We pooled data from 6 valsartan-related studies including 3,658 diabetic and 11,624 nondiabetic patients to evaluate blood pressure (BP) outcomes after approximately 90 days of second- or later-line valsartan treatment. Hierarchical linear and logistic regressions were applied to identify determinants of BP outcomes. Similar reductions in BP values and similar BP control rates were achieved in both groups after approximately 90 days of therapy. The modeling analyses identified several common and different patient- and physician-related determinants of BP outcomes for both groups, many of which are modifiable or clinically manageable. Through varying in terms of association and influence between the diabetic and nondiabetic groups, patient-related determinants included age, BP at diagnosis of hypertension, risk factors, valsartan regimen, concomitant antihypertensive treatment, and adherence; and physician-related determinants included gender, years in practice, and hypertension management. In summary, in both diabetic and nondiabetic patients, the use of valsartan-centric treatment regimens in second- or later-line antihypertensive treatment is associated with significant reductions in BP level and improvement in BP control. The determinants identified in modeling provide guidance to clinicians in the common and differential management of hypertension in diabetic and nondiabetic patients. Hypertension and glucose intolerance are highly associated chronic conditions. Over two-thirds of diabetic patients have elevated blood pressure . DiabeteFor long, the recommended systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets were <140 mmHg and <90 mmHg for nondiabetic patients but <130 mmHg and <80 mmHg for diabetic patients. The most recent European  and NortWe have conducted seven observational studies on real-world practice patterns and associated outcomes in patients with hypertension treated for approximately 90 days (hereafter “90 days”) with valsartan , an angiotensin receptor blocker . All patLowering blood pressure and especially achieving blood pressure control are more difficult in diabetic than in nondiabetic patients, as both randomized controlled trials and observational studies have shown –6. ThereIn the comparative analysis reported here, we aimed (1) to evaluate blood pressure values (in mmHg) and blood pressure control rates (in %) observed after 90 days of treatment with a valsartan-centric regimen and (2) to identify patient-related and clinician-related determinants of these blood pressure outcomes using hierarchical linear and logistic regressions. Implicit to the choice for hierarchical models of statistical analysis was the hypothesis, evaluated and confirmed in each of the constituent studies in this pooled analysis; that part of the variance in BP values at the end of the observation period could be attributed to a class effect for the treating physician. Also, our aim was to evaluate similarities and differences in the determinants of blood pressure outcomes between diabetic and nondiabetic patients as strata and therefore we opted for our analysis method rather than evaluating models of determinants and using diabetic status as a cofactor. The studies were conducted before the change in guidelines concerning BP targets from <140 mmHg/90 mmHg for patients in general but <130 mmHg/80 mmHg for diabetic patients. However, we adopted the recent <140 mmHg/<90 mmHg targets as the threshold for BP control.The methodology common to all of the studies included in this pooled analysis has been described in detail elsewhere . We summAll six studies were prospective, multicenter, pharmacoepidemiological studies of hypertensive patients in the setting of routine “real-world” clinical practice involving hypertensive patients whose GPs prescribed a valsartan formulation, in monotherapy or combination therapy, as second- or later-line antihypertensive therapy because prior treatment failed to achieve the intended therapeutic benefit or was not tolerated. Patients BP was measured when valsartan therapy was initiated and again after approximately 90 days of therapy. The latter visit occurred as physician and patient schedules permitted in routine clinical practice and may not have been exactly 90 days (hereafter referred to as “90 days”). The decision to prescribe valsartan was made by the prescribing physician per best clinical judgment.Note that the one study excluded from this pooled analysis did not collect data using the Basel Assessment of Adherence Scale and in particular the item asking patients whether they had missed any doses in the preceding four weeks. Consistently, previous analyses have shown adherence to be a significant determinant of blood pressure outcomes and this single item has been shown to be highly predictive of outcomes . Hence, As the constituent studies were observational in design, all data were recorded as available from routine clinical practice. There were no mandatory tests or other assessments. The common data model for this study has been described extensively elsewhere . In addiA subject was considered evaluable if SBP and DBP values (mmHg) were available at both baseline and 90 days. Patients were stratified as diabetic or nondiabetic based on whether a diabetes diagnosis was recorded by their treating physician.We treated diabetic status as a stratification variable and hence distinguished between the strata of diabetic and nondiabetic patients. This was driven by our aim to evaluate not only blood pressure outcomes but also especially the similarities and differences in the determinants of blood pressure outcomes between diabetic and nondiabetic patients as strata. Hence, we did not use diabetic status as a cofactor in an omnibus model and opted for stratified analyses.We assumed that the patients recruited by a given GP had the commonality of being treated by the same GP and thus within the knowledge, experience, treatment preferences, and practice patterns of this GP. This violates the statistical assumption of independence of observations, which can be corrected by hierarchical (multilevel or mixed-effects) modeling. In this modeling, the variance observed in an outcome variable  is partitioned between the treating physicians and the patients being treated. This enables differentiation of the proportion of variance attributable to, in this case, the treating physician as a class effect (expressed in the metric of intraclass correlation coefficient [ICC]) and the residual variance to the patients being treated . ConditiThe constituent studies differed to some extent in the potency of the valsartan formulations that were evaluated . Hence sP value less than 0.05 was considered as statistically significant. Statistical analyses were performed using SAS v.9.4 .All tests were two-tailed and a Of the 15,282 patients in the evaluable sample, 3,658 (23.9%) were diabetic and 11,624 (76.1%) were nondiabetic. P < 0.001) (P = n.s.). Similarly, SBP, DBP, and combined SBP/DBP control rates improved significantly during the 90-day study period . The nominal differences in control rates were statistically similar as well .In both the diabetic and nondiabetic groups, SBP and DBP values (mmHg) decreased significantly over the course of treatment  . The nomIn the diabetic group, from an intercept of 111.02 mmHg, SBP values increased as a function of the SBP recorded at the time of the hypertension diagnosis, total cholesterol levels at start of the study, higher valsartan and hydrochlorothiazide (HCTZ) doses prescribed (including a study effect for the PREVIEW study), and the need for concomitant beta-blocker therapy. At the physician level, being treated by a male GP was associated with higher SBP values . In contIn the nondiabetic group, from an intercept of 105.79 mmHg, SBP values rose as a function of patient age, the SBP recorded at the time the hypertension diagnosis was made, total cholesterol levels, body mass index (BMI), higher valsartan and hydrochlorothiazide (HCTZ) doses prescribed, and the need for concomitant beta-blocker therapy. At the physician level, years in practice and male gender were associated with higher SBP values . PatientIn the diabetic group, from an intercept of 74.14 mmHg, DBP values rose as a function of the DBP recorded at the time of the hypertension diagnosis, total cholesterol levels at start of the study, and higher valsartan and hydrochlorothiazide (HCTZ) doses (including a study effect for the PREVIEW study). At the physician level, years the GP had been in practice were associated with higher DBP readings . AlternaIn the nondiabetic group, from an intercept of 69.26 mmHg, DBP values increased as a function of the DBP recorded at the time of hypertension diagnosis, total cholesterol levels, body mass index (BMI), and higher valsartan and hydrochlorothiazide (HCTZ) doses prescribed. At the physician level, male gender was associated with higher DBP values . PatientIn the diabetic cohort, the odds of controlled SBP at 90 days decreased as a function of total cholesterol levels and the need for higher valsartan and HCTZ doses . The oddIn the nondiabetic cohort, the likelihood of controlled SBP at 90 days increased if the patient was adherent and (per the INSIST study effect) was treated with the single-pill combination of 160 mg valsartan and 25 mg HCTZ . ImpairiIn the diabetic group, the likelihood of controlled DBP at 90 days increased as a function of patient age, patient adherence, and treatment with proportionately more potent valsartan and HCTZ formulations (as indicated by the study effect for the IMPROVE study) . The oddIn the nondiabetic cohort, the odds of controlled SBP at 90 days increased with age and if the patient was adherent and (per the INSIST study effect) was treated with the single-pill combination of 160 mg valsartan