Hypertension is one of the most important causes of end-stage renal disease, but it is unclear whether elevated blood pressure (BP) also accelerates the gradual decline in the glomerular filtration rate (GFR) seen in the general population with increasing age. The reason may be that most studies have considered only baseline BP and not the effects of changes in BP, antihypertensive treatment and other determinants of GFR during follow-up. Additionally, the use of GFR estimated from creatinine or cystatin C instead of measurements of GFR may have biased the results because of influence from non-GFR related confounders. We studied the relationship between BP and GFR decline using time-varying variables in a cohort representative of the general population using measurements of GFR as iohexol clearance.We included 1594 subjects aged 50 to 62 years without baseline diabetes, kidney-, or cardiovascular disease in the Renal Iohexol-clearance Survey in Tromsø 6 (RENIS-T6). GFR, BP, antihypertensive medication and all adjustment variables were ascertained at baseline, and at follow-up after a median observation time of 5.6 years in 1299 persons (81%). The relationship between GFR decline and BP was analyzed in linear mixed models.p < 0.05). The association was stronger in persons on antihypertensive medication than in others (p < 0.05 for the interaction between BP and antihypertensive medication).The mean (standard deviation) GFR decline rate was 0.95 (2.23) mL/min/year. The percentage of persons with hypertension  increased from 42 to 52% between baseline and follow-up. In multivariable adjusted linear mixed models using time-varying independent variables measured at baseline and follow-up, higher systolic and diastolic BP were associated with slower GFR decline rates by 0.10 and 0.20 mL/min/year/10 mmHg, respectively  contains supplementary material, which is available to authorized users. Hypertension is one of the most important causes of end-stage renal disease –6. HowevThere are several possible explanations for the divergent results of observational studies. One important explanation could be that the great majority of these investigations have studied GFR decline as an effect of BP and antihypertensive treatment at baseline. Since both BP and treatment are dynamic parameters, they will change during follow-up and exert a variable influence on GFR. Because the effect of BP on GFR is commonly believed to be continuous and not limited to a one-time baseline event, this approach may give a distorted picture of the relationship between them. To our knowledge, no previous study of age-related GFR decline in the general population has considered this issue. Additionally, previous studies have relied on GFR estimated from creatinine or cystatin C instead of actual measurements of GFR. These estimates are known to be influenced by several non-GFR factors that may have biased the results –28.We have measured GFR as iohexol clearance in the Renal Iohexol-clearance Survey in Tromsø 6 (RENIS-T6) and again in the RENIS Follow-up Study (RENIS-FU) after a median observation time of 5.6 years. Iohexol clearance is recognized as a precise method for measuring GFR . As far This study is a follow-up of RENIS-T6 which measured baseline iohexol-clearance in 1627 people between 50 and 62 years of age between 2007 and 2009. We included a representative sample of subjects from the general population without self-reported kidney disease, myocardial infarction, stroke or diabetes from the municipality of Tromsø in Northern Norway, as previously described in detail . In the This study complied with the Declaration of Helsinki and was approved by the Norwegian Data Inspectorate and the Regional Committee for Medical and Health Research Ethics of North Norway. All subjects provided written consent. All procedures were in accordance with institutional guidelines.Both RENIS-T6 and RENIS-FU were conducted in the Clinical Research Unit at the University Hospital of North Norway. A health questionnaire with questions about alcohol and tobacco use and all current medications was administered on both occasions. Tobacco use was coded as the number of cigarettes currently smoked daily. Alcohol use was coded as 1 for the use of alcohol more than once a week and 0 otherwise.Baseline and follow-up GFR were measured using single-sample plasma clearance of iohexol, which has been validated against gold standard methods –36. RENI2. All baseline GFR measurements reported in this study were adjusted by adding this constant to the original measurements, as described previously [A 6% random sample of blood samples from the baseline investigation previously frozen at −80 °C were thawed and reanalyzed to adjust for a possible drift in the method between baseline and follow-up. The mean difference in the GFR between follow-up and baseline was 2.28 mL/min/1.73 meviously .A total of 87 subjects had a repeated follow-up measurement of GFR. The mean coefficient of variation  for the intra-individual GFR variation was 4.2% (3.4–4.9%) . The repAttended BP measurements were performed by trained study nurses in the seated position after 2 min rest using an automated device and the appropriate cuff size . BP was measured three times with 1 min between measurements. The average of the second and the third measurement was used in the analyses. Hypertension was defined as systolic BP (SBP) ≥ 140 mmHg, diastolic BP (DBP) ≥ 90 mmHg or the use of antihypertensive medication. Mean pulse pressure (PP) was defined as SBP minus DBP and mean arterial pressure (MAP) as DBP plus one-third of the PP.crea and eGFRcys) [Fasting serum glucose, creatinine, cystatin C, triglycerides, and LDL- and HDL-cholesterol, hemoglobin A1C and the urine albumin-creatinine ratio (ACR) were measured with standard methods as described previously , 38. SereGFRcys) .t-test or Wilcoxon signed-rank test for continuous variables and McNemar’s test for paired dichotomous variables.Mean (standard deviation (SD)) or median (IQR) for skewed variables were used for descriptive statistics. Differences between baseline and follow-up were tested with the paired n = 1594), follow-up (n = 1299) and/or repeated follow-up (n = 87). Absolute GFR in mL/min was used as the dependent variable. Observation time from baseline was used as the independent time variable. Associations between the BP components  and the rate of change in GFR were estimated by including two-way interaction terms between the BP variable in question and the time variable. Separate regression analyses were performed for each BP component. The linear mixed regression used time-varying values measured at both baseline and follow-up for all the independent variables, including BP components, antihypertensive treatment and adjustment variables.The GFR measurements were analyzed in linear mixed models with random intercept and slope , 41. AllThe linear mixed regression analyses were adjusted for baseline age, sex and the following two sets of time-varying adjustment variables: Model 1  and model 2 .Non-linear effects of the BP components on the GFR rate of change were explored by including second-degree fractional polynomial transformations of the BP components in the interactions with time in the linear mixed regression models .n = 6), ACR (n = 5) or triglycerides (n = 4) at baseline, and one subject with missing data for alcohol use at follow-up were excluded from the analyses. There were no missing data for the other independent variables or for GFR.Subjects with missing data for alcohol use .The same linear mixed regression analyses as described above were performed with change in estimated GFR assessed by eGFRp < 0.05). Except for the percentage of current smokers , there were only small differences in baseline characteristics between those included and those lost to follow-up, as reported previously [A total of 1299 (81%) of the 1594 participants in the baseline cohort were investigated at follow-up after a median (IQR) observation time of 5.63 years (5.23–6.03)  rate of change for the absolute GFR in the study period was −0.95 (2.23) mL/min/year. A negative change signifies a decline in GFR.p < 0.05) (Table The absence of associations between baseline BP components and the GFR decline rate has been reported previously . When an5) Table , i.e. thThere were no statistically significant non-linear relationships between the BP components and GFR rate of change.p < 0.001). The interactions indicate that the associations between GFR decline and SBP, DBP and MAP were stronger when combined with antihypertensive medication  and SBP, DBP, and MAP respectively in the fully adjusted models in Table ion Fig. .Fig. 2As2  and for persons with GFR greater than 60 ml/min/1.73 mBSA) and estimated GFR based on either creatinine or cystatin C (eGFRcrea and eGFRcys) were analyzed (Additional file crea or eGFRcys. The results for GFRBSA were similar to those for absolute GFR in Table The associations between BP components and GFR decline assessed by body-surface adjusted GFR (GFRThe regression models in Table The results of this investigation do not support the hypothesis that elevated BP causes accelerated age-related GFR decline in the general population during almost 6 years of follow-up Table . On the In randomized controlled trials of antihypertensive drugs in CKD patients, an initial drop in GFR is commonly observed when treatment is started, followed by a subsequent slower decline , 47. ThiTo our knowledge, the present study is the first to assess the association between BP and GFR decline in the general population using measurements rather than estimates of GFR. Studies that have used serum creatinine, estimated GFR, or creatinine clearance have given mixed results –14, 50. The finding of an association between higher BP and a slower GFR decline seems to be inconsistent with observational studies that have found hypertension a risk factor for both ESRD , 2, 5. aConditions with both low BP and low GFR, such as advanced heart failure and serious infections, could possibly confound the association between low BP and a faster GFR decline, but are unlikely to explain the findings in this relatively healthy, ambulatory cohort. Only subjects without cardiovascular disease at baseline were included, and an analysis after excluding subjects with self-reported heart disease at follow-up made essentially the same findings as in the main analysis (Additional file The principal strength of the present study is the use of measured GFR rather than estimated GFR from creatinine or cystatin C. When we repeated the analyses with estimated GFR instead of iohexol clearance, the regression coefficients were attenuated and not statistically significant (Additional file The most important limitation of our investigation was that conclusions about causality cannot be drawn from an observational study. In particular, the use of time-varying variables in the regression analyses does not allow us to establish the temporal precedence of elevated BP relative to a change in GFR decline, and can only demonstrate an association between these variables. The direction of causality is also uncertain, as subclinical renal damage has been suggested as a possible cause of primary hypertension . In addiWe conclude that higher BP is not associated with an accelerated mean age-related GFR decline in the general population, but that lower BP because of antihypertensive treatment is associated with a medium-term steeper GFR decline. This finding is still consistent with a long-term beneficial effect of antihypertensive treatment on GFR decline, but indicates that a possible long term slowing effect on the decline may be preceded by a phase of reduced hyperfiltration of longer duration than previously thought. This should be investigated in studies with longer follow-up and repeated measurements of GFR. In primary hypertension, randomized controlled trials of the effect of antihypertensive treatment on renal endpoints should employ substantially longer follow-up than in previous trials.


