To assess whether B-type natriuretic peptide (BNP) can serve as a predictor of end-stage chronic heart failure (CHF) in patients with severe systolic dysfunction of the systemic right ventricle (SRV).We performed a retrospective analysis in 28 patients with severe systolic dysfunction of the SRV (ejection fraction 23 ± 6%) who were evaluated as heart transplant (HTx) candidates between May 2007 and October 2014. The primary endpoints of the study (end-stage CHF) were progressive CHF, urgent HTx, and ventricular assist device (VAD) implantation. Plasma BNP levels were measured using a chemiluminescent immunoassay.P˂0.001). The following variables with corresponding areas under the curve (AUC) were identified as the most significant predictors of end-stage CHF: BNP (AUC 1.00), New York Heart Association functional class class III or IV (AUC 0.98), decompensated CHF in the last year (AUC 0.96), and systolic dysfunction of the subpulmonal ventricle (AUC 0.96).During median follow-up of 29 months , 3 patients died of progressive CHF, 5 patients required an urgent HTx, and 6 patients underwent VAD implantation. BNP was a strong predictor of end-stage CHF (hazard ratio per 100 ng/L: 1.079, 95% confidence interval, 1.042-1.117, BNP is a powerful predictor of end-stage CHF in individuals with systolic dysfunction of the SRV. Transposition of the great arteries (TGA), the aorta and the pulmonary artery, is a congenital heart defect with a morphologically right ventricle pumping blood into systemic circulation. It occurs either as complete TGA (D-TGA) or congenitally corrected TGA (ccTGA). D-TGA is characterized by dextroposition of the systemic ventricle, sinistroposition of the subpulmonal morphologically left ventricle, and right-sided rotation of the great arteries. On the other hand, the term ccTGA describes sinistroposition of the the systemic ventricle, dextroposition of the subpulmonal morphologically left ventricle, and left-sided rotation of the great arteries . PreservTricuspid regurgitation, systolic dysfunction of the SRV, and chronic heart failure (CHF) were associated with impaired survival both in individuals with D-TGA -4 and ccWe performed a retrospective analysis in all patients with SRV who were referred to the Heart Failure Clinic of our institution  between May 2007 and October 2014. Available demographic, clinical, laboratory, electrocardiographic, and echocardiographic data from the first visit to our clinic were collected from the institutional database. Doses of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers were expressed as a percentage of the maximum recommended daily dose according to the latest European Society of Cardiology guidelines (The study group consisted of 28 consecutive patients with SRV. This group included 21 patients (75%) after atrial switch due to D-TGA  and 7 patients (25%) with ccTGA. The following associated lesions were corrected during the primary cardiac surgery: ventricular septal defect in 6 patients with atrial switch, ventricular and atrial septal defect in 1 patient with ccTGA, and ventricular septal defect and valvular pulmonary artery stenosis in another patient with ccTGA. 5 patients had a history of reoperation: 3 patients with atrial switch and 1 patient with ccTGA required tricuspid valve replacement, while additional 1 patient after atrial switch underwent aortic valve replacement due to severe regurgitation. All 20 men (71%) and 8 women (29%) with mean age of 34 years (range 15-65) had at the first evaluation severe systolic SRV dysfunction with mean ejection fraction of 23 ± 6% ranging from 14% to 35%. Median BNP plasma level was 618 ng/L (interquartile range [IQR] 86.5-1363.5) (Table Blood samples for the measurement of BNP plasma levels were collected into chilled tubes containing EDTA (1 mg/mL) and aprotinin . Test tubes were immediately centrifuged. Plasma BNP levels were measured using a chemiluminescent immunoassay . The lower limit of detection was 10 ng/L, intra-assay coefficient of variation (CV)<3.8%, and inter-assay CV<5.3%. For serum creatinine assessment, we used an enzymatic method .Echocardiography was performed by experienced operators in accordance with the current guidelines of the American Society of Echocardiography ,16. Stan2 analysis or Fisher exact test. Continuous variables were assessed for normality using the Kolmogorov-Smirnov test. Normally distributed continuous variables are shown as a mean and standard deviation. Not-normally distributed continuous variables are shown as a median and interquartile range. Continuous variables were compared using the t test for unpaired data or non-parametric Mann-Whitney test where appropriate. Univariate Cox regression models were used to identify the predictors of the primary endpoint. Kaplan-Meier curves were constructed to illustrate the relationship between selected variables and time-dependent events. Due to limited sample size and number of events, we could not apply multivariate Cox regression analysis. Receiver operating characteristic curve (ROC) analysis and Youden’s index (sensitivity + specificity – 100) were used to assess and compare the performance of selected variables to predict the primary endpoint. For all tests a probability value of P < 0.050 was considered significant. All analyses were performed using the statistical software SPSS, version 17.0 .Categorical data were described using absolute and relative frequencies, and compared using χDuring a median follow-up of 29 months (IQR 9-50), 14 patients experienced the primary endpoint. 3 patients (11%) died of end-stage HF after 5, 14, and 15 months. 5 patients (18%) required an urgent HTx (after 4-14 months) and 6 patients (21%) underwent VAD implantation  after 0-17 months as a bridge to transplant. The remaining 14 individuals were free of the primary endpoint , whereas the above mentioned 14 patients were included in the group B (unfavorable outcome).Unfavorable outcome in group B was predicted by the following signs of advanced CHF: a history of decompensated HF in the last 12 months, higher New York Heart Association (NYHA) functional class, higher heart rate, lower systolic blood pressure, markedly elevated plasma levels of BNP , higher To the best of our knowledge, this is the largest clinical study that evaluated the prognostic value of BNP in individuals with severe systolic dysfunction of the SRV. First, BNP was found to be a powerful predictor of end-stage CHF in individuals with systolic dysfunction of the SRV. Second, NYHA functional class III or IV and a history of decompensated CHF, well-known predictors of adverse outcome in patients with SRV, and any dysfunction of the subpulmonal ventricle provided additional important prognostic information.Systolic SRV dysfunction limits the long-term prognosis both in individuals with atrial correction of D-TGA and ccTGA who frequently die of CHF or malignant arrhythmias. Recent studies demonstrated a cumulative survival after Mustard correction of D-TGA in the range of 80% and 68% at 20 and 39 years, respectively . AnotherAlthough most patients with systolic dysfunction of the SRV receive conventional pharmacotherapy for CHF, it should be noted that in this population beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers showed mixed results -27. ManaThere are several limitations of this study. First, the limited number of patients and retrospective study design that reflect the rare occurrence of CHF due to SRV failure may limit general applicability of the study results. A larger study, perhaps a multicenter one, might increase the strength of our findings. However, relatively high mortality and morbidity of the studied population allowed even prognostic assessment. Second, limited number of events precluded the use of multivariate models. Already two variables in one model would result in the risk of “overfitting” . FinallyIn conclusion, BNP is a powerful predictor of end-stage CHF in individuals with congenital heart disease and systolic dysfunction of the SRV. NYHA class III or IV, a history of decompensated CHF, and any systolic dysfunction of the subpulmonal ventricle provided important additional prognostic information. These findings might facilitate prognostic stratification in patients with CHF due to the SRV failure and could improve the timing of heart transplant enlistment or VAD implantation.


