An objective method to predict individual visual field progression will contribute to realise personalised medication. The purpose of this study was to establish a predictive formula for glaucomatous visual field progression in patients with Primary open-angle glaucoma, mainly including normal tension glaucoma. This study was a large-scale, longitudinal and retrospective study including 498 eyes of 312 patients visiting from June 2009 to May 2015. In this analysis, 191 eyes of 191 patients meeting all eligible criteria were used. A predictive formula to calculate the rate of glaucomatous visual field progression (mean deviation slope) was obtained through multivariate linear regression analysis by adopting “Angle of Retinal Nerve Fibre Layer Defect” at the baseline, “Vertical Cup-Disc ratio” at the baseline, “Presence or absence of Disc Haemorrhage” during the follow-up period, and “Mean IOP change (%)” during the follow-up period as predictors. Coefficient of determination of the formula was 0.20. The discriminative ability of the formula was evaluated as moderate performance using receiver operating characteristic analysis, and the area under the curve was approximately 0.75 at all cut-off values. Internal validity was confirmed by bootstrapping. The predictive formula established by this type of approach might be useful for personalised medication. In the Guidelines for Glaucoma (3rd edition) by the Japan Glaucoma Society, Terminology and Guidelines for Glaucoma (4th edition) by the European Glaucoma Society, and Primary Open-Angle Glaucoma Preferred Practice Pattern Guidelines by the American Academy of Ophthalmology, it is recommended that IOP-reducing therapy should be performed by setting the target IOP for individual patients based on the risk factors, stage of disease, and life expectancy9. However, no method to predict visual field progression or lifetime prognosis of individual patients has been established, and treatment is conducted based on physicians’ subjective evaluation. Therefore, we need an objective method to predict individual visual field progression or lifetime prognosis for setting an appropriate target IOP. These methods will contribute to consideration of optimal medical decisions, practices and/or interventions based on the risk factors in individual glaucoma patient.Glaucoma is a primary cause for visual disorderset al. indicated a formula to predict the rate of change in the mean deviation (MD) using the clinical data from the New York Glaucoma Study10. Similarly, Ernest et al. prepared a formula to predict the rate of change in the visual field index using the clinical data from the Dutch Research Project on Treatment Outcome in Glaucoma Patients Study11.Recently, several formulas to predict the rate of visual field progression through statistical analysis using clinical data were reported. Moraes 12. Based on the results of previous epidemiological studies, the prevalence of NTG substantially differs among regions, and NTG accounts for the greater portion of POAG patients in Japan/Asia14. As described above, there have been studies on formulas to predict the rate of visual field progression, but no study involving Japanese/Asian patients with a high prevalence of NTG has been conducted. Predictive formula for these patients will contribute adequate IOP-reducing therapeutic strategies, improving their quality of life.Primary Open-angle glaucoma (POAG) is classified into two types: primary open-angle glaucoma (high tension glaucoma) (POAG (HTG)), with an IOP of >21 mmHg, and normal tension glaucoma (NTG), with an IOP of ≤21 mmHg. POAG (HTG) and NTG are same spectrum as glaucomatous optic neuropathy (GON), but the onset and progression of GON are observed at a lower IOP in NTG patientsIn this study, we investigated a predictive formula regarding the rate of visual field progression using the clinical data from glaucoma patients, including a high percentage of NTG, and performed internal validation of the formula.15. The reproducibility of measuring the retinal nerve fibre layer defect (RNFLD) angle by the three raters showed excellent intra-rater  = 0.962–1.000) and inter-rater  .The candidate variables used in this study are summarized in Fig. In this study, 498 eyes of 312 patients were included and 284 eyes of 191 patients met all eligible criteria. A flow chart of the selection process of eyes for the analysis is shown in Fig. The demographics and ocular characteristics of patients are summarized in Table st and 2nd step), phase 2; selection of predictive formula . Model development scheme of variables and formulas selection is shown in Fig. The prediction model for an individual MD slope was developed through two phases: phase 1; selection of suitable explanatory variables (117. There was a strong correlation between the untreated IOP and mean IOP change (%) (correlation coefficient (r): −0.707, Pearson’s product-moment correlation coefficient); therefore, the untreated IOP was excluded. In addition, the multicollinearity between remaining 3 variables ) and other candidate variables was also evaluated. There was a strong correlation between the spherical equivalent and axial length ; therefore, axial length was excluded from the candidate variables. In this step, 20 variables were refined to 18 variables.We conducted screening of candidate variables before conducting multiple regression analysis because the correlation among candidate variables  was expected and avoiding multicollinearity was needed. Age, spherical equivalent, untreated IOP, and mean IOP change (%) were regarded as the candidate variables applied to linear regression analysis without any preselection because these are previously reported as risk factorsst step ) and each variable in 4 categories  were applied in a linear regression analysis using the forced entry method, respectively. The results of analysis demonstrated that the representative variables from the 4 categories were the RNFLD angle at baseline in Category 3, vertical C/D at baseline in Category 4, mean IOP value in Category 5, and presence or absence of DH in Category 6. As the central corneal thickness (CCT), presence or absence of β-peripapillary atrophies (PPA), and presence or absence of γ-PPA in the “patient background” category are different clinical parameters, they were regarded as candidate variables. In this step, 18 variables were refined to following 11 variables: age, spherical equivalent, CCT, presence or absence of β-PPA, presence of absence of γ-PPA, MD at baseline, RNFLD angle, vertical C/D, mean IOP change (%), mean IOP value, and presence of absence of DH.For the refinement of variables, the three variables remained in the 1nd step was performed by the round-robin forced entry method, and conducted the 1st screening for a candidate predictive formula. Adopting age, spherical equivalent and mean IOP change (%) were adopted in all candidate predictive formulas, hence all combinations of other 8 variables (8C1 + 8C2 + 8C3 + 8C4 + 8C5 + 8C6 + 8C7 + 8C8 = 255) were evaluated. The selection of formulas was conducted comprehensively considering the following criteria; 1) raising the R2 statistical value, 2) lowering the number of variables, 3) including the variables prioritised in 1st screening as possible. As for the results, the 255 candidate predictive formulas were refined to 154 formulas. The candidate predictive formula, including all 11 variables using the round-robin forced entry method is shown in Supplementary Table Exhaustive GLM analysis using the 11 candidate variables selected in the 2rd step, GLM analysis was performed using the stepwise method. Predictive formulas which p-value of all variables was <0.1 were selected. As the results, total 17 candidate predictive formulas were selected.Concerning the 154 candidate predictive formulas refined in the 3th step, we selected predictive formula with a p-value of <0.05 and the highest R2 statistic. The characteristic of selected predictive formula is shown in Table Of the 17 candidate predictive formulas selected in the 4MD slope (dB/year) = 0.581 + [(Baseline RNFLD angle) × −0.002] + [ × −1.079] + [(Presence of DH) × −0.184] + [(Mean IOP change (%)) × −0.006]2 was 0.195, and the adjusted R2 was 0.170. Using this predictive formula, the MD slope was calculated based on representative vertical C/D and RNFLD angle for the combination of the presence or absence of DH and mean IOP change (from 0 to −30%) . The optimism-corrected R2 was 0.224 ± 0.051 (adjusted R2: 0.200 ± 0.053) and the AUC was calculated ranged from 0.736 to 0.772 for detecting the MD slope from −0.1 to −0.5 (dB/year)  of receiver-operating characteristic (ROC) curves for detecting the MD slope from −0.1 to −0.5 (dB/year). The AUCs for detecting the MD slope were calculated using development sample and bootstrap sample Table . All AUCIn this study, we established a formula to predict the rate of visual field progression in patients with POAG, mainly including NTG using clinical data. We performed single correlation analysis using the MD slope as an objective variable. There were correlations between glaucomatous structural abnormalities and the MD slope. Furthermore, a predictive formula to calculate the MD slope was obtained through multivariate linear regression analysis by adopting the RNFLD angle at baseline, vertical C/D at baseline, presence or absence of DH during the follow-up period, and mean IOP change during the follow-up period as predictors. The accuracy of this formula was confirmed as moderate performance by ROC analysis and internal validation.13 or 77%18 of all patients with POAG. Of the 191 patients analysed in this study, NTG accounted for 88%. This percentage was similar to that in the epidemiological studies. Hence, this predictive formula is considered to be appropriate to predict visual field progression in POAG patients in Japan/Asia.Glaucoma is a neurodegenerative disease, and visual field loss associated with glaucomatous structural abnormality is common among POAG (HTG) and NTG. Most of the variables in this study represent these common glaucomatous structural abnormalities, not true disease causes. Therefore, both POAG (HTG) and NTG were included in the development sample. In epidemiological studies in Japan/Asia, it was reported that NTG accounted for 92%et al. investigated the relationship between glaucomatous structural abnormalities at baseline and the visual field progression involving the patients obtained in the Advanced Imaging for Glaucoma Study, suggesting that structural abnormalities of the optic nerve head and presence of RNFLD accelerate the progression19, as indicated in our study. In our previous study, the enlargement of the RNFLD angle and rate of visual field progression were accelerated in NTG patients with DH using long-term follow-up data20. As shown in Table The results of this study suggest that glaucomatous structural abnormalities, vertical C/D and RNFLD angle, DH are risk factors accelerating the rate of visual field progression. Sehi 21. In the Collaborative Normal-Tension Glaucoma Study, the visual field progression was compared between a treatment group (IOP reduction ≥ 30%) and an untreated group, and the effectiveness of IOP-reducing therapy for NTG was confirmed21. Similarly, we clarified the influence of IOP-reducing therapy on the rate of visual field progression in NTG patients through this study. Concretely, the regression coefficient of the mean IOP change was estimated to be −0.006; therefore, in case the target IOP change is set as −30%, inhibitory effect on rate of visual field progression is calculated as −0.006 × (−30) = 0.18 (dB/year). The influence of 30% IOP-reducing therapy on the rate of visual field progression is shown in Table A large-scale, randomized, comparative study demonstrated that IOP-reducing therapy was the only evidence-based treatment method for not only POAG (HTG) but also NTG patients22. As a result, both examinations demonstrated that the R2 for the predictive formula obtained was approximately 0.2. Furthermore, we performed ROC analysis using these samples, establishing the cut-off value of the MD slope as −0.1 to −0.5 (dB/year). At all cut-off values, the AUC was approximately 0.75, confirming that the accuracy is moderate: AUC: 0.5 to 0.7, less accurate; 0.7 to 0.9, moderately accurate; and 0.9 to 1.0, highly accurate24. The R2 for the predictive formula obtained in this study (0.2) was higher than previous reports , and our AUC (0.75) was similar to precious reports 11.In this study, we conducted internal validation using original and bootstrap sample which is classified as a resampling method among statistical estimation procedures12. The predictive formula obtained in this study