In this Perspective on the clinical trial by Rita Alloway and colleagues, Simon Ball explains the benefits to healthcare systems and individual patients of the bioequivalence established between generic and brand-name formulations of an immunosuppressive drug in transplant recipients. PLOS Medicine, Alloway and colleagues have addressed an important question regarding the bioequivalence of different formulations of tacrolimus in transplant recipients. Bioequivalence is a prerequisite for the extrapolation of clinical outcome study results using the originator’s formulation to the use of generic formulations [In many healthcare systems, the high cost of long-term immunosuppression is borne by the transplant recipient. Even in the world’s wealthiest economies the annual cost of an individual’s immunosuppression is a significant proportion of median income. This can contribute to nonadherence with the prescribed immunosuppressive regime and therefore economically driven health inequality, even in the most highly developed healthcare systems . In deveulations .The calcineurin inhibitor tacrolimus was approved by the United States Food and Drug Administration (FDA) for immunosuppression of liver transplant recipients in 1994 and kidney transplant recipients in 1997. By 2007, it was administered to more than 80% of kidney transplant recipients in the US Renal Data System. In that year the ELiTE-SYMPHONY study was published comparing 4 different immunosuppressive regimes in kidney transplantation [Tacrolimus has a narrow therapeutic index and is subject to routine therapeutic drug monitoring and dose adjustment. High peripheral blood concentrations of tacrolimus are associated with the nonspecific consequences of over-immunosuppression and specific effects of calcineurin inhibition, notably nephrotoxicity, neurotoxicity, and thrombotic microangiopathy. Low peripheral blood concentrations of tacrolimus are associated with acute rejection. In kidney transplant recipients, there is also evidence that high within-patient variability in trough tacrolimus concentration is associated with adverse outcomes, including acute rejection, chronic antibody mediated rejection, and ultimately allograft failure . This asGiven a narrow therapeutic index and the clinical significance of high within-patient variability in drug exposure, there has been some reluctance amongst clinicians and patients to consider changing tacrolimus formulation . PatientIn response to the concerns of patients and professionals and a resulting call for investigator-led studies by the FDA, Alloway and colleagues have undertaken a detailed prospective, pharmacokinetic study in kidney and liver transplant recipients . The oriThese data suggest that the use of generic formulations of twice-daily tacrolimus in adults with stable allograft function is likely to be safe. However, it is notable that only 7 of the 71 patients studied were African American. This may be relevant since the African American population exhibits different pharmacokinetics and within-patient variability compared with the white population , and thiThe study by Alloway and colleagues is a significant achievement, providing good evidence of bioequivalence between twice-daily formulations of tacrolimus. It accounts for within-patient variability in drug exposure over time in ways that have not previously been adequately dealt with in the literature. Given the importance of consistent dosing with optimal immunosuppression and the well-documented economic barriers to doing so in different settings, this high level of assurance for the use of generic formulations will not only improve value derived across healthcare systems but, crucially, also improve individual patient-level outcomes in the long-term and patient access to treatment across a range of healthcare economies.


Postoperative atrial fibrillation, acute kidney dysfunction and low cardiac output following coronary surgery are associated with morbidity and mortality. The purpose of this study is to determine if the preoperative autonomic control is a determinant of these postoperative complications. This is a prospective cohort study on 150 adult patients undergoing surgical coronary revascularization with cardiopulmonary bypass. The patients received an autonomic control assessment after the induction of anesthesia. Baroreflex sensitivity was computed by spectral analysis and expressed as BRSαHF and BRSαLF for measure respectively in the high and low frequency domains. Atrial fibrillation was adjudicated at any postoperative time during the hospital stay. Acute kidney dysfunction was defined as any increase of serum creatinine levels from preoperative values within the first 48 hours after surgery, and acute kidney injury was adjudicated at a 50% increase. Low cardiac ouput syndrome was defined as the need for inotropic support > 48 hours. Thirty-eight (26.4%) patients experienced postoperative atrial fibrillation; 32 (22.2%) had acute kidney dysfunction and 5 (3.5%) acute kidney injury; 14(10%) had a low cardiac output state. No indices of baroreflex sensitivity were associated with atrial fibrillation or acute kidney injury. A low value of BRSαLF was associated with acute kidney dysfunction and low cardiac output state. A BRSαLF < 3 msec/mmHg was an independent risk factor for acute kidney dysfunction  and of low cardiac output state . Preoperative baroreflex sensitivity is linked to postoperative complications through a number of possible mechanisms, including an autonomic nervous system-mediated vasoconstriction, a poor response to hypotension, and an increased inflammatory reaction. A reduction in the baroreceptor-heart rate reflex , has been reported in hypertension, coronary artery disease, myocardial infarction and heart failure.  The majooreflex. , 5A maladaptation of the autonomic nervous system (ANS) is involved in a number of post-surgical complications including atrial fibrillation (AF), acute kidney dysfunction (AKD), and injury (AKI), and low cardiac output syndrome (LCOS).In cardiac surgery, new onset AF can be found in approximately 20% to 40% of the patient population depending on the type of surgery and the patient profile, ,7 and itIn addition to cardiac function, the ANS is also involved in the modulation of kidney function.  DependinFollowing cardiac surgery, LCOS is observed in up to 20% of the patients.  The inabThe experimental hypothesis of the present study is that the preoperative autonomic control, defined in terms of BRS, may be an independent determinant of AF, renal function impairment, and LCOS following cardiac surgery.Prospective cohort study performed according to the declaration of Helsinki. The study design was approved by the Local Ethics Committee . All the patients gave a written informed consent.The study population was constituted by 150 adult (> 18 years) patients undergoing elective or urgent coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). Exclusion criteria were emergency surgery, known ANS pathology, non-sinus rhythm. Withdrawal criteria were mortality within the first 48 hours from surgery and technical impossibility of recording post-anesthesia induction data..kg-1 and infusion of remifentanil 0.2 μg.kg-1.min-1. Maintenance of anesthesia was achieved with a continuous infusion of propofol at 3 mg.kg-1.h-1 and a remifentanil infusion range from 0.05 to 0.5 μg.kg-1.min-1. Additional inhalatory agents (sevorane) could be used as requested.According to our standard practice, the patients received a premedication with intramuscular atropine (0.5 mg) and fentanyl (100 μg) about 1 hour before reaching the operating theater. Anesthesia was induced with an intravenous bolus injection of propofol at 1.5 mgPreoperative data included demographics, co-morbidities, serum creatinine value (mg/dL), cardiovascular profile, and mortality risk stratification using the European System for Cardiac Operative Risk Evaluation (EuroSCORE II). Intraoperative data included the presence of additional surgical procedures, lowest temperature on CPB, and CPB duration. Postoperative data included in-hospital mortality, need for postoperative inotropic support, mechanical ventilation time (hours), intensive care unit (ICU) and hospital stay (days). The presence of AF was adjudicated in case of any AF event recorded during the postoperative period, from the admission to the ICU to the hospital discharge, and detected by continuous ECG monitoring during the ICU stay or by daily ECG control after discharge from the ICU.Postoperative renal dysfunction was assessed based on the peak postoperative serum creatinine level within 48 hours from surgery. The presence of AKI was adjudicated according to the Acute Kidney Injury Network criteria as AKI stage 1  or higher stages, within 48 hours from surgery. AKD was defined as any increase in serum creatinine value from baseline within 48 hours from surgery. LCOS was defined as the need for inotropic support for more than 48 hours after surgery.The experimental protocol was already described in details.  Lead II The sampling frequency was 1000 Hz and the recording session lasted 10 minutes.2 and mmHg2. Power spectral density was estimated through a parametric approach. [The beat-to-beat series of R-R interval (R-R) and systolic arterial pressure (SAP) were extracted during the entire recording period from ECG and arterial pressure respectively. R-R and SAP mean and variance were extracted and expressed in milliseconds (ms), mmHg, mspproach.  A spectrBRS was evaluated through spectral approach.  