and 25 mg HCTZ and, counter-intuitively, had cardiovascular disease . At the In the diabetic group, the odds of having both SBP and DBP controlled at 90 days were a function of patient adherence and the counterintuitive finding of having cardiovascular disease . The oddIn the nondiabetic cohort, the likelihood of controlled SBP/DBP increased with patient adherence and treatment with potent valsartan and HCTZ formulations (per the INSIST study effect) . LowerinThe first principal finding of this pooled analysis comparing 3,658 patients with diabetes and 11,624 patients without diabetes treated with valsartan (second or later line) is that similar reductions in BP values and similar BP control rates can be achieved in both groups. However, the patient- and physician-level determinants of these outcomes differ between these groups. On average, in diabetic patients, SBP was reduced by 17.1 mmHg and DBP by 8.8 mmHg, compared to 18.9 mmHg and 9.9 mmHg in nondiabetic patients. In both groups, at follow-up, eight out of ten patients had controlled DBP, half of the patients had controlled SBP, and slightly less than half had controlled SBP/DBP. Thus, in our analysis, diabetic patients showed similar decreases in blood pressure values and achieved similar blood pressure control rates as nondiabetic patients. These findings are remarkable for diabetic patients because of the known difficulty in lowering BP and achieving BP control in this population.The second principal finding is that the diabetic and nondiabetic strata have some common but also some unique determinants of blood pressure outcomes. Where the same determinants were observed, the strata often differed in the impact and weight of a given determinant on blood pressure outcomes. Summarizing key results, higher blood pressure at the time of diagnosis, elevated total cholesterol, and higher valsartan and concomitant HCTZ doses were associated with an undesired effect on blood pressure outcomes in both strata of patients. However, generally, these effects were more pronounced in diabetic patients. In contrast, adherence had a desired effect on blood pressure outcomes in both strata but especially among diabetic patients.There were also some isolated effects, desired and undesired, for diabetic and nondiabetic patients. The need for concomitant beta-blocker therapy was associated with worse BP outcomes. There was also a trend of poorer outcomes among patients whose GP had been in practice longer and, we can presume, may therefore also have been older. In both diabetic and nondiabetic patients, age was associated with better DBP outcomes. In contrast, among nondiabetic patients, age was associated with poorer SBP outcomes. BMI had an undesired effect on blood pressure values in nondiabetic patients.At the physician level, diabetic patients benefitted from their physicians spending more time with them when they were diagnosed with hypertension. Nondiabetic patients, in contrast, showed better BP outcomes if their GPs had a large volume of hypertensive patients. For both diabetic and nondiabetic patients, there was an association between male physician gender and poorer blood pressure outcomes. This may be tied also to the observed association of poorer outcomes in patients followed by older physicians.We determined BP control rates using the most recent European  and NortAt the time of the studies, valsartan was indicated for second- or later-line treatment if prior-line treatment did not achieve the intended therapeutic benefit or was not tolerated. Our analyses yielded a perhaps paradoxical finding: higher doses of valsartan and HCTZ, and perhaps the addition of a beta-blocker, were associated with poorer BP outcomes in both diabetic and nondiabetic patients. Keeping in mind that the studies were in the GP setting, this may reflect that these clinicians were trying to bring this previously uncontrolled BP under control but may not have yet achieved this for many patients during the 90-day observation period. Also, note that being a subject in the IMPROVE  and PERSIST  studies was associated with better BP outcomes to which can be added the EXCELLENT study  as this was the reference study. These two trends in the data may reflect the real-world fact that, despite being treated with combination therapies, some patients may still not achieve the desired BP outcomes, while other patients receiving the same or different combination therapies do show beneficial BP outcomes. The issue may not be whether or not combination therapies are indicated. Rather, there may be a need to assess which combinations of agents are effective for which profiles of patients. Future studies, in first instance in diabetic patients, are needed to evaluate which antihypertensive combination therapies will yield for specific patients the greater reductions in BP and larger proportions of patients with controlled BP. This need for additional investigations, especially in diabetic patients, is also supported by the finding that lower cholesterol levels were associated with better outcomes, underscoring the need for lipid-lowering therapy and lifestyle modifications. This also applies to the nondiabetic group. Moreover, in this cohort, BMI was retained as a determinant in some models, indicating the importance of weight management in this population.Our findings emphasize the importance of adherence in patients in general but certainly in diabetic patients. Adherence was associated with lower SBP and DBP values and higher odds of achieving BP control. In an analysis of this same pooled data set comparing adherent and nonadherent patients, BP values and BP control rates were consistently better among adherent patients . Interesn = 1501) of the Hypertension Optimal Treatment (HOT) trial, where DBP ≤ 80 mmHg was associated with a significant reduction in major cardiovascular events compared to those assigned to the goal of ≤90 mmHg [Focusing specifically on our findings for diabetic patients, previous studies have shown that tight BP control in diabetic individuals is associated with better morbidity and mortality outcomes. In the UK Prospective Diabetes Study (UKPDS), diabetic patients with high BP were randomly assigned to receive either tight (<150/85 mm Hg) or less tight blood pressure control (<180/105 mm Hg) for a median follow-up of 8.4 years. Compared to the less intensively treated group and taking into account the fact that these targets are well above current guidelines, tight BP control was associated with a significant reduction in the diabetes endpoint and in the diabetes-related death, stroke, and microvascular endpoints , 12. The≤90 mmHg , 14.Some of our findings were counter-intuitive; specifically, cardiovascular disease  and renal impairment were associated with better BP outcomes. As we have argued before , the retBP outcomes are determined, at least in part, by the treating physician, in the case of our data, the GP. The intraclass correlation coefficients confirm that about a quarter of the variation in BP readings at follow-up may be accounted for by a clinician class effect . FurtherOur pooled analyses have limitations. All six studies were noncontrolled observational studies, not randomized controlled trials. On the other hand, the fact that the studies shared a nearly identical methodology and yielded a pooled sample in excess of 15,000 patients emphasizes the strength of the observed associations in the diabetic and nondiabetic groups. The groups were unbalanced in size, though they mirrored the distribution of diabetic and nondiabetic patients with hypertension. This could have affected the intercept and other estimates and their relative precision. Although not a guarantee, the large sample and the variation in outcomes observed should have buffered against this, thus foregoing the need to apply corrections to the intercept. We were interested in a comparative analysis of diabetic and nondiabetic patients; hence we did not construct a model that uses diabetic status as a cofactor. Relatively few physician-specific determinants were retained in the models, despite the finding that about a quarter of the variance in BP readings was attributable to a physician class effect. The six constituent studies involved valsartan-centric regimens and the findings may not be generalizable to other regimens. Applicable though not specific to our study, diurnal blood pressure variation could have affected measurements, though this would be difficult to control or account for in observational studies of real-world practice patterns and outcomes. The lack of generally agreed upon goodness-of-fit metrics for hierarchical linear and logistic regressions may have lent some subjectivity to the adoption of models.In both diabetic and nondiabetic patients, the use of valsartan-centric treatment regimens in second- or later-line antihypertensive treatment was associated with significant reductions in SBP and DBP values and with significant increases in SBP, DBP, and combined SBP/DBP control rates. Common and unique patient- and physician-related determinants of these outcomes were identified. These provide guidance to the management of hypertension in diabetic and nondiabetic patients treated with valsartan: the need for timely diagnosis of hypertension; the importance of aggressive treatment and avoiding therapeutic inertia; attention to such factors as BMI, lipid levels, comorbidities, adverse events, and relevant medical history; and assessing and promoting patient adherence. On the clinical side, clinicians are advised to spend more time with diabetic patients when they are first diagnosed with hypertension and to gain extensive clinical experience in managing hypertension. Valsartan proved to be both effective and safe in reducing blood pressure in adults with essential hypertension.


