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Background: Long-lasting shared research databases are an important source of epidemiological information and can promote comparison between different healthcare services. Here we present PROSAFE, an advanced international research network in intensive care medicine, with the focus on assessing and improving the quality of care. The project involved 343 ICUs in seven countries. All patients admitted to the ICU were eligible for data collection., Methods: The PROSAFE network collected data using the same electronic case report form translated into the corresponding languages. A complex, multidimensional validation system was implemented to ensure maximum data quality. Individual and aggregate reports by country, region, and ICU type were prepared annually. A web-based data-sharing system allowed participants to autonomously perform different analyses on both own data and the entire database., Results: The final analysis was restricted to 262 general ICUs and 432,223 adult patients, mostly admitted to Italian units, where a research network had been active since 1991. Organization of critical care medicine in the seven countries was relatively similar, in terms of staffing, case mix and procedures, suggesting a common understanding of the role of critical care medicine. Conversely, ICU equipment differed, and patient outcomes showed wide variations among countries., Conclusions: PROSAFE is a permanent, stable, open access, multilingual database for clinical benchmarking, ICU self-evaluation and research within and across countries, which offers a unique opportunity to improve the quality of critical care. Its entry into routine clinical practice on a voluntary basis is testimony to the success and viability of the endeavor.

Accumulating evidence indicates that oxidative stress plays a role in the pathophysiology of chronic kidney disease (CKD) and its progression; during renal replacement therapy, oxidative stress-derived oxidative damage also contributes to the development of CKD systemic complications, such as cardiovascular disease, hypertension, atherosclerosis, inflammation, anaemia, and impaired host defence. The main mechanism underlying these events is the retention of uremic toxins, which act as a substrate for oxidative processes and elicit the activation of inflammatory pathways targeting endothelial and immune cells. Due to the growing worldwide spread of CKD, there is an overwhelming need to find oxidative damage biomarkers that are easy to measure in biological fluids of subjects with CKD and patients undergoing renal replacement therapy (haemodialysis, peritoneal dialysis, and kidney transplantation), in order to overcome limitations of invasive monitoring of CKD progression. Several studies investigated biomarkers of protein oxidative damage in CKD, including plasma protein carbonyls (PCO), the most frequently used biomarker of protein damage. This review provides an up-to-date overview on advances concerning the correlation between plasma protein carbonylation in CKD progression (from stage 1 to stage 5) and the possibility that haemodialysis, peritoneal dialysis, and kidney transplantation improve plasma PCO levels. Despite the fact that the role of plasma PCO in CKD is often underestimated in clinical practice, emerging evidence highlights that plasma PCO can serve as good biomarkers of oxidative stress in CKD and substitutive therapies. Whether plasma PCO levels merely serve as biomarkers of CKD-related oxidative stress or whether they are associated with the pathogenesis of CKD complications deserves further evaluation., Competing Interests: We wish to confirm that there are no known conflicts of interest associated with this publication., (Copyright © 2020 Graziano Colombo et al.)

Female and male very elderly intensive patients (VIPs) might differ in characteristics and outcomes. We aimed to compare female versus male VIPs in a large, multinational collective of VIPs with regards to outcome and predictors of mortality. In total, 7555 patients were included in this analysis, 3973 (53%) male and 3582 (47%) female patients. The primary endpoint was 30-day-mortality. Baseline characteristics, data on management and geriatric scores including frailty assessed by Clinical Frailty Scale (CFS) were documented. Two propensity scores (for being male) were obtained for consecutive matching, score 1 for baseline characteristics and score 2 for baseline characteristics and ICU management. Male VIPs were younger (83 ± 5 vs. 84 ± 5; p < 0.001), less often frail (CFS > 4; 38% versus 49%; p < 0.001) but evidenced higher SOFA (7 ± 6 versus 6 ± 6 points; p < 0.001) scores. After propensity score matching, no differences in baseline characteristics could be observed. In the paired analysis, the mortality in male VIPs was higher (mean difference 3.34% 95%CI 0.92-5.76%; p = 0.007) compared to females. In both multivariable logistic regression models correcting for propensity score 1 (aOR 1.15 95%CI 1.03-1.27; p = 0.007) and propensity score 2 (aOR 1.15 95%CI 1.04-1.27; p = 0.007) male sex was independently associated with higher odds for 30-day-mortality. Of note, male gender was not associated with ICU mortality (OR 1.08 95%CI 0.98-1.19; p = 0.14). Outcomes of elderly intensive care patients evidenced independent sex differences. Male sex was associated with adverse 30-day-mortality but not ICU-mortality. Further research to identify potential sex-specific risk factors after ICU discharge is warranted.Trial registration: NCT03134807 and NCT03370692; Registered on May 1, 2017 https://clinicaltrials.gov/ct2/show/NCT03370692 .

Background: Prognostic models are often used to assess the quality of healthcare. Several scores were developed to predict mortality after cardiac surgery, but none has reached optimal performance in subsequent validations. We validate the most used scores (EUROSCORE I and II, STS, and ACEF) on a cohort of cardiac-surgery patients, assessing their robustness against case-mix changes., Methods: The scores were validated on 14,559 patients admitted to 16 Italian cardiosurgical ICUs participating to Margherita-Prosafe project in 2014 and 2015. Calibration was assessed through Hosmer-Lemeshow Test, standardized mortality ratio, and GiViTI calibration test and belt. Discrimination was measured by the area under the ROC curve., Results: The study included 10,317 patients who were eligible to the calculation of the STS Score (4156 isolated valve, 4681 isolated CABG and 1480 single valve and CABG) which calibrated well in these subgroups. The ACEF Score and EUROSCORE I and II were available for 14,139, and 14,071 patients, respectively. EUROSCORE I significantly overestimated mortality; EUROSCORE II calibrated well overall, but underestimated mortality of patients undergoing complex surgery and non-elective ones. The ACEF Score calibrated poorly in elective and non-elective patients. Discrimination was acceptable for all models (AUC>0.70), but not for the ACEF Score., Conclusions: Cardiac surgery scores calibrate poorly when the case-mix of validation and development samples differs. To grant reliability for benchmarking, they should be validated in the clinical settings on which they are applied and updated periodically. Advanced statistical tools are essential for the correct interpretation and application of severity scores.

Background: Moderate to severe iron deficiency anaemia is a common finding in patients admitted to the Emergency Department (ED). According to Patient Blood Management principles, intravenous iron should be the therapy of choice instead of blood transfusion for selected cases affected by chronic iron deficiency anaemia. However, this option is only rarely taken into account by physicians in the ED. As a result, in many circumstances, treatment of iron deficiency anaemia in the ED can differ from that of the Anaemia Clinic. With the aim of reducing inappropriate transfusions, and to implement intravenous iron usage, we shared a specific protocol with the ED., Material and Methods: We reviewed the medical records of all subjects admitted to the ED (n=267, Post-protocol group) with hemoglobin ≤9.0 g/dL and mean corpuscular volume <80 fL in a 13-month period, except if the massive transfusion protocol was activated, and results were compared with an equivalent Pre-protocol historical cohort (n=226)., Results: In comparison with the Pre-protocol series, the number of patients transfused did not change, but the appropriateness in terms of transfusion and red blood cell volume transfused improved sharply (87.0 vs 13.3%; p<0.001) with a significant increase in intravenous iron administration (50.2 vs 4.4% of cases; p<0.001). As a positive consequence, both the time spent in the ED by patients who were then directly discharged and costs per subject treated dropped by 37.9% and 59.0%, respectively. Treatment with infusion only in comparison with transfusion only led to a statistically significant Relative Risk reduction in transfusion on the ward and post-discharge transfusion of 55.6% and 44.4%, respectively., Discussion: The implementation of Patient Blood Management principles and early intravenous iron therapy in the Emergency Department have proved to be effective tools to optimise resources both in terms of units transfused and costs.