BRS was Data are presented as median with interquartile range for continuous, non-normally distributed variables, and as number with percentage for dichotomous variables. Normality assumption was tested using a Kolmogorov-Smirnov test. The difference between the recorded parameters in the AF and non-AF, AKD/AKI and non-AKD/AKI, and LCOS and non-LCOS groups was investigated at an univariate analysis using parametric (Student’s t test) and non-parametric (Mann Whitney U test) tests as appropriate. Differences in dichotomous variables frequencies were tested with a Fisher’s exact test or Pearson’s chi square as appropriate. The predictive ability of the identified variables was tested with a receiver operating characteristics (ROC) analysis, producing areas under the curve (AUC). Adequate cut-off values were identified according to the best coupling of sensitivity and specificity values with the pre-requisite of a specificity of t least 90%.A subsequent multivariable analysis (logistic regression) was applied to the BRS dichotomized according to the identified cut-off value, and to all the factors having an association with the outcome variables at a P value of 0.05 or less. For each outcome, the independent risk factors were identified and expressed as odds ratios and 95% confidence interval. For all the statistical tests, a P value < 0.05 was considered statistically significant. All the statistical analyses were performed with computerized packages .The general characteristics of the patients population are depicted in Tables Patients with LCOS had a significantly lower ejection fraction, higher serum creatinine values and EuroSCORE II, and were significantly more likely to receive an associated mitral valve repair. They had a significantly longer mechanical ventilation time, ICU stay, and hospital stay. Patients with AF were significantly older, more often females and with a lower hematocrit, and had a significantly longer ICU and hospital stay.The predictive properties of BRSαLF for AKD and LCOS were investigated with an ROC analysis . The disThe multivariable predictive models for AKD and LCOS are reported in The main results of our study are: (i) BRS as determined by the αHF is not associated with any of the considered outcomes, (ii) conversely, the BRSαLF is an independent predictor of AKD and LCOS, and (iii) postoperative AF is not associated with preoperative measures of BRS.2+ homeostasis. [Even if negative with respect to AF, our study offers new insights into the role of baroreflex dysfunction in the development of clinical complications following cardiac surgery. Impaired baroreflex function results in increased sympathetic activity and vagal withdrawal. Several mechanisms can account for the detrimental effects of a depressed BRS (in the context of cardiac surgery). Besides the well-known electrophysiological effects of vagal and sympathetic activity,  baroreflostasis.  Ackland ostasis.  analyzedostasis.  The sameostasis.  They fouThe exquisite sensitivity of baroreceptors to changes in arterial pressure implies that baroreflex mechanisms come into play any time a concurrent pathological event results in a transient decline in blood pressure. The sequence of events initiated by hypotension leads to a vagal withdrawal and to a generalized increase in sympathetic activity that favours a return of arterial pressure toward normal. On this background, inadequate baroreflex-mediated sympatho-excitation during a rapid rhythm  or an inAll the above mentioned mechanisms may account for the independent association between BRS and LCOS found in our study. Of notice, BRSαLF remains independently associated with LCOS even after correction for the preoperative factor (left ventricular ejection fraction) generally considered the main predictor of LCOS.The second finding of our study is the independent association of BRSαLF with AKD. Although the limited number of events (seven) did not allow to find associations between the BRSαLF and the more clinically relevant pattern of AKI stage 1, the finding of an independent association between BRS and minor degrees of renal dysfunction is not deprived of clinical relevance. As a matter of fact, even a minimal increase of serum creatinine levels after cardiac surgery is a determinant of increased early and long-term mortality.  AKD in pOur data support a recent study in high-risk surgical patients showing that baroreflex dysfunction might contribute to the development of post-operative morbidity.  The cut-There are some limitations in our study. The patient population was at low risk and many co-morbidities were probably underestimated being consequently a possible source of undetected bias. The low rate of AKI events did not allow us for a comprehensive statistical analysis. Finally, the reader must consider that the measurements done were certainly affected by the effects of anesthesia drugs, and namely by propofol, which is known to depress BRS.  For futuAlthough the present study, lacking a prospective validation, should be mainly regarded as a “proof of concept” study, we can draw some clinical considerations. By anticipating the assessment of BRS at an earlier stage in the evaluation of candidates to cardiac surgery, this would allow to take advantage of a number of measures that can improve the autonomic balance. Exercise training is known to improve BRS  even in S1 FileOriginal data set including all variables for the overall population (N = 144).(SAV)Click here for additional data file.


The aim of the study is to investigate risk factors for future falls in subject with primary open angle glaucoma (POAG).All participants answered the following question at their baseline ophthalmic examination: Have you had any falls in the last year? (Yes/No). All study participants answered the same question every 12 months for 3 years. The means of total deviation values in the whole, superior peripheral, superior central, inferior central, and inferior peripheral visual fields (VF) were calculated. The relationship between these mean VF measurements, and various clinical factors against patients’ future falls was analyzed using multiple linear regression.Two-hundred ninety four POAG patients answered the baseline and follow-up fall questionnaires over a period of three years. Among 294 subjects, 69 patients experienced a fall during the three-year follow-up. History of falls at baseline (coefficient = 1.22), history of fear of falling at baseline (0.53), best corrected visual acuity in the worse eye (7.37), prevalence of diabetes mellitus (0.60), prevalence of systemic hypertension (0.53) were selected in the optimal model.Visual acuity in the worse eye, history of falls, fear of falling, diabetes mellitus, and systemic hypertension are risk factors for falling in subjects with POAG.The online version of this article (10.1186/s12886-017-0613-1) contains supplementary material, which is available to authorized users. Glaucoma is a disease with progressive loss of retinal ganglion cell which proceeds to peripheral visual field loss, central visual filed loss, and vision loss. Aging is a risk factor for onset and progression of glaucoma . Tham etFall is one of the leading causes of injury and death in daily living. In 2010, 21,649 people over 65 in the United States had fatalities due to falls . Fall isn = 21) increased the risk of falling by more than 4 fold  after adjustment for visual acuity  with a lue <1%) ; and (3)Subjects were excluded, if they had an ophthalmological disease other than POAG that could potentially compromise visual acuity or contribute to visual field loss, such as age-related macular degeneration. Subjects were also excluded if they had a decimal best corrected visual acuity (BCVA) of less than 0.7, or had a mental disorder that prevented them from understanding the questionnaire, as registered by the doctor who performed informed consent. Of the POAG patients screened, 164 patients were excluded. The reasons for excluding subjects were as follows (the numbers in parentheses indicate the number of subjects excluded): younger than 40 years old (28 patients), older than 85 years old (25), refusal to participate (10), walked with a cane (12), dementia (3), low visual acuity (24), post retinal-detachment (21), diabetic retinopathy (36), bullous keratopathy (2), age-related macular degeneration (2), other ocular disease (1). As a result, 392 POAG patients were eligible for the study.Can you walk without assistance? (Yes/No)Do you use a cane or any kind of walking aid? (Yes/No)How long do you spend walking on average per day? (The number of minutes was recorded.)Are you afraid of falling? Have you had any falls in the last year? (Yes/No) *All study participants answered the following questionnaire in Japanese (translated) at baseline ophthalmic examination The definition of fall in our study was an event whereby a person comes to rest inadvertently on the ground.Demographic information, recorded for all subjects, included age, sex, height, weight, alcohol intake (yes/no), smoking history (yes/no/previous), current and previous illnesses , and medical history, including oral medications such as sleeping aids, anti-hypertensive drugs, or tranquilizers.All study participants answered the following question every 12 months ±1 month after the baseline questionnaire  were calculated, following the mapping in the 24–2 and 10–2 visual fields in the HFA  was calculated for each patient by merging a patient’s monocular HFA VFs, using the ‘best sensitivity’ method, where the IVF total deviation (TD) at each point was calculated using the maximum TD (least negative) value from each of the two overlapping points, as if the subject was viewing the field binocularly . The IVFDescriptive statistics were calculated for the demographic, medical, and visual-function variables both in patients with a history of falls and patients without history of fall. Differences were tested using the Wilcoxon test or chi square test.SP, mTDSC, mTDIC, mTDIP, body mass index, sedative or sleeping aid use, average walk minutes per day at baseline, history of diabetes mellitus, history of systemic hypertension, history of fall at baseline, and history of fear of falling. The optimal linear model was then selected among all possible combinations of 15 predictors (215 patterns) using the second order bias corrected Akaike Information Criterion (AICc) index. This is because the degrees of freedom in a multivariate regression model decreases when the number of variables is large and it is therefore recommended to use model selection methods to obtain the optimal model fit by removing redundant variables [The relationship between the incidence of falls and the following confounding factors were analyzed using the multivariable logistic regression model: age, sex, worse BCVA, better BCVA, mTDariables , 19.p value less than 0.05 was considered statistically significant. Decimal visual acuity was converted to LogMAR visual acuity for analysis. All data were analysed with IBM SPSS statistics software version 21.0  or statistical programming language R .A Among 392 POAG patients, 294 POAG patients (75.0%) answered the baseline and follow-up fall questionnaires over a period of three years. The characteristics of these patients are summarized in Table The comparison of systemic and ocular demographic characteristics, including BCVA in the better eye and in the worse eye, MD in the better eye and in the worse eye, and systemic factors were shown in Tables SP, mTDSC, mTDIC, mTDIP, age, sex, body mass index (BMI), BCVA in the worse eye, BCVA in the better eye, average walking minutes in a day at baseline, prevalence of diabetes mellitus, prevalence of systemic hypertension, use of sedative and/or sleeping aid, history of fall at baseline, history of fear of falling, only a subset were included in the