might not completely explain the rate of visual field progression. Second, in the step of variable selection for model arrangement, there was a strong correlation between variables representing refraction, that is, the axial length and spherical equivalent (r = −0.829). To avoid multicollinearity, we should select either one. The intraocular lens influences the spherical equivalent; therefore, the axial length may more accurately reflect the condition. However, in this study, the spherical equivalent in pseudophakic eyes was measured in only 7.3% of the patients; therefore, to establish a commonly available predictive formula, the spherical equivalent was selected as a candidate variable in the 1st step. Third, the stepwise selection of candidate variables is prone to cause overfitting of the model to the study population and might limit its generalizability. Fourth, DH is easily missed on fundus examination if physicians are not specially examining for it. The prevalence of DH was reported as 20.5% or 33.3% in Japanese/Asian NTG patients26. In our daily practice, optic disc was carefully observed using stereo fundus camera and DH was observed in 32.5% of the development sample. Kitazawa et al. reported that 92% of DHs exist at least for 4 weeks and over half of them were recurrent25. It could be considered that not all DHs were detected in this study because the fundus examination was performed mostly every three months. Fifth, the data obtained from stereo fundus camera were used as baseline parameter. Stereo fundus camera has installed in our hospital at 2010; therefore we considered the value from earliest examination during follow-up period as a baseline value in this analysis. Sixth, corresponding evaluation between structural abnormality and functional disorder is important in daily practice and thus indices based on this concept were reported28. In this study, we also performed the preliminary analysis of structural-functional relationships using the hemifield total deviation slope, but the results were not statistically superior to those of the MD slope. Thus, we selected the MD slope as an objective variable because it is more commonly used in glaucoma management. Seventh, concerning the confirmation of the accuracy, internal validation using the data obtained in this study alone was conducted, because we had no eligible data for conducting external validation. Therefore, in the future, the accuracy of this predictive formula should be confirmed by performing external validation using data obtained in other institutions or a prospective study.These are some limitations in this study. First, as the primary purpose of this study was to find a formula with optimal accuracy, we examined the development sample and combination of several variables, and selected an optimal predictive formula. Although only worse eyes were included in the development sample, this predictive formula was considered to be reasonable because predicting visual filed progression of worse eye is meaningful for clinical use. Variables for the rate of visual field progression that negatively affects the accuracy of the predictive formula were not selected. Therefore, the involvement of risk factors that are not contained in this predictive formula in the rate of visual field progression is not disclaimed. In addition, glaucoma is a multifactorial disease, and presence of uncertain risk factors in the progression of the condition is suggestedIn conclusion, a formula to predict the rate of visual field progression in patients with POAG, mainly including NTG was obtained using clinical data. We consider this formula could be moderately predictive and useful for establishing an appropriate target IOP for individual patients and selecting therapeutic strategies, thereby contributing to adequate IOP-reducing therapy.This study was a large-scale, longitudinal, retrospective study. The data was obtained from POAG (HTG) and NTG patients visiting Fukui-ken Saiseikai Hospital regularly from June 2009 to May 2015. Patients received routine follow-up examinations mostly every three months and standard medical care prescribed by only one ophthalmologist (N.K.). This study was approved by the institutional review board. And this study was conformed to the tenets of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects . The institutional review board also approved the use of “opt-out” patient consent before inclusion in the study.29, RS-3000 advance . We determined the angle of the RNFLD . The visual field was measured mostly every six months. The PPA was evaluated based on the status of Bruch’s membrane from 3 B-scan images obtained from optical coherence tomographyFLD Fig. . The sub30. The diagnostic criteria for POAG (HTG) were 1) more than 21 mmHg IOP mostly three times without any glaucoma medication. 2) open-angle, 3) GON with corresponding visual field loss, and 4) the absence of other optic neuropathies. The diagnostic criteria for NTG were 1) 21 mmHg or less IOP mostly three times without any glaucoma medication. 2) open-angle, 3) GON with corresponding visual field loss, and 4) the absence of other optic neuropathies. GON was evaluated according to the guidelines of the Japan Glaucoma Society: 1) the vertical C/D of the optic nerve head is 0.7 or more, 2) the rim width at the superior portion (11-1 hours) or inferior portion (5–7 hours) is 0.1 or less of the disc diameter, or 3) the difference of the vertical C/D is 0.2 or more between both eyes, or 4) a RNFLD is found7.Eligible patients fulfilled all the following criteria for at least one eye: 1) 20 years or older at the start of the follow-up period (baseline), 2) observed mostly every three months during the follow-up period, 3) diagnosed as POAG (HTG) or NTG at baseline, 4) accurately measurable IOP , 5) observable fundus without mydriatic, 6) no history or complication of retinal disease , and 7) had at least 6 reliable visual field tests during follow-up period. POAG (HTG) and NTG were diagnosed according to the guidelines of the Japan Glaucoma Society and the European Glaucoma SocietyAs a parameter of visual field loss progression, the MD slope (dB/year) per eye was calculated using data on reliable visual field tests at least ≥ 6 points meeting the following criteria: 1) fixation losses < 20%, 2) false positive or false negative < 33%. MD slope was calculated assuming linearity by plotting the MD values obtained from reliable visual field tests. Patients having a history of glaucoma surgery, those who did not receive any treatment during the follow-up period, or treatment with over 4 agents were excluded.The IOP change (%) was calculated as [ − ]/ × 100. The mean IOP change (%) was calculated as (sum of the IOP change (%) at each measurement point during the follow-up period)/. The mean IOP value and its fluctuations were defined as the mean and SD of IOP values during the follow-up period. The maximum IOP value was defined as the mean of upstream 25% values of IOP during the follow-up period. The frequency of DH was defined as /(follow-up period). In case DH was observed more than one position in an examination, the number of appearance was summed.3), Category 5) IOP: mean IOP change (%), mean IOP value (mmHg), maximum IOP value (mmHg), and mean IOP fluctuation (mmHg), Category 6) DH: presence or absence of DH, and its frequency of during follow-up period (times/year). Only the baseline value was used in Category 1 to 4 because the object of this study was to establish the predictive model estimates of the MD slope in the early phase of treatment. Meanwhile, the follow-up value was used in Category 5 and 6 because to evaluate the effect of IOP-lowering treatment was one of the aims of this study and the presence of DH could not be estimate in a single observation.The rate of visual field progression was expressed by the MD slope for each eye. The following 20 variables in 6 categories were included as candidate variables for the MD slope in the evaluation of the prediction model: Category 1) Patient background: age at baseline (year), spherical equivalent (dioptre), axial length (mm), CCT (μm), presence or absence of β-PPA, presence or absence of γ-PPA, and untreated IOP (mmHg), Category 2) Visual field information: MD at baseline (dB), Category 3) RNFLD: presence or absence of RNFLD and its angle (degree), Category 4) Stereo fundus camera: vertical C/D, mean rim width of the upper and lower sides (mm), rim-disc area ratio, and rim volume  was applied to develop a model to predict an individual MD slope with candidate variables. Multivariate analysis expresses one objective variable with two or more explanatory variables. Model development was performed following 5 steps. The model development was performed using IBM SPSS Statistics 18 software.17. In the case that the high correlation between the explanatory variables, i.e. multicollinearity, is observed, there is a possibility that prediction accuracy would be reduced. Therefore, in this step, the multicollinearity among the above 4 candidate variables was evaluated.Age, spherical equivalent, untreated IOP, and mean IOP change (%) were regarded as the candidate variables applied to linear regression analysis because these are known as risk factorsst step and each variable in 4 categories  involving several candidate variables were applied in a linear regression analysis using the forced entry method, respectively. A variable with a highest coefficient of determination (R2) was selected as a representative variable of each category.For the refinement of variables, the variables adopted in the 1st step and 2nd step was performed by the round-robin forced entry method for 1st screening of a candidate predictive formula. The forced entry method is a method of forcibly incorporating all variables as explanatory variables to construct a multiple regression formula.Exhaustive GLM analysis using the variables preselected in the 1rd step was performed using the stepwise method, for the 2nd screening of the formula. The stepwise method is a method of constructing an optimal multiple regression formula by adding or removing one explanatory variable step by step.GLM analysis of the candidate predictive formula refined in the 32 of the formula.Final predictive formula was selected referring p-value of variables and R31. Furthermore, the model was internally validated using 200 bootstrap samples from 191 eyes by calculating the expected R2 and AUC. Bootstrap is one of random sampling method with replacement. The size of bootstrap sample is same as original sample, but the composition element is different. The validation was performed using IBM SPSS Statistics 18 software.The discriminative ability was evaluated using a development sample of the final model. The discriminative ability was tested by calculating the AUC of ROC curves. A value of AUC 0.5 indicates that the model has no discriminative ability to identify progressive patients and 1.0 indicates that has perfect discriminative abilityThe dataset generated during the current study is available from the corresponding author on reasonable request.Supplementary Information