In chronic kidney disease (CKD), the impairment of the excretory function leads to elevation in the blood concentrations of urea, creatinine, and various protein metabolic products. Advanced oxidation protein products (AOPP), along with protein carbonyls, protein-bound di-tyrosines and S -thiolated proteins, are considered biomarkers of oxidative stress in end-stage renal disease (ESRD) patients on maintenance haemodialysis (HD). In this study, we evaluated the correlations between plasma levels of AOPP (measured by size exclusion/gel filtration high performance liquid chromatography) and those of protein-bound di-tyrosines, protein carbonyls, albumin and fibrinogen in 50 nondiabetic ESRD patients on maintenance HD. Considering that AOPP could represent the bridge between oxidative stress and inflammation, having been identified as proinflammatory mediators, we also evaluated the association between AOPP levels, C-reactive protein concentration and white blood cells count. Finally, we assessed the associations between plasma level of AOPP and serum concentrations of creatinine and urea, both of which showed a strong dependence on the chronological age of haemodialysed patients. Taken together, our results confirm the robust relationship between uraemia and oxidative stress, especially when measured as biomarkers of severe protein oxidative damage (e.g. plasma AOPP).

Objective: Malnutrition is a frequent complication in patients on hemodialysis (HD), even if its adequate appraisal remains one of the most complicated challenges in the HD scenario because of the limits of current malnutrition biomarkers. The aim of our study was to assess the relation of subjective nutritional tools Subjective Global Assessment (SGA) and Dialysis Malnutrition Score (DMS) with the objective malnutrition tool Geriatric Nutritional Risk Index (GNRI) in elderly patients on HD., Methods: This is a cross-sectional study involving 71 patients on maintenance HD. Mann-Whitney U and chi-square tests were used to compare data of male and female patients on HD. Linear and logistic regression models were used to assess the variables tested in all patients., Results: GNRI was not different between male and female patients on HD, and it was negatively related to SGA and DMS: B, -0.05 (95% confidence interval, -0.08 to -0.02) P = 0.00 and B, -0.30 (95% confidence interval, -0.47 to -0.14) P = .00, respectively. Both continuous and categorical GNRI data were predictive of SGA = 3: Odds Ratio (OR), 0.74 (0.63 to 0.87) P = 0.00 and OR, 6.74 (1.54 to 29.45) P = 0.01, respectively. Similarly, GNRI data were related to DMS > 13: OR, 0.85 (0.76 to 0.85) P = 0.00 and 3.29 (1.08 to 10.05) P = 0.03, respectively. Continuous GNRI data remained significant in both male and female patients separately, whereas categorical GNRI data, only in male patients., Conclusions: GNRI is a reliable nutritional tool predictive of subjective malnutrition scores SGA and DMS, pointing out a relation between objective and subjective malnutrition indexes in both genders., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction:: Malnutrition is a well-recognized risk factor for all-cause mortality in hemodialysis patients. However, its role for arteriovenous fistulas outcome has not been exhaustively investigated. Our aim was to point out the impact of Subjective Global Assessment-Dialysis Malnutrition Score as independent predictor of arteriovenous fistulas thrombosis (vascular access thrombosis) and/or significant stenosis (vascular access stenosis). In addition, we compared it with the widespread Charlson Comorbidity Index., Methods:: We assessed 57 hemodialysis patients for a 2-year interval and evaluated the incidence of vascular access thrombosis and/or stenosis. Linear regression analysis was used to test the relation of variables with Subjective Global Assessment-Dialysis Malnutrition Score at baseline. Logistic and Cox regression analysis evaluated markers as predictors of both vascular access thrombosis and stenosis. Receiver operating characteristic curve analysis was used to compare area under the curve values of Subjective Global Assessment-Dialysis Malnutrition Score, Charlson Comorbidity Index, and modified Charlson Comorbidity Index., Results:: Age and Charlson Comorbidity Index were positively related to Subjective Global Assessment-Dialysis Malnutrition Score: B = 0.06 (95% CI = 0.01; 0.11) and B = 0.31 (95% CI = 0.01; 0.63). Higher albumin and normalized protein catabolic rate levels had a protective role against vascular access failure: OR = 0.67 (95% CI = 0.56; 0.81) and OR = 0.46 (95% CI = 0.32; 0.67), respectively. Higher Subjective Global Assessment-Dialysis Malnutrition Score and Charlson Comorbidity Index values were significant risk factors: HR = 1.42 (95% CI = 1.04; 1.92) and HR = 1.48 (95% CI = 1.01; 2.17), respectively. Area under the curve of Subjective Global Assessment-Dialysis Malnutrition Score was significantly higher than those of both Charlson Comorbidity Index and modified Charlson Comorbidity Index: 0.70 (95% CI = 0.50; 0.88) versus 0.61 (95% CI = 0.41; 0.80) and 0.55 (95CI% = 0.41; 0.70)., Conclusion:: Subjective Global Assessment-Dialysis Malnutrition Score, as well as Charlson Comorbidity Index, are useful tools to predict vascular access failure and should be carefully and periodically evaluated in order to check significant variations that may compromise vascular access survival.

Background: Malnutrition is an important risk factor for cardiovascular mortality in hemodialysis (HD) patients. However, current malnutrition biomarkers seem unable to accurately estimate the role of malnutrition in predicting cardiovascular risk. Our aim was to investigate the role of the Subjective Global Assessment-Dialysis Malnutrition Score (SGA-DMS) compared to two well-recognized comorbidity scores-Charlson Comorbidity Index (CCI) and modified CCI (excluding age-factor) (mCCI)-in predicting cardiovascular events in HD patients., Methods: In 86 maintenance HD patients followed from June 2015 to June 2017, we analyzed biohumoral data and clinical scores as risk factors for cardiovascular events (acute heart failure, acute coronary syndrome and stroke). Their impact on outcome was investigated by linear regression, Cox regression models and ROC analysis., Results: Cardiovascular events occurred in 26/86 (30%) patients during the 2-year follow-up. Linear regression showed only age and dialysis vintage to be positively related to SGA-DMS: B 0.21 (95% CI 0.01; 0.30) p 0.05, and B 0.24 (0.09; 0.34) p 0.02, respectively, while serum albumin, normalized protein catabolic rate (nPCR) and dialysis dose (Kt/V) were negatively related to SGA-DMS: B - 1.29 (- 3.29; - 0.81) p 0.02; B - 0.08 (- 1.52; - 0.35) p 0.04 and B - 2.63 (- 5.25; - 0.22) p 0.03, respectively. At Cox regression analysis, SGA-DMS was not a risk predictor for cardiovascular events: HR 1.09 (0.9; 1.22), while both CCI and mCCI were significant predictors: HR 1.43 (1.13; 1.87) and HR 1.57 (1.20; 2.06) also in Cox adjusted models. ROC analysis reported similar AUCs for CCI and mCCI: 0.72 (0.60; 0.89) p 0.00 and 0.70 (0.58; 0.82) p 0.00, respectively, compared to SGA-DMS 0.56 (0.49; 0.72) p 0.14., Conclusions: SGA-DMS is not a superior and significant prognostic tool compared to CCI and mCCI in assessing cardiovascular risk in HD patients, even it allows to appraise both malnutrition and comorbidity status.

Objective: MargheritaTre is an electronic health record developed by the Italian Group for the Evaluation of Interventions in Intensive Care Medicine designed to support clinical practice in intensive care units (ICUs) and ensure high-quality data for research purposes., Approach: MargheritaTre was developed in collaboration with clinical experts, researchers, and IT specialists. It is currently installed in 40 ICUs and its database contains complete records of more than 65,000 patients. To facilitate data analysis, information is mostly stored in structured or partially structured form., Main Results: Data collected with MargheritaTre allow one to conduct research studies on complex clinical problems from manifold perspectives and with different levels of detail, such as epidemiological studies, analyses of the process of care and physiopathological investigations, at both single-organ and organism level. In this paper we describe some of the first projects based on this electronic health record to illustrate its potential for research., Significance: The MargheritaTre database is a huge and rapidly growing mine of data that will be exploited by our laboratory and shared with other groups to address complex and innovative research and clinical questions. The ultimate aim of these projects is the improvement of the quality of care and patient outcomes, through the development of expert systems integrated in the electronic health record to support clinical practice.

