Prediction of preeclampsia is a challenge to overcome. The vast majority of prospective studies in large general obstetric populations have failed in the purpose of obtain a useful and effective model of prediction, sometimes based on complex tools unavaible in areas where the incidence of preeclampsia is the highest. The goal of this study was to assess mean arterial blood pressure (MAP) levels at 19–21, 27–29 and 37–39 weeks of gestation and performance of screening by MAP for the prediction of preeclampsia in a Brazilian cohort of healthy nulliparous pregnant women.This was a cohort approach to a secondary analysis of the Preterm SAMBA study. Mean arterial blood pressure was evaluated at three different time periods during pregnancy. Groups with early-onset preeclampsia, late-onset preeclampsia and normotension were compared. Increments in mean arterial blood pressure between 20 and 27 weeks and 20 and 37 weeks of gestation were also calculated for the three groups studied. The accuracy of mean arterial blood pressure in the prediction of preeclampsia was determined by ROC curves.Of the 1373 participants enrolled, complete data were available for 1165. The incidence of preeclampsia was 7.5%. Women with early-onset preeclampsia had higher mean arterial blood pressure levels at 20 weeks of gestation, compared to the normotensive group. Women with late-onset preeclampsia had higher mean arterial blood pressure levels at 37 weeks of gestation, than the normotensive groups and higher increases in this marker between 20 and 37 weeks of gestation. Based on ROC curves, the predictive performance of mean arterial blood pressure was higher at 37 weeks of gestation, with an area under the curve of 0.771.As an isolated marker for the prediction of preeclampsia, the performance of mean arterial blood pressure was low in a healthy nulliparous pregnant women group. Considering that early-onset preeclampsia cases had higher mean arterial blood pressure levels at 20 weeks of gestation, future studies with larger cohorts that combine multiple markers are needed for the development of a preeclampsia prediction model. The prediction of preeclampsia is challenging. It is a complex syndrome, with multiple phenotypes, each with its own particularities of pathophysiology and clinical manifestations . EffectiThe majority of prospective studies in large general obstetric populations have demonstrated a modest capacity to predict preeclampsia by clinical risk factors, and approximately only a third of these cases are identified . A prediBlood pressure measurement is part of routine surveillance during antenatal care. High blood pressure may be the first sign of a hypertensive disorder and is a diagnostic tool. Oscillations in BP measurements in a pregnant woman may reflect a trend for hypertensive disorder, and is a predictive test . Since tThus, to assess the accuracy of mean arterial blood pressure (MAP) in a group of nulliparous pregnant women, this study showed the distribution of MAP levels at 19–21, 27–29 and 37–39 weeks of gestation and evaluated the accuracy of MAP at these three different time periods  as a predictor of preeclampsia.This was a secondary analysis of the Preterm SAMBA study, a multicenter cohort study performed in 5 different centers in Brazil. From July 2015 to March 2018, 1200 healthy nulliparous pregnant women were enroled and received follow-up during prenatal care, including only singleton pregnancies, without any fetal malformations or previous chronic maternal disease .Criteria for participant enrollment were nulliparous women with singleton pregnancies between 19 and 21 weeks of gestation. Exclusion criteria included: previous history of chronic hypertension, use of medication, fetal malformations, diabetes mellitus, nephropathy, autoimmune diseases (systemic erythematous lupus or antiphospholipid syndrome), sickle cell disease, uterine malformations, previous cervical surgery, previous cerclage, history of 3 or more abortions, HIV infection, chronic use of corticosteroids or aspirin or calcium above 1 g/day or fish oil above 2.7 g/day or vitamin C above 1000 mg/day or vitamin E above 400 UI/day or heparin. This criteria is in accordance with another cohort study published previously . We also calculated the difference in mean blood pressure with measurements at 19–21 weeks and 27–29 weeks and measurements at 19–21 weeks and 37–39 weeks. Calculation was made in two steps: first, the difference was determined for each woman; and second, the mean difference was calculated.During the first visit, maternal characteristics and medical history were recorded. In addition, blood and hair samples were collected and stored appropriately in a biobank for subsequent analysis by metabolomics technology. Gestational age was estimated from the date of the last menstrual period and confirmed by an early ultrasonography performed before 20 weeks. For each scheduled visit, blood pressure was measured 3 times. Women were allowed to rest for 15 min before the first blood pressure measurement was performed. Between blood pressure measurements, the investigator waited for at least 2 min. During the examination, participants remained in a sitting position, with their right arm supported at the level of their heart. An adult blood pressure cuff was used, selecting the proper size for each participant. Pressure reading at phase V of Korotkoff sounds corresponded to diastolic pressure. Mean arterial blood pressure was obtained by the equation (2DBP + SBP)/3. The mean blood pressure at each gestational age for the three measurements was obtained by the average of three mean blood pressure measurements  on dipstick testing or spot urine protein/creatinine ≥30 mg/mmol [0.3 mg/mg]) or any signs of organ dysfunction . SystemiAfter delivery, each woman was classified as having a normal pregnancy (control group) or preeclampsia (case group). Cases were categorized into early-onset preeclampsia (women who developed preeclampsia before 34 weeks of gestation) and late-onset preeclampsia (women who developed preeclampsia after 34 + 1 weeks of gestation)  .Initially, the three groups were compared regarding sociodemographic characteristics of women using a Chi-square design-based test. Mean arterial blood pressure was then compared among the three groups  using Student’s t-test. The mean difference in MBP measured at 27 and 37 weeks was estimated and compared to values at 20 weeks. Finally, we checked to see whether mean arterial blood pressure had any predictive power at three time periods  by comparing the area under the receiver-operating characteristic curves (AUROC). Analyses were performed using SPSS and Stata software.p value = 0.02)  has remained the target of scientific research in quest for the prediction of preeclampsia over time. It is a feasible tool and part of antenatal surveillance. Few studies have shown blood pressure patterns among low- risk nulliparous pregnant women –15. Our p = 0.003). In our study, the increment observed among late-onset preeclampsia cases was superior to the value seen among the early-onset preeclampsia group. We hypothesized that it was possible that the latter group had already started antihypertensive medication at 27 and 37 weeks of gestation. The lack of information about the exact time when antihypertensive medication was initiated was a weakness of our study.In uncomplicated pregnancies, arterial blood pressure pattern usually consists of a steady decrease in blood pressure during the first half of pregnancy, then an increase until the time of delivery . In contAlthough we demonstrated that women with early-onset preeclampsia had a higher MAP at 20 weeks of gestation than the remaining participants, MAP performance was modest as a predictor, with an Area Under the Curve of only 0.619. This is not in accordance with a systematic review from 2008, which demonstrated that mean arterial blood pressure measured during the first or second trimester of gestation in a general low-risk pregnant population was a better predictor of preeclampsia, with an Area Under the Curve of 0.76. For the high-risk pregnant women group, this review indicated that diastolic blood pressure is the best predictor of preeclampsia, when measured between 13 and 20 weeks of gestation . The verFurthermore, some studies have demonstrated a higher predictive power when MAP is measured during the first trimester of pregnancy , 15, 21,Our study has many strengths. First, this was a prospective examination of a large population of low-risk nulliparous pregnant women. Second, there was data recording of maternal characteristics and medical history to identify risk factors associated with preeclampsia. Furthermore, we measured arterial blood pressure with a manual sphygmomanometer which was standardized in the protocol for noninvasive blood pressure monitoring . On the In the last 20 years, improvement in diagnostic tools has led to the prevention and prediction of different conditions, including obstetric health issues. Therefore, considerable effort has been devoted to identifying and modifying individual risk factors during the first half of pregnancy , 26. Clo


Hypertension (HTN) is the single leading risk factor for human mortality worldwide, and more prevalent in sub-Saharan Africa than any other region –althoughWe sought to evaluate the consistency of HTN program delivery within the SEARCH study (NCT01864603) among 95,000 adults in 32 rural communities in Uganda and Kenya from 2013–2016. To achieve this objective, we designed and performed a fidelity evaluation of the step-by-step process (cascade) of HTN care within SEARCH, calculating rates of HTN screening, linkage to care, and follow-up care. We evaluated SEARCH’s assessment of each participant’s HTN status against measured blood pressure and HTN history.SEARCH completed blood pressure screens on 91% of participants. SEARCH HTN screening was 91% sensitive and over 99% specific for HTN relative to measured blood pressure and patient history. 92% of participants screened HTN+ received clinic appointments, and 42% of persons with HTN linked to subsequent care. At follow-up, 82% of SEARCH clinic participants received blood pressure checks; 75% received medication appropriate for their blood pressure; 66% remained in care; and 46% had normal blood pressure at their most recent visit.The SEARCH study’s consistency in delivering screening and treatment services for HTN was generally high, but SEARCH could improve effectiveness in linking patients to care and achieving HTN control. Its model for implementing population-scale HTN testing and care through an existing HIV test-and-treat program–and protocol for evaluating the intervention’s stepwise fidelity and care outcomes–may be adapted, strengthened, and scaled up for use across multiple resource-limited settings. Cardiovascular disease (CVD) is the leading cause of death worldwide, and hypertension (HTN) is the leading risk factor for both cardiovascular disease and all-cause mortality . BetweenPrevious work demonstrates community-level programs to screen and treat CVD risk factors in sub-Saharan Africa are efficacious and cost-effective. Most successful models have leveraged nurses, community health workers, and other non-physicians ,15,16,17The Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603) is a large cluster-randomized trial evaluating the impact of a multi-disease test-and-treat strategy on HIV incidence in rural Uganda and Kenya . Adults We defined the HTN cascade as a sequential process of blood pressure checks and interpretation, referral and linkage to follow-up care for apparent HTN, and subsequent medication and counseling, within 32 non-adjacent rural Ugandan and Kenyan communities, enrolled in the SEARCH Study , in threvisits [Following initial education on the campaign, and registration against community census enumerations performed by SEARCH, all adult CHC attendees were screened for HTN by two independent methods. First each attendee was to undergo a direct blood pressure check by a SEARCH nurse, as detailed below. Second a SEARCH staff member was to ask each attendee 1) if they were ever diagnosed with HTN and 2) if so, whether they have taken HTN medication in the last three months. SEARCH devised its own pair of criteria for defining an attendee as screening “positive” for HTN per that protocol: first, all persons who reported a history of HTN with recent medication use as above were deemed positive by history criteria, regardless of measured blood pressure. Second, all persons whose