The tongue pressure was significantly lower in patients with pneumonia than in those without pneumonia. Using a Cox proportional hazard model for pneumonia onset with a cutoff tongue pressure value of 21.6 kPa and adjustment for age, sex, and National Institutes of Health Stroke Scale score at admission, the tongue pressure had additional predictive power for pneumonia onset . In the group with low tongue pressure, 27 of 95 patients showed improvement of tongue pressure within 2 weeks. Pneumonia occurred frequently in patients without improvement of tongue pressure, but not in patients with improvement . Tongue pressure is a sensitive indicator for predicting pneumonia occurrence in acute stroke patients.Swallowing dysfunction caused by stroke is a risk factor for aspiration pneumonia. Tongue pressure measurement is a simple and noninvasive method for evaluating swallowing dysfunction. We have hypothesized that low tongue pressure may be able to predict pneumonia occurrence in acute stroke patients. Tongue pressure was measured using balloon-type equipment in 220 acute stroke patients. The modified Mann Assessment of Swallowing Ability (MASA) score was evaluated independently on the same day. Tongue pressure was measured every week thereafter. An improvement in tongue pressure was observed within the first 2 weeks. Receiver operating curve analysis was performed to determine the ability of tongue pressure to predict modified MASA score <95, which suggests swallowing dysfunction. The optimal cutoff for tongue pressure was 21.6 kPa (χ Swallowing dysfunction is a critical issue in stroke patients. Prevention of aspiration pneumonia and improvement of nutrition are associated with reduced duration of hospitalization and mortality –3. PneumAmong the organs of the oral cavity, the tongue plays a major role in swallowing . The tonThe Mann Assessment of Swallowing Ability (MASA) score is an established bedside assessment tool that indicates the risk of swallowing dysfunction in stroke patients . The MASSwallowing dysfunction is a risk factor for pneumonia, and patients with low MASA score are at a significantly higher risk of aspiration pneumonia and mortality than patients with high MASA score . KnowingThe study protocols were approved by the ethics committee of Suiseikai Kajikawa Hospital and performed according to the guidelines of the national government based on the Helsinki Declaration of 1964. Written informed consent was obtained from all patients or their relatives. All data analyses were blinded.Consecutive acute stroke patients who were admitted to Suiseikai Kajikawa Hospital from September 1, 2014 to February 28, 2015 were enrolled in this prospective study. We included stroke patients with both ischemic and hemorrhagic stroke who were admitted within 1 week from onset, were aged ≥20 years, and consented to this study . Some patients had a history of stroke. We excluded patients who were in a coma , underwent craniotomy, or were on mechanical ventilation.Stroke subtype was determined according to the Trial of Org 10172 in Acute Stroke Treatment criteria . The diaThe balloon-type equipment consists of a disposable oral probe, an infusion tube as a connector, and a recording device. For tongue pressure measurement, the subjects were placed in a relaxed sitting position and asked to place the balloon in their mouths, holding the plastic pipe at the midpoint of their central incisors with closed lips. The subjects were asked to maintain this position as clinicians adjusted the probe and confirmed that it was in the correct position. The subjects were then asked to raise their tongue and compress the small balloon with their palate at maximum voluntary effort for 7 seconds as described previously . This meThe reliability of intraindividual measurement was previously reported . In thisThe modified MASA score and tongue pressure measurements were evaluated in the sitting position. These evaluations were performed every week until the patients were discharged from the hospital. The NIHSS score, tongue pressure, and modified MASA score were evaluated by different physicians or therapists who were blinded to the other findings.We monitored patients for signs of pneumonia during the 30 days following admission. If patients were discharged earlier than the 30th day, we monitored the patients until the day of discharge.t-tests or χ2 tests as appropriate. The baseline data in the stroke patients were analyzed, and two-step strategies were employed to assess the relative importance of variables in their association with tongue pressure using least square linear regression analysis. First, a univariate analysis was performed. Then, a multi-factorial analysis was performed with selected factors that had p<0.20 on univariate analysis. Receiver operating characteristic (ROC) analysis was performed to determine the tongue pressure predicting a modified MASA score <95, which suggests swallowing dysfunction. Kaplan–Meier and Cox proportional hazard regression analyses were performed to test the difference in the development of pneumonia between the high and low tongue pressure groups. A univariate split-plot approach was utilized for changes in tongue pressure over time, with the last observation carried forward for missing data. We considered p<0.05 as statistically significant.The data were expressed as the mean ± standard deviation or the median  for continuous variables and frequencies and percentages for discrete variables. Statistical analysis was performed using JMP 11 statistical software . The statistical significance of intergroup differences was assessed using During the study period, 296 stroke patients were admitted in our hospital. Nineteen patients or their relatives did not consent to this study, 19 patients were admitted >1 week after onset, 30 patients were in a coma, and 8 patients underwent craniotomy. Therefore, 220 patients were included in this study. The subjects’ backgrounds and characteristics at the time of enrollment are shown in t-test (p<0.001). In addition, the patients showed a significant increase with repeated measurements in tongue pressure during the observation period .We evaluated the change of maximum tongue pressure every week . An impr2 = 45.82, p<0.001, sensitivity 95.9%, specificity 91.8%, AUC = 0.97). Scatter diagrams for the association of tongue pressure with modified MASA score and NIHSS score are shown in Potential factors associated with tongue pressure at admission were evaluated from the factors listed in Thirty-five subjects developed pneumonia during the observation period. No patient had pneumonia before stroke onset. We compared the maximum tongue pressure at admission between patients with and without pneumonia. The tongue pressure was significantly lower in patients with pneumonia than in those without pneumonia . The resIn the group with low tongue pressure, 27 of 95 patients showed improvement of tongue pressure up to 21.6 kPa within 2 weeks from admission. Only two of them (7.4%) developed pneumonia during the observational period. In contrast, in the non-improved patients, 31 out of 68 patients (45.6%) developed pneumonia. There was a significant difference in pneumonia onset between the patients with improvement and those with no improvement .In this study, we measured tongue pressure in constitutive acute stroke patients using balloon-type equipment and found that it was significantly associated with the modified MASA score, which has been established as a reliable bedside assessment for detecting swallowing dysfunction . We alsoTongue pressure has been reported as low on the paralyzed side using sensor sheets in acute stroke patients . In thisThe MASA score is a reliable tool for evaluating the risk of swallowing dysfunction and can be used at the patient’s bedside with no special instruments ,13,20. HIn this study, the modified MASA score increased according to the tongue pressure and reached a maximum at a tongue pressure >21.6 kPa. Among Japanese healthy subjects, using the same balloon-based equipment, the standard maximum tongue pressure was found to be reduced with aging . The relationship between low tongue pressure and pneumonia onset might be explained by the presence of swallowing dysfunction.Tongue pressure improved favorably over the first 2 weeks of admission in this study. The onset rate of pneumonia was significantly higher in the group without improvement of tongue pressure than in the group with tongue pressure improvement. It has also been reported that tongue exercise in stroke patients significantly increases tongue pressure and reduced penetration . In thisThis study had several limitations. First, the tongue pressure may not be accurately evaluated in patients with a disturbance of consciousness, aphasia, or attention disorders. Regardless of tongue function, these conditions usually increase the risk of aspiration and pneumonia. In this study, we excluded patients in a coma, but included patients with a mild disturbance of consciousness, aphasia, or attention disorders, which limited the potential for selection bias. The modified MASA score includes factors such as consciousness, aphasia, and communication ability. Tongue pressure may decrease in association with a low modified MASA score and thus reflect the risk of swallowing dysfunction. A hybrid evaluation of modified MASA scores and tongue pressures may improve the assessment of swallowing function. Second, tongue pressures cannot reflect all functions of swallowing. Videofluoroscopic examination has been used for evaluating aspiration but has limitations, such as exposure to radiation and difficulties in conducting examinations in disabled patients and analyzing the biomechanics of swallowing organs . AdditioTongue pressure is a sensitive indicator for predicting pneumonia in acute stroke patients. Therefore, as a bedside assessment tool, tongue pressure measurements may be helpful for evaluating swallowing function.