Active mobilization is not possible in patients under deep sedation and unable to follow commands. In this scenario, passive therapy is an interesting alternative. However, in patients with septic shock, passive mobilization may have risks related to increased oxygen consumption. Our objective was to evaluate the impact of passive mobilization on sublingual microcirculation and systemic hemodynamics in patients with septic shock.p values <0.05 were considered significant.We included patients who were older than 18 years, who presented with septic shock, and who were under sedation and mechanical ventilation. Passive exercise was applied for 20 min with 30 repetitions per minute. Systemic hemodynamic and microcirculatory variables were compared before (T0) and up to 10 min after (T1) passive exercise. p = 0.029), without any change in other microcirculatory variables. There was a reduction in heart rate (HR) (T0 (mean ± SD): 95.6 ± 22.0 bpm; T1 (mean ± SD): 93.8 ± 22.0 bpm; p < 0.040) and body temperature (T0 (mean ± SD): 36.9 ± 1.1 °C; T1 (mean ± SD): 36.7 ± 1.2 °C; p < 0.002) with no change in other systemic hemodynamic variables. There was no significant correlation between PPV variation and HR , cardiac index  or mean arterial pressure  variation.We included 35 patients  Simplified Acute Physiologic Score (SAPS) 3 score: 66.7 ± 12.1; median [IQR 25–75%] Sequential Organ Failure Assessment (SOFA) score: 9 [7.0–12.0]). After passive mobilization, there was a slight but significant increase in proportion of perfused vessels (PPV)  contains supplementary material, which is available to authorized users. Patients with sepsis who require intensive care usually receive interventions that promote immobilization, mainly the administration of sedative and analgesic drugs to facilitate invasive mechanical ventilation (MV) and reduce pain, agitation, and anxiety , 2. Seps2) and a decrease in venous oxygen saturation (SvO2) [Early mobilization in mechanically ventilated patients who are critically ill reduces the effects of ICU-acquired weakness –11. Thisn (SvO2) , 19. Conn (SvO2) , 19. Nonn (SvO2) , 20–24.No previous studies have explored the effects of mobilization on microcirculation. In these severely ill patients, it might be possible that passive mobilization can increase the blood flow to the working muscles and decrease splanchnic blood flow. These physiologic changes could lead to alterations in sublingual microvascular flow, density, and heterogeneity. However, as the relationship between systemic hemodynamics and microcirculation are not straightforward , 26, theThis study was carried out in two medical-surgical ICUs within the same university hospital. The local ethics committee approved the study (number: 1056/11), and the patients’ next of kin signed informed consent forms allowing their participation. This study was conducted according to the principles of the Declaration of Helsinki and the Brazilian National Council of Health Resolution 466/2012.We included patients if they met all the following criteria: 18 years of age or older, septic shock  with norThe exclusion criteria were intracranial hypertension, status epilepticus, or cardiac arrhythmia at the time of the study; acute myocardial infarction (Killip classification 4); thrombocytopenia ; hemoglobin <7.0 g/dL; leukocytosis , peripheral arterial disease, worsening oxygenation status in the last 6 h , circulatory shock of multiple causes, or pregnant and moribund patients. We also excluded patients with medical conditions that prevented the use of a mobilization protocol, such as bone tumors, unconsolidated or unstable bone fracture, amputation, postoperative period for placement or removal of upper and lower limbs bone prosthesis, deep vein thrombosis or phlebitis, musculoskeletal deformity, and compartment syndrome in the upper or lower limbs. In addition, we excluded patients with mucosal injury or recent maxillofacial surgery that interfered with imaging acquisition.®  with 5 min for each limb, totaling 20 min of exercise. One of the investigators (TTP), a trained physiotherapist, applied the passive mobilization protocol. Although this protocol is a standard of care in our unit, it is not routinely applied in those severely ill patients.Patients were kept in a semi-recumbent position (30°). Passive movements of the upper limbs  and lower limbs  were performed in a counter-clockwise direction starting from the upper right. The frequency of 30 movements per minute was assured by a digital metronome MA-1 BLBKWe observed all patients for 20 min before passive movement to assure that there were no significant variations in sedative and vasoactive medication infusions as well as hemodynamic and respiratory parameters. Before the intervention, the vasopressor dose was titrated by the attending physician targeting a mean arterial pressure of at least 65 mmHg. The protocol was interrupted if any of the following adverse events occurred: detection of active movement, hypoxemia (pulse oximetry <88%), hemodynamic instability (heart rate (HR) <45 bpm, mean arterial pressure (MAP) <60 mmHg or >120 mmHg), and changes in the doses of vasoactive or sedation drugs.®; MicroVision Medical, Amsterdam, Netherlands). To ensure image quality and adequate reproducibility, we adopted recommended techniques for video acquisition [® software  for automated vascular analysis. The correct procedure for vascular video analysis with AVA 3.0® software includes some manual analysis steps, including erasing incorrectly detected vessel segments and adding undetected vessel segments. Two investigators (TTP and ATB) analyzed the images off-line. The images were presented in a random order to prevent image pairing. Microcirculatory parameters included the microcirculatory flow index (MFI), the total vascular density (TVD), the De Backer score (DBS), the perfused vascular density (PVD), the proportion of perfused vessels (PPV), and the heterogeneity index (HI) [We recorded systemic hemodynamics and sublingual microcirculatory variables before (T0) and up to 10 min after (T1) passive movements. We assessed the sublingual microcirculation using sidestream dark field (SDF) imaging (Microscanuisition . After rdex (HI) . To calcThe cardiac index (CI) was measured by transpulmonary thermodilution , pulmonary thermodilution using the traditional bolus method , or echocardiography  in patients without invasive monitoring. We also collected data on age, gender, body mass index, severity scores such as Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiologic Score (SAPS) 3, admission diagnosis, Charlson index, comorbidities, source of infection, sedative drugs, vasoactive drugs, time on vasopressors, mechanical ventilation parameters, ICU length of stay, and ICU mortality.t test, the required sample size was 34 patients.To calculate the sample size, we hypothesize a mean decrease of 0.25 and a standard deviation of the difference of 0.5 in the MFI after passive mobilization using 0.05 as the significance level of 0.05 with a power of 80%. Using a paired sample t test, as appropriate. For the systemic hemodynamic variables, we defined post hoc as clinically relevant those changes greater than 10% using as reference the baseline [t test or Wilcoxon test, as appropriate. We also measured the intensity of variation between T0 and T1 and compare the results of all microcirculatory variables between the groups using Mann–Whitney test or t test, as appropriate. The correlation between induced changes in systemic hemodynamics and microcirculatory variables was assessed using a Spearman correlation test.The data are expressed as a number (percent), the mean ± standard deviation, or the median (interquartile range), as appropriate. Continuous data were tested for normality by Shapiro–Wilk’s test. The systemic hemodynamic and microcirculatory variables were compared at T0 and T1 using a paired Wilcoxon test or paired baseline . As our p values <0.05 were considered significant. For the sample size calculation, we used MedCalc software 14.12.0 .We used SPSS version 22.0 for Windows  for statistical analysis. The results with We collected data from October 2013 to May 2015. Over the study period, 2877 patients were admitted to the ICU, of whom 302 (10.5%) had septic shock and were mechanically ventilated. After the exclusion criteria were applied, 36 patients were included. However, one patient presented active movement during the protocol and was subsequently excluded  and severely ill, as assessed by their SOFA 9; 7.0–12.0) and SAPS 3 (66.7 ± 12.1) scores. The lung was the main source of sepsis, and the mortality rate was high (60%). All patients were included after the initial phase of shock resuscitation. The patients were submitted to passive movements at approximately 39 h; 24.0–72.0 h after vasopressor infusion. The minimum duration of vasopressor infusion was 8 h. The baseline characteristics are listed in Table 2.0 and Sn = 14), transpulmonary thermodilution (n = 8), and transthoracic echocardiography (n = 12). In one patient, we were not able to record the velocity–time integral of flow through the left ventricular outflow tract. Systemic hemodynamic variables before and after passive movements are provided in Table p < 0.040) and body temperature . There was no change in the lactate levels or in the central venous oxygen saturation levels.We obtained the cardiac index by pulmonary thermodilution (phy n = 1. In one p < 0.029), without any change in other microcirculatory variables. The microcirculatory variables are provided in Table r = −0.010, p = 0.955, ∆CI: r = 0.218, p = 0.215, and ∆MAP: r = 0.276, p = 0.109)   %; T1: 80.0 (75.2–85.1) %, .9  %; T1Our data suggest that passive mobilization of patients with septic shock after an initial phase of hemodynamic resuscitation does not compromise the microcirculation or the systemic hemodynamics. Passive mobilization was associated with an isolated and discrete improvement in the PPV. We also observed significant, although clinically non-relevant, reductions in HR and temperature.2 and a reduction in SvO2 after passive cyclic movements of the lower limbs. In our study, we were not able to find this reduction in SvcO2. However, one of the studies analyzed a small number of patients, which compromises the reproducibility of their results [Although passive mobilization has been widely used in the ICU over the years , 32, few results . In the  results . In cont results , 20–24.The absence of significant changes in systemic hemodynamics can be explained by the deep sedation of our patients. Deep sedation would reduce the occurrence of adrenergic stimuli as a function of physical exercise. The passive movement applied in our study probably did not activate the exercise pressor reflex, activated by muscular ergoreceptors, which generally stimulate sympathetic autonomic activity, generating cardiovascular alterations . In addiAccording to our results, microcirculatory indices were also not compromised by passive mobilization. These data are consistent with our results for systemic hemodynamics, suggesting that passive exercise does not harm patients with septic shock. We did not find previous studies that evaluated the impact of these maneuvers on microcirculation, which makes our results novel. We demonstrated that passive mobilization discretely increased the PPV, an important variable for microcirculation evaluation, since it has previously been shown as a marker of disease severity . This fi2 gradient values, SvO2 and lactate levels, although still using moderate doses of noradrenaline. This suggests that their mildly affected systemic variables parallel their mildly affected microcirculation. By contrary, this does not mean their survival rates would be lower. They are severely ill patients, and the determinants of sepsis survival in low- and middle-income countries are far beyond the factors analyzed in this study.Of notice, our microcirculatory variables, except the PPV, were only mildly affected, which are not a usual finding in severely ill septic shock patients with high SOFA and SAPS 3 scores and a high mortality rate. Some studies have shown that high levels of noradrenaline and the presence of hyperlactacidemia were associated with deranged microcirculatory parameters –38. A poThis study has some strengths. The inclusion of patients was consecutive. To the best of our knowledge, this is the first study to evaluate the impact of passive exercise on sublingual microcirculation using videomicroscopy. Microcirculation analysis is important, as studies in patients with sepsis have suggested that microcirculatory variables may remain altered despite the normalization of classic tissue perfusion variables . AnotherThis study also has some limitations. First, the single-center nature of our study might compromise the generalization of the results. Second, we analyzed systemic hemodynamics and microcirculation only in two periods, before and after exercise, and it is possible that changes occurred during mobilization. However, it is not possible to analyze the microcirculation during exercise. Third, our sample size does not allow a reliable analysis of the effects of different vasopressors on the microcirculation. Fourth, we found a high density and perfusion values in a very sick population and a bias in the software-assisted analysis cannot be rule out as we have consciously manually added undetected vessel segments during the analysis. However, our paired analysis minimizes the impact of this potential bias. Finally, three different methods were used to obtain CI due to ethical concerns. We used invasive monitoring only when the patient already required it for his own clinical condition. In patients without any invasive monitoring we used transthoracic echocardiography. However, we used the same technique before and after exercise in each patient, which attenuates this potential limitation as the patient was his own control and all the analysis were done using paired tests. Although cardiac output estimated by transthoracic echocardiography is not accurate and precise , it accuIn patients with septic shock after the initial phase of hemodynamic resuscitation, passive exercise does not seem to be associated with relevant changes in microcirculation or in the systemic hemodynamics.