blood pressure, as checked by the SEARCH nurse on the day of the CHC, was consistently elevated, were deemed to screen “positive” for HTN regardless of their stated history. Specifically, SEARCH nurses used an electronic sphygmanometer (Omron 742) to check each attendee’s blood pressure on their upper arm as they sat in a chair. Adults whose measured pressure was greater than or equal to 140 mm Hg systolic or 90 mg Hg diastolic pressure on this test, underwent two additional blood pressure checks, at least one minute apart from each other and from the first test. If the lowest of the three screenings was greater than or equal to 140 mg Hg systolic or 90 mg Hg diastolic, SEARCH staff recorded a positive HTN screen. For purposes of integration and scale-up with the national health systems of Uganda and Kenya, we based these criteria on the Uganda Ministry of Health’s 2012 National Guidelines for the Management of Common Conditions , which dvisits ; the Ugavisits .”Participants with a positive screen by either their measured blood pressure or self-reported use of HTN medication were to receive an appointment at a health center for follow-up, regardless of any current or prior HTN care they were separately receiving and regardless of their blood pressure level. All adults who met neither of these criteria were to be designated as screening negative for HTN, and to receive no referral to HTN care. SEARCH staff were also to measure the height, weight, blood glucose, and HIV status of all adult participants, among other factors.Participants with a positive HTN screen were to receive an appointment at a health center (HC) corresponding to their CHC site, on a sub-clinic dedicated to patients with HTN and diabetes, called the chronic disease clinic. Participants who appeared at this clinic without an appointment also received care, if they were confirmed as SEARCH participants and reported a positive HTN screen at a CHC as above. As per guidelines at Ugandan HCIII, HCIV, and equivalent Kenyan non-dispensary clinics ,37, geneAt their initial visit, participants with a blood pressure result under 140 mm Hg systolic and 90 mm Hg diastolic were to receive no intervention, only an appointment for a 6-month follow-up visit; those with a blood pressure 140-<160 mm Hg systolic or 90-<100 diastolic were to receive lifestyle counseling and a recheck at a later visit; and participants with blood pressure ≥160 mm Hg systolic or ≥100 diastolic were to receive HTN medication according to a stepwise algorithm . At follWe defined a stepwise cascade for evaluating the fidelity by which SEARCH conducted HTN-related activities based on the algorithm described above, measuring at each step the proportion of participants whose status was in fact measured as expected, and when possible, whether it was measured correctly: for example, whether SEARCH’s recorded interpretation of a participant’s HTN screen aligned with their actual blood pressure readings and stated history of HTN. We treated missing data, therefore, as itself a result rather than the absence of findings. However, in addition to evaluating SEARCH’s effectiveness in HTN care relative to care delivery intent , we also measured its impact in achieving key results in HTN control , via a series of steps validated in HTN control studies globally ,43. The Each SEARCH participant was invited to appear at a single CHC during the initial study year, but those who screened HTN+ were referred to HC care for multiple follow-up visits. Therefore, CHC analyses evaluated consistency of care per participant, whereas HC analyses evaluated consistency of care per visit. Because CHC data included both participants’ actual blood pressure and self-reported HTN status, as well as SEARCH staff interpretation of this status , we calculated the sensitivity and specificity of SEARCH’s designation of HTN status, relative to the documented blood pressure and history values: in other words, SEARCH’s accuracy in interpreting the data it gathered.labeled as HTN-positive, as well as the proportion of participants whose blood pressure and history was in fact confirmatory for HTN, who received an appointment to HC care. Among participants who received an appointment, we calculated the proportion who appeared in a HC at least once (linked to care) between their CHC visit and May 2016. Because SEARCH operated separate, discrete research and clinical operations across the three regional village clusters , we stratified data across these three sites, as well as by body mass index (kg/m2) and diabetes status (12 or more mmol/L blood glucose on spot check).Because all participants whom SEARCH deemed HTN-positive at each CHC were to receive an appointment to HC care, we calculated the proportion of participants whom SEARCH All SEARCH participants who presented to the HC were treated for HTN based on self-report of their CHC screen rather than CHC data, because the latter was unavailable to HC providers: at their first HC visit, participants were queried about whether they came to the clinic due to a positive screen for HTN, diabetes, or both; and their recall was presumed to be correct and duly recorded. We therefore calculated fidelity of HTN care for all persons reporting a positive HTN screen, regardless of prior CHC data. All SEARCH patient HC visits for HTN involved a blood pressure check; a query for HTN medication adherence; and a decision on medication treatment based on blood pressure and prior medication use . For theSEARCH required that all HTN participants at NCD clinics receive a follow-up within 6 weeks . We therHeads of household provided written consent for all household members to participate in the SEARCH trial. We obtained verbal consent from all participants to participate in the CHC intervention. The Makerere University School of Medicine Research and Ethics committee; the Uganda National Council on Science and Technology; the Kenya Medical Research Institute Ethical Review Committee; and the University of California, San Francisco Committee on Human Research each approved the study.The study sponsors had no role in the study design, data collection, data analyses, data interpretation, or publication decisions associated with this study.and queries regarding HTN history and HTN medication use), 16% screened positive in Eastern Uganda, 13% in Western Uganda, and 4% in Kenya. SEARCH recorded 14% of all participants as positive for HTN in Eastern Uganda and 12% in Western Uganda. In Kenya, SEARCH did not record its assessment of HTN or diabetes status, contrary to its intentions, due to limited staff and logistical capacity directed chiefly at the HIV/AIDS care cascade.Participant demographics are displayed in Across the three CHC sites, 91% of all participants were fully screened for HTN , of whicThese results varied substantially across the three sites . All butAt Health Centers, 66% of persons returned at least once after their initial visit , but onlAmong persons who reported current use of antihypertensive medication, 93–94% were asked about adherence over the prior three days in Eastern and Western Uganda and 71% in Kenya. 78% of visits ended with the patient receiving a follow-up appointment in Eastern Uganda and 83% in Western Uganda, but only approximately half of these appointments were scheduled in under 6 weeks. Among persons who came to the health center at least twice and had a blood pressure checked on their final visit, just under half were controlled in Eastern and Western Uganda . Notably, this result constitutes only approximately 22% of persons retained in care, because blood pressure was checked in only 44% of patients’ most recent follow-up visits .Results also varied as a function of body mass index (BMI) and diabetes status, both at CHCs and HCs . PersonsThe uncertainty associated with results across the treatment cascade increased cumulatively. Our work demonstrates that it is possible to leverage HIV test-and-treat interventions for the control of HTN across low-resource rural settings in sub-Saharan Africa, but it also suggests opportunities to improve the intervention fidelity—and care outcomes—of NCD interventions that leverage HIV care delivery. Approximately 90% of the 95,000 adults who presented to SEARCH’s community health campaigns received not only an initial blood pressure check, but two more if the initial check was elevated–showing that nurses can perform and act on this test reliably. Because almost 100% of those persons were also queried regarding prior HTN history, their assessed HTN status was confirmable by globally-established standards ,39,43,45Moreover, in Eastern and Western Uganda, SEARCH demonstrates that supervised non-physician providers can provide consistent clinical care for HTN according to established algorithms, and retain patients over time, achieving treatment rates comparable to high-income countries . PatientDespite these results, SEARCH’s HTN treatment outcomes were hampered by cumulative attrition across multiple stages of the HTN care cascade, including linkage to care, treatment initiation, and blood pressure control; and its blood pressure prevalence data is not consistent with nationwide surveys in Uganda and Kenya. SEARCH fully screened 86,676 persons for HTN across the three sites 91.3%); but only 9,649 (11.1%) screened positive, including only 1,004 (4%) in Kenya–substantially lower than population-level estimates of 25% in adults in this region 1.3%; but,13, suggOur study has several limitations. We used data on HTN care performed (such as blood pressure results or reported disease history) as a proxy for the care itself. It is therefore possible that in some cases, these data were spuriously entered into SEARCH records—but the test or intervention itself overlooked or incorrectly performed. Conversely, the absence of certain data does not necessarily mean the appraisal did not occur: SEARCH still referred the majority of persons with HTN to HCs for follow-up care. This result especially impaired our interpretation of the incomplete Kenya data as above. SEARCH has since prioritized standardized protocols for collection of HTN data, such that future analyses may better identify disparities in care. The instruments and equipment used by SEARCH were sometimes imperfect: the blood pressure cuffs were calibrated but not independently validated, for example; the 3-day medication recall instrument may not reflect long-term adherence thoroughly; and patients at HCs may not have accurately remembered their HTN status when asked at the initial visit. Additionally, our treatment cascade presumes a linear, stepwise progression of participants from one phase of treatment to the next, when in fact some patients were lost from elements of the cascade but returned for others. For example, not all patients who presented to care at HC had prior appointments or HTN screens- but SEARCH HC providers treated all self-identified HTN patients regardless ; for thiLastly, the complexity (and ambiguity) of the SEARCH HTN care algorithm sometimes precluded a one-directional sequential analysis. For example, SEARCH trained HC providers not to give a HTN patient medication at their initial visit unless blood pressure exceeded 160 mm Hg systolic or 100 mm Hg diastolic . PatientOur findings suggest several means to better improve the fidelity, and outcomes, of HTN care through studies like SEARCH. For example, direct observation of providers at CHCs and HCs, and more detailed instruments to record their clinical findings, would permit more accurate evaluation of care delivery. Interviews with providers and patients could identify underlying barriers to care linkage and treatment, such as inconsistent counseling messages or delays in scheduling follow-up. In the past two years, SEARCH launched several participant-oriented reforms including faster appointments; new education materials, and appointment reminder cards; evaluation of these interventions is ongoing.More broadly, however, this analysis defines a framework to evaluate the fidelity of screening and treatment for HTN, the leading preventable risk factor for death and disability—in a resource-limited setting requiring leveraging non-physician health workers and existing health delivery programs designed for HIV. A recent systematic review , which iOur work developed a sequential “cascade” for the implementation and evaluation HTN care, derived from cascade models now aiding universal delivery of HIV treatment in multiple settings ,51. We hS1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.


Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects.We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters.1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same.606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEVWe identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status. Peripheral neuropathy (polyneuropathy) is one of the common comorbidities in COPD with a prevalence range of 5 to 100% . In two COPD and Systemic Consequences - Comorbidities Network) which incorporated clinically established diagnostic tools for peripheral neuropathy.Beyond its pure presence as a comorbidity, peripheral neuropathy might have a functional impact in COPD, as indicated by the finding that the same degree of lung function impairment was associated with lower physical performance in patients with peripheral neuropathy compared to those without . Neuropan = 1329) scheduled 3 y after inclusion, as this visit comprised the assessment of peripheral neuropathy. We only included patients with GOLD grades 1–4 with complete information on age, gender, BMI, smoking status and packyears (n = 1160), moreover with complete information regarding FEV1, FVC, RV/TLC,TLCO, mMRC and exacerbation risk (n = 1031) [n = 858), on CRP and leukocyte numbers (n = 840), on tuning fork testing, monofilament testing and neuroscore (n = 793), and on blood gas parameters saO2, CaO2, paO2, paCO2, BE and pH (n = 745). Data of three single patients were omitted based on a multivariate Mahalanobis criterion as they turned out to be completely isolated outliers (n = 742). Among these, we then excluded 115 patients with the diagnosis of diabetes mellitus in order to avoid interferences with peripheral neuropathy that could mask specific effects of COPD (n = 627) [n = 606 patients. The COSYCONET study has been approved by the ethical committees of all study centers, and all patients gave their written informed consent [COSYCONET is a multi-center COPD cohort focusing on the role of comorbidities in stable COPD and initially comprising 2741 patients . The pre = 1031) . Furtherears n = 60, moreon = 627) . For the consent .1), forced vital capacity (FVC), the ratio of residual volume to total lung capacity (RV/TLC), and the single-breath transfer factor for carbon monoxide (TLCO), each expressed as percent predicted [2, PaCO2, pH, BE and SaO2 were determined from arterialized capillary blood of the earlobe. From these parameters the oxygen content of blood was computed, using an established formula and measured haemoglobin concentrations [Study protocol and basic assessments of COSYCONET have been described in detail previously . All patredicted , 25, exctrations .1, and GOLD groups were based on exacerbation risk and symptoms according to the GOLD 2017 criteria using the mMRC [To quantify physical activity and the risk to fall, the 6-min walk distance (6-MWD) and the timed-up-and-go test (TUG) were used . Spiromethe mMRC . The ankthe mMRC , 27 and n = 74), the outcome measures had been compared with measurements of nerve conduction velocity (m/s) and amplitude (μV) of nervus suralis using the NC-stat® DPNCheck in order to validate the assessments [Peripheral neurological function was assessed via standard procedures using the Rydel-Seiffer tuning fork for the big toe basal joint (BTBJ) and end joint (EJ); the respective results were used as continuous variables. Furthermore, the monofilament testing using a 10 g filament (Tip Therm®/TwinTip), bending at a nominal force of 0.1 N, was applied at five places of the toe two times . Moreoveessments . All meaessments , 21.Median values and quartiles were computed for patients’ description. The two groups of patients with positive or negative neuroscore were compared with the Mann-Whitney-U-test for continuous variables; categorical data were compared using Chi-squared statistics. As most variables turned out to be dependent on age, BMI, packyears and gender within regression analyses, all subsequent computations were performed with variables adjusted for these four covariates. To detect relationships between COPD characteristics and the three quantitative parameters of peripheral polyneuropathy, multiple linear and logistic regression analyses were used. Correlation analyses were based on Spearman rank correlations. An exploratory factor analysis was used to verify the relationship between all three indices of polyneuropathy.In combination with pathophysiological considerations, the results of these analyses were then used to construct a structural equation model (SEM) . This isp < 0.05.For computation of the SEM, we used the generalized least squares estimation (GLE) and checked whether the results were in concordance with those obtained by the maximum likelihood or asymptotically distribution-free method; this was always true. The goodness of fit was evaluated via the comparative fit index (CFI), the root mean square error of approximation (RMSEA) and the chi-square statistics, following usual criteria , 19. All2 and 6-MWD (p < 0.05 each). Twenty-nine of 606 patients reported a doctor-based diagnosis of peripheral neuropathy but this subgroup was not separately analysed due to its small size.Baseline characteristics of patients are given in Table p < 0.001 each). The relationship between the three parameters was confirmed by factor analysis showing that all variables belonged to one component (explained variance 72.6%); this was also true after adjustment for age, BMI, packyears and gender (explained variance 71.4%); this justified that in the construction of the SEM these three variables were assigned to a latent variable.BTBJ, EJ and MF were correlated with each other (p < 0.01 each) between FEV1, FVC, RV/TLC, TLCO, 6-MWD and ABI. Furthermore, FEV1, RV/TLC and TLCO were correlated with BE, paO2 and saO2 (p < 0.001 each). 6-MWD correlated with all blood gas parameters except pH (p < 0.05), whereas ABI was only related to 6-MWD (p < 0.001) in these analyses.An analogous correlation analysis was performed to understand the relationship between functional parameters, always using values adjusted for age, BMI, packyears and gender. There were significant associations (p < 0.05 each). Conversely, BE was dependent on BTBJ, oxygen saturation and RV/TLC (p < 0.05 each); in these analyses, paCO2 and pH were omitted due to their trivial correlation with BE. 6-MWD depended on FEV1, TLCO, ABI, TUG, exacerbation risk and CRP (p < 0.01 each); FVC was omitted in this and further analyses due to its high collinearity with FEV1. The ABI was dependent on EJ and 6-MWD (p < 0.05), with a tendency towards an additional dependence on TLCO (p = 0.052). Exacerbation risk was dependent on FEV1, 6-MWD and CRP (p < 0.05 each).In the next step the relationships to the three measures of polyneuropathy, as dependent variables, were determined by stepwise linear regression analyses, again using values adjusted for age, BMI and gender. We additionally included blood gas parameters and CRP as predictors. BTBJ was linked to ABI and BE, EJ to TUG and BE, and the monofilament reading to TUG  oxygen saturation turned out to be the best correlated and most informative parameter, thus the other parameters were omitted.The three measures of polyneuropathy were implemented as indicators of a latent variable called PNP. Lung function parameters were kept separately as they showed markedly different relationships to the other parameters, in accordance with physiological expectations. To account for their mutual correlations, these were explicitly included into the model (indicated by double-headed arrows). Regarding their effects on other parameters, RV/TLC had an effect on BE, FEVp = 0.287). When the directions of single arrows were inverted, in all cases the reversion resulted in a reduction or loss of statistical significance, thereby underlining the validity of the model.The final model fitted with an CFI of 0.991, an RMSEA of 0.013 , and chi-square value of 63.553, with 58 degrees of freedom (n = 742), virtually the same results were obtained, and all dependences within the structural equation model were still significant. This model fitted with a CFI of 0.980, an RMSEA of 0.019 , and chi-square value of 73.867, with 58 degrees of freedom (p = 0.078). Conversely, when 13 of 606 patients who had reported a history of alcohol abuse were omitted, all links were still significant, especially that from BE to PNP (p = 0.024), while the link from ABI to PNP was at the border of significance (p = 0.072). We performed two different sensitivity analyses to account for possible associations between metabolic changes linked to renal impairment especially with PNP and BE. First, we additionally introduced kidney function in terms of glomerular filtration rate (GFR) as computed according to Levey et al. [p = 0.015 and 0.004, respectively), and a satisfying overall fit . International guidelines define chronic kidney disease as (a) GFR < 60 ml/min per 1.73 m2 or (b) markers of kidney damage, or both, of at least 3 months duration [n = 529 patients. All dependences within the structural equation model remained significant. This model fitted with a CFI of 0.991, an RMSEA of 0.013 , and chi-square value of 63.042, with 57 degrees of freedom (p = 0.303). Especially the link from BE to PNP remained significant (p = 0.026), again confirming the robustness of the SEM.The results described above were obtained for patients without the diagnosis of diabetes and/or elevated (> 6.5%) values of HbA1c. When the complete analysis was repeated including patients with diabetes and/or elevated HbA1c  from the initial COSYCONET visits using direct measurement of nerve conduction velocity [The validity of the measurements regarding peripheral neuropathy had been checked in a subset of patients (velocity ; indeed,Naturally, the present cross-sectional analysis does not allow to infer causal relationships, although the directionality of the SEM may be suggestive of causal associations. The tuning fork and monofilament tests are well established in clinical practice but may not be the most sensitive measures, especially compared to nerve conduction velocity. Overall, the alterations identified by us were largely subclinical and the associations were weak as indicated by the standardized regression coefficients. Despite this, the robustness of the findings when including diabetes patients, as well as their consistency with known data from patients with and without COPD, suggests that these associations were valid. It is unlikely, that interference with neuropathy-inducing medication was relevant in our study population, especially when considering the relatively low frequency of potentially problematic medications in COSYCONET . MoreoveUsing data from the COSYCONET cohort, we analysed peripheral neuropathy in stable COPD patients without diabetes, with the aim to identify those COPD characteristics that were the primary determinants of neuropathy. It turned out that base excess and ankle-brachial index, which are often found to be impaired in COPD patients, were the most relevant factors related to peripheral neuropathy. Other associations, especially those with lung function, oxygen saturation and exercise capacity were only indirect and mediated by these determinants. Circulatory disorders and the long-term metabolic compensation of respiratory acidosis could therefore contribute to the occurrence of polyneuropathy in COPD. These findings underline the role of the internal environment, including the microenvironment of peripheral nerves, for the development of comorbidities in COPD. A potential clinical conclusion could be that patients with marked abnormalities in base excess and vascular function should be screened for peripheral neuropathy.