Socioeconomic status-related factors have been associated with access to kidney transplantation, yet few studies have investigated both individual income and education as determinates of access to kidney transplantation. Therefore, this study aims to explore the effects of both individual income and education on access to kidney transplantation, controlling for both medical and non-medical factors. We linked the Swedish Renal Register to national registers for a sample of adult patients who started Renal Replacement Therapy (RRT) in Sweden between 1 January 1995, and 31 December 2013. Using uni- and multivariate logistic models, we studied the association between pre-RRT income and education and likelihood of receiving kidney transplantation. For non-pre-emptive transplantation patients, we also used multivariate Cox proportional hazards regression analysis to assess the association between treatment and socioeconomic factors. Among the 16,215 patients in the sample, 27% had received kidney transplantation by the end of 2013. After adjusting for covariates, the highest income group had more than three times the chance of accessing kidney transplantation compared with patients in the lowest income group (odds ratio (OR): 3.22; 95% confidence interval (CI): 2.73–3.80). Patients with college education had more than three times higher chance of access to kidney transplantation compared with patients with mandatory education . Neither living in the county of the transplantation center nor gender was shown to have any effect on the likelihood of receiving kidney transplantation. For non-pre-emptive transplantation patients, the results from Cox models were similar with what we got from logistic models. Sensitive analyses showed that results were not sensitive to different conditions. Overall, socioeconomic status-related inequities exist in access to kidney transplantation in Sweden. Additional studies are needed to explore the possible mechanisms and strategies to mitigate these inequities. Patients with End-Stage Renal Disease (ESRD) face many challenges, including increased burden of comorbidities, reduced life expectancy and impaired quality of life, compared to general population ,2. RenalPrevious studies have shown that inequities exist in access to kidney transplantation. Evidence, mainly from the USA, indicate that there is an association between kidney transplantation and race/ethnicity , gender In order to explore the role of SES on access to kidney transplantation, the first thing is the definition of SES. Three classic defining indicators of SES are income, occupation, and education . HoweverTwo studies have investigated the effect of education on access to kidney transplantation in the US, however the effect of education was inconsistent. Schaeffiner et al.  showed tThe studies above vary with regard to study design, patient selection, sample size, time period, statistical methodology, outcomes of interest, SES measures, and availability of potential confounders. Beyond this, the health care systems are also different across countries. For SES measures, previous studies generally only used one of the three classic defining indicators of SES, and (or) used the ZIP code or residential postcode data as the only SES indicator, which potentially lead to less accurate estimates of individual level SES ,15,17. FSweden is a country with universal health care system and has no waiting lists for ESRD care except for kidney transplantation, as assessment and allocation of kidneys are based on numerous factors . StudyinTherefore, the aim of this study is to assess the impact of SES on access to kidney transplantation using a Swedish population sample and register data. The main contributions of the present study are that we used longitudinal register-based individual SES measured as two of the main indicators of SES before start of RRT; individual disposable income and education. In addition, we also control extensively for both medical and non-medical factors.The Swedish Renal Register (SRR)  was linkThe LISA data set combines information from several demographic and socioeconomic population registers , such asThe study population was defined as all patients aged 18 years and older who started RRT between 1 January 1995, and 31 December 2013, as recorded in the SRR. During this period there have been no changes to the Swedish kidney allocation policy. Patients whose current treatment modality are unknown and patients who recovered or died within 91 days after start of RRT were excluded, in order to only include patients with chronic conditions. We lack information on counter-indication, i.e., we cannot identify patients that were never suitable for kidney transplantation. We therefore assumed that all patients starting renal replacement therapy were suitable for kidney transplantation.(i) Study outcome and SES indicatorsThis study investigated the association between SES and access to kidney transplantation, in terms of probability of receiving kidney transplantation. Access to kidney transplantation was defined as receiving a first living- or deceased donor kidney transplant during the study period.SES was measured in terms of income and education before the patient started RRT. Income was defined as the individual disposable income the year before the patient started RRT, derived from the household disposable income using consumption weights . We adju(ii) Control  variablesWe identified several baseline demographic and clinical variables before the patient started RRT, in order to adjust for potential confounding based on prior studies. These factors included age at start of RRT ,9, gende(iii) Statistical analysisWe described the frequency and distribution of patient characteristics in We used conventional logit models to study the association between SES and access to kidney transplantation, first in univariate models of the association between kidney transplantation and education and income respectively . For non-pre-emptive transplantation patients, we also used multivariate Cox proportional hazards regression analysis to assess the association between treatment and socioeconomic factors. We also conducted a sensitivity analysis where the sample were limited to the working aged patients (20–65 years of age) as there are concerns that employment status determines treatment choice . p-values < 0.05. All the statistical analyses were performed using Stata software, version 14.0 . The study has been approved by Lund Regional Ethical Review Board (Dnr: 2014/144).Statistical significance was assumed for 7 SEK). The final sample constituted of 16,215 adult patients (age ≥ 18 years) with RRT, of whom 4392 (27.1%) received a living or deceased donor kidney transplantation by 31 December 2013. The frequency and distribution of patient baseline characteristics were displayed in p < 0.001). For example, 25% of the patients in the transplantation group had only mandatory education while this was the case for over 50% of patients in dialysis. A small but significant difference in terms of citizenship was also noted where, against expectation, the proportion with Swedish citizenship was higher in the dialysis group. Patients were excluded if they had missing information for the main variables of interest, i.e., income , education , marital status . We also excluded patients with negative income  and extreme income   found thAxelrod et al.  found thAccess to kidney transplantation probably depends on both patients and physicians. In Sweden, the decision of RRT was made by nephrologists, based on the Swedish guidelines  and the One suggested explanation for shown income and education discrepancies is communication barriers between patients and health care provider, which might be easier to overcome for higher SES patients . This thSweden is a high-income country with universal health care system with a goal to achieve equity in health. Sweden has relatively strong income equity and low degree of inequity in terms of education ,34. HoweInteresting to note is that in the income models, there is no significant association between sex and access to kidney transplantation in our study, which is inconsistent with most other studies. This could potentially be explained by the large number of covariates included in the current study, including socioeconomic status. Further, our study confirmed the results of a previous study  where maWe conducted multifaceted analyses of SES-related variables in relation to access to kidney transplantation by using individually linked national register data, which provided us vast and detailed information. As many confounding factors as possible were adjusted for in order to minimize systematic errors. Furthermore, the Swedish Renal Register has an excellent coverage which gives the study high power and excellent generalizability for end-stage renal disease patients. We used individual SES-related data, which is expected to give more accurate effect estimates compared to geographically defined SES. The measures of SES were also measured before start of RRT, thanks to the longitudinal nature of the data. We also took into account all major comorbidities before start of RRT which is better when controlling for confounding, compared to studies in USA , AustralThe present study was in absence of biochemical data  which are known factors influencing access to kidney transplantation. However, these biochemical covariates are not expected to be strongly correlated with SES . The outAccess to kidney transplantation among Swedish end-stage renal disease patients is associated with common measures of socioeconomic status. Low income and education both reduced the chance of having kidney transplantation. However, reasons for these socioeconomic differences in the Swedish health care are unknown. The principal goal of Swedish healthcare system is to provide good and equal healthcare for all Swedish citizens. To this end, further studies are needed to identify the mechanisms of these inequities in order to construct effective interventions and policies. Moreover, since waiting list process is a key intermediate step to kidney transplantation, further studies can break down inequity of wait listing vs. inequity of kidney allocation, if data on the waiting list is available.


We aimed to determine the degree to which control targets of glycaemia and cardiovascular risk factors were achieved among patients with type 2 diabetes and to investigate sex- and age-related differences in this population.n = 32,638 cases). The proportions of patients who met control targets were determined according to sex and age groups. Comparisons between groups were conducted with t-tests for continuous variables, tests for trends in proportions for categorical and ordinal variables, and Pearson’s chi-square tests and binary logistic regression models for categorical variables.This cross-sectional, population-based study was conducted in Spain. Glycated hemoglobin (HbA1c), blood pressure, LDL-c, HDL-c, triglycerides, BMI, and smoking history were obtained from electronic clinical primary care records , blood pressure (130/80 mmHg), and LDL-cholesterol (100 mg/dl) were 60, 40 and 41 %, respectively. Women were less likely than men to meet the control targets of HbA1c (59 vs 61 %), LDL (35 vs 45 %), and HDL (58 vs 78 %). Patients under 65 years of age presented poorer control than older age groups. Only a minority of patients with type 2 diabetes met the composite target objectives for glycemic control, blood pressure, and LDL.There are differential gaps in the control results of female patients and younger patients, which should prompt improvements in case management and care. There is room for further improvement in the cardiometabolic control of patients with type 2 diabetes.The online version of this article (doi:10.1186/s12875-016-0533-9) contains supplementary material, which is available to authorized users. In 2015, there were an estimated 415 million diabetics worldwide, corresponding to 8.3 % of the population. This figure is estimated to increase to 642 million by 2040 [Chronic complications of diabetes impose morbidities that reduce life quality and expectancy. The Diabetes Control and Complication Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) showed that improved glycemic control was associated with a reduction in the risk of complications in type 1 and type 2 diabetics, respectively, and subsequent studies have shown that patients with diabetes can largely reduce the risk of cardiovascular disease by lowering blood pressure