optimal model. These were history of falls at baseline (coefficient = 1.22), history of fear of falling at baseline (0.53), worse BCVA (7.37), prevalence of diabetes mellitus (0.60), prevalence of systemic hypertension (0.53)  is identical to the mTD value of whole VF, we carried out this analysis replacing the values of mTDSP, mTDSC, mTDIC, mTDIP with mTD of whole VF, however completely same variables were selected.Among the 15 variables of mTDSP, mTDSC, mTDIC, mTDIP were selected.In the current study, the incidence of falls in subjects with POAG was surveyed for three years and the risk factor for future falls was investigated. As a result, we have shown that History of falls at baseline, history of fear of falling at baseline, BCVA in the worse eye, prevalence of diabetes mellitus, prevalence of systemic hypertension were the risk factors for the occurrence of a future fall in subjects with POAG. Among the variables related to visual function, only the worse BCVA was selected as a risk factor of fall, but none of better BCVA, mTDIn a Singapore Malay Eye study, severe visual impairment (LogMar >1.0) in the worse eye significantly increased the risk of falling , but that in the better eye did not . In the Coleman et al. reported that subjects with history of frequent falling is five times more likely to experience multiple fall in a large sample prospective study . In the In this study, we can’t find the association between glaucomatous visual field defect and a fall. Whether glaucoma is associated with falling is controversial , 20–27. We showed that a history of fear of falling at baseline is a risk factor for future falling. To the best of our knowledge, this is the first study that shows fear of falling is a risk factor for future falling in subjects with POAG. Fear of falling is defined as anxiety about falling and limitation of the activities in daily life . Fear ofPrevalence of systemic hypertension, was selected as risk factor for future falling. Tinettie et al. reported that adjusted hazard ratios for serious fall injury were 1.40  in the moderate- intensity antihypertensive groups compared with non anti-hypertensive medication users . HoweverPrevalence of diabetes mellitus was also chosen as a risk factor for future falling. Maurer et al. reported that subjects with diabetes mellitus is 4 times more likely to fall  in a prospective study . Severalp < 0.05, chi-square test). We included the interaction between history of falling and fear of falling, but the parameters selected in the optimal model were not changed. Also, adding this interaction resulted in the increase of AICc value by 2.1. Among other variables of age, sex, BMI, BCVA in the worse eye, BCVA in the better eye, average walking minutes in a day at baseline, BCVA in the worse eye and BCVA in the better eye had the highest correlation coefficient, but it was merely 0.60. Furthermore, adding the interaction between these BCVAs resulted in the same variables in the optimal model. Other intercorrelation had much lower values of correlation coefficient, thus the results obtained is influenced by multicollinearity among the variables.Fear of falling and previous episodes of falls are inter-correlated . (DOCX 16 kb)Additional file 2:Follow-up questionnaire. Follow-up fall related questionnaire in this study which was performed once a year (translated from Japanese to English). (DOCX 15 kb)


To test the hypothesis that bacterial infections in pregnancy are related to maternal blood pressure.Bacterial infection was assessed using antibiotic usage as a surrogate and its association with blood pressure in pregnancy tested in the Cambridge Baby Growth Study.Antibiotic usage in pregnancy was self-reported in questionnaires. Blood pressure measurements at four time points in pregnancy were collected from the hospital notes of 622 women.−3, from 621 individuals). Further analysis revealed that antibiotic usage was associated with diastolic  mmHg; p = 7.0 × 10−3) more than systolic blood pressure  mmHg; p = 0.2). The effect size associated with antibiotic usage appeared to rise slightly after the first trimester.Using all the available blood pressure readings (adjusted for weeks gestation) antibiotic usage was associated with a higher mean arterial blood pressure across pregnancy: antibiotics used 85  mmHg vs. no antibiotics used 83  mmHg  mmHg, p = 9.6 × 10Bacterial infection in pregnancy, as assessed by self-reported antibiotic usage, is associated with small rises in blood pressure. Its established risk factors include null parity, maternal age >40 years, multiple pregnancy, extended times between pregnancies, the presence of antiphospholipid antibodies, prior pre-eclampsia in a previous pregnancy or a positive family history, chronic hypertension or gestational hypertension during pregnancy, pre-gestational or gestational diabetes, obesity and use of assisted reproductive technology A number of studies have sought associations between infections in pregnancy and the development of pre-eclampsia. Whilst not all studies have found significant associations 22.1The prospective and longitudinal Cambridge Baby Growth Study recruited 2229 mothers (and their partners and offspring) attending ultrasound clinics during early pregnancy at the Rosie Maternity Hospital, Cambridge, United Kingdom, between 2001 and 2009 2.2Each of the study participants were given a printed questionnaire at recruitment to fill in and return once the pregnancy was completed For the purposes of this study only the category based on antibiotic usage was employed. The timings when the antibiotics were reported having been taken were divided into trimesters . Of the 1271 women that filled out questionnaires, 173 (13.6%) reported that they had taken antibiotics during pregnancy and 1098 had not. Of the women that reported having taken antibiotics in pregnancy 51 reported first trimester usage, 68 second trimester and 54 third trimester . Specific antibiotic usage was reported as follows: amoxycillin (71 women), cephalexin/cefalexin (16), penicillin (16), erythromycin (15), flucloxacillin (6), clarithromycin (3), augmentin (2), cephradine (2), ampicillin (1), cefaclor (1), cefotaxime (1), ciproflaxine (1), metronidazole (1), trimethoprim (1) and ‘antibiotic(s)’ (37).2.3The most common reason given for taking antibiotics during pregnancy was to treat UTIs. Of the 1271 women that filled out their questionnaires, 53 (4.2%) self-reported that they had experienced UTIs at some point during their pregnancy. Of these women 19 reported having had UTIs in the first trimester of pregnancy, 25 in the second trimester and 14 in the third trimester; some women reported having had UTIs in more than one trimester and some did not disclose when in pregnancy they were infected.2.4Routine blood pressure measurements during pregnancy that had been recorded in hospital notes were collected from a total of 968 women in the Cambridge Baby Growth Study  2.5The Cambridge Baby Growth Study was approved by the local ethics committee, Addenbrooke’s Hospital, Cambridge, United Kingdom. All procedures followed were in accordance with the institutional guidelines. Written informed consent was obtained from all the study participants.2.6Blood glucose concentrations were measured using a routine glucose oxidase-based method. Plasma insulin concentrations were measured using a DSL ELISA kit  according to the manufacturer’s instructions.2.7https://www.dtu.ox.ac.uk/homacalculator/Mean arterial blood pressure was estimated as twice the diastolic plus the systolic blood pressure all divided by three. The body mass index (BMI) before pregnancy was calculated as the pre-pregnancy body weight divided by the height squared. HOMA S was calculated using the online calculator available at 2.8The associations between antibiotic usage (or UTI) at any time during pregnancy and blood pressure  were tested using general estimation equation modelling, adjusting for weeks of gestation (and sometimes BMI) when the blood pressure readings were taken. Associations at individual time points and between antibiotic use and HOMA S (insulin sensitivity) or between blood pressure and antibiotic use/UTIs in specific trimesters were assessed by linear regression. Values for those women that experienced UTIs were compared with those from women who did not report any antibiotic usage at all . Unless otherwise stated all other data are presented as means . Statistical analyses were performed using Stata 13 . P < 0.05 was considered statistically significant throughout.33.1−3, from 621 individuals)  mmHg vs. no antibiotics used 83  mmHg  mmHg, p = 9.6 × 10viduals) . Further−3), although further adjustment for BMI weakened the relationship as the 95% confidence interval for the diastolic blood pressures of those women who used antibiotics widened: antibiotics used 70  mmHg vs. no antibiotics used 68  mmHg  mmHg, p = 0.08, from 434 individuals).Separating the mean arterial blood pressure into its component systolic and diastolic parts, antibiotic usage was not associated with systolic blood pressures over the four readings taken over pregnancy: antibiotics used 115  mmHg vs. no antibiotics used 114  mmHg  mmHg, p = 0.2). Further adjustment for BMI led to even more overlap between the two groups: antibiotics used 114  mmHg vs. no antibiotics used 114  mmHg  mmHg, p = 1.0, from 434 individuals). Antibiotic usage, however, was associated with diastolic blood pressure over the same readings: antibiotics used 70  mmHg vs. no antibiotics used 68  mmHg  mmHg, p = 7.0 × 103.23.3−6, n = 465), week 31.4 , week 37.0  and week 38.8 . However there was no association between antibiotic usage and HOMA S: antibiotics used 109.4  %S (n = 123) vs. no antibiotics used 109.6  %S (n = 751) (p = 1.0).Each of the blood pressure readings were associated with reduced week 28 HOMA S: week 11.8  during pregnancy and overall mean arterial blood pressure was not statistically significant: UTI 85  mmHg (n = 27) vs. no antibiotic use 84  mmHg (n = 516)  mmHg, p = 0.6). 