Strategies to improve hypertension control are clearly warranted in light of the frequently expressed view that only 50% of treated hypertensive patients are able to meet their target blood pressure levels.While data from the USA has shown improved control over recent years , a study1In primary-care, public-sector facilities in South Africa, special efforts to improve hypertension management have shown that 68% of patients treated for their hypertension can achieve their targeted blood pressure levels.Reducing the cardiovascular and renal consequences of hypertension is dependent on sustained, long-term blood pressure control, implying that patient compliance is also a key factor for success. The physician’s choice of effective therapy will take this aspect fully into account and he/she will adopt approaches that will sustain patient compliance.Modern therapeutic agents that block the renin–angiotensin–aldosterone system (RAAS) and protect target organs without causing compliance-reducing symptoms should be the first choice in at-risk patients with hypertension.Once-a-day dosagePatients typically prefer to take their medication in the morning as part of their everyday routine. Compliance is improved by once-daily medication and physicians are keen to ensure that the prescribed antihypertensive medication meets the criteria of full 24-hour control and provides cover for the early morning rise in blood pressure. This rise in blood pressure is due to both orthostatic changes and the circadian rhythm of the RAAS system. It is also linked to an increased risk of cardiovascular events during the early morning hours.3Accurate assessment of blood pressure control is determined by self-measurement of blood pressure or by automated ambulatory 24-hour measuring devices. The MICARDIS Community Access Trial of Telmisartan in the primary-care setting (MICCAT-2)4 study showed that telmisartan alone or in combination with HCTZ produced significant reductions in blood pressure, which extended into both day and night time. Telmisartan reduced systolic and diastolic blood pressure (SBP/DBP) by 17.2/10.ARB efficacy versus ACE inhibitorsARBs are a good choice for hypertensive patients with the metabolic syndrome (associated obesity) and there are compelling indications for their use in postmyocardial infarction, left ventricular hypertrophy, chronic kidney disease, type 2 diabetes with microalbuminuria or albuminuria for ACE-intolerant patients and for the secondary prevention of stroke.Telmisartan provided more effective blood pressure lowering in this study and was particularly more efficient in the last six hours of the 24-hour dosing interval. Similar results were obtained by PRISM-2, which was conducted in the USA and Canada. A pooled analysis of both trials also showed a greater blood pressure lowering with telmisartan (–14.1/–9.6 vs –11.1/–7.2 mmHg).Telmisartan is the only ARB that has demonstrated therapeutic equivalence to the ACE inhibitor ramipril in hypertensive patients at increased vascular risk. The patient population in this study (ONTARGET) is of particular interest as it is representative of the majority of hypertensive patients seen in everyday clinical practice.The findings from this study showed that telmisartan 80 mg per day was as efficacious as the proven dosage of ramipril (10 mg/day) in reducing risk of cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure in a broad cross section of highrisk cardiovascular patients. It achieved these results with far fewer side effects, resulting in significantly fewer patients discontinuing therapy.Choosing telmisartan over other ARBs: the evidencePharmacological evidence of telmisartan’s efficacy in terms of blocking the angiotensin II type 1 receptor is accumulating. A recent Japanese study of constructed models of ARB molecules has found that the delta lock structure of telmisartan offers a superior fit to the receptor, compared to the other ARBs.10bChoosing the combination of telmisartan + HCTZBlood pressure control in some patients is ineffective with just monotherapy, and combinations of antihypertensive agents offer an opportunity to intensify treatment without adding to the pill load.In African patients where there may be evidence of less involvement of the RAAS system, the initial choice in the public sector is often a diuretic. A recent study in KwaZulu-Natal looked at prescribing habits in 54 public-sector hospitals in this region and compared this to supply data and to the SA Hypertension Guidelines.11It found that the most commonly used agents were diuretics (42%) and ACE inhibitors (27%) and that these prescriptions correlated well with supply data for these frequently used medications. Calcium channel blockers and beta-blocker usage was 6% each.Clearly, as ARBs become more available in the public sector, the opportunities offered by the combination of telmisartan and HCTZ should receive wider use. Publicity given to the lack of dialysis facilities for kidney failure in the public sector in South Africa should also add to the imperative to improve hypertension control.The blood pressure of patients who are at particular risk of cardiovascular disease, such as those who are obese or have type 2 diabetes, are often difficult to control. The SMOOTH study (Study of Micardis on Obese/Overweight Type 2 diabetes patients with HypErtension) showed the superior effect of telmisartan 80 mg plus HCTZ 12.5 mg, compared to valsartan 160 mg plus HCTZ 12.5 mg over 24 hours and especially in the early morning period.12The elderly patient also frequently falls into a difficult-to-treat category. A study in this patient group recruited 1 000 patients over the age of 60 years with isolated systolic hypertension and compared control between telmisartan plus HCTZ and amlodipine plus HCTZ. Referred to as the ACTOS study,A recent evaluation of more than 48 000 patients taking either a diuretic of a fixed-combination antihypertensive with a diuretic showed greatly improved compliance with the fixed combination . The fixed combination of the ARB/HCTZ achieved improved persistence and adherence to therapy even over the ACEI/HTCZ.The wider use of telmisartan in moderate hypertension as an early therapy can be substantiated at both a pharmacological and clinical level.


Each group took four test tablets (43 μg LRA/day) or four placebo tablets daily. The decrease in blood pressure in the test group compared with the placebo group was the primary outcome. Adverse events were recorded and hematological/urinary parameters measured to determine the safety of the supplement, which was the secondary outcome. In total, 87 participants completed the study. The SBP of the test group at 12 weeks was significantly lower than that of the placebo group (p = 0.0497). No serious adverse events were observed. Daily consumption of a rice bran supplement containing PRB can safely improve mildly elevated blood pressure.The anti-hypertensive effect of processed rice bran (PRB) was recently reported, for which the novel peptide Leu-Arg-Ala (LRA) was identified as the functional substance. The purpose of this study was to assess the anti-hypertensive effects of a rice bran supplement containing PRB in individuals with high-normal blood pressure (systolic blood pressure (SBP): 130–139 mmHg and/or diastolic blood pressure (DBP): 85–89 mmHg) or grade 1 hypertension (SBP: 140–159 mmHg and/or DBP: 90–99 mmHg). One hundred individuals with high-normal blood pressure or grade 1 hypertension were recruited to participate in this double-blind, randomized, placebo-controlled study. Participants were randomly allocated to the placebo group ( Approximately one billion people worldwide suffer from hypertension, which is thought to be the main modifiable risk factor for cardiovascular disease ,2. HyperOryza sativa) is one of the three major food grains consumed worldwide, and is a staple food for about half of the world’s population [Rice ; those with a history of cardiovascular disease; those with diabetes; those with an allergy to brown rice, rice bran, or rice; those who had experienced adverse reactions to having blood drawn in the past; those who were excessive drinkers  or heavy smokers (average 21 cigarettes/day or more); those on an extremely irregular diet (due to shift work or for other reasons); those on medications that may have affected this trial, such as anti-hypertensive drugs; those who regularly consumed specific supplements or foods with functional claims that may have affected this trial and who did not consent to refrain from consuming them for 1 week before preliminary test 2; those with secondary hypertension; those with a history of major gastrointestinal surgery such as stomach resection, gastrointestinal anastomosis, gastrointestinal surgery, or intestinal resection (excluding appendix resection); and those judged inappropriate for participation in the study based on the participant’s background, physical examination, and interview by the principal investigator. These exclusion criteria are based on previous clinical studies and the criteria of the NIPPON DATA 80 study [Hokkaido residents were recruited to participate in this study through a website from 8 June 2017 to 14 July 2017. Those who wished to participate in this trial were invited to Fukuhara Hospital , where the details of the study and potential risks were thoroughly explained and written informed consent obtained. Inclusion criteria were age 45–64 years, high-normal blood pressure (SBP 130–139 mmHg and/or DBP 85–89 mmHg) or grade 1 hypertension (SBP 140–159 mmHg and/or DBP 90–99 mmHg) during the pre-observation period (at both 6 and 2 weeks prior to administration of the test supplement or placebo), and a body mass index (BMI) of less than 30.0 kg/m80 study ,19,20.Participants were randomly assigned to two groups by the block randomization method, stratified by age and sex and subsequently stratified by condition (SBP or DBP). The randomization was performed by an allocation coordinator independent from the investigators, and the randomization code was kept in a sealed envelope to maintain blinding. Thus the investigators, participants, and other study personnel were blinded to the treatment assignments for the duration of the study.The trial was conducted in Hokkaido, Japan between 26 July and 9 December 2017. All study products (the test food and the placebo) were prepared as tablets that were identical in terms of appearance and flavor. The nutrient composition of the test products is described in The primary outcomes of the study were SBP and DBP each week from the date on which the first dose of tablets was consumed. Safety, a secondary outcome, was evaluated by the number of adverse events, adverse event occurrence rate, number of side effects, and side effect occurrence rate.Blood pressure, pulse rate, and body temperature—Blood pressure, pulse rate, and body temperature were measured seven times in total: at 6 and 2 weeks before starting to take the tablets, on the day the participants started taking the tablets, and at 4, 8, 10, and 12 weeks after starting to take the tablets. Blood pressure was measured using an automatic sphygmomanometer  based on the method described in the Japanese Society of Hypertension guidelines for the management of hypertension [Weight and height—Body weight was measured a total of six times: at 6 weeks before starting to take the tablets, on the day that participants began taking the tablets, and at 4, 8, 10, and 12 weeks after starting to take the tablets. Body height was measured once—at 6 weeks before starting to take the tablets—and the measured value was used to calculate the BMI.Laboratory tests—Laboratory tests were carried out five times in total: at 6 weeks before starting to take the tablets, on the day the participants started to take the tablets, and at 4, 8, and 12 weeks after starting to take the tablets. Blood (10 mL) and urine (7 mL) were collected.For blood tests, white blood