and LDL-cholesterol levels and avoiding tobacco consumption –8. AccorHowever, despite the scientific evidence and the high degree of consensus reached by experts, clinicians, and planners, achieving control targets remains a challenge. Several studies have shown that there is an important gap between recommendations and clinical practice, and only a minority of diabetic patients achieve the optimal control of glycaemia and cardiovascular risk factors –18.Electronic information systems that maintain updated information on every contact with patients are promising sources of information, particularly for the identification of health needs and the evaluation of interventions, because they can provide clinical practice information in real conditions. Thus, electronic information systems may help characterize which diabetic patients achieve or do not achieve control targets and may help identify the factors that determine those achievements, both of which are key issues to optimize in intervention strategies.This population-based study used existing electronic medical primary care records. The aims of this study were to assess the actual degree of achievement of glycemic control and cardiovascular risk factors and to investigate differences by sex and age among patients with type 2 diabetes.This cross-sectional study was conducted in Navarra, a community in northern Spain with over 600,000 inhabitants. In Navarra, Primary Care was developed in the 1980s and provides universal health coverage to the population. The territory is divided into 57 Basic Zones, each of which contains a team of general practitioners, nurses, and pediatricians who belong to the Regional Health Service of Navarre (RHSN). The populations of the Basic Zones range from 5000 inhabitants in rural areas to 25,000 in urban areas. The RHSN is essentially financed by general taxes, and health services, hospitalizations, and diagnostic procedures are free of charge for all citizens. A fraction of the medication cost is paid by patients, depending on their work status and income. Antidiabetic drugs are subsidized at least by 90 %.Within the RHSN, all patients with type 2 diabetes are managed by primary care teams. If the patients do not achieve an acceptable glycemic control they are derived to the ambulatory specialized care and then attended by endocrinologists. Also, they are treated by specialists when they are hospitalized or have complications. Thus, the Primary Care Electronic Medical Record System, named Atenea, contains information related to all the patients with type 2 diabetes managed by the RHSN. Specifically, it contains data about diagnoses, clinical variables, life styles, laboratory results, and prescriptions. Primary care electronic medical records were established in Navarra in the early 2000s and have been thoroughly used by all professionals since 2008. Electronic prescriptions were established in 2013.th, 2014. We obtained the following patient information: glycated hemoglobin (HbA1c), systolic and diastolic blood pressure (SBP and DBP), LDL- and HDL- cholesterol levels, triglycerides, weight, height, body mass index (BMI), smoking history, medications, date of registration in the information system, date of diabetic onset, and birth date. We obtained the latest results available within the 15 months prior to the data extraction date. We provide the number of data entries available for each of the study variables. Missing values imply that the patients had not had controls performed within the previous 15 months, and they can be regarded as a negative indicator of the process of care.The study population comprised all of the patients who were registered in Atenea with a diagnosis of type 2 diabetes , T90) on May 15The continuous variables were summarized by the mean and standard deviation; the categorical variables were summarized by frequencies. Comparisons by gender and age groups were conducted with t-tests for continuous variables, tests for trends in proportions for ordinal variables, and Pearson’s chi-square tests for categorical variables. The differences in the degree of achievement of control targets between men and women were assessed by binary logistic regression models, which included age and the duration of diabetes as covariates. The statistical analyses were conducted with IMB-SPSS 20 and R 3.2.0.The total number of registered Navarra Regional Health Service patients over 20 years of age with type 2 diabetes was 32,638. There were 18,188 men and 14,018 women with diabetes, which yielded an overall prevalence of 6.6 %  or 7.5 %  in males and 5.6 %  in females. The prevalence of diabetes was higher in men than in women among all age groups, peaking in the 80–85 year old group (25 %) and in the 85–90 year old group (20 %) for men and women, respectively . The overall duration of diabetes was 10.2 years, and the duration was an average of 1 year longer among women  than men (67.3 years) p <0.00. The ovep <0.001).The average HbA1c level was 7.1 % (64 mmol/mol), both in men and in women; 60.1 % of the patients had HbA1c levels less than 7 % (53 mmol/mol), 82.9 % had HbA1c levels less than 8 % (64 mmol/mol), and 3.4 % had HbA1c levels greater than 10 % (86 mmol/mol) (Tables p = 0.958) . Similar estimates were obtained after adjusting for age and diabetes duration . Some differences between age groups were observed. Among men, the proportion of patients with HbA1c levels less than 7 % (53 mmol/mol) was lower in the group younger than 65 years, whereas among women, there was no significant difference between age groups . Regarding HDL, 78 % of males and 58 % of females met the gender-specific targets. Adjusting for age, the men’s odds of having HDL levels greater than 35 mg/dL were 2.65 times higher than the women’s odds of having HDL levels greater than 45 mg/dL .Overall, 40.5 % of the patients with diabetes had an LDL level less than 100 mg/dl, 69.4 % had an HDL level greater than the target level , and 64.5 % had fasting triglyceride levels less than 150 mg/dl Table . The meap <0.001), whereas among women, no trend was observed across age groups. Using less stringent targets for HbA1c (8 % (64 mmol/mol) in patients over 75 years), the overall proportion of patients achieving the composite control objectives remained low (less than one out of six), and it remained lower in women as well.The proportion of patients achieving the composite triple target (simultaneous HbA1c <7 % (53 mmol/mol), BP <140/90 mmHg, and LDL <100 mg/dl; target A in Table 2 was greater than that of females. The largest difference in BMI was more than 10 percentage points among the 65–74 year age group. In both men and women, the prevalence of obesity decreased as age increased (p <0.001). The prevalence of smoking was lower among women than among men in all age groups  in our population were similar or slightly lower than those from other Spanish regions  and EuroThe proportion of patients meeting the blood pressure target of 130/80 mmHg in our study (40 %) was between 8 and 30 percentage points higher than those found in other European countries, but it was 10 percentage points lower than those reported in Canada, and in the USA from the National Health and Nutrition Examination Survey (NANHES) , 23, 24.Regarding lipid control, the proportion of patients who met the 100 mg/dl target for LDL in Navarre (40.5 %) was similar to those reported from the Spanish studies conducted in other regions and cited above, with differences of less than three percentage points. However, they were 15 percentage points lower than the proportions reported by Stone for eight European countries and the NHANES (2007–2010) for the USA. Additionally, we found poorer achievement of LDL control targets among women and younger patients. Beyond its statistical significance, it was remarkable that the proportion of target-meeting patients was an average of approximately 8 percentage points lower among women than among men and over 10 percentage points lower among patients younger than 65 years than among those older than 75 years. In other words, in terms of risk estimates, a woman’s likelihood of achieving cholesterol targets was notably lower than that of a man.Only a minority (14 %) of patients met all three control targets for HbA1c, BP, and LDL. Even if less stringent targets are combined, such as 8 % HbA1c (64 mmol/mol) for patients over 75 years, the composite target is only met by less than one-fifth of the patients. Women and patients under 65 years of age were less likely than men and older adults to achieve the composite control targets, following the same patterns observed for LDL and HbA1c. Because early control of the risk factors for microvascular and macrovascular disease may confer benefits, these results suggest that women and younger patients with diabetes require further attention.There are few studies about the inequalities in cardiometabolic control among patients with diabetes that combine sex and age. Poorer results among younger adults were also found by NHANES 2007–2010) in the USA, in which younger adults were less likely than older adults to meet goals for treatment and preventive practices. In general, sex inequalities were more often reported to be related to cardiovascular risk factors, and poorer glycemic control results were reported to be more related to younger ages, irrespective of the presence of complications , 20, 25.07–2010 iIn connection with sex-related control inequalities of cardiovascular risk factors, physician attentiveness and selective treatment prescription were suggested as factors that may account for the observed gaps. However, studies conducted in Europe did not support this hypothesis because they did not find therapies to be less stringent among females , 25. MorThis study provides representative snapshots of the degree of cardiometabolic control in a population of patients with diabetes in a Spanish region. Only a minority of patients met the goals of HbA1c, LDL, and blood pressure. Female patients and younger patients were less likely to achieve the control goals. The high prevalence of type 2 diabetes implies that a large portion of the population could benefit from general improvements in control and from reducing age and sex inequalities.