Biomarkers are widely used to confirm the presence of infection. However, it would be of the greatest importance to predict in advance the occurrence or worsening of organ dysfunction in infected patients allowing timely antibiotic escalation. This study investigates the ability of procalcitonin (PCT) and MR-proADM to predict the transition to sepsis in infected patients. The study was conducted in a neurointensive care unit over a three-month period. We included both patients with and without infection to investigate the specificity of organ dysfunction prediction in infected patients. Daily measurement of PCT and MR-proADM, SOFA, Pitt, and CPIS were performed. To measure the correlation between each biomarker and each severity score, linear mixed-effects models were developed. For each biomarker-score combination we tested the correlation of the score with the biomarker measured one and two days before, the same day, and the day after. Sixty-four critically ill patients, 31 with infection, were enrolled. The statistically significant biomarker-score combinations were PCT-SOFA, MR-proADM-SOFA, MR-proADM-Pitt, and MR-proADM-CPIS. The MR-proADM models predicting Pitt and CPIS variations with 24-hour anticipation showed the best fit. The scores increased by 0.6 ± 0.3 and 0.4 ± 0.2 for each unitary biomarker increase, respectively. The MR-proADM-SOFA combinations were equivalent when the biomarker was measured the day before or the same day (score increases were 1.5 ± 0.4 and 1.9 ± 0.4, respectively). The PCT-SOFA model had the best fit when PCT was measured the same day of the score. There was no difference in the predictive ability of the biomarker in infected and non-infected patients. This was a pivotal study conducted in a single neurointensive centre on a limited number of patients, and as such it does not provide definitive conclusions. PR-proADM predicted occurrence and worsening of organ failure in critically ill patients with and without infection. The combination with infection diagnostic biomarkers such as PCT would allow predicting evolution to sepsis in infected patients., Competing Interests: In the last two years Bruno Viaggi has received honoraria for speaking at symposia from ABBOTT - ACCELERATE DIAGNOSTICS - ADA - ALIFAX - BECTON & DICKINSON - BELLCO - MERCK SHARP & DOHME - PFIZER - THERMOFISCHER SCIENTIFIC. Stefano Finazzi has been supported by Fondazione Cariplo through grant no. 2014-1962. The study was supported unconditionally by THERMOFISCHER SCIENTIFIC, which provided the immunoassays and the use of the analyser. THERMOFISCHER SCIENTIFIC that will pay the fee to Plos One for the article publication. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Purpose: We investigate the impact on outcome of different levels of supportive treatment in Ebola virus disease (EVD). The NGO EMERGENCY delivered care sequentially at two Ebola Treatment Centres (ETC) in Sierra Leone: first at Lakka (fluids, symptomatic, antibiotic, antimalaria treatment, and hospital level medical care), and thereafter in Goderich, adding organ support in the only African ETC with an equipped and staffed intensive care unit (ETC-ICU)., Methods: The primary outcome in this retrospective cohort study was in-ETC mortality. Secondarily, we used multivariable logistic regression to investigate the independent impact of the IC on mortality by comparing patients in two ETCs, adjusting for potential confounders, including the viral load (base-10 logarithm in copies/ml) (LVL), modelled as a piecewise linear function. Mortality was plotted versus LVL. Confidence bands were constructed by a bootstrap technique. The number of hospital-free days within 28 was computed to assess the burden of EVD., Results: Data from 229 EVD patients were analysed (123 in Lakka, 106 in Goderich). Crude analysis showed a non-statistically significant difference in mortality (57.7% in Lakka vs 50.0% in Goderich; p = 0.19). Age and LVL were associated with mortality. Adjusted mortality was lower at the Goderich ICU-ETC (p = 0.055). This difference was observed with 80% confidence for patients with LVL between 7.5 and 8.5 copies/ml. Hospital-free days (of 28 days) were greater (7.7 vs 5.5; p = 0.03) for patients treated in the ICU-ETC., Conclusions: Provision of critical care to patients with EVD is feasible in resource-limited settings and was associated with improved survival and less time in hospital.

Patients with end-stage renal disease (ESRD) undergoing haemodialysis (HD) experience oxidative/carbonyl stress, which is postulated to increase after the HD session. The influence of diabetes mellitus and sex on oxidation of plasma proteins in ESRD has not yet been clarified despite that diabetic nephropathy is the most common cause of ESRD in developed and developing countries and despite the increasingly emerging differences between males and females in epidemiology, pathophysiology, clinical manifestations, and outcomes for several diseases. Therefore, this study aimed to evaluate the possible effect of type 2 diabetes mellitus, gender, and dialysis filter on plasma level of protein carbonyls (PCO) in ESRD patients at the beginning and at the end of a single HD session. Results show that mean post-HD plasma PCO levels are significantly higher than mean pre-HD plasma PCO levels and that the type of dialysis filter and dialysis technique are unrelated to plasma PCO levels. The mean level of plasma PCO after a HD session increases slightly but significantly in nondiabetic ESRD patients compared to diabetic ones, whereas it increases more markedly in women than in men. These novel findings suggest that women with ESRD are more susceptible than men to oxidative/carbonyl stress induced by HD.

Diabetes is a complex disease of increasingly common occurrence worldwide. Attaining optimal glycemic control is the main challenge to prevent the development of diabetes-related complications and/or to stop their progression. In recent years, the pharmacologic toolkit for the treatment of diabetes has considerably expanded, thus paving the way to more pathophysiology-oriented therapies. For instance, the sodium-glucose cotransporters SGLT2 and SGLT1 have been in the spotlight because of better knowledge of their physiology and therapeutic potential. At present, whereas the SGLT2 inhibitors are widely applied in current clinical practice as an effective and well-tolerated treatment that increases the urinary excretion of glucose, less is known about the use of SGLT1 inhibitors. SGLT1s are of primary importance in the small intestine, an organ that does not express SGLT2, while in the kidney they are expressed in the late renal proximal tubules, where it reabsorbs the glucose escaped from the upstream SGLT2. Hence, SGLT1-mediated glucose reabsorption in the kidney is increased when the tubular glucose load overwhelms the capacity of SGLT2 or when the latter is inhibited. The role of SGLT1 in intestinal and renal glucose transport makes the transporter a potential target for antidiabetic therapy. Here, we briefly report the evidence on LX2761, a new inhibitor against SGLT1 and SGLT2 in vitro, which acts in vivo as a selective inhibitor of SGLT1 in the gastrointestinal tract. LX2761 improves glycemic control without the glycosuria-related side effects of SGLT2 inhibitors, particularly genitourinary tract infections. However, whether it represents a valid therapeutic option for all patients with diabetes or is more appropriate for specific phenotypes, e.g., patients with concomitant diabetes and chronic kidney disease, who may benefit less from the renal mechanism of selective SGLT2 inhibitors, remains to be tested in large randomized controlled trials.

Background: The number of elderly patients undergoing major surgical interventions and then needing admission to intensive care unit (ICU) grows steadily. We investigated this issue in a cohort of 232,278 patients admitted in five years (2011-2015) to 163 Italian general ICUs., Methods: Surgical patients older than 75 registered in the GiViTI MargheritaPROSAFE project were analyzed. The impact on hospital mortality of important chronic conditions (severe COPD, NYHA class IV, dementia, end-stage renal disease, cirrhosis with portal hypertension) was investigated with two prognostic models developed yearly on patients staying in the ICU less or more than 24 hours., Results: 44,551 elderly patients (19.2%) underwent emergency (47.3%) or elective surgery (52.7%). At least one severe comorbidity was present in 14.6% of them, yielding a higher hospital mortality (32.4%, vs. 21.1% without severe comorbidity). In the models for patients staying in the ICU 24 hours or more, cirrhosis, NYHA class IV, and severe COPD were constant independent predictors of death (adjusted odds ratios [ORs] range 1.67-1.97, 1.54-1.91, and 1.34-1.50, respectively), while dementia was statistically significant in four out of five models (adjusted ORs 1.23-1.28). End-stage renal disease, instead, never resulted to be an independent prognostic factor. For patients staying in the ICU less than 24 hours, chronic comorbidities were only occasionally independent predictors of death., Conclusions: Our study confirms that elderly surgical patients represent a relevant part of all ICUs admissions. About one of seven bear at least one severe chronic comorbidity, that, excluding end-stage renal disease, are all strong independent predictors of hospital death.