Intradialytic hypertension was associated with a high mortality risk. We examined the relationship between intradialytic hypertension and metabolic disorders in hemodialysis treatment patients.Kt/V for urea. Normalized protein catabolic rate (nPCR), as a marker of protein intake, was calculated. Sodium removal was determined as percent sodium removal. Metabolic acidosis was determined by serum bicarbonate less than 22 mmol/L. Interdialytic urine volume more than 100 ml was recorded. Intradialytic hypertension was defined by an increase in systolic blood pressure equal to 10 mmHg from pre- to posthemodialysis. Arterial stiffness was assessed as carotid-femoral pulse wave velocity (c-fPWV) and carotid augmentation index (AIx). Chi-square tests and logistic regression analysis were applied for intradialytic hypertension prediction. We studied 76 patients in online hemodiafiltration. Dialysis adequacy was defined by Kt/V for urea, than patients without intradialytic hypertension. They also had increased sodium removal and pulse pressure related to less urine output. Serum bicarbonate was inversely associated with c-fPWV . Chi-square test showed significant association between intradialytic hypertension and serum bicarbonate < 22 mmol/L , which was supported by an adjusted model. Patients with intradialytic hypertension were older and had significantly lower hemoglobin, nPCR, urine output, and serum bicarbonate and significantly higher c-fPWV, though similar  The intradialytic hypertension was significantly associated with metabolic disorders including malnutrition/inflammation and uncontrolled metabolic acidosis in hemodialysis treatment patients. Severe metabolic acidosis may reflect sodium imbalance and hemodynamic instability of these patients resulting in volume overload and increased vascular resistance. In chronic kidney disease, hypertension is influenced by both blood pressure (BP) and the progression of renal disease. In end stage renal disease (ESRD) on maintenance hemodialysis, hypertension is a main feature and more than 85% of new patients with ESRD present with hypertension .Hypertension in these patients is multifactorial. Significant implicating factors include persistent hypervolemia and elevated peripheral vascular resistance. In patients with 3 hemodialysis sessions per week, blood pressure increases during the interdialytic interval according to weight gain, particularly in older patients and those with higher dry weight. The main goal of hemodialysis treatment is the control of extracellular volume (ECV), because inadequate sodium and fluid removal results in fluid overload, increased BP, and increased mortality . ElevateThe association of hypertension with adverse outcomes has been demonstrated, due mainly to its relationship with abnormalities in cardiac structure and cardiac function including left ventricular hypertrophy, diastolic dysfunction, and arterial stiffness –6.However, BP shows a dynamic nature during dialysis procedures, including modest decreases, a common phenomenon, and intradialytic hypotension and hypertension, which are two special situations significantly related to an increased risk of mortality in these patients , 8. It hIn this study, we examined the relationship between intradialytic hypertension and metabolic disorders in permanent hemodialysis treatment patients.This is a dual-center observational cross-sectional study, which was reviewed and approved by the “Laïko, University General Hospital of Athens” and the Renal Unit of “Diagnostic and Therapeutic Center of Athens Hygeia SA” Institutional Review Board. 76 patients  were included in the study, and they or their legal guardian provided informed oral consent prior to study enrolment.The applied hemodialysis modality was online-predilution hemodiafiltration (onl-HDF) in all subjects. The median time in hemodiafiltration therapy was 5 years ± interquartile range 3–10.2 surface area by high-flux synthetic membrane, defined by an ultrafiltration coefficient > 20 ml/h [Kt/V/session  [Kt/V/session was less than 1.2.The hemodiafiltration treatment was performed 3 times weekly with a dialysis time of 4 h per session. We used a filter of 1.5–2 m 20 ml/h  in all p volume) . We exclWe also excluded patients <18 years of age at initiation of dialysis treatment and patients with less than 6 months of follow-up or those without regular vascular hemodialysis access. Subjects with autoimmune diseases, infections, and atrial fibrillation malignancy and those with interdialytic weight gain of more than 5% of total body weight were not included in the study. Interdialytic weight gain was calculated as the mean value over the exposure period of one treatment month.The enrolled patients were on a free regular diet and they did not apparently have interdialytic peripheral edema or extradialytic orthostatic hypotension. Nineteen of the participants were current smokers (a ratio of 25%). Twenty of the enrolled patients disposed residual renal function defined by an interdialytic urine volume of more than 100 ml (a ratio of 26.3%).3 per os or warfarin therapy. All the included patients were treated by erythropoietin α or β agents.Only calcium-free phosphate binders including sevelamer carbonate, lanthanum, and/or aluminium hydroxide were prescribed in combination with vitamin D derivatives for the regulation of bone disease (a ratio of 44.7%). None of our participants was receiving NaHCOIn our data, the cause of renal failure included hypertensive nephrosclerosis at a ratio of 32.9%, chronic glomerulonephritis at a ratio of 28.9%, polycystic disease at a ratio of 11.8%, diabetic nephropathy at a ratio equal to 9.2%, and other causes at a ratio of 17.1%.Blood pressure data were considered over a treatment month, as the exposure period, which typically included 12 dialysis sessions per patient. Systolic blood pressure (SBP) was measured with the patient in the seated position using automated oscillometric devices immediately before, after, and during  all treatment sessions. We excluded treatments in which SBP was measured <3 times.n = 15, a ratio 19.7%).We defined intradialytic hypertension as an increase in SBP equal to 10 mmHg from pre- to posthemodialysis according to previous reports . ParticiOn the other hand, the measurement of blood pressure at home was requested using an automatic sphygmomanometer Omron M4-I . The blood pressure was doubly measured two times per day, in the morning after rising and in the evening in a fasting, calming, and resting state, and two means were recorded per day. Their average was used for statistical analysis. Mean peripheral blood pressure (MBP) was calculated as MBP = DBP + 1/3 (SBP − DBP).We also used a 24-hour ambulatory blood pressure monitor with the Mobil-O-Graph device for verification of measurements and whether the mean blood pressure values significantly differed from home recorded values; the means of 24-hour monitoring were used for statistical analysis rather than the means by home measurements.n = 29, a prevalence of 38.2%) assessed by 24-hour monitoring and/or home measured according to recommended standard protocol or subjects with an individual hypertension history were considered hypertensive and every one of them was regularly receiving antihypertensive therapy including calcium channel blockers, beta-blockers, or inhibitors of angiotensin II AT1 receptors.In accordance with the KDOQI hypertension threshold , the parBefore the midweek dialysis session, the participants rested for at least 10 minutes and hemodynamic measurements were performed. Arterial stiffness was measured as carotid-femoral pulse wave velocity (c-fPWV) and carotid augmentation index (AIx) using the SphygmoCor System®  according to the manufacturer's specifications . In eachKt/V for urea [Kt/V for urea per dialysis session during a treatment month was used for statistical analysis.Blood samples were obtained just before the start of the mean weekly dialysis session in a twelve-hour fasting state from the vascular access of enrolled subjects and serum was separated and processed for various assays. At the end of the session, blood samples was drawn at 2 min after dialysis from the arterial dialysis tubing after the reduction of blood pump speed to less than 80 ml/min in order for the dose of dialysis session to be calculated using sp for urea . The mea2, which determines the metabolic acidosis presence, rather than respiratory alkalosis, which is another clinical condition that causes decreased bicarbonate level, but without acidemia [In each subject, four sequences of samples (every week within the exposure period) were obtained for the serum bicarbonate measurements, and their average was used for statistical analysis. We paid attention thus to the low serum bicarbonate level to be combined with low arterial pH (acidemia) and decreased PCOacidemia .+) levels both at the start and at the end of the treatment session were also measured by biochemical analysis. Sodium removal was determined as percent sodium removal (PSR) using the following formula: (Na+ pre − Na+ post/Na+ pre) × 100.Albumin, calcium (Ca) corrected for the albumin levels, phosphate (P), high-density lipoproteins (HDL), and low-density lipoproteins (LDL) were measured by photometric biochemical analysis . The ratios of LDL/HDL and Ca × P products were calculated. Sodium  assuming that the change in body weight during a dialysis session represents the change in extracellular volume due to ultrafiltration, in combination with clinical characteristics related to an incorrect dry body weight including the presence of interdialytic peripheral edema, interdialytic orthostatic hypotension, or extradialytic uncontrolled blood pressure.Hematological analyzer  was used for hemoglobin (Hb).The concentration of intact parathormone (i-PTH) was measured by radioimmunoassay .High sensitivity C-reactive protein (hsCRP) serum concentrations were measured using enzyme-linked immunosorbent assay  according to the manufacturer's specifications.Metabolic acidosis was defined by serum bicarbonate concentrations less than 22.0 mmol/L, which were measured in gas machine  by an electrode-based method taking care of the blood specimens .Normalized protein catabolic rate for dry body mass (nPCR) was calculated from the urea generation rate . Body mat-test for two groups and data that showed skewed distributions were compared with Mann–Whitney U test.Data were analyzed using SPSS 15.0 statistical package for Windows  and expressed as mean ± standard deviation or as median value (interquartile range) for data that showed skewed distribution. Differences between mean values were assessed using unpaired p values less than 0.05 were considered significant. We built a model using logistic regression analysis by enter method in order to define the risk factors which could impact the installation of intradialytic hypertension in our data using traditional and specific variables for these patients.Correlations between variables were defined by Spearman's coefficient and the relationships between categorical variables were defined by chi-square tests. n = 15) and without (n = 61) intradialytic hypertension are shown.In We observed that the patients with intradialytic hypertension were older and had significantly lower Hb, nPCR, urine output, and bicarbonate serum concentrations than patients without intradialytic hypertension. However, they had significantly higher c-fPWV and AIx in comparison with patients without intradialytic hypertension. They also had higher sodium removal, Ca × P products, PP, dialysis vintage, and hsCRP, but lower i-PTH than patients without intradialytic hypertension. Both groups of patients had similar BMI, albumin, dialysis sufficiency, and interdialytic weight gain.x2 = 5.6, p = 0.01 and x2 = 4.2, p = 0.04, resp.)  and sympathetic nervous system, endothelial cell dysfunction, erythropoiesis-stimulating agents, and bone mineral disease abnormalities has been suggested.Hypervolemia is a well-recognized risk factor for hypertension among dialysis patients. Patients with intradialytic hypertension have been found to be more chronically volume-overloaded than other hemodialysis patients, although they typically may have small interdialytic weight gain and clinically do not appear to be volume-overloaded , 22. IndTo obtain a good BP control in dialysis patients, we must define the correct dry weight and individualize the adequate sodium concentration in dialysate, thus to achieve a zero intradialytic sodium balance . ElevateOn the other hand, although a causal role of volume overload has not been established, factors beyond volume overload are important mediators of intradialytic hypertension in many patients . A link Clinical characteristics associated with intradialytic BP rise include older age, lower body weight, lower serum creatinine and albumin, and utilization of more antihypertensive medications , 33. LowMalnutrition and anemia have already been reported as specific cardiovascular risk factors for dialysis patients and each of the MIA syndrome components worsens the survival of these patients , 36. MalKt/V for urea and they followed the same therapy rules. However, the older age, the cooccurrence of malnutrition/inflammation, the bigger dialysis vintage, and the lower urine output may contribute to a higher metabolic acidosis state in intradialytic hypertension patients. The unadjusted association between uncorrected metabolic acidosis and intradialytic hypertension was found to be significant in our data, as a confirming finding.In this study, we observed that our subjects with intradialytic BP rise had significantly lower serum bicarbonate levels than the other patients. This finding cannot be attributed to reduced dialysis treatment adequacy or other treatment related conditions, because both groups of patients had obtained a similar spInterestingly, our subjects with intradialytic hypertension and higher metabolic acidosis state had simultaneously less urine output and increased arterial stiffness markers, which also reflect fluid overload apart from vascular injury, as it was explained above. Moreover, we did note significantly inverse association between c-fPWV and serum bicarbonate concentrations. In support, our adjusted model discovered that the low serum bicarbonate in conjunction with high sodium removal, older age, and a long dialysis time were important risk factors for manifested intradialytic hypertension adjusting for diabetes mellitus, dialysis adequacy, extradialytic hypertension, and MIA syndrome components. Particularly, the high sodium removal increased the risk for intradialytic BP rise to 1.9-fold (1.09–3.2) in our data.These findings could suggest that uncorrected metabolic acidosis results in intradialytic BP rise in hemodialysis patients, due to its relationship with sodium imbalance and volume overload in these patients, even if clinically nonapparent, apart from its role in the increased ionized plasma calcium, which is already associated with hypertension . PreviouThe manifestation of intradialytic hypertension was significantly associated with metabolic disorders including malnutrition/inflammation and uncontrolled metabolic acidosis in permanent hemodialysis treatment patients. Severe metabolic acidosis may reflect sodium imbalance and hemodynamic instability of these patients resulting in volume overload, despite being clinically nonapparent and despite the increased vascular resistance.