cell count, erythrocyte count, hemoglobin, hematocrit, platelet count, total protein, albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase isozymes, γ-glutamyltransferase, creatine kinase isoenzyme, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting blood glucose, hemoglobin A1c , uric acid, urea nitrogen, creatinine, sodium, chloride, potassium, and calcium were measured. Urinalysis was performed to determine specific gravity, pH, ketone bodies, occult blood reaction, urobilinogen , bilirubin , sugar , protein , sodium, creatinine, potassium, estimated daily urinary sodium excretion, and estimated daily urinary potassium excretion. Gram creatinine correction was performed for the estimated daily urinary sodium excretion and estimated daily urinary potassium excretion. These parameters were measured by an auto-analyzer .Sample size was calculated based on the results from a previous study (a test performed to determine the optimum concentration) in which administration of 43 μg of LRA derived from 1 g of PRB significantly reduced blood pressure compared with the placebo group (unpublished data).The parameters analyzed in this study are presented as means and standard deviation (SD). The efficacy analysis was based on the per-protocol set. The safety analysis was based on a modified intention-to-treat principle .t-test was performed, while in the case of unequal variance an Aspin–Welch t-test was performed. For the semi-quantitative values derived from the urinalysis, a Mann–Whitney test was performed. For all two-sided tests, the significance level was set at 5% or 1%.To compare the numerical data for the placebo group and the test group at each time point, an F-test of equality of variances was performed. In the case of equal variance Student’s For the efficacy analysis, a repeated-measures analysis of variance was also performed to compare the blood pressure at week 0 with the blood pressure at weeks 4, 8, 10, and 12 in each group. If a significant difference was found, the average values were compared by Dunnett’s method.For the safety assessment, Fisher’s exact test was performed to detect differences between groups in terms of the number of side effects and number of adverse events. For the laboratory test data and physical findings, a repeated-measures analysis of variance was performed. If a significant difference was found, the average values were compared by Dunnett’s method. A Wilcoxon signed-rank test was performed for the semi-quantitative values obtained from the urinalysis.A subgroup analysis was planned by dividing the subjects into two groups  according to the blood pressure values recorded when the participants started taking the tablets.In total, 250 participants were recruited and screened. One hundred participants were enrolled and randomly allocated to the test or placebo group . Four pan = 43) and placebo (n = 43) groups are shown in p = 0.0497). There was no difference in effectiveness between male and female participants. In contrast, the mean DBP did not differ significantly from that of the placebo group at any subsequent time point.The mean SBP values at each time point in all subjects with high-normal blood pressure and grade 1 hypertension in the test (p = 0.0014) and week 12 (p = 0.0397) compared with the placebo group, while the DBP did not differ significantly from that of the placebo group. In the grade 1 hypertension subgroup, no significant difference was observed  compared with baseline. Twelve-week interventions with treatments such as angiotensin II type 1 receptor blockers and DASH (Dietary Approaches to Stop Hypertension) diets reduced SBP by 5–10 mmHg in patients with grade 1 hypertension [In the present study, it was demonstrated that taking an anti-hypertensive food product for 12 weeks reduced SBP. Hypertension is one of the important risk factors for cardiovascular disease. It is well established that medical therapies for hypertension can reduce the rate of death from cardiovascular disease, myocardial infarction, and stroke ,22. Thusrtension ,26. The Previous clinical studies have shown that rice bran reduces SBP when combined with other interventions such as energy restriction or the administration of sesame oil ,28. This50 value was reported to be 0.1 μM, the most potent value for all known grain-derived anti-hypertensive materials [The activity of most anti-hypertensive food-derived peptides is based on angiotensin I-converting enzyme (ACE) inhibition ,30,31. Saterials . Chlorogaterials ,33. Physaterials . Taken tIn this study, a difference in effectiveness between male and female participants was not observed, whereas some studies have shown estrogen to activate the NO system and play a key role in such a difference . LRA is Our stratified analysis showed that test food reduced SBP in subjects with high-normal blood pressure A. SeveraAs shown in The strengths of this study are three-fold. First, this is the first report showing that a rice bran supplement alone can reduce blood pressure without being combined with another intervention. The dietary intervention in this study appears to be feasible for clinical practice, especially in Asian countries where rice is a staple food. It was also shown that the anti-hypertensive effect of the rice bran supplement was independent of any reduction in body weight, decrease in blood lipid level, or change in glucose metabolism. Second, the SBP was effectively reduced in human subjects with high-normal blood pressure and grade 1 hypertension in a trial with a relatively small but sufficient sample size. Third, the safety of the rice bran supplement was demonstrated, as it was associated with a low prevalence of adverse events. However, this study also has some limitations. The intervention period lasted only 12 weeks, and only one dose of the rice bran supplement was tested. In addition, the mechanism underlying the anti-hypertensive effect observed was not investigated. It is also possible that the test food contained one or more functional substances other than LRA. Finally, only individuals with high-normal blood pressure and grade 1 hypertension, without other serious disease such as diabetes, were assessed in this trial; the effectiveness of this intervention should also be tested in patients with grade 2 and 3 hypertension, other diseases, or individuals with a smoking habit.To sum up, a 12-week intervention involving LRA derived from PRB effectively reduced the SBP in individuals with grade 1 hypertension and high-normal blood pressure. Stratified subgroup analysis showed that this anti-hypertensive effect was statistically significant in the subgroup with high-normal blood pressure.In conclusion, it has been shown for the first time that 12-week administration of a rice bran supplement containing the functional peptide LRA significantly reduced the SBP in patients with grade 1 hypertension and high-normal blood pressure in comparison with a placebo group in a double-blind, randomized, placebo-controlled study. Stratified analysis showed that the rice bran supplement had a potent anti-hypertensive effect on subjects with high-normal blood pressure, indicating that the rice bran supplement could be useful for preventing the progression of patients with pre-hypertension to grade 1 hypertension.


Robot-assisted laparoscopic radical prostatectomy (RLRP) can increase intracranial pressure (ICP) related to a change in position. Increasing ICP may result in various ocular complications, which are rare but serious, such as a corneal abrasion and ischemic optic neuropathy. We performed a prospective observational trial using ultrasonographic measurements to compare optic nerve sheath diameter (ONSD) related to ICP between patients who received either propofol or sevoflurane and underwent RLRP. n = 16; group S: sevoflurane, n = 16). ONSD, end-tidal partial pressure of CO2, and blood pressure were measured 10 min after induction of anesthesia (T0), 30 min (T1), 60 min (T2), and 90 min after changing to the steep Trendelenburg position and introducing a pneumoperitoneum (T3) and 10 min after returning the patient's position to supine (T4) during surgery.  Thirty-two male patients scheduled to undergo RLRP were assigned into groups according to the anesthetic agent used , respectively. The mean left ONSDs were 38.4 and 40.8 mm at 30 min (p=0.021) after changing to the Trendelenburg position. The ONSDs between the two groups were significantly different during surgery.  No significant differences were observed in the demographic data of the patients, surgery time, or intraoperative variables, including hemodynamic and respiratory variables, at any of the time points. The mean right ONSDs in the propofol and sevoflurane groups were 37.3 and 40.1 mm at 30 min ( ONSD increased more in the sevoflurane group than in the propofol group during RLRP. Intravenous anesthetics could alleviate the increase in ICP during RLRP. Prostate cancer is the second most common cancer in men worldwide. Robot-assisted laparoscopic radical prostatectomy (RLRP) has become a very popular treatment because it has better outcomes, less blood loss, and decreased recovery time compared to other options . HoweverMeasuring optic nerve sheath diameter (ONSD) by ultrasonography is a very useful method for evaluating intracranial pressure (ICP); it is strongly correlated with invasive ICP measurements estimated using intraventricular and intraparenchymal devices .All inhaled anesthetics have a direct, dose-dependent vasodilator effect on the cerebral vessels that increases cerebral blood volume and blood flow . SevofluIn the present study, we hypothesized that ONSD in the sevoflurane group would increase more than that in the propofol group.http://cris.nih.go.kr, 9/11/2018, KCT 0003332). After obtaining written informed consent, we enrolled 32 male patients between 19 and 79 years of age with an American Society of Anesthesiologists (ASA) physical status of I–III who were undergoing RLRP. Patients with a previous neurological disease or cerebrovascular disease that could increase ICP or patients with a history of ophthalmological disease or surgery were excluded.This study had a prospective, randomized, double-blind design and was approved by the Institutional Review Board of the National Cancer Center (NCC2017-0065). It is registered with the Korean Clinical Trials Registry  between 35 and 40 mmHg. The random assignments were generated by using a computer with block sizes of 2 and 4 with a 1 : 1 assignment using the random block size permutation method. Patients were randomized into two groups: group S or group P. In group S, anesthesia was maintained with 1-2 vol% sevoflurane and an infusion of remifentanil. In group P, anesthesia was maintained with propofol and an infusion of remifentanil. The end-tidal concentration of sevoflurane or propofol was adjusted to maintain a bispectral index score of 40–60, and the targeted effect-site concentration of remifentanil was adjusted to 1.0–3.0 ng/mL using a target-controlled infusion (TCI) device.After preoxygenation, anesthesia was induced with remifentanil and propofol followed by rocuronium (0.6 mg/kg) to facilitate tracheal intubation. After endotracheal intubation, the patients were mechanically ventilated with a 50% oxygen-air mixture, using a tidal volume of 8 mL/kg ideal body weight at a respiratory rate of 10–14/min to maintain end-tidal COThe vaporizer and TCI pump were concealed from the anesthesiologist by using a screen. The blinded anesthesiologist measured ONSD, evaluated as described previously . Briefly2, blood pressure, and heart rate (HR) were measured at each time point. We also measured surgery time and the volume of infused fluid. In pilot study, the mean standard deviation of ONSD was 38.83 ± 2.23 mm in the sevoflurane group and 36.17 ± 3.31 mm in the propofol group. The difference was about 3 mm in the pilot study. However, the difference of about 10% was considered clinically significant. We