This study was undertaken to assess the feasibility and safety of ECCO2R managed with a renal replacement therapy (RRT) platform to enable very low tidal volume ventilation of patients with mild-to-moderate acute respiratory distress syndrome (ARDS).Extracorporeal carbon-dioxide removal (ECCOn = 8) or moderate (n = 12) ARDS were included. VT was gradually lowered from 6 to 5, 4.5, and 4 ml/kg, and PEEP adjusted to reach 23 ≤ Pplat ≤ 25 cmH2O. Standalone ECCO2R (no hemofilter associated with the RRT platform) was initiated when arterial PaCO2 increased by > 20% from its initial value. Ventilation parameters , respiratory system compliance, Pplat and driving pressure, arterial blood gases, and ECCO2R-system operational characteristics were collected during at least 24 h of very low tidal volume ventilation. Complications, day-28 mortality, need for adjuvant therapies, and data on weaning off ECCO2R and mechanical ventilation were also recorded.Twenty patients with mild . The PaO2/FiO2 ratio and respiratory-system compliance were not modified after VT reduction. Mild respiratory acidosis occurred, with mean PaCO2 increasing from 43 ± 8 to 53 ± 9 mmHg and mean pH decreasing from 7.39 ± 0.1 to 7.32 ± 0.10 from baseline to 4 ml/kg VT, while the respiratory rate was not altered. Mean extracorporeal blood flow, sweep-gas flow, and CO2 removal were 421 ± 40 ml/min, 10 ± 0.3 L/min, and 51 ± 26 ml/min, respectively. Mean treatment duration was 31 ± 22 h. Day-28 mortality was 15%.While VT was reduced from 6 to 4 ml/kg and P2R device managed with an RRT platform easily and safely enabled very low tidal volume ventilation with moderate increase in PaCO2 in patients with mild-to-moderate ARDS.A low-flow ECCOClinicalTrials.gov, NCT02606240. Registered on 17 November 2015. Recognition of ventilation-induced lung injuries (VILIs) has led to radical modifications of the ventilatory management of these patients , 2. The 30 cmH2O . Decreaspatients .plat induces severe hypercapnia, which raises intracranial pressure, causes pulmonary hypertension, decreases myocardial contractility, reduces renal blood flow, and releases endogenous catecholamines [2R) may be used to achieve VT < 6 ml/kg, thereby lowering Pplat and driving pressure in this setting [2R devices, especially those based on a renal replacement therapy (RRT) platform, are limited to animal [VT reduction to < 6 ml/kg to achieve very low Polamines , 8. Thisolamines . Extraco setting –13. Howeo animal  or singlo animal , 15–17 s2R device managed by an RRT platform  to enable very low tidal volume ventilation in patients with mild-to-moderate ARDS.The aim of this prospective, multicenter study was to evaluate the safety and feasibility of a low-flow ECCOwww.clinicaltrials.gov .This pilot study was conducted during a 14-month period (March 2016–June 2017) in five medical and surgical intensive care units (ICUs) experienced in the care of ARDS patients and use of extracorporeal gas-exchange devices. It was approved by appropriate legal and ethics authorities . The clinical trial protocol was registered with 2/FiO2) < 300 mmHg with positive end-expiratory pressure (PEEP) > 5 cmH2O on MV expected to last > 24 h; and bilateral opacities on chest imaging. Exclusion criteria were: age < 18 years, pregnancy, patients with decompensated heart failure or acute coronary syndrome, severe chronic-obstructive pulmonary disease, respiratory acidosis with partial pressure of blood carbon dioxide (PCO2)> 80 mmHg, acute brain injury, severe liver insufficiency (Child–Pugh scores > 7) or fulminant hepatic failure, heparin-induced thrombocytopenia, systemic anticoagulation contraindicated, decision to limit therapeutic interventions, catheter access to femoral vein or jugular vein impossible, pneumothorax, and platelet count < 50 G/L.As predefined, 20 consecutive patients were included. Inclusion criteria were: mild-to-moderate ARDS according to the Berlin definition , 100 mmH2R was provided by a low-flow, standalone (without concomitant RRT), CO2-removal device  integrated into the Prismaflex® platform (Gambro-Baxter). The polymethylpentene, hollow fiber, gas-exchanger membrane (surface area 0.32 m2) was connected to the extracorporeal circuit, with standard tubes and a Luer-Lock system. A 13-Fr hemodialysis venous catheter  was aseptically and percutaneously inserted under ultrasonography guidance into the right jugular (15 cm) or the femoral (25 cm) vein after an unfractionated heparin bolus (80 IU/kg). Systemic heparinization was started after catheter insertion aiming for an activated partial thromboplastin time ratio (aPTTr) 1.5–2.0× that of the control. Blood was drawn from the superior vena cava and reinjected into the right atrium through the distal lumen. The Prismaflex® device monitored continuous venous, arterial line, and filter pressures.ECCOplat of 28–30 cmH2O; and respiratory rate (RR) set at 20–35 breaths/min to maintain approximately the same minute ventilation as before study initiation. After priming, the Prismaflex® device was connected to the patient and extracorporeal blood flow was progressively increased to 400–450 ml/min. Sweep-gas flow through the membrane remained at 0 L/min during this phase such that, initially, no CO2 was removed.Patients were sedated, paralyzed, and ventilated in accordance with the EXPRESS trial protocol : VT at 6plat ≤ 25 cmH2O. At each VT level: if arterial PaCO2 rose by > 20% from the baseline PaCO2 obtained at 6 ml/kg, the sweep-gas flow through the ECCO2R device was switched on with 100% oxygen at 10 L/min; if PaCO2 was maintained within ± 20% of baseline PaCO2, VT was gradually decreased to a minimum of 4 ml/kg; and if PaCO2 remained < 20% at 4 ml/kg PaCO2 under the aforementioned ECCO2R settings, the RR could be decreased to 15–18 breaths/min. On the other hand, the RR could also be increased up to 35 breaths/min to maintain PaCO2 within the targeted range. If undesirable hypercapnia/acidosis persisted , VT was reincreased to the previous step level. Refractory hypoxemia and/or hypercapnia could be managed, at the attending physician’s discretion, with nitric oxide, prone positioning, and/or venovenous extracorporeal membrane oxygenation (ECMO).Following a 2-h run-in time, VT was gradually reduced from 6 to 5, 4.5, and 4 ml/kg PBW every 30 min and PEEP adjusted to reach 23 ≤ P2R-facilitated very low tidal volume ventilation strategy was continued for at least 24 h. The potential for weaning off very low tidal volume ventilation and ECCO2R was assessed daily if PaO2/FiO2 > 200 by setting MV according to conventional ARDSnet settings  and switching off the sweep-gas flow through the ECCO2R device. If, under these conditions, the patient remained stable for at least 12 h with Pplat < 25 cmH2O and PaCO2 < 50 mmHg , the ECCO2R device and venous catheter were removed. The manufacturer determined the Prismalung® membrane’s maximum duration to be 72 h.The ECCOplat, minute ventilation, FiO2), hemodynamic parameters  and arterial blood-gas values , heparin dose, and aPTTr were collected at baseline, after the run-in-time, 30 min after every VT reduction, and at least twice a day during the subsequent days on ECCO2R. Blood-chemistry determinations were obtained daily. Respiratory-system compliance and driving pressure were calculated according to the standard formulas [2 clearance by ECCO2R (ml/min) during the first 24 h was calculated as follows [Ventilator settings  × 22.4 × ECCO2R blood flow / 1000, = (0.0307 × PCO2) + HCO3−actual.where CtCO2R discontinuation, subjects were monitored for AEs until hospital discharge or day 8 post enrollment, whichever occurred first.Serious adverse events (SAEs) were prospectively defined as: any event that is fatal or immediately life-threatening, permanently disabling, severely incapacitating, or requires prolonged hospitalization; OR any event that may jeopardize the patient and requires medical or surgical intervention to prevent one of these outcomes; AND any event that the attending physician perceives might be directly related to enrollment in the clinical trial. An AE was defined as: study related when it could be attributed to a study procedure and could readily have been produced by the study procedure; or nonstudy related when it was related primarily to the underlying disease or to ARDS and its sequelae. Other AEs not fulfilling this definition were recorded in the patients’ case-report forms. After ECCOp < 0.05 defined statistical significance. Analyses were computed with StatView v5.0  and SPSS v22  software.Statistical analysis was performed by one-way analysis of variance (ANOVA) for repeated measures, followed by a Bonferroni post-hoc test for comparison between different times. Results are expressed as mean ± SD and n = 8) or moderate ARDS (n = 12) were included; 18 underwent jugular cannulation. Patients’ baseline characteristics are reported in Table 2O. VT was gradually lowered to 4 ml/kg for all but one patient . Mean PaCO2 increased from 43 ± 8 to 53 ± 9 mmHg and mean pH decreased from 7.39 ± 0.1 to 7.32 ± 0.10 from baseline to 4 ml/kg VT, while RR was not modified. The mean CO2-removal rate was 51 ± 26 ml/min with 421 ± 40 ml/min blood flow and sweep-gas flow set at 10 ± 0.3 L/min. Importantly, VT and driving pressure reductions with ECCO2R were not accompanied by significant changes of PaO2/FiO2, respiratory-system compliance, and hemodynamic status . Amato et al. [plat, and PEEP, normalizing VT to respiratory-system compliance (Crs) and using a ratio as an index indicating the “functional” size of the lung might provide a better predictor of ARDS patients’ outcomes than VT alone. That ratio, termed the driving pressure (ΔP = VT / Crs), can be routinely