Measurement of albuminuria to stratify risk in chronic kidney disease (CKD) is not done universally in the primary care setting despite recommendation in KDIGO  guidelines. Pharmacist medication therapy management (MTM) may be helpful in improving CKD risk stratification and management.2 and uncontrolled blood pressure (≥150/85 mmHg). In the three pharmacist MTM sites, pharmacists were instructed to follow a protocol aimed to improve adherence to KDIGO guidelines on testing for proteinuria and lipids, and statin and blood pressure medical therapy. In the four control clinics, patients received usual care. The primary outcome was proteinuria screening over a follow-up of 1 year. A telephone survey was administered to physicians, pharmacists, and patients in the pharmacist MTM arm at the end of the trial.We conducted a pragmatic, cluster-randomized trial using seven primary care clinic sites in the Geisinger Health System to evaluate the feasibility of pharmacist MTM in patients with estimated glomerular filtration rate (eGFR) 45–59 ml/min/1.73 mn = 24) and control (n = 23) patients, although pharmacist MTM patients tended to be younger  and less likely to have diabetes  or baseline proteinuria screening . Mean eGFR was 54 ml/min/1.73 m2 in both groups. The pharmacist MTM intervention did not significantly improve total proteinuria screening at the population level . However, it tended to increase screening of previously unscreened patients . In general, the intervention was well-received by patients, pharmacists, and providers, who agreed that pharmacists could play an important role in CKD management. A few patients contacted the research team to express anxiety about having a CKD diagnosis without prior knowledge.Baseline characteristics were similar between pharmacist MTM (Pharmacist MTM may be useful in improving risk stratification and management of CKD in the primary care setting, although implementation requires ongoing education and multidisciplinary collaboration and careful communication regarding CKD diagnosis. Future studies are needed to establish the effectiveness of pharmacist MTM on slowing CKD progression and improvement in cardiovascular outcomes.NCT02208674ClinicalTrials.gov, Registered August 1, 2014, first patient enrolled September 30, 2014 Chronic kidney disease (CKD) affects one in seven adults in the U.S. and is estimated to account for more than 20 % of annual Medicare expenditures , 2. OptiDespite these recommendations, adherence to CKD guidelines is low; for instance, proteinuria screening rates in CKD patients range from 10 to 45 % across different health systems. –10 SimilPharmacist medication therapy management (MTM) has been shown to be effective in treating hypertension , 17, diaThe pilot study was a prospective 2-arm, cluster-randomized pragmatic trial, funded by Geisinger Clinic. We recruited participants from seven primary care clinic sites at Geisinger, a large integrated health system that includes 43 community practice clinic sites across central and northeastern Pennsylvania and an extensive pharmacist-led MTM program. The Geisinger Clinic institutional review board (IRB Number 2014-0251) approved the protocol. A modified informed consent process was utilized, which entailed full disclosure and explanation to eligible patients (delivered by mail) and to participating providers (by email) at the primary care sites. Eligible patients were asked to respond within 7 days if they wished not to participate; if no response was received participation was assumed. Health care providers were informed of their patients’ participation in the study.2 and uncontrolled blood pressure (mean blood pressure over past year ≥ 150/85). To ensure that patients were regularly receiving care at Geisinger, we only included those who had at least two outpatient blood pressure measurements within the last 12 months, and a serum creatinine scheduled within the next 30 days. Exclusion criteria included hospitalization in the past year or positive pregnancy test during the past 12 months. The first participants were enrolled into the study in September 2014 and the last participant finished the study in February 2016.Trial participants were adults actively receiving primary care with Geisinger Health Plan insurance at one of the 7 Geisinger primary care clinic sites with eGFR between 45 and 59 ml/min/1.73 mWe utilized a cluster randomized design, with primary care sites at Geisinger defined as the cluster unit. From a total of 43 primary care clinic sites, an initial six sites were selected based on the presence of an MTM pharmacist on site and similar numbers of patients, physicians and physician assistants. These six initial clinic sites were randomized 1:1 using a computer program into the pharmacist MTM or a control arm. A 7th clinic site was added in December 2015 due to slow recruitment in the control arm. We used the electronic health record (EHR) to identify eligible patients.All Geisinger clinics include a pharmacist trained in the management of common chronic conditions, such as dyslipidemia, diabetes, and hypertension. Training for hypertension management included a lecture from a hypertension expert, 8 week self-study of hypertension training modules, clinician shadowing, and an annual hypertension competency exam. The approach to hypertension management included assessing medication adherence, lifestyle modification , medication initiation/titration according to Journal of the American Medical Association (JAMA) Hypertension 2014 guidelines [Patients in the control clinics did not receive any additional care for this study although all primary care providers received a lecture and brief written summaries about KDIGO guideline-based CKD risk stratification and management before the study began . PatientThe primary study outcome was screening for proteinuria by urine ACR or protein/creatinine ratio (PCR) within 1 year of the enrollment date. Exploratory outcomes included screening for hyperlipidemia within 1 year of the enrollment date, end-of-trial statin treatment, achievement of blood pressure goals , and treatment with ACEI or ARBs for proteinuric CKD. Outcomes were ascertained by extraction of EHR data and chart review. Blood pressure outcomes were assessed by averaging all outpatient clinic blood pressure readings up to 1 year after the enrollment date. Proteinuric CKD requiring more aggressive BP goal and ACE/ARB therapy was defined as ACR ≥ 30 mg/g for patients with diabetes and ACR ≥ 300 mg/g for patients without diabetes, per KDIGO guidelines .At the end of the study, we administered telephone surveys of patients, providers, and pharmacists to assess the acceptability of the pharmacist MTM intervention. Patients were asked about the effectiveness of the pharmacist in providing kidney care, their comfort level with the pharmacist, and whether they wished to receive further pharmacist care. Pharmacists were asked about their confidence in managing blood pressure and lipids in patients with CKD, how helpful they believed their actions were for patients, and whether pharmacists should play an active role in managing blood pressure, lipids, and other aspects of CKD. Providers were asked whether they were aware that the pharmacist was managing some of their patients with CKD, and if so, how confident and satisfied they were in the pharmacists managing blood pressure and lipid-lowering medications. Providers were also asked whether pharmacists should play an active role in managing blood pressure, lipids, and other aspects of CKD.We used data from the clinic visit closest to the enrollment date to determine baseline characteristics including age, gender, systolic blood pressure, diastolic blood pressure, serum creatinine, smoking status, use of statin, angiotensin converting enzyme inhibitor (ACEI), and angiotensin receptor blocker (ARB) medications, and International Classification of Diseases, Ninth Revision (ICD-9) diagnoses of hypertension, diabetes, coronary artery disease, dyslipidemia, and heart failure.Assuming proteinuria screening rates of 30 % in the control group and 80 % in the intervention group, we estimated that a sample size of 72 patients would give us > 80 % power to detect a difference in screening rates between study arms at an alpha level of 0.05 with a small-moderate intracluster correlation coefficient.Descriptive statistics including mean and standard deviations for continuous variables, and frequency percentages for categorical variables are presented. Demographic and clinical characteristics between the MTM and the control arms were compared using t-test and chi-squared tests for continuous and categorical data, respectively. We used random effects logistic regression to determine the effects of pharmacist MTM on each outcome in the total population. For the proteinuria screening outcome, we conducted a subgroup analysis only including patients who were unscreened at baseline, accounting for the clustered design. We also conducted sensitivity analyses, adjusting for differences in baseline age, diabetes, and