4per se. This rise in blood pressure appeared to relate to the diastolic more than the systolic blood pressure measurements. Those women who reported that they took antibiotics had slightly higher pre-pregnancy BMIs than those that did not  but adjusting for this did not change the outcome so the antibiotic-associated change in blood pressure did not relate directly to obesity.In this study we have shown that in our population self-reported general antibiotic usage in pregnancy is associated with a small increase in mean arterial blood pressure of around 2–3 mmHg. Although infections, such as those requiring treatment with antibiotics, have previously been shown to be associated with severe hypertensive disorders of pregnancy T. gondiiAlthough there appears to be a link between infection and pre-eclampsia There are a number of other possible explanations to explain the associations between antibiotic usage in pregnancy and increases in blood pressure, although they appear to be less convincing. Firstly antibiotics could have a direct effect on blood pressure in pregnancy, although we do not know of any published evidence of this. Secondly rises in blood pressure can sometimes be associated with effects of antibiotic allergy In vitro studies of human umbilical vein endothelial cells suggest that infectious stimuli are able to lower eNOS gene expression In our study the mechanism behind the raised blood pressure did not appear to involve altered insulin sensitivity, despite the established link between insulin resistance and hypertensive syndromes of pregnancy Although the results from this study are interesting it does have limitations. Firstly it appears underpowered to detect associations with UTIs, with antibiotic usage at specific time points and with specific antibiotic usage, especially when the overall rise in mean arterial blood pressure in women who took antibiotics in pregnancy was only 2–3 mmHg. Another study limitation is that self-reporting prescription drug intakes can be affected by recall bias, and recall for drugs with short-term use such as antibiotics may be lower than that for drugs used to treat chronic conditions In summary we have shown for the first time that self-reported antibiotic use in pregnancy, most likely reflecting bacterial infections of sufficient severity to merit antibiotic treatment, is associated with a modest rise in mean arterial blood pressure. Partially consistent with our findings, in a study over 6000 (non-pregnant) women of all ages from the 1960s the mean systolic blood pressures of women with significant bacturia were around 3 mmHg higher than those without bacturia, although statistical significance was not reached on this occasion


Management of delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH) is difficult and still carries controversies. In this study, the effect of therapeutic hypervolemia, hemodilution, and hypertension (HHH-therapy) on cerebral blood flow (CBF) was assessed by xenon-enhanced computerized tomography (XeCT) hypothesizing an increase in CBF in poorly perfused regions. Bedside XeCT measurements of regional CBF in mechanically ventilated SAH patients were routinely scheduled for day 0–3, 4–7, and 8–12. At clinical suspicion of DCI, patients received 5-day HHH-therapy. For inclusion, XeCT was required at 0–48 h before start of HHH (baseline) and during therapy. Data from corresponding time-windows were also collected for non-DCI patients.P = 0.001). There was a concomitant increase in regional CBF of the worst vascular territories, and the proportion of area with blood flow below 20 ml/100 g/min was significantly reduced. Non-DCI patients showed higher CBF at baseline, and no significant change over time.Twenty patients who later developed DCI were included, and twenty-eight patients without DCI were identified for comparison. During HHH, there was a slight nonsignificant increase in systolic blood pressure (SBP) and a significant reduction in hematocrit. Median global cortical CBF for the DCI group increased from 29.5 (IQR 24.6–33.9) to 38.4 (IQR 27.0–41.2) ml/100 g/min (HHH-therapy appeared to increase global and regional CBF in DCI patients. The increase in SBP was small, while the decrease in hematocrit was more pronounced, which may suggest that intravascular volume status and rheological effects are of importance. XeCT may be potentially helpful in managing poor-grade SAH patients. The complex mechanisms leading to secondary brain injury and the sometimes devastating course of delayed cerebral ischemia (DCI)  after anAfter early repair of the aneurysm, most guidelines propose fluid therapy to ensure normovolemia or mild hypervolemia, monitoring of blood pressure and vasoactive support if necessary to avoid hypotension , 8. At sThe aim of this study was to evaluate the effects of HHH-therapy on CBF, testing the hypothesis that HHH-therapy increases global CBF and also regional CBF (rCBF) in areas at risk of ischemia. Bedside xenon-enhanced computerized tomography (XeCT) was used to assess rCBF prior to clinical suspicion of DCI and during the treatment to resolve DCI.2 >0.6, the absence of informed consent, and futility or “do not resuscitate” order.Patients diagnosed with severe spontaneous SAH admitted to Uppsala University Hospital during the time period 2013–2016 were prospectively enrolled in the study. The diagnosis of SAH was verified by CT. As ventilator treatment is a prerequisite for bedside XeCT in our setting, only patients requiring intubation due to their neurological state at admission or neurological deterioration day 0–1 were included, i.e., patients with more severe SAH. Exclusion criteria were severe intracranial hypertension, deep sedation with thiopental, respiratory problems requiring FiOAccording to our standard NIC protocol, CBF measurements were scheduled for three time intervals: day 0–3, 4–7, and 8–12. Patients with clinical diagnose of DCI received HHH-therapy as described below. For inclusion in this study, a XeCT measurement within 0–48 h before the start of HHH-therapy was required (used as baseline), and the intention was to perform the next XeCT measurement during ongoing therapy when logistically possible. Data were also collected for non-DCI patients with corresponding XeCT measurements in the same time-windows as a reference group for comparison.2. ROIs in areas of hematoma or with artifacts from ventricular drains were excluded.The XeCT procedures in our NIC unit are conducted as described by Gur et al. and Yonas et al. –14, usin®, Fresenius Kabi AB, Uppsala, Sweden) is titrated in the interval 0–4 mg/kg/h, and morphine  is administered as needed. Patients with suspicion of hydrocephalus or altered level of consciousness receive a ventriculostomy catheter for monitoring of intracranial pressure (ICP) and drainage of cerebrospinal fluid. Elevated ICP (>20 mmHg) is treated with open ventricular drainage against a pressure level of 15 mmHg. The general policy is to treat aneurysms early with endovascular coil embolization as first choice when possible or surgical clipping. After the aneurysm repair, patients are kept mildly hypervolemic if not contraindicated by intracranial mass effect or elevated ICP. The volume status is maintained by fluid administration in the higher normal range with addition of albumin infusion  if needed and monitored by central venous pressure, clinical evaluation and rigorous fluid balance calculation. Nimodipine  is given from day one and onwards.Management of all patients followed our standard NIC procedures for SAH as earlier described by Ryttlefors et al. , where t®, Meda AB, Solna, Sweden) and 200 ml albumin  and were kept in supine position. In our standard NIC protocol, emphasis is on avoiding severe side effects and the blood pressure targets during HHH-therapy are moderate. The systolic blood pressure (SBP) was closely monitored and kept above 140 mmHg using vasoactive agents if needed. As first line, dobutamine  was used for inotropy or, if insufficient, norepinephrine  was added as vasopressor. The clinical effect of the HHH-therapy was repeatedly evaluated.To detect DCI, patients were monitored for general and focal neurological changes by repeated wake-up tests . In the Global cortical CBF ml/100 g/min) was calculated as mean of all ROIs at all scan levels used  with local CBF below the threshold divided by the total analyzed ROI area in each patient.To detect and quantify the extent of areas with low blood flow and near-ischemic flow, thresholds for local CBF were set to 20 and 10 ml/100 g/min , 20. Thedead.Clinical course outcome was defined as neurological state at discharge from the NIC unit and determined as good , poor , or Cerebral infarcts visible on follow-up CT at 12 days or later after admission to the NIC unit were categorized as <20 mm, 20–39 mm, >40 mm, or multiple.t test. CBF data for groups of patients are presented as median values and interquartile range because of non-normal distribution. Differences in CBF parameters between related samples were tested by Wilcoxon signed-ranks test, and between independent samples by Mann–Whitney U test. Statistical significance level was set at P < 0.05.SPSS statistics 23.0 software  was used for statistical analyses of the collected data. Differences in systemic physiological parameters between measurements were tested by paired samples A total of 119 intubated SAH patients underwent one or more XeCT measurements during the time period 2013–2016. During this period, 20 patients with clinical suspicion of DCI were identified where XeCT measurements of CBF had been taken within 0–48 h before the initiation of HHH-therapy (baseline), and during the 5-day HHH-therapy  were small; mean arterial pressure (MAP) mean 92.5 mmHg (CI 90.0–95.0) versus 89.9 (CI 87.6–92.2), ICP mean 14.3 mmHg (CI 13.2–15.4) versus 14.4 (CI 13.5–15.4), PCO2 mean 5.41 kPa (CI 5.29–5.53) versus 5.51 (CI 5.40–5.63). No adverse events were observed in relation to the procedures.Hemodynamic parameters and ventilation were clinically stable 2, and hematocrit at start of the XeCT measurements at the different time-windows for the DCI and non-DCI groups are presented in Table SBP, MAP, cerebral perfusion pressure (CPP), pCOThe use of inotropes and vasopressors was low in all groups. The number of patients and dose range for each group are also presented in Table P = 0.005).Results of the XeCT measurements are presented in Table P = 0.001), while no significant change over time was seen in the non-DCI group. No statistical analyses were performed for differences between DCI patients during HHH-therapy and non-DCI patients at the corresponding time-window.During HHH-therapy, the DCI group showed an increase in median global cortical CBF from 29.5 (IQR 24.6–33.9) to 38.4 (IQR 27.0–41.2) ml/100 g/min (P = 0.005). Concerning regions with low or near-ischemic CBF, the DCI group had a larger proportion of ROI area with blood flow below 20 ml/100 g/min  and flow below 10 ml/100 g/min  compared to the non-DCI group.At baseline, there were also significant differences in regional CBF parameters between the DCI and non-DCI groups Table ; Fig. 3;P = 0.006) (Table P = 0.019). The area with flow below 10 ml/100 g/min was small already at baseline but tended to decrease . The relative blood flow in the worst vascular territory compared to the best hemispheric blood flow (CBF index