Coupled plasma filtration and adsorption (CPFA) is an extracorporeal blood purification technique proposed for the treatment of septic-shock. By removing pro- and anti-inflammatory mediators from plasma, CPFA is supposed to have a therapeutic effect on the abnormal inflammatory response seen in this condition. Recently, blood predilution with citrate solution has been adopted to prevent clotting in the CPFA circuit-one of the main problems of the technique. Taking into account the patient's hematocrit, we worked out a formula for the volume of plasma effectively treated by CPFA after predilution. Neglecting this effect, as is commonly done, introduces significant distortions in the estimation of the volume, possibly causing under-treatment. The distortion is stronger when the hematocrit and the predilution fraction are large and weaker when both values shrink. By correctly indicating the daily dose of plasma adsorption received by patients, this formula is essential for assessing the therapeutic efficacy of CPFA and, subsequently, establishing its optimal doses., (© 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

A prognostic model is well calibrated when it accurately predicts event rates. This is first determined by testing for goodness of fit with the development dataset. All existing tests and graphic tools designed for the purpose suffer several drawbacks, related mainly to the subgrouping of observations or to heavy dependence on arbitrary parameters. We propose a statistical test and a graphical method to assess the goodness of fit of logistic regression models, obtained through an extension of similar techniques developed for external validation. We analytically computed and numerically verified the distribution of the underlying statistic. Simulations on a set of realistic scenarios show that this test and the well-known Hosmer-Lemeshow approach have similar type I error rates. The main advantage of this new approach is that the relationship between model predictions and outcome rates across the range of probabilities can be represented in the calibration belt plot, together with its statistical confidence. By readily spotting any deviations from the perfect fit, this new graphical tool is designed to identify, during the process of model development, poorly modeled variables that call for further investigation. This is illustrated through an example based on real data., (Copyright © 2015 John Wiley & Sons, Ltd.)

Calibration is one of the main properties that must be accomplished by any predictive model. Overcoming the limitations of many approaches developed so far, a study has recently proposed the calibration belt as a graphical tool to identify ranges of probability where a model based on dichotomous outcomes miscalibrates. In this new approach, the relation between the logits of the probability predicted by a model and of the event rates observed in a sample is represented by a polynomial function, whose coefficients are fitted and its degree is fixed by a series of likelihood-ratio tests. We propose here a test associated with the calibration belt and show how the algorithm to select the polynomial degree affects the distribution of the test statistic. We calculate its exact distribution and confirm its validity via a numerical simulation. Starting from this distribution, we finally reappraise the procedure to construct the calibration belt and illustrate an application in the medical context., (Copyright © 2014 John Wiley & Sons, Ltd.)

Purpose: More recent severity scores should be more reliable than older ones because they account for the improvement in medical care over time. To provide more insight into this issue, we compared the predictive ability of the Simplified Acute Physiology Score (SAPS) II and SAPS 3 (originally developed from data collected in 1991-1992 and 2002, respectively) on a sample of critically ill patients., Methods: This was a prospective observational study on 3,661 patients from 103 Italian intensive care units. Standardized mortality ratios (SMRs) were calculated. Assessment of calibration across risk classes was performed using the GiViTI calibration belt. Discrimination was evaluated by means of the area under the receiver operating characteristic analysis., Results: Both scores were shown to discriminate fairly. SAPS 3 largely overpredicted mortality, more than SAPS II (SMR 0.63, 95 % CI 0.60-0.66 vs. 0.87, 95 % CI 0.83-0.91). This result was consistent and statistically significant across all risk classes for SAPS 3. SAPS II did not show relevant deviations from ideal calibration in the first two deciles of risk, whereas in higher-risk classes it overpredicted mortality., Conclusions: Both scores provided unreliable predictions, but unexpectedly the newer SAPS 3 turned out to overpredict mortality more than the older SAPS II.

The cosmological constant is one of the most pressing problems in modern physics. We address this issue from an emergent gravity standpoint, by using an analogue gravity model. Indeed, the dynamics of the emergent metric in a Bose-Einstein condensate can be described by a Poisson-like equation with a vacuum source term reminiscent of a cosmological constant. The direct computation of this term shows that in emergent gravity scenarios this constant may be naturally much smaller than the naive ground-state energy of the emergent effective field theory. This suggests that a proper computation of the cosmological constant would require a detailed understanding about how Einstein equations emerge from the full microscopic quantum theory. In this light, the cosmological constant appears as a decisive test bench for any quantum or emergent gravity scenario.

Introduction: Hemodialysis (HD)-induced inflammation has a pathogenetic role in patients with end-stage renal disease (ESRD). The aim of the present study was to assess whether pentraxin-3 (PTX3) could be a reliable biomarker of HD-induced inflammation and of membrane biocompatibility., Methods: We prospectively enrolled 31 HD patients. Blood samples for determining PTX3, C-reactive protein (CRP), leukocytes and neutrophils were drawn from the arterial needle, before dialysis after the long dialysis-free interval (time 0), at the end of the index session (time 1) and before the next dialysis session (time 2). In 22 of 31 patients, 30 minutes after start of dialysis, PTX3 and CRP plasma levels were measured in blood collected from both the arterial and venous lines (time A - time V) of the dialyzer. In 7 of 22 patients intracellular PTX3 levels in neutrophils were measured at the end of session., Results: PTX3 venous levels were significantly increased at the end of the index session compared with baseline and in blood samples drawn from the venous line compared with the arterial line of the dialyzer. At time 1, a reduction of intracellular PTX3 in neutrophils was noticed. In contrast, CRP plasma levels were stable during the HD session., Conclusions: Our findings suggest that PTX3, which is rapidly produced by several cell types and released by neutrophils upon stimulation, could be a biomarker of HD-induced inflammation and of blood-membrane bioincompatibility.

Purpose: Uncertainty about the severity of the A(H1N1) pandemia persists. Information about disease severity can be obtained by investigating intensive care unit (ICU) admissions, especially when historical comparisons can be made with cases of community-acquired pneumonia (CAP)., Methods: This prospective observational study was conducted in 155 ICUs contributing to the GiViTI national database. To assess the impact on ICU workload, the occupancy rate during the epidemic phase was compared with influenza periods in previous years. A logistic regression model was developed to assess the prognostic importance of A(H1N1) influenza., Results: The characteristics of the 319 A(H1N1) cases were similar to those reported in other studies, confirming the young age of patients (mean 43 years) and the higher prevalence among pregnant women and obese people. At the epidemic's peak (October-December 2009) the occupancy rate did not significantly differ from the same period of the previous year, and was significantly lower than the 2009 seasonal influenza outbreak (January-March 2009). Compared with CAP of other origin (3,678 patients), A(H1N1) pneumonia was associated with a lower risk of death. However, after adjusting for confounding this was no longer the case (OR 0.88; 95% CI 0.59-1.31; p = 0.52)., Conclusion: This study confirmed the specific features of critically ill A(H1N1) patients (i.e., young age, pregnancy, obesity). The pandemic did not increase ICU workload compared with other periods. A(H1N1) pneumonia did not have a higher risk of death than CAP of different origin among patients admitted to the ICU.

Prognostic models applied in medicine must be validated on independent samples, before their use can be recommended. The assessment of calibration, i.e., the model's ability to provide reliable predictions, is crucial in external validation studies. Besides having several shortcomings, statistical techniques such as the computation of the standardized mortality ratio (SMR) and its confidence intervals, the Hosmer-Lemeshow statistics, and the Cox calibration test, are all non-informative with respect to calibration across risk classes. Accordingly, calibration plots reporting expected versus observed outcomes across risk subsets have been used for many years. Erroneously, the points in the plot (frequently representing deciles of risk) have been connected with lines, generating false calibration curves. Here we propose a methodology to create a confidence band for the calibration curve based on a function that relates expected to observed probabilities across classes of risk. The calibration belt allows the ranges of risk to be spotted where there is a significant deviation from the ideal calibration, and the direction of the deviation to be indicated. This method thus offers a more analytical view in the assessment of quality of care, compared to other approaches.

Background: Type 2 diabetes patients on chronic hemodialysis have a high prevalence of cardiovascular complications and often show a poor glycemic control. Single-spot glycemic measurements are not always meaningful, and the hemoglobin A1c (HbA1c) value does not reflect short-term variations in glucose metabolism in this patient category. Therefore, to better understand their metabolic balance, we studied a group of diabetes patients on hemodialysis by a continuous glucose monitoring (CGM) system., Methods: Twelve insulin-treated type 2 diabetes patients on hemodialysis were studied by a microdialysis-based subcutaneous glucose sensor over a period of 2 days, including the dialysis day (HD) and the following inter-dialytic period ("free" day [FD])., Results: The mean 24-h glycemic value, the mean amplitude of glucose excursions, and the SD of mean glucose were significantly higher in the HD than the FD (186 ± 50 vs. 154 ± 25 mg/dL, P<0.05; 75 ± 22 vs. 56 ± 15 mg/dL, P<0.05; and 57 ± 6 vs. 35 ± 11 mg/dL, P<0.05, respectively). Considering the 48-h recording, there was a direct correlation between the mean glucose concentration and the HbA1c (r=0.47, P<0.05), whereas no association was observed between the measures of glucose variability and HbA1c., Conclusions: Insulin-treated diabetes patients on hemodialysis showed different glucose profiles between the HD and the FD. In particular, in the HD they have had an increased glycemic variability, which may represent an adjunctive risk factor for cardiovascular complications. Therefore the use of a CGM system, as a means of assessing the measures of glycemic variability, could improve the management of insulin therapy in these patients.