adherence to the particular outcome. For the proteinuria screening outcome, this analysis only included the previously unscreened subgroup, and only adjusted for age as all patients with diabetes successfully achieved this outcome.All analyses were performed using SAS Statistical Software .There were 73 patients eligible for the study  who were contacted from September 2014 to February 2015. Of the 73 eligible patients, 26 patients  opted out of the study prior to any intervention, leaving 24 pharmacist MTM patients and 23 control patients with data for analysis , and more likely to have an ICD-9 diagnosis of diabetes  (Table p = 0.6), dyslipidemia , coronary artery disease , and congestive heart failure (0 % in both groups). Mean baseline eGFR was similar in both groups , as was systolic blood pressure , diastolic blood pressure , use of ACEI or ARB medications , and use of statin medications . At baseline, 24/47 (50.1 %) of the patients already met the proteinuria screening goal, 19/47  already met lipid screening goals.Patients in the control group tended to be older . At the end of the trial, proteinuria screening was not significantly different between the pharmacist MTM group and the control group . However, among patients who were previously unscreened, 11/14 (78.6 %) in the pharmacist MTM group and 3/9 (33.3 %) in the control group completed proteinuria screening  (Table p = 0.04). The proportion of patients who completed lipid screening increased from 87.5 to 100 % in the pharmacist MTM group; all patients in the control group had already completed lipid screening at baseline.At the baseline visit, 10/24 (41.7 %) of the pharmacist MTM and 14/23 (60.9 %) in the control group had already achieved the proteinuria screening goal (p = 0.9). Findings were consistent when adjusted for differences in baseline characteristics . The pharmacist MTM intervention also had no significant effect on statin therapy ; the proportion of patients in the pharmacist MTM group who were on statins was 54 % at baseline and 50 % at the end of the trial compared to 70 % at baseline and 74 % at the end of the trial in the control group. Results were largely unchanged after adjustment for baseline characteristics . The proportion of proteinuric CKD patients taking an ACEI or ARB increased from 2/4 (50 %) at baseline to 4/4 (100 %) at the end of the trial in the pharmacist MTM group; 3/3 (100 %) patients in the control group were taking an ACEI or ARB at the beginning and the end of the trial. Orders written by pharmacists in the pharmacist MTM arm included urine albumin/creatinine ratios (14), lipid profiles (1), statin medications (5), ACEI or ARB medications (3), and other blood pressure medications (2).Pharmacist MTM had no significant effect on blood pressure control or statin therapy Table . The proA total of 14/24 58.3 %) of patients, 9/9 (100 %) of primary care providers, and 4/4 (100 %) pharmacists of the three intervention clinic sites answered end-of-study surveys. Only 6/14 (43 %) patients recalled having contact with a pharmacist during the trial; these patients in general were very satisfied with the care they received, felt better-informed about kidney health, and were interested in receiving future pharmacist care . Indeed our pharmacist intervention was effective in improving proteinuria screening only in previously unscreened patients, and we were not powered to show significant differences in blood pressure or statin treatment outcomes. Still, our pilot study provides valuable insights in conducting a pragmatic randomized trial in a health system, and suggests that pharmacist MTM to provide CKD care is feasible and generally well-accepted by patient, pharmacists, and providers.A few studies have examined the use of non-physician providers in addition to nephrologists to improve management of CKD. A randomized trial of 474 patients with CKD in Canada found no benefit of nurse-coordinated care in collaboration with a nephrologist versus usual care, on eGFR decline or controlling risk factors . InitialVariability in the success of team-based approaches on blood pressure control may be due to differences in the intervention, study population, and access to nephrology care. Important intervention characteristics to consider include the intensity of the intervention, the ability of non-physicians to order medications, and the method by which blood pressure is measured. Recent randomized trials utilizing home blood pressure monitoring, delivered by pharmacists, have demonstrated success in achieving improvements in blood pressure control , 17. WheThere were several valuable lessons learned during this pilot study that may help inform conducting future pragmatic trials in health systems. Many patients initially included in the study met their blood pressure and other KDIGO goals at their most recent appointment, and did not receive any specific pharmacist MTM intervention. However, blood pressure readings can vary substantially, and some of these controlled patients later had blood pressure readings higher than their goal range. Use of real-time registry data may assist pharmacists/providers in tracking blood pressure readings over time and intervening when appropriate. Some providers and pharmacists questioned the appropriateness of following KDIGO guidelines that conflicted with 2013 ACC/AHA lipid guidelines  and JAMAAn unexpected complication of the trial was patient concern created by the ‘opt-out’ letter mailed to eligible patients during the early phase of the trial. While actively receiving care, several patients were not aware that they had CKD. The reasons for the lack of awareness cannot be identified. However, it seems likely that providers are either not recognizing or prioritizing moderate CKD, and thus may not have educated their patients about this condition. It is also important that future pragmatic trialists utilizing a similar, modified informed consent process recognize the possibility of disease unawareness amongst eligible patients. As a result of the opt-out process, there may have been selection bias as more patients in the pharmacist MTM arm opted out of the study compared to patients in the control arm. Future pragmatic trials trying to optimize CKD management should consider altering the study design (e.g. delayed randomization), such that waived consent is acceptable to the IRB, provided risk is minimal. This would help prevent selection bias that may have occurred by patients opting out of the research study. Considering concerns about lack of representativeness in past trials and the desire to demonstrate real-world effectiveness, pragmatic trials will likely become more and more common in the future .There were limitations in our small pilot study. Cluster randomization of a small number of clinics resulted in some marginal differences in baseline age and diabetes status and recruitment was stopped early; however, the goal of the study was less about efficacy and more about identifying potential barriers for a full pragmatic trial. Perhaps the most important result from this pilot study was that power may be a significant concern – many patients were already adherent to KDIGO screening and management guidelines. A full pragmatic trial may require a system-wide intervention, or even involvement of multiple health systems. Utilization of other healthcare staff or automated ordering in risk stratifying CKD patients may be needed to optimize healthcare resources. Another limitation was that blood pressure was measured routinely in clinic and not standardized. A future pragmatic trial involving blood pressure as a major outcome needs to standardize clinic blood pressure readings in a way that minimizes interruptions to clinic workflow, and may want to consider utilizing home blood pressure monitoring. Although the vast majority of patients reported high levels of satisfaction with the pharmacist MTM arm, there was a higher rate of opt-out in this arm, which may have resulted in more compliant patients in the pharmacist MTM arm. Our study population was limited to a mostly white, rural population in an integrated health system; thus, results may not be generalizable to other populations. On the other hand, our pragmatic study design in an integrated health system represents a strength. The intervention was easily implementable given the infrastructure at Geisinger where pharmacists are available at all primary care clinic sites and already actively managing diabetes, anticoagulation, and hypertension. Both pharmacists and providers expressed considerable enthusiasm for extending management to include more aspects of CKD care. Future pragmatic trials involving pharmacists may want to incorporate other dimensions of CKD care, such as CKD-related drug safety.In conclusion, pharmacist MTM improved proteinuria screening in previously unscreened patients with CKD, and was generally well-received by patients, pharmacists, and providers. Future research is needed to examine whether pharmacist MTM could improve KDIGO guideline adherence and CKD patient outcomes.