of worst vascular territory) showed a small but statistically significant increase during HHH-therapy. In the non-DCI group, there were no significant changes from baseline to the second time-window regarding rCBF in the worst vascular territory or the proportion of ROI area with local blood flow below the specified thresholds. In this group, there was a small, but statistically significant reduction in the CBF index of worst vascular territory between the two measurements.During HHH-therapy, median rCBF of the worst vascular territory for the DCI group increased from 19.6 IQR 15.0–24.2) to 27.3 (IQR 17.8–34.1) ml/100 g/min  after the start of HHH-therapy, suggesting a sustained increase in CBF after initiation of the therapy. Early and repeated measurements would be preferred to better evaluate a direct relationship between HHH-therapy and CBF changes, but an increased number of measurements might be questionable due to radiation exposure and also logistically difficult.We find bedside XeCT feasible for clinical use in NIC to estimate rCBF in unconscious, mechanically ventilated patients, but the procedure takes the resources of a trained team of intensive care and radiology personnel. Regarding safety issues, XeCT using 28% inhaled xenon is previously reported safe , and allThe initial low global CBF found in patients diagnosed with DCI was significantly elevated during HHH-therapy. A concomitant increase in rCBF was also found in the worst perfused regions and the proportion of ROI area with blood flow below the threshold of 20 ml/100 g/min decreased significantly, which indicate a true effect of HHH-therapy. The increase in SBP was small, while the decrease in hematocrit was more pronounced, which may suggest that intravascular volume status and rheological effects are of importance. We found bedside XeCT to be a feasible and potentially clinically valuable tool in NIC.


High aldosterone level may contribute to pathogenesis of hypertension, vessels damage and cardiovascular system deterioration in chronic kidney disease patients. Besides its classical action via mineralocorticoid receptor, aldosterone is also involved in cell growth, inflammation, oxidative stress, endothelial dysfunction and exerts fibroproliferative effects. The aim of the study was to assess whether aldosterone antagonist treatment may influence serum level of inflammatory, fibrosis, thrombosis and mineral-bone metabolism markers in peritoneal dialysis (PD) patients and blood pressure, aortic stiffness, echocardiographic indices after 12 months of treatment.Twenty-two patients on PD were assigned to spironolactone treatment in dose of 50 mg daily during 12 months. Fifteen PD patients were assigned to control group. Echocardiographic indices, PVW, SBP, DBP  and biochemical parameters such as: aldosterone, osteopontin, IL-6, selectin-P, TGF-β, PTH, MMP-2 were performed at the beginning and after 12 months in spironolactone and control group.There were no statistically significant differences in echocardiographic indices, PWV, BP (ABPM readings) and biochemical markers: MMP-2, serum aldosterone, TGF-β, IL-6, selectin-P, PTH level after 12 months of spironolactone treatment. There was statistically significant rise in osteopontin level after 12 months of spironolactone treatment. Episodes of life-threatening hyperkalemia were not reported.Aldosterone antagonists use in PD patients seems to be safe. Longer duration or higher dosage of spironolactone seems to be more effective in improving cardiovascular system status in PD patients. Further studies are required to determine relationship between mineralocorticoid receptor blockade and mineral-bone disturbances in PD patients. Activation of renin-angiotensin-aldosterone system (RAAS) plays crucial role in pathogenesis of essential hypertension, hypertension related with kidney diseases and congestive heart failure (CHF). There is a lot of evidence that excess of aldosterone is an important risk factor of cardiac hypertrophy and fibrosis, subclinical inflammation, endothelial dysfunction, tissue fibrosis and vessels obliteration. Moreover, persistent hyperaldosteronemia plays an important role in progression of chronic kidney disease (CKD) . Based o® device  were performed in each individuals at the onset and after 12 months of the study. Blood samples for serum aldosterone level [pg/ml], metalloproteinase-2 (MMP-2), osteopontin (OPN), transforming growth factor-beta (TGF-β), P-selectin, interleukin-6 (IL-6) were taken in each subject at the commencement and after 12 months of the study. Serum PTH was measured using a chemiluminescent immunoassay on the DiaSorin LIAISON. Serum aldosterone, osteopontin, IL-6, TGF beta, MMP-2, P-selectin were determined by a sandwich ELISA method. Serum Aldosterone using IBL International ELISA. Osteopontin, IL-6, TGF beta, MMP-2 and P-selectin using R&D Systems ELISA. During the observation period, patients were on conventional APD (Baxter system) using 1.36%/2.27% glucose solution  with 5–6 overnight exchanges. The conventional APD schedule was: single dwell volume: 2.0–2.3 L, dwell time was—1.0 h and 30 min, the total dialysis time was about 10–11 h. We do not use Physionel and Nutrineal. Extraneal was used in 10 pts with overhydration signs. During the observation period we routinely carried out dialysis adequacy test (assessment of kt/v index) and peritoneal permeability tests (PET). Residual renal function (RRF) was present in all individuals, 10 pts with RRF decline and daily diuresis <500 ml was reported. During the observation period, there were no dropouts, transfers to HD related to either technique failure or infectious complications such as peritonitis or exit site infection. Clinical characteristics of the patients are shown in Table Thirty-seven Caucasian patients (pts) were examined: 21 female (F) and 16 male (M), mean age 52, 85 ± 15.8 years . They were recruited from PD center of Department of Nephrology, Hypertension and Internal Medicine in University Hospital in Bydgoszcz. All patients were on conventional automated peritoneal dialysis (APD) using Home Choice or Home Choice Pro devices delivered by Baxter. The causes of end-stage renal disease (ESRD) were: diabetic kidney disease—20 pts , non-diabetic nephropathies—17 pts. The latter group included as follows: chronic glomerulonephritis (CGN)—10 pts; obstructive nephropathy—2 pts; hypertensive nephropathy—5 pt. Comorbid conditions at the onset of the study were: coronary artery disease was diagnosed in 15 pts, symptoms of CHF were present in 10 pts. All of the patients enrolled into the study suffered from hypertension, and they required antihypertensive medication (2 or more antihypertensive agents). Treatment of hypertension was in accordance with current guidelines of ESH/ESC. The goal of treatment was to reach blood pressure below <140/90 mmHg. The following medications were prescribed: ACE-Is—29 pts, ARBs—8 pts, calcium channel blockers—26; Beta-blockers—15 pts, loop diuretics—30 pts with residual renal function. Chronic kidney disease–mineral and bone disorder (CKD-MBD) were treated according to KDIGO guidelines 2016 (update on the management of CKD-MBD) using conventional therapy: vitamin D  and calcium–phosphorus binders . There was no need to use calcimimetics. At the beginning of the study patients were divided into 2 groups. Twenty-two patients were treated with spironolactone orally in the dose of 50 mg daily during 12 months. Fifteen patients who refused spironolactone treatment as an additional medication  served as a control group. There were 12 diabetic patients in spironolactone group and 8 diabetic in control group. Inclusion criteria were: PD treatment time >6 months, stable clinical condition 6 weeks prior to enrollment without any inflammation, age >18 years old, written informed consent, no data of immunological disease with need for immunosuppressive treatment. Patients were eligible for spironolactone group when mean serum potassium level after 3 ambulatory visits was <5.0 mmo/l. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) using A&D TM 2430 device was performed in each patient at the onset of the study and after 12 months. Echocardiographic evaluation (LVMI), arterial stiffness with assessment of carotid-femoral pulse wave velocity (PVW) using the Compliort test. If any variable was not normally distributed, the U Mann–Whitney test was used. Qualitative data were compared by means of the χ2-test. Linear correlation between variables was analyzed using: Spearman rank correlation coefficient  and Pearson’s correlation coefficient  also. P value < 0.05 was considered as statistically significant.Statistical analysis was performed using the Statistica 7.0 PL software . The obtained data are presented as mean ± standard deviation (SD), and the median and top and bottom quartiles are given for variables that were not normally distributed. Distribution of variables was analyzed using the Shapiro–Wilk test. Statistical analysis was performed using the Student’s r = −0.91; p < 0.05) at the onset of the study. Statistically significant correlation between TGF-β versus aldosterone  was found in control group after 12 months of observation. Moreover, significant correlation was found between ΔOPN versus ΔTGF-β , ΔP-selectin versus ΔTGF-β  and ΔPWV versus ΔOPN  in spironolactone treatment group. These data are presented in Table Mean values and median values of investigated parameters at the onset and after 12 months of the study in spironolactone and control group are shown in Table Cardiovascular complications are major cause of increased mortality in dialysis patients and tend to aggravate in the course of dialysis treatment. Increased aldosterone level is considered to be one of the non-traditional cardiovascular risk factors which may be responsible for unsuccessful prognosis in PD patients. Hyperphosphatemia, increased PTH level, inflammation, endothelial dysfunction, oxidative stress are also common non-traditional markers of high CV risk in dialysis patients . AldosteIn opposite to other investigators reports, there were not any significant differences in blood pressure, LVMI, PVW in spironolactone group at the baseline versus after 12 months . Data concerning the influence of spironolactone or eplerenone treatment on ameliorating cardiovascular damage in PD patients are sparse. Most trials were performed in hemodialysis patients . Ito andIn conclusion, in our opinion aldosterone antagonist’s therapy is considered to be safe in PD patients and should be used more frequently. Further studies are necessary to evaluate their role in cardiovascular system protection and relationship with mineral-bone disturbances in PD pts.