Aortic stiffness assessed by carotid-femoral pulse wave velocity (CF-PWV) is a predictor of mortality in several populations. However, little is known in kidney transplant recipients. Our objectives were to evaluate the ability of CF-PWV measured 3 months following transplantation to predict mortality, graft loss and its potential links to measured Glomerular Filtration Rate (mGFR) or kidney graft microvasculature parameters.The study is based on a monocentric retrospective cohort including 220 adult kidney graft recipients evaluated three months after transplantation. CF-PWV measures, clinical, laboratory and histological data performed at 3 (M3) and 12 months (M12) following transplantation were retrospectively collected. The two primary endpoints were all-cause mortality and occurrence of end stage renal disease (ESRD) defined by initiation of dialysis.After a median follow up of 5.5 years , death and graft loss occurred in 10 and 12 patients respectively. M3 CF-PWV was an independent mortality risk factor , despite no aortic stiffness variation during the first year of transplantation. Of notice, M3 CF-PWV was not associated with M12 mGFR or ESRD outcome. Graft microcirculation assessed by Banff vascular fibrous intimal thickening score (cv) worsened between M3 and M12 (p = 0.01), but no link was found with CF-PWV, mGFR or ESRD outcome. Surprisingly, acute rejections at M3 were associated after adjustment with mortality (p = 0.03) but not ESRD.Aortic stiffness measured 3 months after kidney transplantation is a strong predictor of mortality with no obvious influence on kidney graft microvasculature or graft loss. Chronic kidney disease (CKD) dramatically increases risk of cardiovascular morbidity and mortality. If renal transplantation significantly improves patients survival in comparison to dialysis , cardiovCarotid-femoral pulse wave velocity (CF-PWV) is a noninvasive and reproducible method currently considered as the gold standard for aortic stiffness measurement , and a mHowever little is known about arterial stiffness in kidney transplant recipients. Indeed, vascular damages occurring during pre-transplantation era appear as one of the main cardiovascular risk factor . Howeverst, 2017.The present study is a monocentric retrospective hospital-based cohort which included adult kidney graft recipients evaluated between June 2007 and January 2016 in the department of renal Physiology  three months after transplantation. Among the 406 recipients recorded, three months CF-PWV data were unavailable for 186 patients. Thus 220 patients were included in the study . Follow All participants signed a written informed consent and data collection was approved by the CNIL according to French legislation (n° 2065902v0).All kidney recipients received a standard immunosuppressive regimen including an induction therapy (methylprednisolone associated with basiliximab or Anti-thymocyte globulin) followed by a tritherapy associating CNI (tacrolimus or ciclosporin), corticosteroids (tapered to 5 mg/day after one month) and Mycophenolate mofetil.Clinical and laboratory data at 3 (M3) and 12 months (M12) after kidney transplantation at the physiology department were retrospectively collected. They included demographics, medical history, primary renal disease diagnosis, height and weight, resting blood pressure (BP), and medications. Elevated blood pressure was defined by a systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg and/or antihypertensive drugs intake. At each visits, GFR was measured by 51Cr-EDTA renal clearance as described previously . In summA protocol kidney graft biopsy was performed at M3 and M12 in n = 170 and 113 patients respectively . Renal graft biopsies were scored according to Banff classification by an experienced pathologist . We collPatients were examined in a quiet, temperature controlled room, and measurements were performed by experienced operators. Blood pressure was measured after 15 min of rest in a supine position using a sphygmomanometer and a cuff of appropriate size. The average of five consecutive measurements was calculated. CF-PWV was measured along the descending thoraco-abdominal aorta using the foot-to-foot velocity method with an automatic device . This method enables online pulse wave recording and automatic calculation of CF-PWV by dividing the distance between carotid and femoral measurement sites by the transit time of the wave. Validation of this method and its reproducibility have been previously reported . CF-PWV The two primary endpoints were all-cause mortality and occurrence of ESRD defined by initiation of dialysis. Events were identified from patients’ medical records or through record linkage with the French national registry of transplant recipients . All survival data and graft survival data were right-censored on January 1st, 2017.In the overall population, we first used non-parametric Wilcoxon Mann-Withney or Fischer’s test as appropriate, to compare patients’ characteristics (at 3 and 12 months after grafting) according to the upper CF-PWV quartile. We then performed cause-specific Cox regression models to estimate crude and adjusted hazard ratios (HR) and their 95% confidence intervals (95% CI) for death associated with 3 months CF PWV, M3 mGFR or Banff vascular parameters. Adjustment covariates were similar in all analyses: recipient age, gender and diabetes. The proportional hazard assumption was checked for each model to ensure of their validity. Kaplan-Meier method was used to represent percentage survival as a function of the presence of the studied outcomes (death or ESRD). A log rank test was used to compare survival curves. All analyses and graphics were performed in R Statistical Software using the R-Studio interface (Version 3.3.2).2, p = 0.15, respectively) whereas renal microvessels ) significantly worsened .Among the 220 patients included in the study , 169 (76.8%) repeated the evaluation at 12 months. After a median follow up of 5.5 years , 12 patients underwent dialysis (5.45%) and overall mortality was reported for 10 patients (4.55%) and cardiovascular mortality for 7 patients (3.2%). Graft rejection was encountered in 11.2% of patients at M3. No patients were lost during follow up . Among tAs shown Tables Among high M3 CF-PWV patients (>10.6 m/s), a significant CF-PWV improvement was noticed between M3 and M12 , despite a similar MBP and no significant cv score or mGFR variation (p = 0.61 and 0.42 respectively). Conversely, in the lower M3 CF-PWV group, no CF-PWV improvement was noticed  though cv score worsened .As shown However, as shown In contrast to mortality, graft survival was similar between M3 CF PWV groups . Indeed,Our results show that M3 CF-PWV value is an independent risk factor for mortality with no influence on renal outcome.Our results are consistent with one previous study reporting in a large cohort of kidney transplant recipients (4.2 years median follow up), that a high 8-week CF-PWV value (above 12 m/s) was indeed a mortality risk factor . HoweverWhen studying the whole population, a striking finding is the fact that M3 CF-PWV value  was a mortality risk factor despite no significant aortic stiffness change during the first year of kidney transplantation. Thus transplantation would exert a protective effect on aortic stiffening compared to dialysis  but obviOf notice, the finding that M3 CF-PWV was associated with mortality  is puzzling and should deserve confirmation in further studies (drug toxicity? immunologic factors?). Nevertheless, our data showing a significant association between acute rejection and M12 mGFR decrease and not ESRD outcome, confirm and extend a previous report showing in living donor renal transplanted patients that rejection was associated only with the first year eGFR decline and not after (at the end of the follow up) .51Cr-EDTA urinary clearance technique. Despite a relatively small cohort size thus explaining few death and graft loss events, our results demonstrate a significant link between a noninvasive aortic stiffness measurement and a hard clinical endpoint: mortality. Cardiovascular mortality was specifically addressed in This study had several strengths. It is the first study to combine two gold standard methods: aortic stiffness assessed by CF-PWV and mGFR measured with Three months CF PWV is a strong predictor of mortality with no obvious influence on renal outcome or kidney graft microvasculature, thus suggesting an efficient hemodynamic graft autoregulation at least in most patients. Slow aortic stiffness evolution reported for most patients, strengthens the view that transplantation, in comparison to dialysis, ensures a significant cardio vascular protection during the first year, and in some cases a reversal of arterial maladaptative remodeling , despiteS1 Dataset(XLSX)Click here for additional data file.S1 Fig(PNG)Click here for additional data file.S1 TableNew onset diabetes after transplantation, mGFR: measured Glomerular Filtration Rate, PRA: panel reactive antibody, MBP: Mean Blood Pressure, PP: Pulse Pressure, SBP: Systolic Blood Pressure, DBP: Diastolic Blood Pressure, Banff CV: vascular fibrous intimal thickening score, Banff ptc: peritubular capillaritis score.ACE: angiotensin-converting enzyme inhibitor, ACR: albumin creatinine ratio, ARB: angiotensin receptor blocker, BMI: Body Mass Index, CCB: calcium channel blocker, NODAT: (PNG)Click here for additional data file.


Individuals with sickle cell disease particularly with the homozygous (SS) genotype historically have relatively low blood pressure. Nonetheless, they develop vasculopathy-associated organ dysfunction and the risk of organ dysfunction increases at blood pressures that are normal in the general population. This phenomenon is termed relative systemic hypertension (RSH) with a systolic blood pressure range of 120–139 mmHg, and diastolic blood pressure range of 70–89 mmHg. The significance of RSH lies in its association with renal insufficiency, pulmonary hypertension, stroke and propensity to progress to systemic hypertension. We conducted a retrospective chart review of 1,000 adults with sickle cell disease at the Ghana Institute of Clinical Genetics, to determine the prevalence of RSH in sickle cell disease in Ghana and associated complications. We found a high prevalence of RSH and hypertension with a relatively low frequency of renal insufficiency. Pulse pressure, a predictor of mortality, was higher in males of all ages. We anticipate that providing an estimate of the burden of RSH will heighten its recognition and clinical management among health care providers. This mutation results in an aberrant hemoglobin (Hb) with altered physical properties, referred to as sickle hemoglobin (Hb S). Hb S polymerizes when deoxygenated, distorting erythrocytes into the characteristic sickle shape. Individuals with SCD have two copies of the βs gene (SS) or one βs gene in combination with hemoglobin C (SC) or β-Thalassemia  mutations. Clinically, SCD is characterized by chronic hemolytic anemia and episodic painful vaso-occlusion of variable severity that culminates in organ dysfunction and reduced life expectancy [Sickle cell disease (SCD) is a hemoglobinopathy caused by a β-globin gene  have lower blood pressure (BP) than age, race and gender-matched controls –5. CompoAnalysis of data from SS adults enrolled in the Sickle Cell Pulmonary Hypertension Screening Study identified a risk of developing, within a 2-year period, new onset or worsening pulmonary hypertension and renal insufficiency at BPs considered to be within normal range for the general population. This obThe birth prevalence of SCD in Ghana which has a population of approximately 28 million is 2% . The preThe Ghana Institute of Clinical Genetics (GICG), Korle-Bu Teaching Hospital in Accra, Ghana has provided medical care to over 25,000 registered individuals with SCD since its inception in 1974. With over 10,000 patient visits per year, it is one of the largest SCD clinics in Africa. Patients with SCD 13 years and older are referred to GICG from other institutions or at age 16 years from the Pediatric Department of Korle-Bu Teaching Hospital.The study population comprised adults with SCD aged ≥ 18 years who visited GICG for care at least once within the period of the