Objectives: The aim of this study was to describe the time course of NT pro-B-type natriuretic peptide (NT pro-BNP) levels in patients with large anterior ST-segment elevation myocardial infarction (STEMI) treated with primary angioplasty (PPCI) and to investigate the relationship between these values and both microvascular reperfusion and left ventricular (LV) function., Background: The clinical efficacy of PPCI is largely dependent on the achievement of microvascular reperfusion. Myocardial blush is an angiographic method to evaluate the presence of effective reperfusion after PPCI. NT pro-BNP is a biomarker of LV stress whose levels are also related to clinical outcome in STEMI., Methods: We studied 84 patients with large anterior STEMI treated with PPCI. NT pro-BNP was measured at baseline, after 2 days (day 2) and 7 days (day 7). Echocardiographic LV ejection fraction (LVEF) was measured at baseline, day 7 and after 6 months. Myocardial blush was graded immediately after PPCI., Results: NT pro-BNP increased from admission to day 2 and decreased from day 2 to day 7 in patients with significant myocardial blush (grade 2-3) as well as in patients with 0-1 myocardial blush. However, in the latter group median NT pro-BNP levels globally increased from admission to day 7, whereas they decreased in patients with significant myocardial blush. Moreover, in such patients LVEF was higher at all time points than in patients with a grade 0-1 myocardial blush., Conclusion: This study shows that the time course of NT pro-BNP in the first week after an anterior STEMI is dependent on the effectiveness of microvascular reperfusion assessed after PPCI and reflects the evolution of LVEF over time.

Background: On the basis of cardiovascular compliance, hemodialysis (HD) patients can be classified as hypotension prone (HP) or hypotension resistant (HR)., Methods: We compare the hemodynamic behavior and myocardial performances in 6 HP and 6 HR patients before and after an isolated ultrafiltration (IU) session removing 3% of total body water., Results: HP show higher basal plasma angiotensin II levels during IU (p<0.01), whereas angiotensin II remained unchanged in HR patients (p<0.001 between groups). The percentage changes of plasma volume (PV) was similar in the 2 groups. A significant reduction of cardiac index was observed only in the HP group (p<0.001 between groups). The mean values of heart rate remained significantly higher, whereas total peripheral resistances significantly fell in the HP in comparison with the HR group (p<0.001 between groups). During IU, the mean arterial pressure (MAP) changes were -10 +/- 3 mm Hg in the HP vs. -3.3 +/- 2 mm Hg in the HR group (p<0.001). Echocardiography data were collected before and after IU. All enrolled patients presented left ventricular hypertrophy; following IU, HP patients showed a reduction of mean left ventricular diameter (p<0.01), left atrial diameters and right atrial diameter, and a change in percentage of right atrium ejection fraction (p<0.001, p<0.01)., Conclusions: In comparison with HR patients, HP patients before and after IU showed a defective arteriovenous tone adjustment to the PV changes, with a hemodynamic picture of abnormal sympathetic stimulation. Moreover, a reduced cardiac preload with both atrial and ventricular underfilling in these patients is at risk for a sudden drop in MAP.

Context: The usefulness of stool calprotectin determination in diagnosis of inflammatory disease of the colon has been reported; information about its usefulness for patients with polyposis are scarce, however., Objective: To evaluate the significance of stool calprotectin concentrations for patients affected by colonic polyposis., Patients: Sixty-three consecutive patients (35 males, 28 females, mean age 60.3 years, range 39-78 years) were enrolled: 26 patients (41.3%) with polyps, 17 patients (27.0%) with asymptomatic diverticular disease, and 20 subjects (31.7%) with normal endoscopic appearance of the colon., Results: Stool calprotectin concentrations were 17.4 +/- 24.5 microg g(-1) for patients with colonic polyposis, significantly higher than concentrations for patients with diverticulosis (7.1 +/- 5.7 microg g(-1); P = 0.026) or for patients with normal appearance of the colon (calprotectin 6.0 +/- 5.8 microg g(-1); P = 0.003). For patients with a single polyp, stool calprotectin concentrations were similar to those for patients with multiple polyps. Calprotectin fecal concentrations for patients with sessile polyps and those with flat polyps were not significantly different. Calprotectin concentrations were not significantly related to the size of the polyps., Conclusion: Our data show that colonic polyposis may cause an increase in stool calprotectin values and that these colonic lesions should be suspected when elevated stool calprotectin concentrations are found.

Ulcerative colitis and Crohn's disease are inflammatory bowel diseases with a chronic relapsing course. Management of both conditions is far from being fully satisfactory. For this reason in the last decade a large number of biological therapies, targeting cytokines involved in intestinal inflammation, has been developed with various results in terms of efficacy, safety and costs. Activated granulocytes and monocytes represent the major sources of pro-inflammatory cytokines in the intestinal mucosa, playing a pivotal role in inducing and maintaining intestinal inflammation. Leukocytapheresis using an adsorptive carrier-based system (Adacolumn) or a removal filter column (Cellsorba) has been proposed as a feasible, safe and effective therapy for ulcerative colitis and Crohn's disease. The objective of this paper is to provide an overview on the current knowledge about mechanisms of action, available clinical data and the possible future perspectives for the use of Adacolumn and Cellsorba in the management of inflammatory bowel diseases., (Copyright 2008 S. Karger AG, Basel.)

Background: Fecal calprotectin determination has been demonstrated to be useful in diagnosing various inflammatory diseases of the gastrointestinal tract; however, data available for patients with pancreatic diseases are scarce. Our aim was to assess fecal calprotectin in order to evaluate the presence of intestinal inflammation in patients with pancreatic disease., Methods: Eligible patients with suspected pancreatic illness were enrolled, and in all of them fecal calprotectin and elastase-1, as well as serum amylase and lipase activities, were assayed using commercially available kits., Results: A total of 90 subjects (47 men, 43 women, mean age 58.6 +/- 14.9 years) were enrolled: 20 (22.2%) had chronic pancreatitis; 15 (16.7%) had pancreatic cancer; six (6.7%) had chronic nonpathological pancreatic hyperenzymemia; 16 (17.8%) had nonpancreatic diseases; and 23 (25.6%) had no detectable diseases. Diarrhea was present in 19 patients (21.1%). In univariate analyses, the presence of diarrhea and low fecal elastase-1 concentrations were significantly associated (P = 0.019 and P = 0.002, respectively) with abnormally high fecal calprotectin concentration, and the multivariate analysis demonstrated that low fecal elastase-1 concentration was the only variable independently associated with a high fecal calprotectin concentration., Conclusions: Pancreatic insufficiency may cause intestinal inflammation, probably because of a modification of the intestinal ecology.

Objectives: The aim of this study was to estimate the prevalence of undiagnosed celiac disease (CD) in the parents of preterm and/or small for gestational age (SGA) infants., Methods: A sample of 1,714 parents (868 women, 846 men) of 905 preterm (<37 wk of gestational age) and/or SGA (<10th percentile of birthweight) infants consecutively born in Lombardy, Northern Italy, and not diagnosed with CD prior to pregnancy, were tested for CD. Diagnosis was based on antitissue transglutaminase and anti-endomysial antibodies and confirmed by duodenal biopsy., Results: The overall prevalence of undiagnosed CD was 0.64% (95% confidence interval [CI] 0.32-1.15%), 0.92% (0.40-1.81%) in women and 0.35% (0.07-1.03%) in men. In the mothers of preterm infants prevalence of CD was 0.39% (0.05-1.39%). In the mothers of SGA infants prevalence of CD was 1.60% (0.64-3.27%), and the observed number of mothers with CD was 2.25 times higher than the expected one in the Italian female population (P = 0.039). Undiagnosed CD in mothers was associated with an increased risk of SGA birth (odds ratio 6.97, 95% CI 1.11-43.55%)., Conclusions: While additional powered studies are needed, the present results suggest that the prevalence of undiagnosed CD in the mothers of SGA infants is higher than in the general female population.