calculated as the Pplat – PEEP for patients who are not making inspiratory efforts. Their analyses indicated that VT reductions or PEEP increases driven by random treatment-group assignment were beneficial only when associated with ΔP decreases and that no other ventilation variable had such a mediating effect on mortality [ΔP was also was also associated with lower ARDS-patient mortality in the large LUNG-SAFE cohort [Total energy determinants  are transmitted to the lung by the ventilator-generated volume, pressure, flow, and RR . Decreasr et al.  demonstrm et al.  showed to et al.  recentlyortality . More reE cohort .2R to mitigate the respiratory acidosis, and its potent deleterious effects [2R devices showed the feasibility of this strategy in ARDS patients, although AEs  were reported [Furthermore, reducing VT to 4 ml/kg PBW in patients already receiving protective ventilation was associated with less inflammatory and morphological signs of VILI in ARDS patients . This pa effects , 8, 24,  effects , 11. Resreported –28.2R with this RRT platform has indeed obtained promising results in animals [plat target of 23–25 cmH2O, we were able to drastically decrease the driving pressure to < 8 cmH2O, which might mean less VILI and ultimately fewer deaths [Our results demonstrated that this strategy might be safely, efficiently, and easily applied to ARDS patients in most ICUs worldwide, because it did not require specific or large venous accesses and the RTT platform we used is widely available with minimal modification of existing devices and a simple software update. ECCO animals . By decrr deaths . Importar deaths , 29, altr deaths , 28, 30.2 increases and more severe hypoxemia after VT reduction, the Prismalung® performance remains unknown in this context. Third, to achieve VT reduction down to 4 ml/kg in a larger population of patients without the risks of inducing major PaCO2 increases not compensated by the low-flow ECCO2R device, we also applied the modified EXPRESS strategy to patients with mild ARDS. Because of higher PEEP settings in this population of patients with higher compliance, it should be acknowledged that this approach may induce overdistension despite lowering the driving pressure. In addition, potential benefits of a very low tidal volume ventilation strategy have only been suggested in moderate-to-severe ARDS patients until now [2-removal rate of the Prismalung® was lower than those reported in other studies using similar blood flows [2 observed during the VT reduction phase. This mild respiratory acidosis might have been corrected by increasing the RR, at the expense of an increase in mechanical power. Indeed, the physicians treating these patients decided to tolerate this mild acidosis, as recent data also suggest an increased RR might be associated with a poorer ARDS prognosis [2R [2R membrane duration, as was the case for RRT hemofilters [Several limitations of our work should be addressed. First, because our population was small, this study should only be considered “a proof-of-concept” demonstrating the feasibility and safety of the strategy tested. We cannot rule out that there is still a substantial risk of adverse events that could have been missed in this small study. Second, our population included only patients with mild or moderate ARDS. Because severe ARDS patients might experience greater PaCOntil now , 11. Fouod flows , 28, exprognosis . Lastly,osis [2R . This teofilters .2R device managed by an RRT platform enabled very low tidal volume ventilation with moderate increase in PaCO2 in patients with mild-to-moderate ARDS. This less-invasive ECCO2R technique was easily and safely implemented. However, before this technique can be widely disseminated, more data are needed to demonstrate the clinical benefit of VT, Pplat, and driving pressure reductions rendered possible by ECCO2R [In summary, our pilot study findings demonstrated that a low-flow ECCOy ECCO2R . The ong


Dementia is one of the most common health problems in the world. Alzheimer’s disease (AD) is the most common form of dementia. The presence of vascular risk factors such as hypertension (HT) may increase the risk of AD . The relation between blood pressure (BP) and dementia has been the subject of numerous epidemiological studies, midlife HT is a risk factor for dementia and AD [3-7] but the association between HT and risk of dementia is lower in the older population [8].A fair modulation of an antihypertensive treatment, based on the cognitive status of the elderly, can avoid multiple complications.A case of an older for whom cognitive improvement and reduced risk of falls were noticed after mild blood pressure elevation is reported. An 88-year-old woman living alone at home was consulted for cognitive decline. She presented hypertension for more than 40 years, diagnosed after her menopause. She had also coronary disease, osteoporosis, osteoarthritis and dyslipidemia. Her treatment was olmesartan 20 mg every two days (which is not standard according to guidelines), since 7 years (her previous treatment with angiotensin-converting enzyme inhibitors was replaced due to cough), bisoprolol 10 mg, nicorandil 10mg, aspirin 75 mg, ezetimibe 10 mg, cholecalciferol and alendronic acid 70 mg/2800 UI, fentanyl 12 µg every 3 days. Drugs were administrated by a visiting nurse. There was no modification in her treatment for more than one year. The medical questioning showed that the patient did not know the reason for our consultation, her birth date nor the number of her children. Her daughter revealed that the patient was an insomniac. Her neighbors found her few times lost outside her home.The clinical examination showed an extrapyramidal rigidity without tremor.She had no visual troubles, but had hearing loss. The geriatric scales showed a Charlson score  at 4, acDuring hospitalization in acute geriatrics unit, we noted repeated falls with traumatic consequences. Falls occurred mostly in the morning, related to low blood pressure (by 110/60).The orthostatic hypotension test was negative many times, excluding an autonomic failure.Neuropsychological assessment  confirmed dementia, according to DSM IV criteria . There w24 h rhythmic monitoring showed normal sinus rhythm with minor disorders like ventricular extrasystole, not sufficient to justify the falls.24 h blood pressure monitoring showed a mean arterial pressure by 120/53 mmHg, based only on the day period; monitoring was not available by night due to behavioral disturbances. The minimal values achieved as 102/43 mm Hg.1). This finding could be related to a hypotension as demonstrated by the blood pressure monitoring.Magnetic resonance imaging (MRI) showed three areas of semi recent ischemia (roughly 3 weeks ago). Vascular alterations were presented by periventricular and deep white matter leukoencephalopathy (Fazekas II), and it was hippocampal atrophy (Scheltens IV). A phase contrast MRI flow sequence (PCMRI), measuring the cerebral arterial circulation , performWe think that the dementia syndrome occurred earlier as her daughter reported minor mnesic problems for few years. We hypothesized that the multiple strokes were caused by low cerebral blood flow in patient treated with antihypertensive drugs in her midlife, her antihypertensive treatment being the same for many years. The diastolic hypotension supported this hypothesis. However, this patient had long-term high blood pressure, dyslipidemia and a history of coronary heart disease and the hypothesis of thromboembolic mechanisms could not be formally eliminated.In an aim to preserve the quality of life of our patient, antihypertensive treatment with the sartans was stopped and β-blockers decreased to 2.5 mg. The mean arterial blood pressure increased up to 150/90 mm Hg. Moreover, the MMSE improved to 16/30 and the patient did not fall anymore during more than one year after.Hanon's study indicated a significant decrease in BP in patients with AD after one year of follow up, independently of age, gender, body mass index and antihypertensive therapy. The largest decrease in BP was observed in patients with the severest impairment in dementia at the baseline, suggesting that blood pressure decrease seems to be mainly a secondary phenomenon in Alzheimer's disorders . The decThe mean arterial blood pressure by 150/90 obtained after drugs modification was closer to guideline recommendations in elderly , 22. HowThe PC-MRI flow sequence is rapid (around 2 minutes), doesn’t require an injection and brings quantitative information of the cerebral arterial flow over the cardiac cycle. Nevertheless, this blood flow investigation is still not used commonly in neurodegenerative pathology.In conclusion, we report the case of a patient with a severe cognitive decline, secondary to multiple strokes caused by low cerebral blood flow in patient treated with antihypertensive drugs since her midlife, which have not been modified when the first signs of memory loss appeared. The decrease of antihypertensive drugs improved her cognitive functions and protected her from falling consequences.Physicians who deal with patients suffering from neurodegenerative diseases must keep in mind that the antihypertensive medication should be reevaluated.All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Attier-Zmudka: Medical care, case reporter, drafting of manuscript, critical revision of manuscript..Sérot: Supervision, critical revision of manuscript.Dao: Interpretation of magnetic resonance imaging.Sorel: Interpretation of rhythmic monitoring Macaret: Neuropsychological statement interpretation. Balédent: Administrative, technical, material support, supervision and interpretation of imaging flow data. None.


Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients have an impaired urine concentrating capacity. Increased circulating vasopressin (AVP) concentrations are supposed to play a role in the progression of ADPKD. We hypothesized that ADPKD patients have a more severely impaired urine concentrating capacity in comparison to other patients with chronic kidney disease at a similar level of kidney function, with consequently an enhanced AVP response to water deprivation with higher circulating AVP concentrations.15 ADPKD (eGFR<60) patients and 15 age-, sex- and eGFR-matched controls with IgA nephropathy (IgAN), underwent a water deprivation test to determine maximal urine concentrating capacity. Plasma and urine osmolality, urine aquaporin-2 (AQP2) and plasma AVP and copeptin (a surrogate marker for AVP) were measured at baseline and after water deprivation (average 16 hours). In ADPKD patients, height adjusted total kidney volume (hTKV) was measured by MRI.Maximal achieved urine concentration was lower in ADPKD compared to IgAN controls , with particularly a lower maximal achieved urine urea concentration . After water deprivation, plasma osmolality was similar in both groups although change in plasma osmolality was more profound in ADPKD due to a lower baseline plasma osmolality in comparison to IgAN controls. Copeptin and AVP increased significantly in a similar way in both groups. AVP, copeptin and urine AQP2 were inversely associated with maximal urine concentrating in both groups.ADPKD patients have a more severely impaired maximal urine concentrating capacity with a lower maximal achieved urine urea concentration in comparison to IgAN controls with similar endogenous copeptin and AVP responses. One of the first clinical features in autosomal dominant polycystic kidney disease (ADPKD) is an impaired urine concentrating capacity that occurs prior to kidney function decline –3. The mAVP is secreted from the pituitary gland when plasma osmolality increases. AVP subsequently binds to the vasopressin V2 receptor of the collecting ducts which stimulates water reabsorption by migration of aquaporin-2 (AQP2) to the apical cell membrane. Besides being important for water homeostasis, AVP has deleterious effects in ADPKD. AVP has been shown to increase intracellular cAMP, which promotes cell proliferation and cyst formation . Indeed,In the present study, we hypothesized that in advanced stages of ADPKD, the increase in AVP in response to water deprivation is stronger than might be expected from impaired kidney function per se ,11. To s2. The control group consisted of IgA nephropathy (IgAN) patients, matched for eGFR, age and sex. The diagnosis of IgAN was based on renal biopsy or clinical history and laboratory values in accordance with clinical practice. IgAN patients were eligible when they were in a stable phase of their disease, as defined by proteinuria <1 g/d and eGFR loss ≤5 ml/min/1.73m2 in the previous year and without use of immunosuppressive medication. Exclusion criteria for both patient groups were: use of medications or concomitant diseases that influence urine concentration capacity other than ADPKD or IgAN , factors that may influence urine concentration capacity  or active cardiovascular disease (e.g. angina pectoris), which is a contraindication for DDAVP administration. This study was approved by our institutional review board, the Medical Ethical Committee of the University Medical Center Groningen, and was performed in adherence to the Declaration of Helsinki. All participants gave written informed consent.Eligible for this study were patients with ADPKD, as diagnosed using the revised Ravine criteria , aged beet al. [All patients routinely collected a 24-hour urine sample the day preceding the water deprivation test. Patients underwent a standard prolonged water deprivation test, based on the protocol originally described by Miller et al. . The dayStandard biochemical evaluation was performed in fresh urine and plasma samples, using a Roche Modular Autoanalyser . Plasma and urine osmolality were measured directly via determination of freezing point depression using an Osmometer , with an intra-assay coefficient of variation <1.0%. eGFR was calculated with the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation .Blood for AVP and copeptin measurement was drawn into a chilled EDTA tube, and immediately centrifuged at 4°C and stored at −80°C until assay. AVP was measured by RIA after an extraction using ODS-silica . The lower limit of detection was 0.2 pg/ml and the intra-assay coefficient of variation 3.5%. Copeptin was measured using a sandwich immunoassay , with a lower limit of detection of 0.4 pmol/L and intra-assay coefficient of variation of 4 and 3% for the copeptin concentrations of 15 and 50 pmol/L, respectively. Urine aquaporin-2 (AQP2) concentration was measured by a direct ELISA  using raNormally distributed variables are expressed as mean±SD, non-normally distributed variables as median (IQR). Differences in baseline characteristics between ADPKD and IgAN patients were calculated with a Chi-square test for categorical data, and for continuous data with a Student’s t-test or a Mann-Whitney U test in case of non-normally distributed data. Percentage change between baseline and maximal urine concentration were tested in the overall population and within study groups using a one sample t-test with 0% change as reference value. Linear regression analyses were performed to test associations between plasma and urine osmolality, AVP, copeptin, AQP2-creatinine ratio, hTKV, albumin-creatinine ratio (ACR) and urine-to-plasma urea ratio (U/P Urea). AVP, copeptin, AQP2-creatinine ratio, hTKV, ACR and U/P Urea were log (ln) transformed to fulfill the requirement of normal distribution of the residuals for regression analysis. To investigate differences between the two study groups the categorical variable ‘study group’ (ADPKD vs. IgAN) was added to the regression analysis. Furthermore, to investigate whether associations between copeptin and other study variables were different between the study groups, interaction was tested by adding product terms including ‘study group’ and the independent variable to this model. Univariate (crude) linear regression models are presented with the correlation coefficient whereas for multiple variable models the standardized regression coefficient beta (St. β) is given.All statistical analyses were performed using SPSS 22 . A p-value of <0.05 was considered to indicate statistical significance and all statistical tests were 2-tailed.Baseline characteristics with respect to age, sex and eGFR were similar between ADPKD patients and the IgAN controls, indicating that matching was successful . Blood pAll patients underwent a standard prolonged water deprivation test. None of the patients met the safety stopping criteria during the test. Plasma osmolality increased significantly in ADPKD patients but not in IgAN controls. Upon water deprivation, copeptin and AVP increased significantly in ADPKD patients and IgAN controls in a similar way . Urine oAt baseline and at maximal urine concentration, copeptin and AVP concentrations were strongly associated . Furthermore, copeptin was associated with plasma osmolality, a stimulus for AVP release, both at baseline and at maximal urine concentration Urine osmolality was inversely associated with copeptin at maximal urine concentration . AdditioThe AQP2 to creatinine ratio at maximal urine concentration was inversely associated with maximal urine osmolality. ADPKD patients had a 110 mOsmol/kg lower maximal urine osmolality in comparison with the control group at a similar AQP2 level   and this held also true at maximal urine concentration , measured routinely in an out-patient clinic setting, may be a marker for maximal urine concentrating capacity . We therIn the present study we found a more severely impaired urine concentrating capacity in ADPKD patients with, surprisingly, similar AVP and copeptin responses in comparison with IgAN control patients at similar low kidney function. Furthermore, more severe ADPKD, assessed as a higher total kidney volume, was positively associated with plasma osmolality, copeptin and albuminuria, and with a more severely impaired urine concentrating capacity during water deprivation.After water deprivation, concentrations of plasma AVP, plasma copeptin and urine AQP2 were similar in both study groups, whereas the maximal urine concentrating capacity was significantly more impaired in ADPKD patients. This shows that the process of urine concentration is complex and comprises more than solely variation in the permeability of collecting duct cells. In addition the medullary osmotic gradient is of great importance. This gradient is determined by a complex mechanism involving intra-renal urea recycling by urea transporters in the renal medulla. The importance of these urea transporters for urine concentration has been confirmed in knock-out mouse models ,22. MicePKD1 and PKD2 transcripts in hypothalamic nuclei that synthesize AVP could be involved [After water deprivation, the increase in copeptin and AVP was similar in both study groups, even though the maximal urine concentrating capacity was more impaired and the increase in plasma osmolality seemed more profound in ADPKD patients in comparison to the control group. In both groups plasma osmolality was comparable at the end of the water deprivation test, which could be the explanation for similar copeptin and AVP levels at the moment of maximal urine concentration. On the other hand, Ho et al. have described the possibility of a central component causing the impaired urine concentrating capacity in ADPKD. These authors hypothesized that expression of involved . They foinvolved ,12–14. BIn this study ADPKD patients with later stages of disease showed markedly higher AVP and copeptin levels at the end of a water deprivation test compared to levels that were achieved in our previous study that was performed in ADPKD patients with earlier stages of disease (9.2 1.4–12.0) pmol/L vs. 1.6 (1.13–2.41) pmol/L, p = 0.007) –12.0 pmo. When cyThe major strength of our study is the inclusion of a control group of eGFR-, age- and sex-matched IgAN patients. This allowed us to conclude whether our observations in ADPKD patients are disease specific or due to impaired eGFR, without misinterpreting data due to differences in age and sex distribution. These latter factors have been shown to be associated with maximal urine concentrating capacity ,26,27. IIn conclusion, ADPKD patients have a more severely impaired maximal urine concentrating capacity with a lower maximal achieved urine urea concentration in comparison to IgAN control patients with a similar level of decreased kidney function. AVP secretion as response to water deprivation was similar in both groups. When disease progresses, AVP secretion upon thirsting increases in ADPKD patients. This increase in AVP can be harmful as AVP is known to enhance cell proliferation and cyst formation. Water deprivation may therefore be deleterious and should be avoided by ADPKD patients.S1 File(XLSX)Click here for additional data file.