The use of extracorporeal membrane oxygenation (ECMO) in cases of near-fatal asthma (NFA) has increased, but the benefits and potential complications of this therapy have yet to be fully investigated.Cases were extracted from the Extracorporeal Life Support Organization Registry between March 1992 and March 2016. All patients with a diagnosis of asthma , who also received ECMO, were extracted. Exclusion criteria included patients who underwent multiple courses of ECMO; those who received ECMO for cardiopulmonary resuscitation or cardiac dysfunction; and those with another primary diagnosis, such as sepsis. We analyzed survival to hospital discharge, complications, and clinical factors associated with in-hospital mortality, in patients with severe life-threatening NFA requiring ECMO support.2), peak inspiratory pressure (PIP), and mean airway pressure, significantly improved after ECMO initiation (rate (breaths/min), 19.0 vs. 11.3, p < 0.001; FiO2 (%), 81.2 vs. 48.8, p < 0.001; PIP (cmH2O), 38.2 vs. 25.0, p < 0.001; mean airway pressure (cmH2O): 21.4 vs. 14.2, p < 0.001). In particular, driving pressure was significantly decreased after ECMO support . The weaning success rate was 86.7%, and the rate of survival to hospital discharge was 83.5%. The total complication rate was 65.1%, with hemorrhagic complications being the most common (28.3%). Other complications included renal (26.8%), cardiovascular (26.1%), mechanical (24.6%), metabolic (22.4%), infection (16.5%), neurologic (4.8%), and limb ischemia (2.6%). Of the hemorrhagic complications, cannulation site hemorrhage was the most common (13.6%). Using multivariate logistic regression analysis, it was found that hemorrhage was associated with increased in-hospital mortality . Hemorrhage-induced death occurred in four patients (1.5%). The most common reason for death was organ failure (37.8%).In total 272 patients were included. The mean time spent on ECMO was 176.4 hours. Ventilator settings, including rate, fraction of inspired oxygen  contains supplementary material, which is available to authorized users. Near-fatal asthma (NFA) is a life-threatening condition caused by acute respiratory failure, and is the most severe clinical presentation of asthma , 2. Althstatus asthmaticus to a greater degree than in other respiratory conditions [ECMO can provide adequate gas exchange during acute respiratory failure, and can help prevent lung injury induced by aggressive mechanical ventilation. Using data from the multicenter Extracorporeal Life Support Organization (ELSO) Registry, a previous study showed that ECMO support improved survival in patients with nditions . Howevernditions , 13.Despite the potential benefits of ECMO in NFA, concerns remain about complications. In general, complications are the primary factor limiting the effectiveness of ECMO in many diseases. Evidence supporting ECMO use in NFA is lacking, and questions about the safety and effectiveness of ECMO in NFA remain unanswered. In this study, we reviewed data from the ELSO Registry collected between March 1992 and March 2016. Our aim was to investigate survival to hospital discharge, complications, and clinical factors associated with in-hospital mortality, in patients with severe life-threatening NFA requiring ECMO support.The ELSO Registry is a worldwide voluntary registry. Currently, data are reported from 350 international ECMO centers. Data are collected using a standardized form, and include patient demographics, pre-ECMO ventilator settings, pre-ECMO arterial blood gas analysis (ABGA), post-ECMO ventilator settings, ECMO complications, and survival to hospital discharge . DrivingN = 568). Patients receiving ECMO support for ECPR or cardiac dysfunction were excluded according to the support type , and multiple ECMO courses were excluded. To discriminate between asthma and other non-asthmatic respiratory ECMO cases, patients with other primary diagnoses were also excluded. For example, a patient with asthma who received ECMO for sepsis was excluded, as sepsis was the primary indication for therapy. In total, 272 patients were included in the NFA group  were entered into stepwise backward multivariable logistic regression, including age as the continuous covariate, to estimate factors associated with mortality prior to hospital discharge. Two-way interaction terms were tested between the remaining significant variables. A 2) ratio of 153.7. The mean values of the ventilator settings were relatively high. Prior to ECMO initiation, the mean peak inspiratory pressure (PIP) was 38.2 cmH2O; mean airway pressure was 21.4 cmH2O; mean PEEP was 8.3 cmH2O; mean FiO2 was 81.2%; and mean driving pressure was 29.2 cmH2O.Among the 24,147 adult patients in the ELSO registry, 568 patients had a diagnosis of asthma according to the ICD-9 code (2.4%). Of these, 272 patients met the criteria for inclusion in the study. The use of ECMO for NFA in adults has been growing rapidly since 1992 , 19.0 vs. 11.3, p < 0.001; FiO2 (%), 81.2 vs. 48.8, p < 0.001; PIP (cmH2O), 38.2 vs. 25.0, p < 0.001; mean airway pressure (cmH2O), 21.4 vs. 14.2, p < 0.001). In particular, driving pressure was significantly decreased after ECMO support  and the rate of survival to discharge was 83.5% (227/272). Among non-survivors, 15.6% (7/45) died after ECMO weaning. The most common reason for death was organ failure , as was the mean pH . Saturation was higher in survivors . In addition, PEEP was lower in survivors . ECMO duration and ventilator settings after ECMO initiation were significantly different between survivors and non-survivors (Table p = 0.035). The values of rate, FiO2, PIP, and driving pressure after ECMO initiation were lower in survivors (rate (breaths/min), 11.1 vs. 12.7, p = 0.043; FiO2 (%), 47.4 vs. 57.4, p = 0.025; PIP (cmH2O), 24.3 vs. 29.7, p < 0.001; driving pressure (cmH2O), 16.2 vs. 21.1, p = 0.002).Baseline ECMO patient profiles were significantly different between survivors and non-survivors Table . The meap = 0.001; Table p = 0.003), especially the rate of oxygenator failure  and clots . The rate of hemorrhage in general , the rate of cannulation-site hemorrhage , and the rate of pulmonary hemorrhage  were higher in non-survivors. Among neurologic complications, the rates of brain death , cerebral infarction , and cerebral hemorrhage  were higher in non-survivors. In addition, renal complications occurred more often in non-survivors , especially the rate of dialysis .The complication rate was higher in non-survivors , mechanical complication , hemorrhage , dialysis on ECMO , pre-ECMO PEEP , pre-ECMO pH , post-ECMO FiO2 , post-ECMO PIP , and post-ECMO driving pressure  were associated with increased in-hospital mortality. Among hemorrhagic complications, cannulation-site hemorrhage , central nervous system hemorrhage , and pulmonary hemorrhage  were associated with increased in-hospital mortality.Univariate and multivariate analyses were performed to investigate the possible predictors of in-hospital mortality in the study population Table . In the p = 0.012), bleeding , pre-ECMO PEEP , post-ECMO FiO2 , and post-ECMO driving pressure  were associated with increased in-hospital mortality.In the multivariate logistic regression model, age . Although bleeding was associated with increased in-hospital mortality, fatal bleeding only occurred in 1.5% of cases and most other complications were not fatal. Therefore, ECMO may be an effective treatment to prevent ventilator-induced lung injury in NFA refractory to mechanical ventilation. In addition, careful monitoring is required to detect and manage complications early and reduce their impact.The mortality rate of patients with asthma is decreasing, but remains significant , 10. WhiTraditionally, overt hypercapnic acidosis in patients with acute severe asthma is significantly associated with higher rates of invasive ventilation; this leads to longer hospital stays, more complications, and a higher mortality rate . In geneDespite limited data about physiologic and ventilator parameters, ventilator settings after ECMO initiation significantly improved, particularly driving pressure and PIP. Driving pressure is considered to be a reasonable surrogate for transpulmonary pressure, and high transpulmonary pressure can cause lung injury or gross barotrauma , 23. TheComplications were common, even though the rates were lower than in previous studies . HoweverThis study had several limitations. First, we analyzed data voluntarily submitted by various international centers; these data may be susceptible to information bias, reporting bias, and uncontrolled confounding factors. Second, we defined patients with NFA as those with a primary ICD-9 diagnosis code of asthma. This may limit the applicability of these results to certain cases. Third, the ABGA values following ECMO initiation were not always present in this dataset, and as such their improvement could not be assessed as a secondary outcome. Furthermore, many of the baseline ventilator settings in this dataset did not adhere to the generally recommended criteria . In thesThe management of NFA remains a significant problem in critical care. Mechanical ventilation of patients with NFA is challenging, and high ventilator settings may cause lung injury and hemodynamic instability secondary to barotrauma and dynamic hyperinflation. As NFA is ultimately reversible, clinicians should actively consider ECMO to both provide adequate gas exchange and prevent lung injury. In this study, ECMO provided full respiratory support in patients with NFA, and its use resulted in acceptable survival to hospital discharge. However, ECMO-related complications are common. To encourage the use of ECMO as a rescue therapy, understanding and reducing ECMO-related complications should be a priority. The use of ECMO to reduce ventilator-induced lung injury may reduce overall NFA mortality worldwide. Further clinical research into the use of ECMO in this context is needed.Additional file 1: Figure S1.This graph shows the increasing trend in extracorporeal membrane oxygenation use in adults with near-fatal asthma. (TIF 80 kb)Additional file 2: Table S1.Table S2. Reason for extracorporeal membrane oxygenation discontinuation and mortality. (DOC 80 kb)Complications.


Sodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms.Neuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used.Dapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased , and pulse-wave-velocity was reduced , even after correction for mean BP. Renal resistive index was reduced . These vascular modifications were not observed in hydrochlorothiazide-treated individuals.An acute treatment with dapagliflozin significantly improves systemic endothelial function, arterial stiffness and renal resistive index; this effect is independent of changes in BP and occurs in the presence of stable natriuresis, suggesting a fast, direct beneficial effect on the vasculature, possibly mediated by oxidative stress reduction. The interaction between renal hemodynamics and BP is a complex issue, and this balance plays a key role in the sodium and water reabsorption by renal tubule. A raise in systemic BP influences intraglomerular pressure; an elevated renal interstitial hydrostatic pressure, direct consequence of systemic hypertension, rapidly inhibits sodium reabsorption by the proximal tubule, and the kidney responds by increasing sodium excretion; however, physiological mechanisms governing this adaptive response are only partially clarified . EndotheSodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of glucose-lowering agents used in the treatment of type 2 diabetes (T2D). By inhibiting the transporter protein SGLT2 in the kidney, they reduce renal glucose reabsorption, promoting its urinary excretion. Unlike other oral antidiabetic drugs, the efficacy of these compounds is independent of insulin secretion and action , being eGiven their selective action on a dual transporter, SGLT2 inhibitors are supposed to increase natriuresis; however, several studies have denied an increased sodium (Na) excretion during SGLT2 inhibition –8; a hypT2D patients show an impaired endothelial function, characterized by reduced NO availability, which can be demonstrated in peripheral arteries ; a furth2, an adequate glucose control (HbA1c < 64 mmol/mol) reached with any oral anti-hyperglycemic drug, clinic BP values < 140/90 mmHg, treatment-naïve status for high BP. Exclusion criteria were an established hypertensive status, a moderate to severe renal function impairment (estimated glomerular filtration rate—eGFR < 60 ml/min/1.73 m2) and presence of clinically relevant cardiovascular/pulmonary/haematologic/hepatic disease, insulin treatment. Given the relatively unexpected significant BP reduction after only 2 days of dapagliflozin treatment, ten T2D patients were selected after the completion of the sixteen cases on the basis of the same inclusion criteria; they followed the same protocol but receiving hydrochlorothiazide (HCT), and served as control group, to test whether the results obtained in cases could be specifically related to the mode of action of dapagliflozin or, more extensively, to its diuretic and BP-lowering effect. This was conceived as a pilot study aimed at testing the aforementioned working hypothesis and planning larger studies in the future.Sixteen patients with T2D, consecutively recruited among those attending our diabetes outpatient’s clinic between January and September 2016 received dapagliflozin. Inclusion criteria were age between 40 and 70 years, BMI < 40 kg/mThe nature and purpose of the study were carefully explained to all subjects before they provided their written consent to participate. The protocol was approved by the local Ethics Committee and registered in the Registry of the Italian Drug Agency .When screened for eligibility, selected participants were advised to keep a daily Na intake of 92 mmol for the week preceding the study and until the end of the experimental protocol. Each subject was studied twice as outpatients: Visit 0, or baseline visit (day 0), and 2 days after a treatment with dapagliflozin 10 mg or HCT 12.5 mg QD ; we chose 48 h on the basis of the pharmacokinetic properties of dapagliflozin . In bothEndothelium-dependent response was obtained by FMD, as previously described . A longiThree velocimetric measurements of the interlobar renal arteries (adjacent to the medullary pyramids) in the mesorenal area of each kidney were taken with a translumbar or anterior ultrasonographic approach. Renal RI was calculated in both kidneys according to the formula: (systolic peak velocity–end diastolic velocity)/systolic peak velocity and assessed both at baseline and 5 min after administration of GTN 25 μg. Dynamic Renal Resistive Index (DRIN) (%) was calculated as: (postGTN RI–baseline RI) × 100/baseline RI . Intra-oArterial tonometry  was performed according to the international recommendations . CentralPlasma renin activity (PRA) and aldosterone were assayed by radioimmunoassay . Plasma norepinephrine and epinephrine were assayed by high performance liquid chromatography.24-h urinary 8-isoprostane concentration was measured by a specific affinity sorbent. Urine samples were centrifuged to remove sediment (10 min at 800 g); aliquots of supernatants were incubated with 8-isoprostane affinity sorbent for 60 min according to the manufacturer’s instructions .2 for categorical variables, as appropriate. Differences between Visit 0 and Visit 1 in the dapagliflozin and HCT treatment arms were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor. Bonferroni post hoc comparison test was also used. A post hoc sample size calculation was performed considering FMD as outcome variable and using the data collected in this study. A sample size of 24 patients was adequate to demonstrate the detected difference in FMD with a power of 0.82 and alpha 0.05.Statistical analysis was performed using NCSS 8 . Data were given as mean ± standard deviation when normally distributed, as median and interquartile range when non-normally distributed, and as count and percentages when discrete. Differences between groups at baseline were analysed by 2-sided paired Student’s t test for normally distributed continuous variables, Wilcoxon rank-sum test for not normally distributed continuous variables, or χp value ≤ 0.05 was considered statistically significant.A 2, p = 0.26); HbA1c tended to be lower, even not significantly, in the HCT arm . Table p = 0.04 for the interaction time*treatment).The two groups were comparable for age , sex  and BMI (30.5 ± 6.7 vs 28.5 ± 4.1 kg/mp = 0.003 for the interaction time*treatment) only in the dapagliflozin group. Both treatments induced a significant rise in plasma renin activity, greater for HCT group (p = 0.001 for the interaction time*treatment), but did not influence aldosterone levels, as well as the neuro-hormonal pattern, given that norepinephrine and epinephrine concentrations were unmodified.At baseline, the two groups slightly differed by haematocrit and serum osmolarity (both higher in the dapagliflozin group). Humoral parameters did not vary in the two treatment arms, with the exception of serum magnesium concentration, which significantly rose  or aortic systolic BP  or to changes in plasma and urinary variables. Systolic BP reduction  and aldosterone increase  were significantly associated with increased osmole clearance.On univariate analysis, performed in the dapagliflozin group, absolute changes in PWV, FMD, and RI were not associated with changes in either brachial  but not by HCT. Urinary 8-isoprostanes reduction was significantly associated with serum magnesium increase  and urinary glucose excretion .Searching for a putative mechanism involved in the specific vascular effects of dapagliflozin, we found that 24 h urinary isoprostanes were significantly reduced by dapagliflozin , crucial for the interpretation of our findings , was notIn type 2 diabetic individuals, acute dapagliflozin administration has direct, beneficial effects on systemic and renal vasculature. These pleiotropic effects, which are conceivably BP- and glucose-independent, could represent a mechanism for cardiovascular protection for this drug class . Further