurance. After the hypertension program was initiated, the visiting nurse and physician supervision was expanded to assess blood pressure measurement, management, and referral by CHWs.Before screening village members, each CHW asked all patients over the age of 18 for consent using a verbal consent script that explained in Tamil the purpose of the intervention and the potential harms. All patients who gave verbal consent were screened for hypertension. Documentation of patient care began with assessments by CHWs. Once measured, a patient's blood pressure value was written on a white medical record card by the CHW and given to the patient. All screened patients, regardless of blood pressure level, were given a white card. If the patient screened positive for hypertension they were given a referral to see a physician at the clinic and were told to bring their medical record card with them to all visits because a clinician would not be able to see them unless they had their card with them. The referral included both a verbal notification that the patient needed to be seen at the clinic and a written note stating this fact. When the patient arrived at the clinic, the clinic administrative assistant would transcribe the date and blood pressure value from the patient's white medical record card on to a blue medical record card. The blue card is the patient's hypertension record for the clinic, which stays in the clinic. When patients are seen in the clinic, blood pressure values from the clinic visit are entered onto both the white and blue medical record cards. Weekly, the clinic staff enters blood pressure data from the blue cards into the computer system; the data are then uploaded onto a secure server for access by authorized local and UCSF program personnel using a password-protected front end.Patients who screened positive for hypertension were sent to the clinic, where they received care from 1 of 4 physicians who rotated through the clinic. The physician rechecked blood pressure and diagnosed hypertension in patients with systolic blood pressure over 140 or diastolic blood pressure over 90 in accordance with the ASH/ISH 2014 guidelines. Patients diagnosed with hypertension were enrolled in the hypertension program and seen by the physician weekly until blood pressure control was achieved. All patients in the program were also screened for diabetes and received baseline laboratory chemistry panels and blood urea nitrogen and creatinine levels. Patients who screened positive for diabetes or chronic kidney disease were managed in the clinic for these conditions. All patients enrolled in the hypertension program were referred to the clinic every 6 months to 1 year in order to check routine lab work. Each year, physicians attend an hour-long refresher lecture from a visiting UCSF faculty member about hypertension diagnosis and management guidelines.After blood pressure control was achieved, a patient would be seen by their CHWs for monthly blood pressure checks. If the blood pressure remained within goal range during the CHW visits, the CHW would continue to provide lifestyle advice and medications as outlined above. If the blood pressure was elevated during a visit, the patient would be referred back to the clinic. Communication between CHWs and physicians occurred monthly, when the CHWs would visit the clinic for ongoing education, feedback, and communication of any patient-specific concerns with the physicians.Communication between CHWs and physicians occurred monthly, when the CHWs would visit the clinic for ongoing education, feedback, and communication of any patient-specific concerns.Beginning in June 2015, THI trained CHWs to document the medications using a color code—each medication having its own color sticker. When a physician, nurse, or CHW dispensed medication, the same color sticker would be placed on the patient's white medical record card. The CHW subsequently would check to ensure that the medication she is dispensing has the same color code as the medication the patient is already on. This acts as a safety measure to ensure that the correct medication is given to the patient, and is particularly important because 7 of the 24 CHWs are semiliterate and not able to read or document numbers accurately some of the time. Because the semiliterate CHWs initially had trouble documenting numbers correctly, the head nurse and visiting nurses spend an additional hour at the end of each monthly teaching session with these CHWs to teach them how to document blood pressure values correctly. When visiting nurses observed the CHWs in the field, their subjective observations suggested no difference in the care rendered by the semiliterate and literate CHWs.Patient demographic and clinical data, including blood pressure data, from the patient blue cards were entered by clinic personnel through a front-end interface  and storRegular informal feedback sessions were held separately with the head nurse, all 24 CHWs at the central clinic, all THI physicians, and a subset of patients who volunteered to talk to the program team. During these feedback sessions, participants discussed their perceptions of the hypertension program, program strengths and weakness, areas for improvement, ways in which the program benefitted or harmed the community, and thoughts about the future trajectory of the program. No formal qualitative data analysis or audio recording were completed during the informal feedback sessions, but we provide a summary of key comments expressed during these sessions. Informal oral patient questionnaires were conducted with 235 randomly selected patients enrolled in the hypertension program 1 year after the program beganThe University of California San Francisco Institutional Review Board and Indian Ethics Committee approved this program.The program had 3 main objectives: (1) a majority of community members over the age of 18 should be screened for hypertension by CHWs, and hypertensive patients were to be enrolled in the program; (2) continuing care should primarily occur in the villages by CHWs, while patients with uncontrolled hypertension should be referred to the clinic; and (3) hypertension control rates should be non-inferior to clinic-based hypertension control rates.By 2016, at the 2-year assessment point, the program had met the first objective, with a majority of people over the age of 18 screened for hypertension and appropriate patients enrolled in the program. A total of 7,176 people over the age of 18 had been screened: 3,445 (48.0%) were women and 3,731 (52.0%) were men . Of thosAt the 2-year assessment point, CHWs had screened more than 7,000 people for hypertension, and about 17% were hypertensive at baseline.The program staff were able to successfully meet the second objective of training the CHWs to perform hypertension management in the field, with chronic care being provided in the community by CHWs, and the clinic being use primarily for care of uncontrolled hypertension. The main outcome assessed was whether CHWs were able to effectively measure and document blood pressure, refer patients with elevated numbers to the physician at the clinic, and provide continuing interventions that were previously given by a physician to patients with well-controlled blood pressure. We were not assessing how well the CHWs were controlling blood pressure, but rather that they were able to successfully implement