Handgrip strength is useful for the diagnosis of sarcopenia. We examined the associations of handgrip strength with all-cause mortality, cardiovascular events, and hospitalization in patients with type 2 diabetes. From April 2013 to December 2015, we conducted a retrospective cohort study to examine patients with type 2 diabetes whose handgrip strength was measured at our hospital. All patients were followed up until May 2016. A total of 1,282 patients (63.8 ± 13.9 years) were enrolled and followed up for 2.36 ± 0.73 years. During the follow-up period, 20 patients (1.6%) died, 14 (1.1%) experienced cardiovascular events, and 556 (43.4%) were admitted to our hospital for any diseases. Multiple regression analyses revealed that handgrip strength was favorably associated with abdominal obesity and renal function. Moreover, Cox proportional hazard analyses with adjustment for potential confounding variables revealed that handgrip strength was significantly associated with occurrence of CVD events and hospitalization in all subjects. In addition, handgrip strength was significantly associated with mortality and hospitalization in men and with hospitalization in women. Handgrip strength could be a prognostic indicator for health as well as a diagnostic marker of skeletal muscle mass loss in Japanese patients with type 2 diabetes. Sarcopenia has been independently associated with physical disability and functional impairment2 and mortality3. From 1990 to 2013, diabetes has been one of the top 20 disease and has consistently contributed to global burden of disease and disability-adjusted life years4. Patients with type 2 diabetes show lower energy expenditure, duration of physical activity5, cardiorespiratory fitness7, and muscle strength9 than those of non-diabetic subjects. Type 2 diabetes has been shown to be associated with skeletal muscle loss in community-dwelling older individuals10. Diabetic neuropathy is also associated with muscle weakness. Patients with diabetic sensorimotor polyneuropathy have significantly lower knee extensor strength than those without the disease11. Resistance training can significantly improve the speed of ankle and knee strength generation in patients with diabetic neuropathy compared with patients without diabetes12. Longitudinal studies have shown that muscle weakness evaluated by handgrip strength is associated with the risk of incident diabetes in older individuals14. Furthermore, sarcopenic obesity (combination of muscle mass decline and excess adiposity)15, which is common in older patients with type 2 diabetes, increases all-cause mortality16. Hence, prevention of sarcopenia is important in the management of type 2 diabetes.Sarcopenia, which is defined as age-related loss of muscle mass, strength, and function17. Previous studies have shown a significant relationship between handgrip strength and mortality in young, middle-aged, and older individuals20. Leong et al.21 recently reported that handgrip strength was negatively associated with all-cause mortality, cardiovascular mortality, myocardial infarction, and stroke, whereas no significant associations of handgrip strength with the incidence of diabetes and risk of hospital admission for chronic obstructive pulmonary disease, pneumonia and respiratory illness were observed. This large, longitudinal, international, joint study also suggested that handgrip strength is a useful predictor for the risk of cardiovascular disease (CVD) and mortality. However, to date, there have been few studies that have investigated the association between handgrip strength and prognosis in a type 2 diabetic population. Thus, this study aims to examine the associations of handgrip strength with mortality, CVD events, and hospitalization in patients with type 2 diabetes.Handgrip strength is a simple and cost-effective method for evaluating overall muscle strength and is useful for the diagnosis of sarcopenia2. The patients’ mean duration with diabetes was 11.7 ± 11.0 years. Demographic, anthropometric, and clinical data at baseline are listed in Table This study enrolled 1,282 patients (709 men and 573 women) with type 2 diabetes. The mean age of study participants was 63.8 ± 13.9 years. The mean body mass index (BMI) was 25.5 ± 5.4 kg/m75), and the number of hospitalizations. In contrast, handgrip strength was positively correlated with BMI, waist circumference, alcohol consumption, exercise time, walking time, amount of locomotive exercise, skeletal muscle mass, systolic and diastolic blood pressure, estimated glomerular filtration rate (eGFR), and duration before hospitalization. Similar correlations were observed in both men and women; however, there was no significant correlation of handgrip strength with walking time, locomotive regular exercise, fat mass percentage, and systolic blood pressure in men and with exercise time, fat mass percentage, and systolic blood pressure in women , augmentation index  died, 14 (1.1%) experienced CVD events, and 556 (43.4%) were admitted to our hospital for any disease. Cox proportional hazards analyses with adjustment for age, sex, BMI, smoking habit, alcohol consumption, exercise time, eGFR, HbA1c, duration of diabetes, and medications, such as antihypertensive agents and glucose lowering agents, revealed that handgrip strength had a significant association with occurrence of CVD events  and hospitalization  33. These findings are consistent with our results. Although we could not deduce a causal relationship, maintaining muscle strength may preserve renal function in patients with type 2 diabetes. Handgrip strength has also been found to be a useful predictor of mortality in patients on maintenance dialysis35 and renal outcome in patients with CKD36. Clinicians could use handgrip strength as an indicator of renal prognosis beyond mere muscle strength in patients with type 2 diabetes.Other noteworthy findings of this study are the inverse association between handgrip strength and UACR and the positive association between handgrip strength and eGFR. Patients with chronic kidney disease (CKD) are exposed to the risk of skeletal muscle loss due to its comorbidities, complications, and treatments37. In the present study, subjects consumed <20 g of ethanol on average, and we found a positive association between alcohol consumption and exercise time after adjustment for age, sex, and BMI . Handgrip strength was positively associated with alcohol consumption because individuals who consume moderate amounts of alcohol may be physically active and have greater muscle strength. In addition, alcohol consumption was associated with increasing energy intake, and current drinkers had significantly higher intakes of protein than never drinkers38. Intakes of nutrients involved in alcohol consumption may influence the handgrip strength. Grip strength was lower in individuals with hypertension than in those without39. However, we observed that diastolic blood pressure was positively associated with handgrip strength. After further adjustment for the use of antihypertensive drugs, diastolic blood pressure was still positively associated with handgrip strength. Recently, a few studies have reported a positive association between blood pressure and muscle strength in the elderly and in adolescents41. Simple regression analysis showed that handgrip strength was inversely correlated with AIx75; however, it was more positively correlated with diastolic blood pressure than systolic blood pressure in the present study. Nürnberger et al. reported that not systolic but diastolic blood pressure is a strong determinant of augmentation index in normotensive subjects42. Ageing and type 2 diabetes advances arterial stiffness and decreases diastolic blood pressure44. Insulin resistance in type 2 diabetes causes delay in vasodilation45. Augmentation index, a measure of wave reflection, which is modulated by arterial elasticity and peripheral vascular resistance, is paradoxically lower, and diastolic blood pressure is also lower in patients with diabetes than in those without diabetes46. Handgrip exercise decreases vascular resistance via a cholinergic mechanism in healthy humans47; however, such a physiological effect may be attenuated in type 2 diabetic patients with autonomic nervous dysfunction. The underlying mechanism was not clear; however, the sympathoexcitatory effect of insulin may explain this result48. Muscle sympathetic nerve activity increases in response to hyperinsulinemia, which increases peripheral vascular resistance and leads to high blood pressure48. In fact, we found a positive association between diastolic blood pressure and serum C peptide levels after adjustment for age and sex. However, to elucidate the mechanism of association between handgrip strength and blood pressure, further investigations are required.A previous review showed that there was a dose–response relationship between alcohol consumption and physical activity levelThis study had several limitations. First, although all subjects were instructed to follow a diet therapy for diabetes, we did not objectively evaluate dietary intake. To maintain muscle strength and mass, dietary intake of a certain amount of protein is needed. Dietary intake may affect handgrip strength. Second, we used consecutive sampling in order to avoid selection bias; however, lack of representativeness could occur. The present study was a single-center study, and the results cannot be generalized to other populations. Third, considering that the study subjects were not newly diagnosed with type 2 diabetes, handgrip strength at baseline could be influenced by many conditions. We performed Cox proportional hazards analysis after adjusting for potential confounding variables; however, residual confounding factors, including comorbidities and socioeconomic status, might have been associated with handgrip strength. In addition, other factors, such as time of clinical examination, that influence subjects’ condition and body composition analysis also need to be controlled. Fourth, the follow-up period was relatively short. Therefore, the number of deaths and CVD events was small. We should continue further investigations. Despite these limitations, we demonstrated that handgrip strength was significantly associated with various health indices in patients with type 2 diabetes.In conclusion, the findings of this study suggest that handgrip strength could be a prognostic indicator for health and a diagnostic marker of sarcopenia in patients with type 2 diabetes. Measuring handgrip strength is quick and inexpensive. Handgrip strength could be a useful tool in the management of type 2 diabetes.We conducted a retrospective cohort study in patients with type 2 diabetes who were treated at the National Center for Global Health and Medicine Kohnodai Hospital. Between April 2013 and December 2015, a total of 1,303 individuals whose handgrip strength was measured at the first medical examination were included. Patients younger than 20 years (n = 2) with type 1 diabetes (n = 16) were excluded. Patients whose handgrip strength could not be measured because of disabilities, such as cerebral infarction sequelae (n = 3), were also excluded. We conducted a post-hoc sample size calculation using the powerlog command in Stata (http://www.ats.ucla.edu/stat/sas/dae/logit_power.htm). Assuming the proportion of death at mean handgrip strength is 1.6%, the proportion of death at one standard deviation above the mean handgrip strength is 0.74%, and the one-tailed alpha level is 0.025, the sample size