assumed that the mean difference was 4.0 mm for the primary endpoint of ONSD at 30 min after changing to the Trendelenburg position with a standard deviation in both groups of 2.8. We calculated that 14 patients in each group would achieve 95% power to reject the null hypothesis of equal means with a significance level of 0.05 using a two-sided two-sample equal-variance t-test. We recruited 16 patients per group, considering a dropout rate of 10%. The primary outcome in this study was the group difference in ONSD at 30 min after the head-down position. The secondary outcomes included were as follows: the group difference in ONSD at 10 min after induction of anesthesia, 60 min and 90 min after head-down position, and 10 min after supine position; end-tidal carbon dioxide pressure; blood pressure at 10 min after induction of anesthesia, 30 min, 60 min, 90 min after head-down position, 10 min after supine position and; infused intravenous fluid at the end of surgery.ETCOt-test was used to evaluate the difference between the propofol and sevoflurane group in regard to changes in ONSD, systolic blood pressure, diastolic blood pressure, mean blood pressure, HR, and ETCO2. The difference between the time points in each group was tested with the paired t-test, and the differences between the two groups over time were compared based on a mixed-effect model. All statistical analyses were performed using SAS version 9.4 .The independent Thirty-two patients scheduled for RLRP were included and evaluated. The patients' characteristics are shown in p=0.638) at T0, 37.3 and 40.1 mm (p=0.003) at T1, 36.7 and 38.8 mm (p=0.036) at T2, 36.3 and 38.9 mm (p=0.011) at T3, and 35.1 and 38.1 mm (p=0.008) at T4, respectively. The mean left ONSDs were 37.3 and 37.2 mm (p=0.950) at T0, 38.4 and 40.8 mm (p=0.021) at T1, 37.4 and 40.2 mm (p=0.019) at T2, 36.8 and 39.7 mm (p=0.017) at T3, and 35.9 and 39.1 mm (p=0.003) at T4 (p < 0.01). ONSDs of the propofol group were significantly increased only in the left from 37.3 (T0) mm to 38.4 mm (T1) (p=0.042).ONSD was measured at 10 min after induction of anesthesia (T0), 30 min (T1), 60 min (T2), and 90 min (T3) after changing to the Trendelenburg position and introducing a pneumoperitoneum, and 10 min after the position changes to supine (T4) in 3) at T4  The ONSD3) at T4 . ONSD inWe investigated changes in ONSD according to the anesthetic agent. We observed significant differences between the sevoflurane and propofol groups. Whitely et al.  reportedMeasuring ONSD is a noninvasive method that correlates significantly with changes in ICP . ONSD vaA prolonged steep Trendelenburg position and increasing intra-abdominal pressure can result in increased cerebral venous pressure, ICP, and cerebral blood flow. Weber et al.  reportedICP can be affected by carbon dioxide, blood pressure, infused fluid, and operation time . In our Many studies have demonstrated that sevoflurane has a dose-dependent cerebral vasodilatory effect and that propofol either decreases or does not affect ICP. In our study, ONSD did not increase in the propofol group. We hypothesized that the use of propofol would not affect ICP in patients at risk for elevated ICP, such as those in the steep Trendelenburg position, and would not increase ONSD. We confirmed this in our study.2 at baseline, which may have affected ICP. However, because EtCO2 has a strong relationship with PaCO2, we maintained EtCO2 partial pressure at 35–40 mmHg over the whole period and adjusted ventilator settings in both groups. No significant difference in EtCO2 was detected between the two groups.Some limitations of this study should be mentioned. We only measured PaCOIn conclusion, ONSD during RLRP increased in the sevoflurane group but not in the propofol group. Intravenous anesthetics could alleviate the increase in ICP during RLRP. We recommend using intravenous anesthetics when performing this surgery in a position that could cause an elevation in ICP, such as the prolonged steep Trendelenburg position and when placing an artificial pneumoperitoneum, because sevoflurane has a cerebral vasodilatory effect although a sufficient compensatory mechanism may weaken the intracranial effects.


Endotracheal tube cuff (ETTc) inflation pressure is usually not regarded as an important aspect during intubation. In this study, we compared measuring ETTc pressure and pilot balloon palpation method in causing post-operative airway complications.2O. Group B patients had their ETTc inflated using the pilot balloon palpation method. Patients were then followed up for post-operative sore throat, hoarseness and cough.Two hundred and ninety-two surgical patients requiring intubation were recruited into this prospective, double-blind, randomised controlled study. Group A patients had their ETTc initially inflated, checked by a cuff pressure gauge, recorded and then set to 25 cmHP < 0.001), hoarseness 6.2% versus 15.1% (P < 0.05) and cough 7.5% versus 21.9% (P < 0.05) in Group A and B, respectively. Group A patients experienced a significant reduction in the incidence and severity of sore throat up to 24 h post-operatively (P < 0.001), hoarseness at the first hour (P = 0.004) and cough at first and 12 h post-operatively (P = 0.002).The overall incidence of post-operative sore throat was 39.0% versus 75.3% (2O reduces post-operative sore throat, hoarseness and cough compared to pilot balloon palpation method.Adjusting the ETTc pressure to 25 cmH Post-operative sore throat (POST) and hoarseness of voice are complications of general anaesthesia requiring tracheal intubation, with reported incidences of sore throat varying from 11% to 48% and hoarseness from 18% to 53% . The mec2O, the blood flow to the tracheal mucosa began to decrease, and when the pressure approached 50 cmH2O, ischaemic injury to the tracheal mucosa occurred. Therefore, many studies on post-intubation airway complications have recommended that ETTc pressure be kept between 20 cmH2O and 30 cmH2O  affects blood supply to the tracheal mucosa, which may result in tracheal mucosal ischemia, ulceration, necrosis or tracheoesophageal fistula . An endo30 cmH2O –9.For brief procedures lasting only a few hours, most clinicians give little attention to the inflation pressure of the ETTc and simply determine the pressure by pilot balloon palpation according to their experience , 9. StudThe aim of this study was to compare the incidence and severity of post-operative sore throat in patients when endotracheal cuff pressure was measured and adjusted versus when the conventional pilot balloon palpation technique was used.Two hundred and ninety-two patients aged 18 years and above with American Society of Anesthesiologists (ASA) physical status I, II or III who were scheduled for elective surgery in the supine position under general anaesthesia requiring oral endotracheal intubation were included in the study. Patients with anticipated difficult intubation, high risk for aspiration, and those undergoing oral and laryngopharyngeal surgery or requiring nasogastric tube or throat pack insertion were excluded.The patients were randomly assigned into two groups [Group A (measured ETTc pressure) and Group B ] by the study coordinator using a computer-generated randomised sequence at the operating theatre on the morning of the surgery. The coordinator and the attending anaesthesiologists were not blinded to the group allocation, whereas the patients and the outcome assessors were blinded.® Video Laryngoscope  with an appropriately sized Macintosh blade.The patients were induced with IV fentanyl 1 mcg/kg–2 mcg/kg, IV propofol 2 mg/kg–2.5 mg/kg and IV rocuronium 0.9 mg/kg and were intubated. The male patients were intubated with an endotracheal tube (ETT)  of 7.5 mm or 8.0 mm in internal diameter, whereas the female patients received a 7.0 mm or 7.5 mm internal diameter ETT. Prior to intubation, all ETTs and stylets were lubricated with lidocaine hydrochloride jelly USP, 2% and all the ETTcs were connected to a three-way stopper to prevent air leakage during measurement. All intubations were performed by an anaesthesiologist or a senior registrar using a C-MAC2O. In Group B, the ETTc was inflated by the attending anaesthesiologist with a syringe according to his or her own personal experience using the pilot balloon palpation method. Cuff pressure was not measured in this group. Any patients requiring more than a single attempt for intubation were removed from the study.In Group A, the ETTc was initially inflated by the attending anaesthesiologist using a syringe, and this was followed by a check of the cuff pressure using a cuff pressure gauge  after securing the endotracheal tube. The initial cuff pressure measured was noted and concealed before setting it to the desired pressure of 25 cmHAnaesthesia was maintained with sevoflurane or desflurane (MAC 0.9–1.0) using only oxygen/air  with a flow rate of 2 L/min. Standard monitoring procedures were followed, with a standard three-lead ECG, non-invasive arterial blood pressure, pulse oximetry and capnography. Intraoperative analgesia and post-operative nausea or vomiting prophylaxis were given at the discretion of the attending anaesthesiologist.At the end of the surgery, the posterior pharyngeal wall was gently suctioned. Reversal of the neuromuscular blockade was guided by a nerve stimulator using a train-of-four count. The head end of the operating table was raised to 45° and the ETTc was deflated. The volatile agent was switched off and 100% oxygen was administered. No further stimulation was allowed in order to achieve smooth extubation. The ETT was removed when the patient was fully awake and displaying adequate recovery of neuromuscular function and spontaneous respiration. The times of tracheal intubation and extubation were recorded in both groups, and the range between them was used to define the duration of anaesthesia in the patients.A medical officer (who was blinded to the study) was assigned to follow up the patients on endotracheal intubation related complications  at 1 h, 12 h, 24 h and 48 h post-extubation, and the assessment was carried out by interviewing the patients. Sore throat was described as present if patients described pain, scratchiness or irritation of the throat, which was further graded using the visual analogue scale (VAS) from 0–10. The severity of the sore throat was regarded as mild (VAS score 1–3), moderate (VAS score 4–7) or severe (VAS 8–10). Hoarseness was described as an abnormal change in voice, such as the voice being breathy, raspy, strained or altered in volume or pitch. Coughs were described as either dry or productive.The sample size was calculated using the Power and Sample size calculation software version 3.1.2 and was estimated based on information gathered from Jain and Tripathi . The powP-value of less than 0.05 was considered statistically significant.The data was analysed using the SPSS  software version 23.0. The Chi-square test was used when appropriate to calculate any significant differences across categorical variables , and an independent t-test was used to determine any significant differences across continuous variables . Data with a non-normal distribution were presented as medians. A A total of 292 patients were recruited into this study, with 146 patients in each group. The demographic and intra-operative data of the patients were comparable between the two groups .P = 0.000), hoarseness 6.2% versus 15.1% (P = 0.014) and cough 7.5% versus 21.9% (P = 0.001) in Groups A and B, respectively. The incidence of sore throat with pain score, hoarseness and cough at the time intervals of 1 h, 12 h, 24 h and 48 h are shown in P < 0.001). The incidence of hoarseness was significantly different between the two groups only at the first hour (P = 0.004) with a marked reduction in Group A but it was not statistically significant beyond the first hour. On the other hand, the incidence of cough in Group A was significantly less up to the first 12 