study.The Ethics and Protocol Review Committee of the School of Biomedical and Allied Health Sciences, College of Health Sciences, University of Ghana, approved the study (Ethics Identification Number: SBAHS-ET/0244365283/AA/HIA/2012-2013)Over a 10-month period (October 2014 to July 2015), we conducted a retrospective review of 1,000 patient charts to determine the prevalence of RSH in adults with SCD receiving regular care at the GICG. The objective for our study was to provide an estimate of the prevalence of RSH in a large representative sample of adults with SCD in Ghana.Charts were selected by convenience sampling when the patients visited the clinic for medical care. The reasons for visiting the clinic were varied and included acute illness, pain, fever, a follow-up after acute illness or a non-acute visit for comprehensive care. Chart reviews were performed by two investigators who obtained blood pressure values and dates on which they were collected, located corresponding laboratory results and averaged out laboratory variables. This data was then entered by the second investigator into a Microsoft Excel spreadsheet. Using a data extraction manual created for the study to optimize inter-rater reliability, we collected demographic, clinical and laboratory data from the charts. A unique study identification number was assigned to each chart selected. All selected charts were marked with labels bearing the study ID to avoid duplication of charts. The charts were reviewed first for eligibility as per the data extraction manual.Individuals 18 years or older with homozygous or compound heterozygous sickle cell disease, seen at least once at the GICG during the study period were eligible for inclusion.Other non-sickle hemoglobinopathiesAge less than 18 yearsFrom each eligible chart, the following data were collected: Hb types (as defined by hemoglobin electrophoresis), gender, age, systolic and diastolic blood pressure, dates on which blood pressures were recorded, CBC, renal function tests, presence of pre-existing diagnoses of hypertension and associated medication. Specifically, the three most recent blood pressure readings taken on three separate days were recorded. The blood pressures were obtained using an automated blood pressure monitor that had been in use in GICG for 2 years including the period of the study. We collected hemoglobin and total white blood cell (WBC) counts obtained on the same days as the blood pressures, averaged them and recorded the average values in the chart. Finally, complications attributable to SCD documented in each eligible chart were recorded.Normal blood pressure was defined as systolic blood pressure <120mmHg and diastolic blood pressure < 70 mmHg in the absence of antihypertensive medication.Relative systemic hypertension was defined as either a systolic blood pressure (SBP) of 120 to 139 mmHg, or a diastolic blood pressure (DBP) of 70 to 89 mmHg in a subject without documented diagnosis of hypertension and not taking antihypertensive medication.Hypertension was defined as either blood pressure of ≥140mmHg (systolic) or ≥ 90 mmHg (diastolic) in the chart or blood pressure of any value along with documented treatment with one or more antihypertensive medications.SCD type–The current diagnostic modality for SCD at GICG is cellulose acetate electrophoresis which can distinguish between hemoglobin S and C but is limited in distinguishing between Hemoglobin S, D and G In the absence of genetic testing or confirmatory tests such as HPLC or Isoelectric focusing to provide a definitive phenotype, the SCD phenotypes “SS, SC, SS/SD, SS/SD/SG” were assigned based on cellulose acetate electrophoresis alone. The latter two phenotypes SS/SD and SS/SD/SG reflect the limitations of cellulose acetate electrophoresis in distinguishing hemoglobin S, D, and G.The prevalence of RSH was calculated using single blood pressure measurements for the sample and then stratified by age, gender and genotype. The prevalence of hypertension was determined. We used ANOVA and Chi-square  to compare the continuous and categorical variables of the following three groups; those with normal blood pressure, RSH and hypertension. Multinomial logistic regression was used to detect significant predictors of RSH and hypertension. In an alternative analysis, the prevalence of RSH and hypertension among patients who had all three blood pressure readings taken within the same year was calculated using averaged systolic and diastolic blood pressure from repeated measures. A p-value of 0.05 or less was considered statistically significant. Stata 14.1  and GraphPad Prism version 7 were used.Of the 1,000 charts reviewed, 875 met the eligibility criteria of having documented phenotype consistent with homozygous or compound heterozygous SCD and age ≥18 years. Of the other 125 charts, two were excluded for having non-SCD hemoglobinopathies, presumed homozygous C disease and β-Thalassemia major; the rest were aged < 18 years or had unavailable data. Female subjects constituted 63% of the sample (n = 555). Total hemoglobin values (Hb) and total white blood cell counts (WBC) were available for 869 and 872 respectively. The median age, characteristics of and complications documented in the study population with confidence intervals where applicable, are shown in The prevalence of RSH in the study population using single most recent blood pressure was 45%. The prevalence of hypertension by the same method was 19%. The age, gender and phenotype-specific prevalence of both RSH and hypertension with 95% confidence intervals are shown in The probability of having normal blood pressure declined rapidly with age starting in the early twenties as relative hypertension peaked at 25–30 years. There was a marked increase in hypertension after 40 years of age .We observed a marked reduction in the proportion of young adults aged 25-30-years with hypertension as well as the peak of relative systemic hypertension in the same age group .The most frequently documented complications in this population were avascular necrosis and leg ulcers. Initial associations of gallstones and leg ulcers with RSH did not reach statistical significance once adjusted for total hemoglobin. white blood cell count and age. We did not find any documented history of stroke in our study though this was certainly searched for. The summary of the association of complication with each blood pressure category is shown in In patients who had multiple blood pressure measures with a one-year period, there was an increase of 1.4 (P = 0.005) in systolic blood pressure and an increase of 0.8 (P = 0.050) in diastolic blood pressure from the first to last measurement. None of demographic or clinical factors predicted the magnitude of time dependent changes in systolic blood pressure. Time dependent increase of diastolic blood pressure was more significant in male (P = 0.016) and younger (P = 0.026) patients.Pulse pressure is a marker of endothelial dysfunction and a predictor of all-cause, cardiovascular and coronary mortality. We found a higher pulse pressure in males of all ages compared to females within our study population. Pulse pressure increased with age .To test the reliability of our single blood pressure measurements, we repeated the analysis of our results using averaged blood pressure for subjects who had multiple measurements during a one-year period (n = 697). With this amendment, the prevalence of relative systemic hypertension and hypertension were 47% and 15%, respectively. Using this definition did not affect the predictors of relative systemic hypertension and hypertension. Also, the predictors of pulse pressure did not change using the average of three BPs.Our study corroborates previous studies that describe lower blood pressure in individuals with homozygous SCD (SS) compared to those with SC. Relative systemic hypertension was present in 45% of the study population while 19% had hypertension. We demonstrate a steady increase with age in the proportion of subjects who met study-defined criteria for hypertension, with a steep rise after age 40. Most importantly, we noted a higher pulse pressure, a predictor of cardiovascular mortality, in males than females at any given age, independent of the total hemoglobin level. Complications identified in the study population are skewed towards those that are symptomatic or evident on physical exam. Young adults aged 25 to 30 years and males were identified as a particularly high-risk group for morbidity from RSH. Interestingly, we did not identify documented strokes while reviewing the charts for complications associated with SCD.Relative systemic hypertension significantly increases the risk of stroke  and mortHypertension is reportedly uncommon in SCD. Previously published studies of hypertension in SCD report prevalence ranging from 3.2 to 10% , 8. A meThe lack of expected age-related increase in BP has been documented in SCD, except for males in whom DBP increased slightly . In contWe attribute these findings to the older age, SC and possibly to SCD-related organ damage. The proximity of BP in SC to that of the general population , 8, 15 mThe SCD-associated complications encountered in our study are listed in Interestingly, our results show elevated pulse pressure in males more than females at all ages. This is likely an important part of reason behind the greater mortality noted in males with SCD. Elevated pulse pressure (PP) has emerged as a strong predictor of all-cause and cardiovascular and coronary mortality and is considered an indirect measure of proximal aortic stiffness . In SCD,The strengths of the study are in the large number of subjects, providing a representative sample of both SS and SC, which make our findings more generalizable. This will facilitate subject enrollment or clinical trials and expedite the translation of novel disease-modifying therapies for SCD worldwide.The limitations of this study are in its retrospective nature and the limited resources at the site of study, which limited our ability to obtain more specific information on Hb types and complications in steady state. Our sample may have inherent selection bias of individuals that seek care more frequently. Some of the blood pressure measurements were done during patient visits for pain or acute illness, situations that can temporarily elevate or lower blood pressure. We did not stratify our study population by the reason for their visit. To reduce this effect, we performed a repeat analysis of a subset of the charts reviewed using 3 blood pressure values taken on different days and if a blood pressure reading was repeated on the same day , we used the second value for that day, presuming the health provider perceived the first value to be abnormal. This introduces a limitation itself but acknowledges that the patients’ clinical complaint or reason for visiting the GICG could modify their baseline blood pressure.Relative systemic hypertension is prevalent in the adult SCD population in Ghana. Young adults aged 25 to 30 years, who have the highest prevalence of RSH, and males with high pulse pressures above a threshold previously associated with increased mortality have emerged as two high-risk sub-groups within the population requiring intervention.