calculation indicates that 796 observations are needed for a power of 0.8. This suggests that our sample size had sufficient power to detect the observed association between handgrip strength and all-cause mortality. At the first visit, patients were instructed to consume a calorie-restricted diet of 25–30 kcal/kg  per day as diet therapy for diabetes by certified nutritional educators and to continue the diet during study period. All patients were evaluated and followed until death or till the end of follow-up in May 2016. We retrieved data, such as date of hospital admission, duration of hospitalization, name of disease for hospitalization, date of occurrence of CVD, and date of death from the electronic health record in our hospital.49.Height was measured using a rigid stadiometer . Weight was measured using calibrated scales . BMI was calculated as body weight in kilograms divided by the square of body height in meters. Waist circumference was measured at the umbilical level at the end of exhalation in a standing position. Handgrip strength was measured using a Smedley analog hand dynamometer  with both hands in a standing position. The measurements were first performed for the dominant hand. Subjects performed two maximum attempts for each hand with approximately 1-min rest period between trials. We used the average handgrip strength in kilograms. According to a consensus report of the Asian Working Group for Sarcopenia, we defined sarcopenic subjects as follows: age, ≥ 65 years and handgrip strength, <26 kg for men and <18 kg for women75 using a pulse pressure analyzer  and a digital automatic sphygmomanometer , respectively.Blood pressure was measured in a seated position using an automatic sphygmomanometer . Arterial stiffness was examined by measuring both baPWV and AIx50. Patients were also asked about their regular exercise habits, and we estimated the amount of locomotive exercise using metabolic equivalent (MET) hours per week. Briefly, the physical activity questionnaire consists of 3 items: 1) “Do you engage in any physical exercise? If yes, what kind of exercise do you perform regularly?”; 2) “How often do you exercise in a week?”; and 3) “How long do you exercise per session?” We calculated MET-hours per week for locomotive physical exercise based on the Compendium of Physical Activities51.For baseline characteristics, trained technicians at the Clinical Research Center of the National Center for Global Health and Medicine at Kohnodai Hospital asked participants at the outpatient clinic about their physical activity levels, smoking, drinking habits, medication, and history of CVD. CVD included stroke, nonfatal coronary heart disease, or peripheral artery disease. To quantify the patients’ smoking habits, the Brinkman index (number of cigarettes per day multiplied by the number of years) was calculated52. UACR, a marker for diabetic nephropathy, was also measured. The urinary albumin levels were measured using an immunoturbidimetric assay , and UACR was calculated by dividing the urinary albumin levels by the urinary creatinine concentration.Blood samples were taken from the antecubital vein in the morning. We measured PG, hemoglobin A1c, insulin, and C-peptide levels. Enzymatic methods were used to assess PG . Serum insulin and HbA1c were measured by automated enzyme-linked immunosorbent assays  and high-performance liquid chromatography , respectively. Serum C-peptide was measured using a chemiluminescent enzyme immunoassay . We calculated eGFR using the revised equation adjusted for the Japanese population53. A previous validation study demonstrated that body composition measured using this device was highly correlated with dual-energy X-ray absorptiometric measurements54.Body composition was analyzed using a bioelectrical impedance analysis device . This method is based on the principle that lean body mass contains higher water and electrolyte content than fat tissue; hence, these tissues can be distinguished by electrical impedance. Body composition was determined using a patented 8-point tactile electrode systemStatistical analyses were performed using SPSS version 23 . All values are expressed as the mean ± standard deviation except for sex and smoking habit. Pearson’s correlation coefficient was calculated to analyze the associations of handgrip strength with physical, biochemical, and physiological data in overall sample as well as in male and female subjects. Multiple regression analysis adjusted for age, sex, and BMI was performed to test independent associations between handgrip strength and clinical data. Furthermore, Cox proportional hazards analysis was performed to assess the independent associations of mortality, CVD events, and hospitalization. We included age, sex, BMI, smoking (Brinkman index), alcohol consumption, exercise time, eGFR, HbA1c, duration of diabetes, and medications such as antihypertensive agents and glucose-lowering agents in the Cox model. The entry variable was the date of the measurement of handgrip strength. Follow-up was censored at the first event, death, or May 1, 2016, whichever came first. We also performed Cox proportional hazards analysis stratified by sex because the difference in handgrip strength is large between men and women. In addition, p values of <0.05 determined by performing a two-sided test were considered to be statistically significant.Because this study was a retrospective cohort study, the opt-out method of obtaining informed consent was adopted. The patients were anonymized to protect their personal information. The study protocol was approved by the Medical Ethics Committee of the National Center for Global Health and Medicine (Reference No. NCGM-G-002052), and the study was performed in accordance with the Declaration of Helsinki.The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.Supplementary information


The patients underwent epidemiological surveys and ultrasonographic measurements of their cervixes, and cervicovaginal fluid and serum were collected during a routine speculum examination performed by the managing gynecologist. The results showed eight significant variables were included in the present analysis, and combination of the positive variables indicated an increased probability of PD in pregnant patients. The accuracy for predicting PD were as follows: one positive – 42.9%; two positives – 75.0%; three positives – 81.8% and four positives – 100.0%. In particular, the combination of ≥2× positives had the best predictive value, with a relatively high sensitivity (82.6%), specificity (88.1%) and accuracy rate (79.2%), and was considered the cut-off point for predicting PD. In conclusion, the new model provides a useful reference for evaluating the risk of PD in clinical cases.In this study, a new model for predicting preterm delivery (PD) was proposed. The primary model was constructed using ten selected variables, as previously defined in seventeen different studies. The ability of the model to predict PD was evaluated using the combined measurement from these variables. Therefore, a prospective investigation was performed by enrolling 130 pregnant patients whose gestational ages varied from 17 The incidence of PD ranges from 5% to 15% worldwide, indicating that approximately 15 million preterm babies were born before 37 completed weeks (W) of gestation, which is the second leading cause of perinatal death2. In America, 6.14 infant deaths per 1,000 live births and 35.2% of infant deaths were related to PD in 20103. In China, there was a 7.1% incidence of preterm births, and 7769 preterm births occurred between 28 and 37 W of pregnancy in 20114. In addition, one survey showed an increased mortality associated with PD with an average annual growth rate of 1.52% since 1996, accounting for 22.6% of infant mortality in 2013. Therefore PD is considered the leading cause of infant death5.Preterm delivery (PD) remains a global problem associated with perinatal morbidity, including low birth weight, growth retardation and irreversible damage to the nervous system6. To date, many studies have been performed regarding the prediction of preterm birth. Although these studies have resulted in improved prediction of PD and a decrease in the number of premature births, at present, the accuracy of predicting preterm births is still a puzzle because of many factors that contribute to the outcome of PD. These factors include a previous history of PD, gestational age, pregnancy complications, psychological and genetic factors7, maternal obesity9, placenta previa10, fat-to-placenta strain ratio value11, serum relaxin12, insulin-like growth factor-binding protein-113, interleukin-1β (IL-1β)14, thioredoxin and interleukin 1 receptor antagonist15, and fetal fibronectin levels and cervical length measurements17. However, some of these factors have shortcomings with respect to sensitivity or specificity, which affects the accuracy of PD prediction. Based on previous studies, and seeking to improve the sensitivity and specificity for predicting PD, the present study proposes a new prediction model for premature birth.Approximately thirty years ago, a risk scoring system was proposed for predicting preterm birth, providing a significant reference for further studyAccording to the study strategy described in the materials and methods section Fig. , ten varP > 0.05). However, cases in the preterm group had a significantly lower gestational age (33.50 vs. 39.20 W) and lower birth weight  than those in the full-term group. Detailed demographic and clinical information are summarized in Table Of 186 pregnant women enrolled in the study, 56 patients were excluded based on exclusion criteria during pregnancy. Exclusion criteria included triple gestation n = 2), threat of abortion (n = 4), serious infection of the genital tract (n = 4), pregnancy-induced hypertension (n = 4), fetal anomaly (n = 4), fetal cytomegalovirus infection (n = 2), and 36 patients lost to follow-up due to refuse cooperation with the gynecologist’s investigation (n = 11) and uninformed absence in scheduled visiting to participating hospitals (n = 9) were also excluded from the present study. The remaining 130 patients were included in the study, and 46 (35.4%) had spontaneous preterm birth before 37 weeks of gestation. 