Recent evidence indicates a possible role of D-dimer in the early diagnosis of ischemic stroke subtypes. Whether D-dimer can also predict the long-term outcome following ischemic stroke is controversial. To define the prognostic role of D-dimer, patients hospitalized after an acute ischemic cerebrovascular event underwent D-dimer measurement (Liatest D-D; normal level < 0.50 microg/ml) on admission and were followed up for recurrent cerebrovascular events, occurrence of other cardiovascular events, and mortality. We enrolled 96 patients (mean age 74.9 years, 42 men). Mean follow-up was 61.5 months; 47 (48.5%) patients died, 23 (48.9%) because of a vascular event. There was no difference in mean D-dimer levels between dead patients and survivors (1.68 and 1.63 microg/ml, P = NS), but the mortality risk was higher with D-dimer of at least 0.50 microg/ml (odds ratio, 5.32; 95% confidence interval, 1.79-15.84). After adjustment for age and stroke subtype, the odds ratio was not significant. Mean D-dimer was similar between patients with and without a new vascular event (1.43 and 1.68 microg/ml, P = NS), and D-dimer of at least 0.50 microg/ml was not predictive of an increased risk of subsequent events. D-dimer levels measured in the acute phase after an acute cerebrovascular event probably do not predict the long-term clinical outcome.

Background: At the onset of sepsis, endotoxins or other components of the gram-negative capsular wall stimulate the synthesis of pro-inflammatory cytokines by activating the monocyte-macrophage system. In this context, interleukin-1 beta (IL-1), tumor necrosis factor-alpha (TNF) and IL-6 are considered co-responsible for the clinical picture of sepsis syndrome. Many organs can be involved, and kidney dysfunction occurs early with a picture of non-oliguric acute renal failure (NOARF) or oliguric acute renal failure (OARF). This study aimed to investigate the role of the kidney in plasma removal of some pro-inflammatory cytokines in the first 24 hr after the diagnosis of sepsis syndrome, when, according to the peak concentration hypothesis, their plasma concentration is maximal. 18 septic patients, six patients with normal renal function (NRF), six with NOARF and six with OARF were selected for the study. We measured the plasma levels and urinary excretion of IL-1, TNF and IL-6 at the moment of sepsis diagnosis (base-line) and 24 hr later. Moreover, urinary excretion of IL-1 and IL-6 was done in the same interval by measuring the percentage of fractional excretion (FE%) of these cytokines., Results: Multivariate analysis (ANOVA) showed no significant difference in plasma IL-1 levels at baseline in the NRF, NOARF and OARF patients (p=0.11), whereas a significant increase was found in OARF patients at 24 hr, p<0.023. OARF patients presented significantly higher IL-6 plasma levels compared with the other two groups, both at baseline (p<0.0002) and at 24 hr (p<0.0001). Plasma TNF levels were not significantly different at baseline (p=0.184), whereas the OARF group showed a significant increase at 24 hr, (p<0.05). The urinary FE of IL-1 was 1.2 +/- 0.6% in NRF, and 1.0 +/- 0.4% in NOARF (ns), the FE of IL-6 was 1.4 +/- 0.8% in NRF and 1.3 +/- 0.3% in NOARF (ns). A negative in-significant correlation was found between the plasma concentration and FE of IL-1 beta (r=-0.33, p<0.07). Urinary excretion of IL-6 was significantly related with urinary IL-1 beta, both expressed as pg/ml/mg of urinary creatinine (r=0.85, p<0.0001). No significant relation was found between IL-1 and IL-6 plasma concentrations or between plasma concentration and FE of IL-6., Conclusion: These results suggest that at disease onset, the kidney removes some pro-inflammatory cytokines from the plasma of septic patients until diuresis is preserved. As it has been demonstrated that NOARF patients have a better prognosis than OARF patients and their survival in sepsis syndrome seems to be inversely related to the plasma pro-inflammatory cytokine levels, diuresis maintenance by diuretic infusion can be important to improve patient prognosis.

Objectives: To evaluate myocardial damage during coronary artery bypass grafting using three different intermittent cardioplegia and then measuring cTnI and CKMBm release., Design and Methods: Forty-two patients belonging to the hypothermic crystalloid (n = 16), hypothermic (n = 13), and normothermic blood (n = 13) groups were collected when removing the aortic cross-clamp (t = 0) and after 4, 12, 24 and 48 h. For each patient, cumulative cTnI and CKMBm release was calculated as the five measurement mean. There were no significant preoperative and operative differences in the three groups., Results: In the normothermic group, cTnI mean values at 4, 12, and 24 h were significantly lower than those in both hypothermic groups; moreover, CKMBm mean values were higher at 4, 12, and 24 h in the hypothermic crystalloid group and at 4 and 12 h in the hypothermic blood group than in the normothermic group. In the normothermic group, the area under the curve of the release of both markers was significantly lower than in the hypothermic groups. No significant difference was reported in the release of both markers in hypothermic groups., Conclusions: A strategy of normothermic cardioplegia seems to preserve myocardium better than hypothermic cardioplegia.

Multiple sclerosis and celiac disease are both considered immune-mediated diseases. Recently, improved serological screening methods provided a higher prevalence of celiac disease (CD) in the general population worldwide and also demonstrated gastrointestinal symptoms may be lacking. The aim of this study was to determine the prevalence of (CD) in an unselected group of 95 adults with multiple sclerosis using transglutaminase antibodies. No patients showed pathological values. Different immune and genetic basis between the two diseases may represent crucial insights to explain our results.

Unlabelled: Fecal elastase is considered to be a highly sensitive and specific non-invasive exocrine pancreatic function test. However, enteropathy may theoretically cause decreased exocrine pancreatic enzyme secretion through alteration of enteric hormone release., Objective: The aim of this study was to evaluate the possible influence of transient small bowel damage on pancreatic elastase secretion., Methods: We studied 166 children (aged 4 months to 14 years, mean 2 years); 114 of these children had acute enteritis and 52 children were control subjects (with gastro-intestinal symptoms or extra-intestinal diseases). Feces were collected from each patient 3 days after the onset of diarrhea and then tested for fecal elastase, bacterial pathogens, Rotavirus, and Adenovirus. Liquid fecal samples were not considered eligible for elastase measurement. Pancreatic elastase was measured using an ELISA method (Sche.Bo.Tech, Germany). We classified the results, expressed in microg/g stool, as: severe pancreatic insufficiency (<100 microg/g), moderate pancreatic insufficiency (100 to 200 microg/g), and normal (>200 microg/g)., Results: In the acute enteritis group we found severe levels in 14 (12%) children, moderate levels in 18 children (16%), and normal levels in 82 children (72%). In contrast, 52 of 52 (100%) control subjects demonstrated normal results. Statistical analysis (Wilcoxon rank test) demonstrated a significant difference between the enteritis and control groups (P < 0.01). Serial measurement of fecal elastase performed in 10 patients with enteritis showed a progressive increase of levels in 6 patients and an early decline with subsequent increases in the other 4 patients., Conclusions: Transient exocrine pancreatic insufficiency may be present in transient small bowel disease, caused by both bacterial and viral infections, possibly related to reduced enteric CCK secretion.

Background: Different coagulation abnormalities according to stroke subtypes have been reported. We have assessed the clinical utility of D-dimer, a product of fibrin degradation, in the early diagnosis of stroke subtypes., Methods: Patients hospitalized after an acute ischemic cerebrovascular event underwent D-dimer assay (STA Liatest D-Dimer) (reference level, <0.50 micro g/mL) on days 1, 6 +/- 1, and 12 +/- 1 and were studied to identify stroke subtypes., Results: We included 126 patients (mean age, 75.5 years) and 63 age-matched control subjects. Stroke subtypes were cardioembolic in 34 patients (27%), atherothrombotic in 34 (27%), lacunar in 31 (25%), and unknown in 27 (21%). At all 3 measurements, D-dimer levels were significantly higher in the cardioembolic group (mean +/- SEM, 2.96 +/- 0.51, 2.58 +/- 0.40, and 3.79 +/- 0.30 micro g/mL, respectively) than in the atherothrombotic (1.34 +/- 0.21, 1.53 +/- 0.26, and 2.91 +/- 0.23 micro g/mL, respectively) (P<.05) and lacunar (0.67 +/- 0.08, 0.72 +/- 0.15, and 0.64 +/- 0.06 micro g/mL, respectively) groups (P<.01). The difference was also significant between the latter 2 groups (P<.01). We found no difference between the lacunar group and controls (0.53 +/- 0.14 micro g/mL). According to day 1 measurements, the optimal cutoff point for predicting cardioembolic stroke was 2.00 micro g/mL, resulting in a specificity of 93.2% and in a sensitivity of 59.3%. For predicting lacunar stroke, the cutoff point was 0.54 micro g/mL, with a specificity of 96.2% and a sensitivity of 61.3%., Conclusion: The increasing use of the D-dimer assay in clinical practice could be extended to patients presenting with acute cerebrovascular ischemic events to help predict stroke subtype.