Emerging evidence has shown a significant deficit in the control of hypertension (blood pressure <140/90 mmHg) among Hispanics or Latinos in about 65%. This study aims to determine the efficacy of the combination in fixed doses of olmesartan and amlodipine  in hypertensive patients treated in daily clinical practice by Colombian doctors.t test was used for paired data, McNemar test, and ANCOVA.This was an observational, retrospective, open-label, multi-center, non-comparative study. The primary outcome was a change in systolic and diastolic blood pressure from the baseline to week 12; the secondary outcome was the proportion of patients achieving a target blood pressure of <140/90 mmHg. Safety and tolerability were also evaluated. For analysis, a student A total of 428 patients were enrolled from 16 centers in Colombia. At 12 weeks, patients’ systolic blood pressure decreased in response to all three doses: by 27.75 ± 20.73 mmHg in 20/5 mg, 31.13 ± 22.23 mmHg in 40/5 mg, and 46.96 ± 20.15 mmHg in 40/10 mg . Furthermore, the diastolic blood pressure decreased by 14.19 ± 12.89 mmHg in 20/5 mg, 16.25 ± 10.87 mmHg in 40/5 mg, and 24.83 ± 10.41 mmHg in 40/10 mg . The percentage of patients achieving target blood pressure was 71.31% in 20/5 mg, 70.16% in 40/5 mg, and 63.33% in 40/10 mg.This study demonstrates the efficacy of the combination in fixed doses of olmesartan and amlodipine in the treatment of Colombian hypertensive patients. Hypertension is a highly prevalent disease that ranges from 30 to 44% and remains under diagnosed and undertreated –3. HighlThis study was an observational, open-label, retrospective, multi-center, non-comparative clinical study with a total treatment period of 12 weeks, conducted at 16 clinical sites in Colombia. The cities included in the study were Barranquilla, Santa Marta, Cartagena, Monteria, Valledupar, Medellín, Bucaramanga, Cúcuta, Bogotá, Villavicencio, Ibagué, Neiva, Cali, Pereira, Armenia, and Ipiales.The sample size was calculated seeking a reduction of 20 mmHg of systolic blood pressure (SBP) and 10 mmHg of diastolic blood pressure (DBP) with the use of olmesartan and amlodipine, with a p value <0.05 and a power of 80%, resulting in at least 246 patients.The inclusion criteria encompassed patients over 18 years old, untreated patients with uncontrolled hypertension (≥140/90 mmHg), creatinine clearance >60 ml/min or creatinine <1.3 mg/dl, with or without other cardiovascular risk factors, who signed the informed consent and had no contraindication for the use of olmesartan and/or calcium antagonists.The patients with any of these conditions such as: secondary hypertension, hypertensive emergency, or target organ damage such as heart failure, unstable angina, hypertensive encephalopathy, myocardial infarction, stroke, history of coronary revascularization, valvular heart disease, and serious arrhythmia. Patients with severe organ dysfunction, as assessed by laboratory abnormality, and pregnancy were excluded.The blood pressure data was collected from the medical records of clinical sites and included baseline, 6, and 12 weeks, according to the combination of olmesartan and amlodipine fixed doses of 20/5, 40/5, and 40/10 mg.The data was processed by the analysis of paired observations, paired student t-test, and the McNemar test for categorical data analysis. The SBP and DBP at weeks 0, 6, and 12 were analyzed using the repeated-measures analysis of covariance (ANCOVA) with covariates of baseline SBP and DBP. Two-tailed p values of less than 0.05 were considered to be statistically significant. Statistical analyses were conducted by using STATA 12 (StataCorp).The primary outcome was a change in SBP and DBP from the baseline to week 12. The secondary outcome was the proportion of patients achieving a target blood pressure of <140/90 mmHg. The reduction of pulse pressure (PP) was defined as the difference between systolic and diastolic pressure for each dose of olmesartan and amlodipine FDC.The blood pressure (BP) was measured with mercury sphygmomanometers that were appropriate for each patient’s anthropometric parameters, and both sides of the arms were measured. The BP used in the study was the mean of three measurements, which were performed after 10 min of rest in the seated position. The BP was read in 2 mmHg intervals to prevent the risk of bias.The study was conducted according to the Good Clinical Practice guidelines and the Declaration of Helsinki.A total of 428 patients were enrolled from 16 centers in Colombia. Of these patients, 46.96% were male, 3.27% were diabetic, 42.7% received olmesartan and amlodipine FDC 20/5 mg, 46.2% received a dose of 40/5 mg, and 10.9% received a dose of 40/10 mg. The mean age was 61.35 ± 12.72 years; the SBP mean was 162.04 ± 18.88 mmHg, and the DBP mean was 96.36 ± 10.53 mmHg.Patients with hypertension stage 1 accounted for 30.84% of the sample, while patients with hypertension stage 2 comprised 69.16%, according to criteria of the Joint National Committee (JNC 8) [The DBP values at 6 weeks also showed a statistically significant decrease from the baseline in all three groups of olmesartan and amdolipine FDC: with a 20/5 mg dose, DBP was 8.79 ± 12.85 mmHg; with a 40/5 mg, DBP was 10.03 ± 10.67 mmHg; and with a 40/10 mg dose, DBP was 20.09 ± 12.44 mmHg . At 12 weeks, the reduction with a 20/5 mg dose was 14.19 ± 12.89 mmHg; with a 40/5 mg dose, the reduction was 16.25 ± 10.87 mmHg, and with a 40/10 mg, the reduction was 24.83 ± 10.41 mmHg . There was no difference between dose groups of 20/5 and 40/5 mg (p = 0.95), 20/5 mg and 40/10 mg (p = 0.108), and 40/5 mg and 40/10 mg (p = 0.33) (see Table The SBP mean of the diabetic patients was 153.36 ± 32.24 mmHg (range: 120-230) and in patients with dyslipidemia the SBP mean was 154.29 ± 25.23 mmHg (range: 70–230). The DBP mean in diabetic patients was 83.84 ± 15.56 mmHg (range: 60–120) and patients with dyslipidemia was 94.82 ± 11.67 mmHg (range 65–120).The reduction in SBP in diabetic patients was 37.12 mmHg (p = 0.072) at 6 weeks and 39.12 mmHg (p = 0.032) at 12 weeks. In hyperlipidemic patients SBP was reduced by 26.64 mmHg (p = 0.45) at 6 weeks and 26.64 mmHg (p = 0.89) at 12 weeks.The reduction in DBP in diabetic patients was 16.43 mmHg (p = 0.064) at 6 weeks and 24.83 mmHg (p = 0.001) at 12 weeks, in patients with hyperlipidemia DBP was reduced by 27.38 mmHg (p < 0.001) at 6 weeks and 32.38 mmHg (p = 0.002) at 12 weeks.The dosage of olmesartan and amlodipine FDC prescribed in hypertension stage 1 was 43.71% in 20/5 mg, 22.23% in 40/5 mg, and 17.03% in 40/10 mg. In stage 2, the dosage was 56.28% in 20/5 mg, 77.78% in 40/5 mg, and 82.98% in 40/10 mg, these proportion of hypertensive patients stage 2 decrease statistically significant to 1.64% with the dose of 20/5 mg, 1.61% in 40/5 mg, and 0% in 40/10 mg at 12 weeks of olmesartan and amlodipine FDC (p < 0.016) . At 12 weeks, 71.31% of patients with a dose of 20/5 mg, 70.16% with a dose of 40/5 mg, and 63.33% with a dose of 40/10 mg had achieved the target (p < 0.016). There were no differences by sex (p = 0.19) or among diabetic (p = 0.625) or hyperlipidemic (p = 0.203) patients  ; dizziness, 5 patients (1.17%); and peripheral edema; 3 patients (0. 7%).In this 12 week study, we found that the olmesartan and amlodipine FDC was effective in controlling systolic and diastolic BP in clinical practice for Colombian patients. There was a statistically significant reduction in systolic blood pressure values after 6 weeks of treatment, between 18 and 36 mmHg, depending on the dose received; the reduction after 12 weeks was between 26 and 47 mmHg. The diastolic blood pressure values were also reduced, between 8 and 20 mmHg at 6 weeks and between 14 and 24 mmHg at 12 weeks.These results are higher than those found in pivotal studies such as the COACH study —a randomized, placebo-controlled study in which the efficiency of dual combination therapy with olmesartan and amlodipine was compared with its components in monotherapy. In patients with hypertension from mild to severe, reductions in SBP values were found between 23 and 30 mmHg; DBP values were reduced between 14 and 19 mmHg . Volpe eIn patients with diabetes and hyperlipidemia, there are interesting results in reducing blood pressure levels with the combination olmesartan and amlodipine FDC, although caution should be exercised in interpreting the results, because of the reduced proportion of patients with diabetes (3.27%) and hyperlipidemia (8.88%) in the study.Interestingly, the dosage of olmesartan and amlodipine FDC prescribed was directly proportional to the stage of hypertension; for example, the dose of 40/10 mg was prescribed more in stage 2, while a 20/5 mg dose was prescribed in stage 1. The proportion of hypertensive patients in stage 2 at the baseline  decreased statistically significant between 0 and 1.64% at 12 weeks (p < 0.016), demonstrating a high antihypertensive efficacy of different doses of olmesartan and amlodipine FDC.In the secondary outcome, this study showed a significant proportion of patients achieving their blood pressure goal <140/90 mmHg) with olmesartan and amlodipine FDC. Between 63 and 71% showed trends similar to previous studies such as COACH (between 42.5 and 51%) [0 mmHg wiRecently, it was found that Latin American patients with high pulse pressure are associated with 2.6 times more likely to have cardiovascular events , and in This study found an important and significant reduction in pulse pressure of 13–22.13 mmHg. In the light of the evidence, this could reduce morbidity and mortality in our patients, but another type of study would be required to determine its effect.Increased blood pressure is an important risk factor for stroke, heart disease, and kidney failure. Many clinical trials have shown that reducing the BP by a variety of strategies reduces the risk of stroke by about 35%, congestive heart failure by 42%, and coronary heart disease by 28% –15. The The limitations of this study are mainly due to its retrospective, open-label design, short study duration, and the possible underreporting of adverse effects. The evidence has shown a range of adverse effects with olmesartan and amlodipine, such as edema (in 0.5%), headache, and dizziness (in 1.6% on average) .In Colombia, the prevalence of hypertension is 23%, of which 59.8% are diagnosed, 36.3% are being treated and only 11.8% are correctly controlled , therefoThe strength of this study is that it is a multi-center study with Colombian representative populations; it provides the first evidence of the effectiveness of olmesartan and amlodipine in daily clinical practice in our country.In this study of daily clinical practice in Colombian patients, the FDC of olmesartan/amlodipine provides excellent systolic and diastolic blood pressure control. More than 63% of patients achieved their blood pressure goal—reduced pulse pressure of 13 mmHg—and the medication combination is well tolerated.


The prevalence of chronic kidney disease (CKD) in rural Vietnam is unknown. We wished to determine the prevalence of CKD and determine whether a simple questionnaire was able to detect individuals at high risk of CKD before expensive confirmatory laboratory testing.MDRD < 60 ml/min/1.73 m2. A two page questionnaire with 23 variables was administered to each participant with queries postulated to be correlated with risk of CKD.A cross sectional study was performed. We recruited 2037 participants from 13 communes of Long An province, Vietnam, for CKD screening with urine albumin/creatinine ratio (ACR) measured by immunoturbidimetric method and serum creatinine to estimate glomerular filtration rate (eGFR). CKD was defined as either ACR ≥ 30 mg/g or eGFR Of the 2037 participants, 260 (12.76%) were found to have CKD. Five questionnaire variables  were correlated with CKD, and used to construct a risk score for CKD.CKD is common in Vietnam. Our questionnaire and risk score tool can be used to detect individuals with a higher likelihood of CKD, and who can then be more economically screened with routine laboratory confirmatory tests. The pficient) . Geograpficient) , 10. In ficient) . In 2010ficient) . Access ficient)  was an eficient) . We now 2 [Long An province, located in the Southwest of Vietnam, about 60 km from Ho Chi Minh City, has a population of 1,477,300 in 2014 with an average population density of 329/km2 . Long An2 . SecondaThis cross sectional study was conducted in Long An province, Vietnam. Long An was divided into 14 “communes” , using the National Population Census of 2009 as a guide. Eight of the communes  were used as regions for sampling. The remaining 6 communes with sparsely population at flood area  were combined into a single region for sampling , place of birth , past and current tobacco use, alcohol use (more than one glass three times weekly), low salt diet , exercise (two or more times per week regularly). Other dichotomous variables as marital status, personal and family histories of diseases diagnosed by previous physician as kidney disease, kidney stone, urinary tract infection, diabetes, hypertension, stroke, cardiovascular disease, congestive heart failure, and amputation secondary to medical disease. All participants were personally interviewed by physicians using standardized language, followed by physical examination. Any abnormal clinical findings requiring treatment and follow-up were referred to the commune health stations, or Long An Hospital. Clinical examination included weight, height, waist to hip circumference ratio, and blood pressure measurement. Blood pressure was obtained in sitting position after a 10 min rest.Morning blood and urine samples were collected and analyzed on the same day at the MEDIC Medical Center at Ho Chi Minh City. Serum and urine creatinine were measured by Kinetic Alkaline Picrate technique and urine albumin measured by immunoturbidimetric method (Abbott Architect