36 patients of which delivered at 32 to 36 weeks for 78.3%, 6 patients delivered at 28 to 31 weeks for 13.0% and 4 patients delivered before 28 weeks for 8.7%. There was no significant difference between the groups in terms of maternal age, parity, the rate of singleton or twin gestations, ratio of nulliparous vs. multiparous, cervical surgery, education grade, work or lifestyle or febrile illness during pregnancy : history of preterm delivery, prepregnancy BMI, the proportion of blue area, mean gray value, cervical dilatation, CL with singleton gestations, levels of fetal fibronectin and IL-1β in CVF. These were significant variables for evaluating PD in the present study. The difference between variables such as the use of tocolytic agents, CL with twin gestations and serum MIF was not significant (P > 0.05). Details are shown in Table Statistical evaluation of the test variables was performed by comparing their positive proportions between PD and full-term delivery. A higher proportion of the following eight variables was present in the PD group than that of the full-term delivery group , specificity (88.1%) and accuracy rate (79.2%) in predicting PD, which is considered a cut-off point for predicting the occurrence of PD. Interestingly, all negative variables in the model had a high probability of association with full-term delivery, which is represented by an accuracy rate of 93.3%.et al.18 and was also higher than the 63.8% or 43.9% sensitivity predicted by cervical dilatation or fetal fibronectin alone21. In addition, the finding that there was no significant association with PD and the “use of tocolytic agents or serum MIF” in our model was inconsistent with the previous studies by Pearce et al.6. The reason for this inconsistency may be attributed to differences in the study methods, sample collection, and geographical differences in patient. Based on the present result of predicting spontaneous PD during the second trimester of pregnancy in women in China, in our opinion, special attention should be given when a patient has two or more positive variables as defined in this study. In addition, some targeted interventions, such as the application of glucocorticoids for promoting fetal lung maturation or the administration of magnesium sulfate to protect the fetal central nervous system, should be performed if appropriate in the clinical situation. Of course, patients with only one positive variable for predicting PD cannot be ignored, as there was still a moderate accuracy rate of 42.9% with only one variable, so observation strict and regular evaluation of the development of the uterus and fetus is necessary to prevent the occurrence of PD.The significant association of the eight variables in the present model with PD occurrence was consistent with the conclusions from the previous studies. However, the inclusion of multiple combinations of these variables in the model showed a higher sensitivity and specificity than single or double combination of these variables in previous studies. For example, our results of 82.6% sensitivity in the combination of ≥2× positive variables was improved compared to a 33.3% sensitivity of a short cervix as a predictor of PD described by Lee In summary, we propose a model of predicting PD by introducing eight predictive indices originating from previous studies. The model showed an effective improvement in the sensitivity, specificity and predictive accuracy compared to previous models for predicting PD. In conclusion, the evaluation model of equal to or more than two positive variables provides a feasible reference for predicting PD in the second trimester of pregnancy in clinical patients. However, there are two limitations in this study. One limitation was the insufficient sample size for validation of the model because of other limitations of time, space and funding in the present study. The lack of sample size is particularly represented in the group with ≥four positive variables. The other limitation was that genetic factors were not included in the present model because of a lack of reference literature. In a future study, we will expand the number of samples by including more pregnant patients from more hospitals, and we will proceed to evaluate the role of genetic factors in the occurrence of PD, seeking to further improve the sensitivity, specificity and accuracy of the model and reduce false-positive results.34, plasma corticotrophin releasing hormone (CRH) levels35, placenta previa10 and bacterial vaginosis36 were excluded from the model because of the lower sensitivity or specificity than the included variables.The study included two steps: establishment and verification of the model. When constructing the model, the test variables were selected discreetly according to the criteria of optimal sensitivity and specificity, which were determined based on previous multicenter or single-center studies of predicting PD in pregnant women from 1997 to 2016. Data involving sample size, cut-off values, sensitivity and specificity, from these studies was acquired using PubMed. As a result, ten variables from 17 original studies were included in the present model. The included variables were as follows: “history of PD, prepregnancy BMI, use of tocolytic agents, cervix tissue elasticity, densitometry of cervix, cervical dilatation, cervical length, fetal fibronectin in CVF, serum MIF, IL-1β in CVF”. Cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) testingFor the verification of the model, the designed prospective study of enrolling pregnant patients was approved from the Medical Ethics Committees in Xiangya Hospital, The Second Xiangya Hospital and Weihai municipal hospital. All experiments were carried out in accordance with the Declaration of Helsinki. A total of 186 pregnant patients who made scheduled visits to three participating hospitals from January 1, 2015 to March 1, 2016 were enrolled in accordance with approved guidelines. All participants were informed and signed a consent form presented by trained interviewers and their general epidemiologic and clinical data were recorded. Their gestational age varied from 17 to 28 weeks and 6 days as determined by the last menstrual period and ultrasonography in the first or early second trimester. Cervicovaginal fluid or serum specimens were collected and measurements from cervical ultrasonography were performed during a routine speculum examination by the managing gynecologist. Additionally, the following conditions were considered for exclusion at the time of enrollment: age <15 years, multiple gestations (≥triple pregnancy), uterine or vaginal deformity, amniotic sac rupture, cervical dilatation ≥3 cm, serious infection of the genital tract, frequent symptoms of threatened abortion such as vaginal bleeding or uterine contractions, and obstetric complications such as hypertension and diabetes mellitus. PD was defined as the spontaneous or non-indicated preterm delivery or preterm premature rupture of the fetal membranes prior to 37 weeks of gestation, and the correspondent data were collected during a follow-up period.28. Cervical length was defined as the distance between the internal and external os, which was measured in a sagittal plane of the cervix. Cervical tissue stiffness was represented by a color scale. Blue is indicative of stiff tissue, green represents average stiffness and red represents soft tissue. Furthermore, the proportion of blue area was calculated in a rectangular region of interest representing the posterior wall of the cervix. Acoustic densitometry  of a region of constant size (10 Diameter Circle) in the cervical tissue was also measured using the US System . Each examination was repeated three times by two different investigators.Ultrasound scans of the uterine cervix were performed with a Premium Ultrasound System . Measurements including cervical length via transvaginal ultrasonography, evaluation of the cervical tissue stiffness by sonoelastography and mean gray analysis were performed using quantitative ultrasound. The methods of detection and evaluation were determined by previous protocols33. An IL-1β human enzyme-linked immunosorbent assay (ELISA) Kit  and fFN Enzyme Immunoassay Kit  were used, and a positive result of IL-1β or fFN was defined as >55 pg/mL or ≥50 ng/mL, respectively. In addition, serum MIF was detected using a sandwich ELISA assay as described by Pearce et al.31, and an anti-MIF polyclonal antibody  was used with a positive result defined as >9.2 ng/mL. All cytokines were determined repeatedly three times by each separate sample according to the manufacturer’s instructions.A total of 10 mL of cervicovaginal lavage fluid was collected, and the centrifugal supernatants were frozen at −70 °C for detecting the concentrations of IL-1β or fetal fibronectin (fFN) as previously described2 test with P < 0.05. Furthermore, sensitivity, specificity and accuracy rates of single or different combinations of positive variables were also calculated for evaluating the efficiency of predicting PD. Then, the prediction efficiency of more than one or several positive results including 2×, 3× or 4× were also evaluated. Ultimately, prediction efficiency and cut-off point of the established model was evaluated by a comprehensive comparison of sensitivity, specificity and accuracy rates among different combinations of positive variables.Positive or negative results of the test variables were calculated according to their corresponding cut-off values in each pregnant patient, and the difference in the distribution of positive variables between the PD group and the full-term delivery group was analyzed using the χAll data generated or analyzed during this study are present in the article; Additional data related to this paper may be requested from the authors.


The results of recent trials have brought some confusion to the treatment strategy for renal artery stenosis (RAS). To evaluate the applicability of percutaneous transluminal renal angioplasty (PTRA) for RAS, we extracted the factors that may affect the effectiveness of PTRA from cases experienced at a hypertension center.p < 0.05), but the estimated glomerular filtration rate (eGFR) did not change significantly. There were no factors associated with the BP lowering effects of PTRA. The baseline resistive index (RI) was negatively correlated with the change in eGFR (p < 0.05). After correction for age, sex, BMI, and the dose of contrast medium, the association of RI with change in eGFR remained significant. We retrospectively assessed the blood pressure (BP) lowering effects and renoprotective effects in 50 consecutive patients that had hemodynamically significant RAS and had undergone PTRA and stenting during 2001–2005. Subjects were diagnosed with atherosclerotic RAS (42), fibromuscular dysplasia (6), or Takayasu disease (2). After PTRA, BP significantly lowered from 152.3/80.3 mmHg to 132.6/73.2 mmHg ( In cases with hemodynamically significant RAS, PTRA lowered BP but was not effective in improving renal function. Higher baseline RI may be a factor for predicting poor clinical course of renal function after PTRA. Renal artery stenosis (RAS) is a cause of renovascular hypertension (RVHT) and ischemic nephropathy and has been demonstrated to be a predictor of future cardiovascular events . PercutaTwo large-scale randomized controlled clinical trials (RCTs), ASTRAL  trial , and CORThe current guidelines for atherosclerotic RAS recommend PTRA for patients with hemodynamically significant RAS or with the following conditions: flash pulmonary edema, rapidly declining renal function or refractory hypertension –15. SuchAfter ASTRAL and CORAL, physicians, such as cardiologists or radiologists, who handle RAS tend to hesitate to perform PTRA. However, recent recommendations and review articles have demonstrated the importance of PTRA , 17. TheThere are few reports on the effectiveness of PTRA, and there are even fewer reports of the Japanese or Asian patients. The aim of this study was to clarify factors associated with outcomes in PTRA for RAS patients with hemodynamically significant stenosis, before ASTRAL and CORAL, to reconsider the effectiveness of PTRA for RAS patients.We retrospectively assessed the influences of several factors on clinical courses of patients who had undergone PTRA. The subjects consisted of 50 consecutive patients who had their first PTRA between January 2001 and September 2005 in the National Cardiovascular Research Center in Osaka, Japan. Patients who had undergone two or more rounds of PTRA for restenosis of the treated lesion or progression of opposite-side RAS were excluded. PTRA was indicated for hemodynamically significant RAS with either of the following: (1) peak systolic velocity ≥ 1.8 m/sec by RDU, (2) diameter or area stenosis rate ≥ 