Background: Fetal and maternal outcomes of 70 pregnancies in 48 women with lupus nephritis were retrospectively analyzed., Methods: In 13 women, lupus nephritis developed during pregnancy (group A). In 38 patients with known lupus nephritis (including 3 patients in group A who had another pregnancy), 57 pregnancies occurred. In 6 patients, a therapeutic abortion was performed. The remaining 51 pregnancies were considered pregnancies in lupus nephritis (group B)., Results: Fetal loss was 36% (38%, group A; 35%, group B); it decreased from 46% in the 1970s to 30% in the last decade. Among 41 live births, there were 13 preterm deliveries and 28 full-term deliveries. At multivariate analysis, proteinuria (P = 0.025), arterial hypertension (P = 0.05), and antiphospholipid antibodies (P = 0.01) were independent predictors of fetal loss. In group A, 3 patients developed acute renal failure, irreversible in 1 patient (7.7%); all other patients recovered after steroid and immunosuppressive therapy. In group B, 12 renal flares and 1 extrarenal flare developed during pregnancy or the postpartum period. Two patients progressed to irreversible renal failure (3.9%), and 1 of the 2 patients died. All other patients recovered. The incidence of renal flares before or during pregnancy was not different (P = 0.51). Renal quiescence at the onset of pregnancy was the only predictor of favorable maternal outcome., Conclusion: Proteinuria, hypertension, and positivity of antiphospholipid antibodies are independent predictors of adverse fetal outcome. Quiescence of renal disease is the only predictor of favorable maternal outcome., (Copyright 2002 by the National Kidney Foundation, Inc.)

In normal subjects, the gastric ionisation of calcium and phosphate seems to be a prerequisite for their intestinal absorption. We investigated the behavior of the plasma calcium and phosphate profile in 30 patients on regular dialysis treatment in the 6 h following a meal containing 1 g of calcium and 2 g of phosphate. Moreover, to assess the role of gastric acidity, the study was repeated after 3 days on omeprazole administration, to nearly abolish gastric acid secretion. Both total plasma calcium and ionized calcium peaked after the meal (at 30 and 120 min, respectively) only in basal study, while no peak was observed after the administration of omeprazole. Surprisingly, both in basal and in the omeprazole study the levels of plasma phosphate did not increase after the test meal. In conclusion, as in normal subjects, the gastric ionization of dietary calcium promotes the intestinal absorption of calcium in uremic patients on dialysis treatment, while the acute gastric acid inhibition by omeprazole reduced the intestinal calcium transport. In contrast, with the "trade off" hypothesis we did not observe any postprandial phosphate peak after the dietary load, and, in contrast with normal subjects, omeprazole administration did not influence the phosphate profile., (Copyright 2002 S. Karger AG, Basel)

Background: The natural history of hepatitis B virus (HBV) infection in patients undergoing maintenance dialysis is still unclear. The aim of this study was to measure the HBV viral load (HBV DNA) in a cohort (n=20) of HBsAg positive chronic dialysis patients over a 12-month observation period. METHODS; HBV DNA was measured by the Amplicor HBV MonitorTM Test Kit, an in vitro test that utilizes Polymerase Chain Reaction (PCR) nucleic acid amplification and DNA hybridisation for the quantitative measurement of hepatitis B viral DNA in human serum. Amplicor HBV MonitorTM Test Kit amplifies a sequence in the pre-Core/Core region of the HBV genome with biotinylated and non-biotinylated oligonucleotide primers., Results: There was no significant difference between the median HBV load at the start and the end of the study, 1.85 x 104 HBV copies/ml (percentile 16.84; 6.35 x 102 - 3.5 x 106 HBV copies/ ml) and 8.5 x 103 HBV copies/ml (percentile 16.84; 5.5 x 102 - 6.38 x 105 HBV copies/ml), respectively. These serum HBV DNA levels were lower than those measured by the same test in patients with chronic hepatitis B and normal renal function (Hepatology 2000; 32: 116-23). In the group of HBsAg positive carriers on dialysis, we identified three patterns of HBV viremia over time: 1) patients (n=6) with persistent HBV DNA, 2) those (n=2) with undetectable HBV DNA and 3) those (n=12) with intermittent HBV DNA. Patients with persistent HBV DNA (median, 3.3 x 104 HBV copies/ml; percentile 16.84; 3.5 x 103 - 2.3 x 106 HBV copies/ml) had higher viral HBV load than those with intermittent HBV viremia (median, 1.2 x 103 HBV copies/ml; percentile 16.84; 3.5 x 102 - 2.3 x 104 HBV copies/ml) (p=0.0001). Patients with persistent HBV DNA had higher frequency of serum hepatitis B e antigen (HBeAg) positivity than those showing intermittent and negative HBV DNA, 50% (3/6) vs. 0% (p=0.04). The frequency of serum IgM antibody against hepatitis B core antigen (IgM anti-HBc) was higher in patients with persistent HBV DNA than those having intermittent or negative HBV DNA, 100% (6/6) vs. 33% (4/12), p=0.03. We detected no difference in aminotransferase activity between patients with persistent HBV DNA and those showing intermittent or negative HBV DNA. In the group with persistent HBV DNA, the mean difference between maximum and minimum values of HBV DNA observed in each individual patient was 6.13+/-1.25 decimal logarithm (Log10) and in patients with intermittent HBV DNA 3.87+/-1.49 Log10 (p=0.006). In the entire group, the fluctuations in HBV DNA values over time between and within individuals were not significant., Conclusions: The viremic HBV load was low and relatively stable over a 12-month follow-up period; three patterns of HBV viremia over time were observed; 30% of the viremic patients had persistent HBV viremia, and those patients had larger viral load and higher frequency of HBeAg and anti-HBc IgM than did patients with intermittent or negative HBV DNA. Prospective studies with longer observation periods are in progress to fully understand the natural history of HBV in these immunosuppressed patients.

Background: A new genus in the family Flaviviridae has recently been discovered; it has provisionally been designated GBV-C/HGV. As determined by virologic techniques [reverse-transcription polymerase chain reaction (RT-PCR)], infection with GBV-C/HGV is frequent in renal transplant (RT) recipients and in patients on chronic hemodialysis (HD). The epidemiology of GBV-C/HGV infection in patients on peritoneal dialysis is scarce and mostly based on RT-PCR technology., Purpose: We report on the prevalence (as detected by serologic and virologic techniques) and the risk factors for GBV-C/HGV infection in a cohort of patients on continuous ambulatory peritoneal dialysis (CAPD). We also tested a control group of blood donors., Methods: Infection by GBV-C/HGV was assessed by serologic and virologic techniques. Cases of GBV-C/HGV viremia (GBV-C/HGV RNA) were detected by RT-PCR. Antibodies to the envelope protein of GBV-C/HGV (anti-E2 GBV-C/HGV antibody) were analyzed by serologic methods., Results: We found a high frequency [17/85 (20%)] of GBV-C/HGV. The rates of GBV-C/HGV viremia and anti-E2 GBV-C/HGV positivity were 10.5% (9/85) and 10.5% (9/85) respectively. In most patients [17/18 (94%)], the presence of anti-E2 GBV-C/HGV antibody was associated with clearance of GBV-C/HGV from serum. No relationship was noted between anti-E2 GBV-C/HGV antibody (or GBV-C/ HGV viremia) and age, sex, race, time on dialysis, anti-HCV antibody, HBsAg status, and anti-HIV positivity. The frequency of GBV-C/HGV infection in CAPD patients was much higher than that in blood donors, even if the difference did not approach statistical significance. No associations between GBV-C/HGV positivity and biochemical liver tests [aminotransferase and gamma glutamyl transpeptidase (GGT)] were apparent., Conclusions: Infection by GBV-C/HGV as detected by RT-PCR and anti-E2 antibody was common in patients on CAPD and in controls alike. No association was seen between GBV-C/HGV and various demographic or clinical factors. The clinical significance of GBV-C/HGV in CAPD remains unclear. Larger investigations are in progress.