CI systems). Spot urine albumin/creatinine ratios (ACR) were calculated and ACR ≥ 30 mg/g was used as the threshold for CKD recommended by the American Diabetes Association 2012  and the MDRD < 60 ml/min/1.73 m2. The eGFR was calculated using the 4 variable MDRD equation. eGFR MDRD (ml/min/1.73 m2) = 175 × (Scr)−1.154 × (Age)−0.203 × . There were no subjects of African descent in the survey. Hypertension at screening was defined as mean systolic blood pressure ≥ 140 mmHg, or diastolic blood pressure ≥ 90 mmHg on three measurements. Increased waist circumference was defined by waist circumference > 90 cm (men) or > 80 cm (women), per the International Diabetes Federation (IDF) cut off points for South Asians, Chinese and Japanese [Chronic kidney disease was defined as either ACR ≥ 30 mg/g or eGFR Japanese . Nocturi® statistical software, version 11.0 . Logistic regression was used to create the prediction model with CKD as a binary outcome. We first analyzed the univariate associations between the independent variables and CKD. We used stepwise logistic regression and backward elimination to reach the final model in which all the predictors in the model were significant at p < 0.001 and with an odds ratio of > 1.7. Using the regression coefficients, we estimated the patient-specific probability of having CKD. The probability of CKD was calculated by the formula 1/(1 + e−A), in which A depended on the final statistic significant variables and their responsible β coefficients (A = β0 + β1 × 1 + β2 × 2· · · + βn × n). A probability for confirmed laboratory CKD was chosen to make the discreet patterns of “yes” and “no” from significant questionnaire variables. The utility of the prediction model was evaluated based on several measures: percentage of positive cases, sensitivity, specificity, positive predictive value, and area under the receiver operator characteristic (ROC) curve. The maximum of area under the curve (AUC) = 1, meant the diagnostic test was perfect to differentiate between the diseased and non-diseased subjects. While AUC = 0.5, meant this differentiation was by chance. The number of persons needed to do lab tests to find 1 CKD subject = 1/(percentage of CKD within each group/100). The cost effectiveness per CKD case with or without using questionnaire before confirmatory laboratory tests was calculated.Independent variables from the questionnaire as well as demographic information and laboratory results were entered into a table for statistical analysis. All analyses were performed using JMP-Pro2  personal history (PH) of hypertension, (7) PH of diabetes, (8) PH of cardiovascular disease,(9) PH of congestive heart failure, (10) PH of stroke, (11) PH of kidney disease, (12) PH of urinary tract infection, (13) PH of kidney stone, (14) PH of nocturia, (15) PH of hematuria, (16) PH of alcohol drinking (either past or present), (17) PH of smoking (quit or present smoking), (18) PH of exercise, (19) PH of low salt intake, (20) family history (FH) of hypertension, (21) FH of diabetes, (22) FH of kidney disease, (23) FH of stroke.We performed univariate analysis with the 23 nominal variables: (1) Age ≥ 50, (2) sex, (3) hypertension at screening, (4) increased waist circumference, (5) BMI > 23 kg/mAfter stepwise logistic regression, only 5 variables that showed statistical significance and had a high (> 1.7) odds ratio were retained for our final model: (1) age ≥ 50 (p < 0.0001), (2) hypertension on screening (p < 0.0001), (3) personal history (PH) of hypertension (p = 0.002), 4) PH of diabetes (p < 0.009) and (5) low salt diet (p = 0.002)  with a risk factor vs. without it was less by 67, 69, 70, 86, and 67% for measured hypertension, PH of diabetes, PH of hypertension, low salt diet, and age ≥ 50 years old, respectively  was 0.71, using the reference group of individuals younger than 50 and absence of the risk factors above. This indicated that the discrimination of the model was fair Fig. .Fig. 2Re2. Repeated screens had the same proportion of microalbuminuria to macroalbuminuria as the original sample. 61% of the patients had persistent albuminuria and 67.6% of them had persistent eGFR < 60 ml/min/1.73 m2. 63.5% of individuals, who met criteria for CKD on initial screening, had CKD confirmed on second screening. Therefore, the estimated prevalence of CKD was 8.1% if based on persistent laboratory abnormalities rather than 12.76% based on a single screen.We repeated the screening within 3 months on 189 out of 260 participants who had either ACR > 30 mg/g, or eGFR < 60 ml/min/1.73 mThe cost of lab tests  is 2.2 USD per person in Vietnam in 2015. Without a pretest questionnaire, the cost of testing 10,000 persons would be 22,000 USD or 27.16 USD for each of the 810 confirmed CKD cases. If the questionnaire should be used in 10,000 people, the total cost of further confirmatory laboratory tests on the 290 individuals expected to meet the threshold would be just 638 USD. The 5.8 USD per each of the 110 cases expected to be confirmed by this strategy compares to the 27.16 USD per confirmed case without using a questionnaire ; 12.7% in England , 10.2% ind Nepal . Other fnd Nepal , 27.We have developed a method based on 5 characteristics  to screen kidney disease in our population. Other characteristics expected to be correlated with CKD did not reach statistic significance but they depended on the prior health records and individual self reporting. Four of our 5 characteristics  were known as risk factors for CKD , and conIn this study we found a paradoxical relationship between low salt diet and CKD. 96/2037 subjects (4.71%) in our study self reported intentional use of low salt diet. Low salt diet was found to be an independent risk factor for CKD in the multivariate analysis. We did not use the 24 h dietary history or timed urinary sodium measurement to estimate the amount of salt intake. No reason for or duration of low salt intake was determined. Whether low salt diet being part of any chronic disease therapy wasn’t known. Those subjects with low salt diet also had other lifestyle modifications . A reduction in population salt intake will lower blood pressure and thereby reduce stroke and fatal coronary heart disease in adults. Other co-morbidity factors in those 96 subjects were statistically higher than the normal salt diet group . Therefore, the association of low salt diet with CKD in our study is puzzling, but may be a covariate of a hidden factor not measured in this study.The transportability of our score remains to be validated in other rural populations coincidentally with using lab tests for CKD diagnosis and adding low salt diet measurement. We cannot rule out the possibility that other co-morbid conditions might also have been misclassified or under-ascertained. The study used only a single random ACR and single eGFR for CKD diagnosis (12.76%) which overestimated the prevalence of CKD required the persistent abnormality either of them (8.1%). In NHANES III study, the reproducibility of data on microalbuminuria on the second visit within 2 months of the initial examination was only 57%, while the repeat serum creatinine showed good agreement with the initial measurement . The cosAlthough the sensitivity of this questionnaire is low (13.8%), the positive predictive value is high enough (60%) to detect a significant number of people at risk. There are fewer than 1.22 physicians and 2.3 total health care workers (including nurses and midwives) per 1000 population in Viet Nam . Travel In conclusion, this questionnaire, along with routine clinical evaluation, is a simple, cost-effective tool to assess CKD which can be implemented in rural areas of Vietnam. It also gives more effectiveness and productivity to each penny spent for health care system in Vietnam.


IL-4 −590 (C>T) gene, especially in Iraqi patients with asthma. We studied forty-eight blood samples collected from patients with asthma and compared with age-matched 25 healthy individuals as controls. The polymorphism results of IL-4 −590 (C>T) gene by using amplification refractory mutation system (ARMS-PCR) showed the presence of C and T alleles and three genotypes . Interestingly the frequency of C allele and CC genotype was higher in patients with asthma in comparison with the same allele and genotype in control (P 1 × 10−6). This increase was associated with an increased risk factor of asthma . Genotypes analysis by using Hardy-Weinberg distribution showed no significant differences between patients with asthma and healthy subjects. In conclusion, the increasing risk of asthma was associated with C allele and the CC genotype and these are revealed as etiological fraction with risk by having this disease, while the T allele percentage ratio in controls was higher when it is compared with asthma patients suggesting that these alleles have a protective effect (preventive fraction). This study is the first investigation in Iraq dealing with genotyping of IL-4 gene located on chromosome 5q23.31: IL-4 [ IL4 gene has been reported to be associated with a reduced IL4 expression, while the TT genotype upregulated the production of this cytokine [ IL4 −590 (C>T) in a sample of Iraqi asthmatic patients with the aim to determine its susceptibility role.Asthma is a complex chronic inflammatory disease that results from the interaction between genetic predisposition and environmental factors . More th31: IL-4 , 7, Amis31: IL-4 , America31: IL-4 , Hutteri31: IL-4 , and Bri31: IL-4 , 12. The31: IL-4 , 14. Stu31: IL-4 , 16. Polcytokine . This woForty-eight asthma patients and 25 controls  subjects were enrolled in the study. The patients were referred to the Al Zahra Center for Allergy and Asthma in Baghdad, Iraq, for diagnosis and treatment. The diagnosis was made by the consultant medical staff according to international criteria. All cases and controls were at the age range 10–65 years. Anticoagulants EDTA tubes were used for collecting the peripheral blood for DNA isolation. IL-4 gene at position −590 (C>T) was genotyped using the amplification refractory mutation system (ARMS-PCR) approach. Primers for this position were used according to [DNA from venous blood was isolated using ReliaPrep™ Blood gDNA Miniprep System kit (Promega). Therding to  and synt IL4 −590 (C>T). AccuPower® PCR PreMix  was prepared according to [μL with nuclease-free water  was also loaded on the agarose gel. Two microliters of bromophenol blue dye was loaded with all reaction mixer samples. The gel electrophoresis was performed by using 75 V for 2 hrs and stained with ethidium bromide  for 30 min. The gel was documented with gel documentation system .http://www.had2know.com/academics.html.Percentage frequencies and significant differences data between patients and controls were given by Fisher's exact test. The odds ratio (OR) and confidence intervals (CI) were analyzed by using Compare 2 Ver.3.04 program designed by J. H. Abramson/2003–2013. Deviations from Hardy-Weinberg were tested using an exact test available at  IL4 −590 (C>T) showed the presence of C and T alleles and three genotypes  by using the specific C, specific T, and reverse primers  were in a good agreement with Hardy-Weinberg equilibrium in asthma patients and controls, as there were no significant differences between observed and expected genotype frequencies . In contrast, the T allele frequency was significantly higher in controls (42%) than in patients (7.29%). The OR for C and T alleles were 9.21 and 0.11, respectively. Such results suggest that C allele has a predisposing effect, while T allele has a protective effect . A further study carried out by Xiaoyan et al. [ IL4-590), and the authors suggested that these genes make little contribution to the development of asthma in children of Chinese Han nationality.Cytokines are key mediators that regulate innate and adaptive immune responses, which are also subjected to the effect of factors such as infection, inflammation, and hormonal condition. However, cytokine gene polymorphisms have a role in the expression of cytokines by immune cells . The C ad et al.  observedn et al.  investig C allele and the CC genotype, while the T allele and CT and TT genotypes were present more in healthy subjects which are thought to have a protective effect (preventive fraction). These alleles dominating in special population compared to others at genetic levels could be used as an indicator of genetic biomarkers that effect on either pathogenesis or protection from the diseases.In conclusion, the increasing risk of asthma was associated with