Cerebral autoregulation status can be derived from NIRS and arterial blood pressure. The relationship of both cerebral and somatic StO2, fractional tissue oxygen extraction (FTOE), and cerebro-splanchnic oxygenation ratio (CSOR) with measured vital sign parameters for Neonatal Intensive Care Unit (NICU) patients has not been well studied.Near-infrared spectroscopy (NIRS) has been used to non-invasively measure specific tissue oxygen saturation .The aims of this study are to determine if significant relationships of brain and somatic StONeonates weighing < 5 kg, preferentially with an arterial catheter, were enrolled in the study. FORE-SIGHT Elite  cerebral and somatic NIRS sensors were placed over the abdominal right upper quadrant and right frontal-temporal area of the forehead for 24 h. Vital signs including arterial MBP were recorded simultaneously from the patients’ bedside monitor. Data were averaged into 60 s windows and analyzed using linear regression. Results were stratified by gestational age (GA), birth weight (BW), and presence of brain abnormality.p value < 0.0001) were noted between NIRS parameters and vital signs. When stratified by BW, there was a positive correlation between brain StO2 (StO2B) and MBP in the <1,500 g BW group (r = 0.193) and a negative correlation in >1,500 g group (r = 0.057). Brain and somatic FTOE in <1,500 g BW revealed a negative correlation with MBP . In patients with an abnormal brain scan, a positive correlation was noted between StO2B and MBP (r = 0.354), and a negative correlation was noted between FTOE-B and MBP (r = 0.305). Generated pressure passive index plots suggested good cerebral autoregulation at low normal MBP ranges for lower weight and GA subjects.Data were obtained from 27 subjects (GA 22.2–42 weeks). Two subjects did not have an arterial line, thus they were not included in the MBP measurements. There were ~28,000–31,000 paired data points per comparison. Significant positive and negative correlations (2 and FTOE with measured vital sign parameters in NICU patients.There is a significant correlation between cerebral and somatic StO Continuous monitoring in the intensive care unit is necessary in evaluating clinical status fluctuations of a patient. Invasive techniques such as blood pressure monitoring via an umbilical arterial catheter or a peripheral arterial line may be the gold standard, but they do pose the risk of bleeding, infection, thrombosis, or vasospasm  require constant monitoring of their vital signs asospasm .via continuous cardiorespiratory monitors and pulse oximetry is most common. It allows for detection of heart rate, respiratory rate, and arterial oxygen saturation. Near-infrared spectroscopy (NIRS) allows for specific tissue oxygen saturation (StO2) measurement continuously and non-invasively by measuring chromophores in the body such as hemoglobin, myoglobin, and cytochrome aa3  of cerebral perfusion to determine the relationship between pressure passivity, cerebral autoregulation, and mean blood pressure (MBP).In this prospective observational study, we sought to determine if there are significant relationships between NIRS cerebral and somatic StOThis study was approved by the Institutional Review Board (IRB) at Children’s National with waiver of documentation of informed consent. Infants were recruited from the 54-bed NICU at Children’s National Health System. After verbal parental agreement for voluntary participation, a study information sheet was provided to the parents of infants admitted to the NICU between July 15, 2015 and December 17, 2016, preferentially with an umbilical or peripheral arterial line. Infants with congenital heart disease, history of abdominal surgeries, and/or surgical necrotizing enterocolitis were excluded. Patients’ demographic and clinical data including gender, race, birth weight (BW), weight at the time of the study, gestational age (GA), age at the time of study, total combined age (GA + age at the time of study), primary diagnosis, brain examination by ultrasound or MRI, length of hospital stay, and morbidity were documented. Abnormal brain scan results included presence of intraventricular hemorrhage, cerebellar hemorrhage, encephalopathy, or structural brain anomalies.2S measurements and right frontal-temporal area of the forehead (StO2B measurements) for 24 h. Arterial lines were placed either prior to transfer to or at Children’s National NICU for patients’ clinical management only. Pulse oximetry (SpO2) was used to obtain arterial oxygen saturations (SaO2). Remaining vital signs  data were obtained from the patient’s bedside monitor. The data were recorded simultaneously every 2 s on a laptop computer. NIRS monitoring did not interfere with patient care and was allowed to be stopped at the option of the caregiver or parents.Twenty-seven infants born between 22 and 42 weeks gestation were enrolled in this study. Subjects were monitored with a pulse oximeter, peripheral or umbilical arterial line, and FORE-SIGHT Elite  cerebral and somatic NIRS sensors. NIRS sensors were placed over the right upper anterior abdominal wall for StO2 (StO2B), somatic StO2 (StO2S), SpO2 and for vital signs, blood pressure , heart rate, and respiratory rate were calculated for each 60-s binned window. Mean StO2B and StO2S data points were omitted for mean arterial blood pressures beyond physiologic range  Brain fractional tissue oxygenation extraction (FTOE-B) was calculated by the following equation: 2B, StO2S, SpO2, FTOE-B, FTOE-S, and CSOR were correlated with vital sign parameters and age indices to determine a correlation coefficient “r” to determine any relationships.Due to numerous data points, the data were averaged into 60-s windows and combined for all subjects for the respective parameter of interest, such as mean value for brain StOO2SStO2B . Using l2B and MBP sampled at 2 s were used for the analysis. PPIs derived from coherence values were calculated in the frequency band of 0.00167–0.15 Hz (6.67 s to 20 min sampling window) and binned every 30 s for the respective MBP epoch if a change in MBP was detected. Once completed, PPI vs MBP epochs were plotted for each subject and then averaged together per MBP epoch in several subject groupings by BW/GA, current weight/total age, and brain scan results  to determine any differences. A high PPI is indicative of poor cerebral autoregulation function for a given MBP range.A PPI of cerebral perfusion as a function of MBP was calculated and binned in 5 mmHg epochs for MBP for each subject using coherence analysis with a prototype cerebral autoregulation algorithm –16. StO2Between July 15, 2015 and December 17, 2016, 27 infants  were enrolled in this study. The median GA was 31.2 weeks (range: 22.2–42 weeks), and median BW was 1,266 g . Median length of stay was 49 days (range: 7–189 days). Two patients had confirmed cases of sepsis, 2 patients had NEC, 11 patients had IVH, and 3 patients died before discharge. Two subjects did not have an arterial line, and thus they were not included in the mean arterial pressure measurements. Table r) values of StO2B, StO2S, SpO2, FTOE-B, FTOE-S, and CSOR compared to blood pressure, heart rate, respiration rate, and subject age indices for all subject data combined using the 60-s binned data. Although the correlations were weak, all comparisons were statically significant (p < 0.0001). The oxygen saturation parameters  showed positive correlation with blood pressure and most age indices and a negative correlation with heart rate. FTOE-B and FTOE-S showed negative correlation with blood pressure and age indices. CSOR did not correlate as highly as the other oxygenation indices with vital signs and age indices. Respiration rate showed low correlation with the oxygenation indices.Table 2B, StO2S, and SpO2) vs MBP of subjects divided into two groups: low birth weight  vs moderate birth weight . The LBW group showed a higher correlation (Pearson r) with the oxygen saturation parameters, where the strongest correlation was with StO2B. Figures r) with FTOE-B and FTOE-S, where the strongest correlation was with FTOE-B. CSOR showed low correlation with MBP, with little differences between LBW and MBW. Figures 2B and FTOE-B vs MBP with subjects grouped by brain scan results: normal brain (n = 10) and abnormal brain (n = 15). Both the linear regression slopes and r values were higher than the previous LBW group for StO2B and FTOE-B vs MBP. Note that 11 of 15 subjects with brain abnormalities were in the LBW group.Figures 2B values are shown for each MBP epoch. StO2B may decrease as PPI increases for low MBP values, while StO2B can become variable with increased PPI in higher MBP ranges. If the upper blood pressure autoregulation inflection point is crossed, resulting in decreased autoregulation function, StO2B may increase due to excessive cerebral perfusion.Figures n = 12)] vs MCW [current weight > 2.2 kg/total age > 35 weeks (n = 13)]. The plots look similar as the LBW and LCW groups were the same subjects except for one subject. Figure n = 10) and abnormal brain (n = 15). Other comparative analyses were limited by insufficient group sizing.Figure 2, cerebral and somatic FTOE, and CSOR parameters with vital signs for neonates admitted to Children’s National NICU with various levels of clinical status severity.This study sought to determine any relationship between NIRS cerebral and somatic StO2 levels of 85–100% were maintained for a wide range of MBP in infants weighing >1.5 kg and >32 weeks GA compared to the LBW group. As anticipated, lower MBP allowed for normal SpO2 levels in the LBW group, as this subgroup of patients has a lower normal range of blood pressures compared to the MBW group.Normal range arterial blood pressures are expected to provide adequate oxygenated blood to target organs. Acceptable SpO2 and MAP, NIRS can serve as a surrogate for cerebral blood flow and possibly assess the integrity of cerebral circulation  at Children’s National. Parents of all the patients in the study, as our patients are neonates and unable to agree to participate in the study, gave verbal agreement for voluntary participation in the study. Parents could also refuse to participate in the study. A study information sheet was provided to the parents of infants who participated in the study. Required written consent for participation in this study was waived by the IRB. The NIRS system is considered a non-significant risk device and is used routinely in the clinical care of many patients in the NICU. This study was observational only and did not affect the care provided to the neonates.BM-B identified and enrolled subjects, collected and analyzed data, drafted the initial manuscript, and approved the final manuscript and is accountable for all aspects of the manuscript. VA and RM determined the conception and design of data acquisition, reviewed and revised the manuscript, approved the final manuscript, and are accountable for all aspects of the manuscript. KR-B identified and enrolled subjects, collected and analyzed data, reviewed and revised the manuscript, approved the final manuscript, and is accountable for all aspects of the manuscript.The authors have no financial interests in the product discussed in this manuscript. Study NIRS monitor and sensors were supplied by CASMedical Systems, Inc. .