75% by magnetic resonance imaging angiography, and (3) prolonged vascular, functional, and distribution phases by renogram. Cases without viability of the affected kidneys  were excluded. Renal artery stenting was done in all cases at the ostial and proximal lesion without distal protection or filtration device. The clinical courses after PTRA in our institute were good overall. Major complications, such as cholesterol crystal embolism, dissection of the renal artery, or other vascular disease, were not observed in the present study subjects.BP was measured on the days before PTRA (w0) and 1-2 weeks after PTRA (w1). Serum creatinine levels (S-Cre: enzymatic method) were obtained at the day before PTRA (W0), 1-2 weeks after (w1), and 1 year (+/−4 weeks) after PTRA (y1).Primarily, we compared the change in mean blood pressure (MBP), use of antihypertensive drugs, and estimated glomerular filtration rate (eGFR) between before and after PTRA.MBP was calculated as follows:Successful BP reduction was defined as a 5 mmHg or more reduction in w1 mean BP compared with the measurement at w0 or reduction in the dosage of one or more antihypertensive medicines. Course of renal function (eGFR) was stratified into “not changed or improved” (w0 ≥ y1) or “worsened” (w0 < y1).2), and the dose of contrast medium by univariate and multivariate analysis. We adapted common log conversion of eGFR and PRA for analysis because they did not follow a standard normal distribution.Additionally, we assessed influences on the BP lowering and renoprotective effects of PTRA by several confounding factors, including age, sex, body mass index (BMI), presence of bilateral stenosis, RI in the affected kidney, impaired glucose tolerance (IGT), DM , dyslipidemia, RI: (1 – (end diastolic velocity/peak systolic velocity)) , plasma t-test. Between the groups of the BP lowering effects, categorical variables were compared by χ2 analysis, and continuous variables were compared by unpaired t-test. The influence of each parameter on the regression of eGFR was analyzed by unpaired t-test or linear regression analysis. p values < 0.05 were considered as statistical significant.All data were analyzed using JMP 9 software . All continuous values were expressed as the mean +/− SD and categorical variables were reported as percentages. BP and eGFR were examined. The time courses of BP and eGFR were examined using the paired 2, and other characteristics and subgroup characteristics divided by causes of RAS are shown in The characteristics of the 50 patients  were as follows. All patients were East Asians. Flash pulmonary edema or rapidly declining renal function was not observed on or before admission. Refractory hypertension and uncontrolled BP (SBP ≥ 140 and/or DBP ≥ 90) despite taking 3 or more antihypertensive drugs, including diuretics, were seen in 8 cases (1 aortitis case and 7 atherosclerotic stenosis cases) among 47 cases . Causes of RAS were atherosclerosis (42 cases), FMD (6 cases), and Takayasu aortitis (2 cases), as shown in p < 0.05, n = 47) at the period of 1-2 weeks after PTRA, but the reduction did not last until 1 year after PTRA (1.95p = 0.39n = 42). Mean BP reduction of 5 mmHg or more was observed in 29 of 44 patients (66%), and reduced dose of antihypertensive drugs was observed in 23 of 50 (46%). Successful BP reduction was observed in 35 of 48 patients (73%). Limited to cases of atherosclerotic RAS, the reduction in BP remained significant . There was a significant correlation between presence of “IGT or DM” and baseline RI . We performed multivariate analysis for regression of renal function accounting for age, sex, BMI, baseline RI, and the dose of contrast medium. Baseline RI remained significant for the regression of renal function  at y1. Univariate analysis of confounding factors for regression of renal function is shown in function . In the In the present study, BP was improved in approximately 70% of patients, but the average eGFR remained unchanged from the baseline. We also demonstrated that patients with a higher RI were associated with a poor renal course, as reported by Radermacher et al. . Higher We also demonstrated that patients with glucose intolerance tended to have worsened renal function. Hyperglycemia causes increased glomerular vascular resistance . RI is rAlthough prognosis of RAS is known to be different between atherosclerosis and FMD , RI demoOn the other hand, 12 subjects in the present study lacked RI measurements. The main reasons why the data were unavailable were undetectable blood flow signals in the kidneys due to severe renal damage or marked stenosis of the renal arteries. There were no significant differences in eGFR values between the subjects with available RI measurements and the subjects for which we could not obtain the RI value. Prognostic factors among such patients remain unclear in the present study.Indication for PTRA in patients with RAS continues to be still controversial because the results of ASTRAL and CORAL failed to demonstrate beneficial effects of PTRA. It is possible that patients who may have benefited from PTRA were excluded and/or patients with mild stenosis were included in these studies.Although our subjects, who were expected to have better outcomes than the subjects of ASTRAL or CORAL, demonstrated hemodynamically significant RAS, overall regression of renal function was not observed. In the results of ASTRAL, the decline in renal function over time was slightly slower in the revascularization group, but the difference was not significant after 34 months of follow-up , 13. RenIt has been reported that approximately 20–45% of patients with atherosclerotic RAS are affected in the bilateral or single-functioning kidney , 23, 24.The limitations of our study are that it was a retrospective and single center design, with a limited number of subjects, which could not detect the difference in clinical course between causes of the RAS, and lack of control groups. Although we applied PTRA for patients with hemodynamically significant RAS, our criteria for applicability of PTRA were not strict, and therapeutic methods were at each doctor‘s discretion in each clinical situation. Furthermore, although the smoking habits of patients seem to be one of the determining factors of clinical outcome , we wereIn cases with hemodynamically significant RAS, PTRA was able to lower BP but was not effective in improving renal function.Higher baseline RI demonstrated a significant correlation with poor renal outcome after PTRA. The presence of IGT or DM may be associated with poor renal outcome. Caution should be taken when PTRA for RVHT is considered in such patients.


Though it is rare, isolated interrupted aortic arch (IAA) could lead to hypertension. Surgical repair is the only effective curative method to treat IAA conditions and patients with IAA can hardly survive to adulthood with medication alone. We report an IAA case that of a 45-year-old male patient who survived for 45 years without surgical treatment.A 45-year-old man was referred to the hospital presenting with abnormal blood pressure level. Both computed tomography angiogram (CTA) and angiography revealed IAA.The patient was diagnosed as IAA based on computed tomography angiogram (CTA) and angiography.The patient's blood pressure was severely high and refractory. He refused surgical treatment and accepted antihypertensive medication for 10 days.The patient's office blood pressure level was abnormal, fluctuating between 140/90 and 160/100 mm Hg, but 24-hour ambulatory blood pressure monitoring showed normal level.Hypertension due to IAA could be controlled with medications, even surgery is not performed. The discrepancy between ambulatory and office blood pressure levels may be due to the white coat effect. It is usually detected in the prenatal period or during infancy with high mortality, if without surgical repair,–5 which is rare in adulthood.IAA is a very rare congenital malformation defined as a complete loss of anatomical continuity between ascending and descending portions of the aorta. It occurs in 3 per million live births and accounts for <1% of all congenital heart disorders.2We report the case study. The committee waived the requirement for approval for a single case study with medical records. Informed consent was given.32. The first medical evaluation in our hospital revealed a regular heart rate of 68 bpm and a grade 4/6 systolic murmur at the position of T1-T3 on back. The murmur conducted to neck. His blood pressure was measured as 183/92 mm Hg in the left arm and 175/95 mm Hg in the right arm, 96/64 mm Hg in the left ankle, and 101/60 mm Hg in the right ankle . It indicated a significant differential blood pressure between the upper and lower limbs. Echocardiography showed the left ventricle did not present severe abnormal dimensions and impaired systolic function, the descending aortic arch could not be observed, and aortic valve regurgitated moderately. Computed tomography angiogram (CTA) revealed a type A interrupted aortic arch with complete discontinuity of the aortic lumen distal to the origin of the left subclavian artery, and a massive aorta arch which included 2 full-fledged collaterals network ensuring blood circulation to distal aorta , which had persisted for >30 years. The patient was found with abnormal blood pressure when he was 10 years old. Maximal blood pressure level at 260/110 mm Hg was recorded during the physical examination for several years. The patient had a smoking history of 20 years and no similar family medical history was reported, but suffers no other significant clinical symptoms. In recent weeks, he suffered dizziness and was treated with oral antihypertensive medications. The treatment regime was nifedipine (controlled release tablets 30 mg Bid), irbesartan and hydrochlorothiazide (tablets 150 mg qd), and irbesartan (150 mg qd). The curative effect is limited and his blood pressure remains at elevated level. On physical examination, the patient had a pulse rate of 68 bpm, a respiratory rate of 18 bmp, a body temperature of 36.7°C, and a body mass index of 23 kg/m00 mm Hg,After 10-day medication, 24-hour ambulatory blood pressure monitoring showed a mean of 24-hour blood pressure at 129/68 mm Hg. The day and night mean blood pressure was 139/79 and 103/54 mm Hg, respectively  for this patient showed normal level with the medication treatment. Restoration of arterial anatomy may be helpful to normalize blood pressure and ensure lower limbs blood supply. The patient's physical condition is sound, indicating that surgery outcome could be promising. Unfortunately, he refused the surgical treatment due to the concern of the additional risk associated with surgery. We will follow the patient and educate him on the accurate way of measuring blood pressure. If conditions are exacerbated, timely surgical therapy is highly recommended.–5The physical examination is important in the diagnosis of secondary hypertension. In our case, the abnormal murmur indicates the possibility of congenital malformation which is a rare reason for refractory hypertension. Aortic arch interruption is classified into 3 type: type A is where interruption occurs distal to the left subclavian artery (as in our case); type B is where interruption occurs distal to the origin of left common carotid artery; and type C is where interruption occurs proximal to the origin of left common carotid artery. All reported adult cases are type A.We gratefully acknowledge the technical assistance of Li-Jiang Tang and Ping Mao .