h postoperatively , but there were no differences beyond that. All of the patients in both groups experienced only mild to moderate post-operative sore throat, which subsided after 24 h, as shown in P < 0.001.This study showed that the overall incidence of POST was 39.0% versus 75.3%  had a pressure reading of above 30 cmH2O before adjustments were made to 25 cmH2O. The highest recorded pressure was 60 cmH2O and there was only one instance in which the ETT cuff was underinflated (to 18 cmH2O).In the group in which ETTc pressure was checked and measured after the initial inflation (Group A), it was found that only 82 (56.3%) patients had a cuff pressure within the recommended range of between 20 cmHIn general, POST, cough and hoarseness are common airway complications after intubation. This may be attributed to airway management, female patients, younger patients, surgery for gynaecological procedures and intra-operative use of succinylcholine , 6. Higg2O, the blood flow in the tracheal mucosa began to reduce, and when the pressure in the cuff approached 50 cmH2O for 15 min, ischaemic injury to the tracheal mucosa occurred. They concluded that impaired tracheal mucosal blood flow was an important factor in the tracheal morbidity associated with tracheal intubation and recommended that a cuff inflation pressure of 30 cmH2O should not be exceeded. Similarly, in an animal study, Nseir et al. reported that excessive inflation of the ETTc to 50 cmH2O for 30 min every 3 h over 48 h in 12 piglets produced high pressure on the tracheal wall, thus affecting the blood perfusion of the tracheal mucosa and resulting in deep mucous ulceration, squamous metaplasia and intense mucosal inflammation (Seegobin and van Hasselt  measuredammation .2O–34 cmH2O), compared to 44% in the control group, in which the palpation method was used. Their findings were consistent with the findings of this study, in which there was a significant reduction in POST in the group for which the ETTc pressure was adjusted to 25 cmH2O. Kaki and Almarakbi found that ETTc inflation guided by pressure volume loop closure resulted in lower ETTc pressure, requiring only 18 cmH2O–19 cmH2O, in contrast with the ‘just to seal’ technique, requiring 32 cmH2O–35 cmH2O, hence a lower incidence of POST with the use of volume loop closure (24% versus 38%). This demonstrates that having an objective assessment of the ETTc pressure can significantly reduce the incidence of airway complications  was only checked, adjusted and set at 25 cmH2O reduces POST, hoarseness and cough compared to the conventional pilot balloon palpation method.Measuring the ETT cuff pressure and adjusting it to 25 cmH


Metabolomics, the latest of the “omics” sciences, has a non-selective approach and can thus lead to the identification of all the metabolites (molecules < 1 kDa) in a biological system. The metabolomic profile can be considered the most predictive phenotype capable of evaluating epigenetic modifications determined by external factors. It is so close to the phenotype as to be considered the phenotype itself in its unique individuality (fingerprinting), both in health (phenome), and disease (diseasome). Urine, compared to other biological liquids, has the advantage of being a complex fluid with many components, including intermediate metabolites. Metabolomics may thus play a role in the study of different kidney diseases and overcome diagnostic difficulties. We shall present the studies that to our knowledge have been published on Nephrology and Pediatric Nephrology. Some are experimental while others are clinical. We have not considered carcinomas and transplantations. Although scarce, the data on adults and the very few ones in pediatrics are quite interesting. Further studies on kidneys are needed to determine the practical clinical impact of metabolomics in kidney renal pathologies. The “multiplatform” “omic” study of urine and namely metabolomics can contribute to improving early diagnosis and the outcome of kidney diseases. The advent of the “omics” sciences  has revolutionized the approach to the study of biology and pathology. Today, the trend is towards “multiplatform” studies corresponding to one or all of these holistic approaches, which are both extremely innovative and promising.The genetic code can be understood as a hereditary predisposition to respond in a given way to a disease, a drug or environmental changes, or develop a given pathology (what may occur). It does not, however, allow evaluation of the changes in the organism as the result of factors outside it, for example diet, drugs or the environment.The study of the genetic expression is transcriptomics, which describes the whole of the mRNA present in a cell or tissue over time. Proteomics is the study of the translation of the proteins, while the proteome is the complete set of proteins expressed in a cell or tissue at every single instant. Integration of the information provided by these sciences contributes substantially to our understanding of the molecular processes involved in the physiological mechanisms in the state of health and their destruction connected with a disease. Expression of the protein and the mRNA can be evaluated only after hours, days or weeks from the time of their production.Metabolomics is the latest of the “omics” sciences, defined in different ways ,2,3, butMetabolomics has a non-selective approach and can thus lead to the identification of all the metabolites (molecules < 1 kDa) in a biological system . Thus, mUnlike the other “omics” sciences, such as genomics and proteomics, metabolomics is a dynamic study that reflects the phenotype of an organism at a specific time. Metabolomics completes the information provided by the first investigative levels: since metabolism is regulated by signaling molecules and enzymes, the gene expression adapts first, then it changes the metabolic processes and finally the concentrations of metabolites. Such modifications are context-dependent, varying on the basis of the development and the physiological or pathological state of a cell, a tissue or an organism. Thus the metabolic profile can be considered the most predictive phenotype capable of evaluating epigenetic modifications determined by external factors .The metabolic expression is the result of the interaction between the several “multiplatform” biological processes, since a single metabolite may derive from different metabolic processes interconnected at different levels and with numerous mechanisms of reciprocal regulation. Its evaluation allows the study of such processes not as isolated phenomena but as part of a network, thus leading to an overall understanding of the biological system . By meanAt present, approximately 2,900 endogenous metabolites can be identified, but if we consider their total number, estimated at 6,500 molecules, this is lower than the 30,000 genes, the 50,000 mRNAs and the more than 100,000 proteins present in the human organism ,9.They are easier to study than the vaster “systems” . This lays the groundwork for simplification in the analysis of the information gained.Metabolomics also allows comparison of the metabolic profiles acquired in the same individual or groups of individuals at different times. Briefly stated, metabolomics is a quick indicator of environmental modifications (seconds instead of hours and days); If we do not consider the cost of the initial equipment, it is economical given the possibility of analyzing hundreds of samples per week with a much lower cost per sample and also closer to the phenotype in that it also takes epigenetics into consideration: it is so close to the phenotype as to be considered the phenotype itself in its unique individuality (fingerprinting), both in health (phenome), and disease (diseasome).The metabolic profiles identified by means of different analytical platforms , and analyzed through multivariate analysis of the results. However, any study that measures a comprehensive metabolic profile can be considered metabolomics, regardless of the analytical platforms. Metabolomics can use any biological fluid  as a sample. Urine, compared to other biological liquids, has the advantage of being a complex fluid with numerous components, including the intermediate metabolites, but its collection in the case of neonates, especially extremely low birth weights (ELBW), may be particularly difficult. For this reason, urine samples are usually taken with a cotton ball, from which the urine is extracted by means of a syringe. The sample is then immediately conserved at −80 °C. The advantages of this way of collection samples are evident: it is noninvasive, simple, economical and appears to be reliable. Kidney disease is one of the most significant emerging chronic conditions in the world, and as such is becoming the center of therapeutic development alongside diabetes and cardiovascular disease.The basic sciences have made an important contribution to the analysis of the molecular mechanisms involved in kidney diseases, but the transposition of such discoveries into clinical practice remains difficult .Kidney diseases are difficult to diagnose at an early stage, to be followed in progression and in evaluating response to therapy; all this increases the complexity and risk of a clinical trial . MoreoveGiven urine’s complexity, with many components including intermediate metabolites, and therefore its suitability for analysis, metabolomics may play a role in the study of different kidney diseases and overcome diagnostic difficulties. For instance, NMR-based metabolomics is capable of following the metabolism in different areas of the kidney and thus obtain important information concerning nephrotoxicity . We shalet al. presents a comparative analysis of new, noninvasive kidney biomarkers and metabolomic changes in male murine models of nephrotoxicity induced by gentamicin.The study by Sieber N,N dimethylglycin. However, we must consider that some of these metabolites  are significantly altered only in high-dosage treatments and therefore cannot be considered biomarkers sensitive to, and useful in, gentamicin toxicity [In the cortex of the treated animals an increase in the expression of Kim-1 and lipocalin-2 can be seen both from the PCR and immunochemistry; furthermore, the ROC curves show that they are more sensitive and specific of gentamicin-induced kidney damage. On the contrary, serum creatinine and γ-glutamyl transferase were found to be less suitable as markers of kidney damage. The main metabolic alterations responsible for distinguishing control animals from those treated are represented by a decrease in citrate, hippurate, trigonellin and 3-indoxyl sulfate (3IS) and an increase in lactate, glucose and toxicity .In Budonock’s work, a combination of gas chromatography mass spectrometry (GC/MS) and liquid chromatography mass spectrometry was used on rats between four and six weeks of age to monitor the biochemical changes induced following daily administration of nephrotoxins such as gentamicin, tobramycin and cisplatin. Many of the markers identified were associated with nephrotoxicity for the first time in the literature: polyammide, 1,5-AG, monoethanolamine, phosphates, glycylproline, glucosamine, sorbitol and 5Me THF. The analysis also confirmed some conventional markers of nephrotoxicity such as the amino acids, glucose and the osmolytes .et al. performed a study using murine models of acute kidney injury (AKI) induced by a powerful agonist of nicotinic acid receptors (NAR), SCH900424. By means of GC-MS and LC-MS techniques, among the metabolites revealed as AKI markers, 3IS stood out. The levels of this metabolite increased markedly in rat plasma and brains. This metabolite apparently derives from tryptophan following the metabolism performed by the intestinal microbiome; the relationship between parasite and host may be an important mechanism in developing this particular chemically induced toxicity. It accumulated in