Background: Control of spread of HBV infection in dialysis units in developed countries has been one of the major advances in managing end-stage renal disease (ESRD). Patients with chronic HBV, however, continue to enter the population pool of dialysis patients and transplant candidates. The clinical significance related to the presence of HBsAg in serum of dialysis patients has not been completely understood., Aim and Methods: We collected demographic, biochemical and virological data from a large (n=464) population of patients on maintenance dialysis. This was done to assess the influence of virological and host factors on hepatocellular damage, as shown by serum aminotransferase activity., Results: The frequency of HBsAg positivity in our dialysis population was 8.2 % (38/464); the rate of HBsAg positive patients showing HBe antigen was 20.6% (7/34). Twenty-two (84.6%) of 26 HBsAg positive patients showed detectable HBV DNA in serum by Amplicor HBV MonitorTM Test. HBsAg positive patients had serum aminotransferase activity significantly higher than HBsAg negative individuals; GOT (AST) 25.1+/-29.9 vs. 16+/-21.5 UI/L (p=0.001), and GPT (ALT) 31.3+/-52.5 vs. 17.7+/-21.9 UIL (p=0.034). In the subset of HBsAg positive dialysis patients, those in the replicative phase HBeAg positive) had aminotransferase activity higher than HBeAg negative individuals, AST, 42.3+/-43.6 vs. 22.4+/-27.3 UI/L (p=0.097) and ALT, 49.41+/-54.7 vs. 29.17+/-55.76 UI/L (NS) respectively. We did a multivariate analysis by standard least square model on the entire patient group and we found independent and significant association between detectable HBsAg in serum and AST (p=0.0089)and ALT (p=0.0159) values. There was an independent and significant relationship between age and ALT (p=0.01)., Conclusions: In our study group, HBsAg positive patients on dialysis had serum aminotransferase activity significantly higher than that measured in HBsAg negative individuals. However, mean transaminase levels in HBsAg positive patients on dialysis were below the upper limit of normal for the reference range of healthy controls. HBsAg positive dialysis patients with active viral replication showed the greatest liver damage. Studies are in progress to understand further HBV-related liver disease in dialysis population.

Background: Renal transplantation is the best possibile form of treatment for chronic renal failure. It offers the patient a longer life expectancy when compared to dialysis. Aim of the study was to evaluate our results with live donor transplantation and the variables that influenced the long-term patient and graft survival., Methods: 190 patients received a live donor kidney transplantation in our Hospital between 1984 and 2000. Thirty-eight of them received a graft from an HLA identical donor, 130 from an HLA haploidentical donor, 22 from a living unrelated donor (spouse). Fourteen patients underwent a pre-emptive transplantation. Aim of the study was to evaluate which variables could influence the long-term patient and graft survival., Results: The median follow-up of recipients was 69.5 months. The 10-year patient and graft survival were 94.7% and 73.4% respectively. Graft half-life was 29.6 years. Six patients died. Twelve patients lost their graft because of vascular thrombosis and five patients because of rejection within the first six months. After the first year, 11 patients lost their graft because of chronic rejection and 4 after recurrence of the original disease. One hundred and forty-four patients are still under observation, and at the last examination their mean plasma creatinine was 2.0+/-1.1 mg/dl. At univariate statistical analysis the absence of locus DR incompatibility was associated with a trend toward a better long-term survival of both patient and graft (P=0.05), while less than one year of dialysis showed a significantly better survival rate (P < 0.01)., Conclusions: Living-donor transplantation offers an excellent long-term patient and graft survival.

Hepatitis C virus (HCV) infection is common in the dialysis population and patients with chronic renal failure (CRF) not requiring dialysis. HCV is the most important cause of chronic liver disease in dialysis patients; however, its role has been underestimated by the lower aminotransferase activity in the dialysis population. Aminotransferase activity in patients with CRF not requiring dialysis has not been adequately addressed to date. The aim of this study is to investigate whether serum aminotransferase levels in predialysis patients with CRF are less than those obtained in healthy individuals and dialysis patients. We also analyzed the potential association between serum aminotransferase activity and demographic, clinical, and biochemical parameters. Aspartate (AST) and alanine aminotransferase (ALT) activity was greater in antibody to hepatitis C (anti-HCV)-positive than anti-HCV-negative patients with CRF not requiring dialysis (AST, 32.3 +/- 19 versus 18.1 +/- 8 IU/L [P = 0.0001]; ALT, 32.9 +/- 28 versus 17.7 +/- 11 IU/L [P = 0.00001], respectively). Predialysis patients with CRF had lower AST and ALT activity in comparison to healthy individuals (AST, 19.7 +/- 11.2 versus 20.4 +/- 6.8 IU/L [P = 0.00001]; ALT, 19.5 +/- 15.1 versus 21.7 +/- 11.3 IU/L [P = 0.00001], respectively). The difference was much greater after correction for viral markers: AST and ALT levels in hepatitis B surface antigen (HBsAg)-negative anti-HCV-negative predialysis patients with CRF were less than those in the healthy population (AST, 17.9 +/- 8 versus 20.4 +/- 6.8 IU/L [P = 0.00001]; ALT, 17.5 +/- 10 versus 21.7 +/- 11.3 IU/L [P = 0.00001], respectively). Comparison of AST and ALT activity between age-matched healthy and predialysis seronegative CRF groups showed lower AST and ALT values in the study population. HBsAg-negative anti-HCV-negative dialysis patients had lower AST and ALT activity than seronegative predialysis patients with CRF (AST, 16.6 +/- 11.6 versus 17.9 +/- 8 IU/L [P = 0.01]; ALT, 16.3 +/- 9.4 versus 17.5 +/- 10 [P = 0.041], respectively). Multivariate analysis in the predialysis CRF population showed an independent association between AST (P = 0.00001) and ALT (P = 0.00001) activity and anti-HCV positivity, and age was negatively linked to AST (P = 0.011) and ALT levels (P = 0.001). AST level was negatively related to serum creatinine level (P = 0.0001). In conclusion, HCV infection causes significant liver injury in predialysis patients with CRF. These patients have decreased aminotransferase activity compared with the general population. Dialysis patients show lower aminotransferase activity than predialysis patients with CRF. Because serum aminotransferase levels are commonly used to screen for liver disease in the dialysis and predialysis CRF population, recognition of liver damage may be hampered by the reduction in aminotransferase values in these patients. Studies aimed to clarify the pathogenesis of this phenomenon are in progress.

The possible role of folate supplementation in reducing hyperhomocysteinemia in dialysis patients has been reported in several recent papers. However, scant data are available for peritoneal dialysis patients; besides, none of these studies investigated either the role of intraerythrocyte folate concentration or the presence of side effects caused by folate administration. Sixty-six peritoneal dialysis patients with hyperhomocysteinemia (>15 micromol/l) and normal folate status (as assessed by erythrocyte folate level >600 nmol/l) were randomly allocated to receive either oral folate (5 mg/day) or no vitamin supplementation. After 2 months of therapy, patients were requested to answer a questionnaire investigating the occurrence of symptoms possibly related to folate supplementation. Twenty-nine treated patients and 30 untreated controls completed the study. In the treated patients, serum and erythrocyte folate increased significantly (p < 0.0001) (respectively from 10.6 +/- 4.9 to 237 +/- 231 nmol/l and from 1,201 +/- 297 to 2,881 +/- 294 nmol/l) to levels at the uppermost limit of detection by laboratory methods. Serum vitamin B(12) levels did not change. Plasma homocysteine levels decreased from 54 +/- 32 to 23 +/- 14 micromol/l after folate supplementation and remained unchanged in the control group. After 4 months of folate therapy, homocysteine concentration was within the normal range in 5 patients (17%) and below 30 micromol/l in the other 21 (72%). Folate therapy resulted in a decrease in homocysteine of more than 50% in 45% of the patients and decrease of more than 20% in a further 38%. No significant symptoms were reported. Thus, serum and erythrocyte folate increase confirms that normal folate levels are inadequate in dialysis patients, even if serum and erythrocyte levels before folate supplementation cannot predict the effect on homocysteine plasma levels., (Copyright 2001 S. Karger AG, Basel)