the system. While all of the 24 CHWs successfully completed training, the 7 semiliterate CHWs needed additional training with the nurses in order to achieve competence. The CHWs were trained to check blood pressure, document blood pressure values, provide lifestyle counseling and medication, and refer patients to the clinic as needed.The competence of the CHWs to check blood pressure, document blood pressure values, provide lifestyle counseling and medications, and refer appropriate patients to the clinic, as described above, was repeatedly assessed with visiting nurse observations that initially took place weekly and later monthly, visiting physician observations twice annually, and monthly didactic sessions with a question-and-answer component at the central clinic. Initially, 4 of the 24 CHWs encountered occasional difficulty recording blood pressure values, but by the end of the training period, these difficulties improved and the visiting nurses assessed all CHWs as competent. Confidence of the CHWs was assessed by monthly feedback sessions with the nurses and physicians at the central clinic.The CHWs reported varying degrees of confidence in their ability to do their job. When the program began, many of the CHWs felt intimidated by the new skills they were asked to master, but after 1 year of implementation, all the CHWs said they felt confident checking blood pressure with a manual blood pressure cuff. Four of the 24 CHWs reported occasional difficulty documenting values because they were unable to write numbers properly. These CHWs reported that they asked other CHWs or members of their community to help with documentation. None of the CHWs expressed uncertainty or difficulty with dispensing medication. The CHWs expressed satisfaction with their work during informal feedback sessions and expressed interest in continuing the work in the future.During one feedback session, a CHW stated, “people in my village respect me now because they know I have knowledge.” Another CHW stated, “now people come to me for help. They don't feel so nervous about being so far from the hospital. I'm here to calm them down. This makes me feel good.” The main challenge CHWs cited was their inability to convince patients to take directed advice. As one CHW stated, “[patients] don't believe me. I tell them not to eat salt but they do anyway.” As the program progressed, THI administration was able to incorporate CHW roles and responsibilities into the work they were already performing in the community.During one feedback session, a CHW stated, “people in my village respect me now because they know I have knowledge.”While CHWs were successfully trained to manage hypertension in the field, feedback from CHWs and patients revealed that the reasons a patient chose to use the clinic instead of community-based care were highly subjective and patient-specific. Informal oral patient questionnaires were conducted with 235 randomly selected patients enrolled in the hypertension program 1 year after the program began. The respondents were asked 2 open-ended questions: (1) “Are you satisfied with the care you are receiving through the hypertension program?” and (2) Do you visit the tribal clinic for hypertension only when directed by your CHW or at other times as well?” Of these respondents, 96 patients (40.9%) expressed satisfaction with the CHWs and stated that they only chose to visit the clinic when directed by the CHW or if they were experiencing an urgent concern. However, 28 patients (11.9%) expressed concern that the care they were receiving from the CHW was inferior to physician and nursing care, and reported visiting the clinic for hypertension management even when their CHW told them it was not necessary. When checked against clinic program data, 165 of the respondents (70.2%) had poorly controlled hypertension, while 70 (29.8%) had well-controlled hypertension. Of the 70 patients, 64 were recorded as having had well-controlled hypertension on their previous CHW encounter in the community, implying that their use of the clinic was due to patient preference as opposed to CHW referral.For the third objective of achieving hypertension control rates that were non-inferior to clinic-based hypertension programs, we found that after 2 years of the program, 898 of 1,184 (75.8%) patients diagnosed as hypertensive achieved blood pressure control, which is defined as a systolic blood pressure less than 140 and a diastolic blood pressure less than 90 sustained over 3 consecutive visits either at the clinic or in the community. An average of 68 days or 2.9 visits were needed to first achieve blood pressure control in these patients with hypertension.We describe a program that used an existing CHW system linked to a central clinic as a mechanism to provide management of hypertension in a remote under-resourced community. We found that after 2 years, this program screened, enrolled, diagnosed, and managed the population of patients with hypertension and met expected objectives. This work demonstrates a feasible model for providing diagnosis and management of chronic conditions that consists of: (1) deliberate stepwise training and supervision of CHWs, (2) empowerment of CHWs with new skills of value to the community, (3) design of a CHW program that includes maintenance and follow up of a chronic condition, and (4) close integration of the CHW program with a clinic and referral system. The training program that was designed for our cohort of CHWs was delivered in separate components—to first screen patients for hypertension, then refer appropriate patients to the central clinic, and lastly manage chronic hypertensive patients in the field—in order to build CHW competence and confidence. From the qualitative data from our CHW training program, we found the CHWs were confident about their ability to do the separate components and found value in their work.This work also demonstrates that using a CHW system linked to a central clinic can be an effective mechanism to shift chronic care management from physicians and nurses to CHWs, despite the subset of patients who seemed to prefer clinic-based care. We were able to show hypertension control rates of 75.8% in this community after 2 years were higher than the approximately 50% control rates reported in the general U.S. population,Using a CHW system linked to a central clinic can be an effective mechanism to shift chronic care management from physicians and nurses to CHWs.While our program was successful, 24.2% of patients identified as hypertensive did not achieve control within 2 years—this may be attributed to lack of adherence to medications, refractory hypertension, or lifestyle factors that were not addressed. Further study is needed to better understand factors related to poor control. We acknowledge that many factors contribute to achievement of blood pressure control, including dietary modification, exercise, adherence to medications, and trust in the health care system. Economic analyses are also needed to determine the cost differential between the CHW program and a physician-staffed clinic program, as the cost of long-term care is a known barrier to CHD risk-factor control in low- and middle-income countries.In conclusion, our program suggests that a CHW system linked to a central clinic is a promising avenue for achieving improvements in hypertension control rates in low- and middle-income countries.