the blood and urine of uremic patients due to reduced or absent urinary excretion during kidney insufficiency. Moreover, 3IS is closely connected to serum albumin  and cannot be removed with conventional methods of blood dialysis. Other plasmatic markers found to be statistically significant are: p-cresol sulfate  and the catabolites of tryptophan  which may have toxicological importance but which have not been studied in depth. The levels of urea and creatinine for low doses of SCH900424 are no different from those found in controls at any point in time. Such data suggest that 3IS may be a potential marker of toxicity both for the kidneys and the central nervous system during chemically-induced AKI [Later, Zgoda-Pols uced AKI .p-cresol sulfate [In Kikuchi’s experimental study the metabolomic approach was applied in research on uremic toxins as possible markers of the effects of AST-120 (carbon particles known for their capacity to accumulate in CKD patients). The serum metabolites in healthy rats and those with CKD before and after the administration of AST-120 were analyzed by means of liquid chromatography/electrospray ionization associated with mass spectrometry (LC/ESI-MS/MS) and with analysis of the main components. Indoxyl sulfate was the main serum metabolite which made it possible to distinguish the CRF rats from the healthy ones; it was followed by hippuric acid, phenyl sulfate, 4-ethylphenyl sulfate and  sulfate .A study of metabolomics applied to Traditional Chinese Medicine TCM) has been published . TCM conIn Gronwald’s study, NMR was used to analyze 54 samples of the urine of patients with autosomal dominant polycystic kidney disease (ADPKD) and a slight reduction in the rate of glomerular filtration. Within this cohort, 35 were receiving therapy for high blood pressure and 19 others were not. The result was compared to the NMR profiles of 46 healthy volunteers, 10 patients with ADPKD in dialysis with residual kidney function, 16 patients with kidney transplantations and 52 patients with type 2 diabetes with chronic kidney disease. Based on the NMR spectra, the authors succeeded in distinguishing patients with moderately advanced ADPKD from those with terminal ADPKD and patients with chronic kidney disease from other etiologies and healthy subjects with an accuracy above 80%. Of the 35 patients with ADPKD who were receiving treatment for high blood pressure, most showed increased excretion of proteins and also methanol. On the contrary, an increase in methanol at the urinary level was found in no control or in other groups of patients. Thanks to this study, we can conclude by stating that the NMR metabolic fingerprints of urine differentiate ADPKD from the other kidney diseases and from subjects with normal kidney function. The diagnostic and prognostic potential of these profiles calls for further evaluation .et al. investigated the possibility of using the metabolomic profile to monitor the state of health of patients affected by urinary tract infections in the context of complicated and febrile forms with E. coli. as the main pathogen, using as study groups not only healthy subjects and affected patients, but also patients who had recovered. Thus, using the H-NMR urine profiles it was possible to classify the samples in agreement with their diagnoses and this indicates a high predictive ability. Comparing the groups of molecules derived from the different analyses, the conclusion was that some compounds  are associated with the presence of the bacterial infection in the urine while others , scylloinositol) may be considered markers of morbidity [The study by Nevedomskay orbidity .et al., a new urinary biomarker, phenylacetylglutamine (PAGN), was identified for its diagnosis. The analysis was performed with the UPLC-MS method based on the metabolomic approach. The following urine samples were analyzed: 10 interstitial cystitis (IC), 10 bacterial cystitis, 10 healthy volunteers. The urinary levels of PAGN compared to creatinine (Cr) were significantly high in patients with IC (about 0.47 mg/mg Cr) and with healthy volunteers (about 0.11 mg/mg Cr). These results established the PAGN/Cr ratio at the urinary level as a new urinary marker of IC and contribute to its diagnosis [In a study on interstitial cystitis performed by Fukuy iagnosis .et al. in an attempt to arrive at a better understanding of the pathogenetic profile of membranous nephropathy (MN).A metabolomic study was carried out by Gao The diagnosis and treatment of this pathology is today based of clinical manifestations, the levels of excretion of the urinary proteins and kidney biopsies. MN patients have been clinically divided into two groups: one with low levels of urinary proteins < 3.5 g/24 h (Low Urinary Protein MN group—LUPM) and the other of patients with high levels of urinary proteins > 3.5 g/24 h (High Urinary Protein MN group—HUMP). From the study of the serum and blood samples of such patients carried out with GC-MS and then from the analysis of the data obtained with PLS-DA, an obvious metabolic difference emerged between HUPM and LUPM patients. Supporting this difference are 26 urinary and 9 serum metabolites; most of these increased in HUPM patients, both in the serum and urine. The metabolites can be divided into five groups in accordance with their trend of change in the urine and serum. Of these different metabolites, only those in the urine of HUPM patients increased significantly: the sugar alcohols, the dicarboxylic acids, the hydroxylic acids and the phenolic acids, which probably derive from the kidney metabolism, while there are no differences between the LUPM and HUPM serum samples. These metabolites are the direct result of kidney damage. The four sugar alcohols (polyols) were found to be incredibly increased in the urine of HUPM patients while their concentration had not increased significantly in the serum samples .et al. [Bairaktari et al.  performeet al. ,28. Theset al. .In Suhre’s work, the possibility of using metabolomics in the study of diabetes and its complications through identification of a series of new and known metabolites was evaluated. The urine of 40 diabetic patients and 60 controls was analyzed with NMR and MS. The interpretation includes perturbation of the metabolic tracts correlated with the kidney dysfunction (3IS), the lipid metabolism , and interaction with the gut microflora (bile acids). The results of this study suggest that the metabolic markers have the potential to identify complications correlated with diabetes already in subclinical conditions in the overall population .et al., using H-NMR and MS methods, succeeded in distinguishing different spectral patterns associated with these three groups of patients with a success rate of approximately 84% [Through analysis of the urine of patients with interstitial cystitis, bacterial cystitis and healthy subjects, Van QN tely 84% .p-aminohippurate) [It is important to underline that some of these findings confirm experimental studies with untargeted metabolomics on the plasma and urine from wild-type and organic acid anion transporter-1 (Oat/Slc22a6) knockout mice, which identified important metabolites. For example indoxyl sulfate derives from Phase II metabolism of enteric gut precursors and accumulate in chronic kidney disease. Similarly indoxyl sulfate and kynurenine, together with xanthurenic acid, interact strongly and directly with Oat1, suggesting a complex communication between the gut microbiome, indicating the importance of Oat1 in the handling of endogenous toxins associated with renal failure and uremia ,32. Agaippurate) . Despite the widespread use of biomarkers in clinical practice, there is little valid information on data relating to those concerning pediatric cases. The biomarkers found for adults are often applied to young children without considering the fact that the pathogenesis of many diseases is different and that the oncogenesis directly impacts on the evolution and response to therapy. New and innovative approaches are necessary to find other reliable and valid biomarkers for use in advanced pediatric assistance . Among tet al. conducted on newborn rats, nephrotoxicity induced by gentamicin was associated with different urinary patterns of metabolites. In particular, 14 parameters were significantly altered following administration of gentamicin: glucose, galactose, N-acetylglucosamine, myo-inositol, butanoic acid and 3-hydroxybutyrate which increased three-fold compared to normal values, followed by citrulline and pseudo-uridin which increased, but to lower levels [In the experimental study by Hanna r levels . et al.) we investigated the possibility of nephrological diseases being associated with a well-defined metabolic pattern. To that end, using 1H-NMR-based metabolomic methods, we analyzed the urine of 21 children affected by nephropathies  and compared it with that of 19 healthy controls. From this study emerged alterations of the amino acid spectra of purine and pyrimidine, as well as alterations of the citric acid cycle [In our study , a metabolite of dopamine, as a new, sensitive, predictive and early AKI biomarker following pediatric heart surgery [Beger  surgery . Table 2i.e., membranous nephropathy is not present in the newborn). May be that in the future metabolomics will be able to identify early and common markers of AKI, since renal injury and failure are also metabolic disorders. In this context, monitoring some metabolites such as 3-indoxylsulfate, p-cresol sulfate, kynurenate, kynurenine, 3-indole lactate, could be interesting and of important practical impact. Further informations could be obtained on geography of damage. For example an increase of urinary TMAO is generally related to medullary injury; similarly an increase of dimethylamine, sorbitol and myo-inositol could be expression of papillary damage. Conversely a reduction of citrate, αketogutarate and succinate is expression of tubulus proximal cells mitochondrial dysfunction, since only proximal tubule cells are able to compensate for inhibition of their mitochondrial Krebs cycle. Moreover some metabolites indicates specific pathologies: in the adult methanol is a marker of ADPKD, fenylacetyl glutamine is a marker of interstitial cystitis, and scylloinositol and p-aminohippuric acid are markers of urinary tract infection (UTI). Very recently in UTIs metabolomics has been defined as a “new uroscope in town” [It is not easy to compare human studies and experimental animal studies. Moreover it is difficult to compare studies in adults and studies in children and neonates. The metabolome greatly varies with age, diet, drugs assumption, lifestyle and, in adults, with gender. The newborn, infant and child are “virgin” organisms, compared to adults . Thus, iin town” . At the in town” . The goain town” . The goaEpiphanie Medicorum describes the possible colors, smells and tastes of urine, and uses them to diagnose disease [Kidney diseases are a vast and heterogeneous group of pathologies not easy to diagnose, with diagnoses often pronounced only in an advanced stage. The science of metabolomics has been practiced in the field of nephrology, although in a very primordial way, for centuries. The urine wheel published in 1506 by Ullrich Pinder, in his book  disease .omics”  are a picture of the complexity of biological systems: simultaneous, and often noninvasive analysis of a large amount of data . This means “self-organized highly interconnected networks”, systems medicine, networks medicine.Today “Metabolomics may represent a technology of potentially great interest in the early diagnosis of kidney diseases. Although scarce, the data on adults and the very few ones in pediatrics are quite interesting. Further studies are needed to determine the practical clinical impact of metabolomics in kidney pathologies ,48,49,50The “multiplatform” “omic” study of urine can contribute to improving early diagnosis and the outcome of kidney diseases . As a ti