After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Additional Telemedicine Rounds as a Successful Performance-Improvement Strategy for Sepsis Management: Observational Multicenter Study.

BACKGROUND: Sepsis is a major health care problem with high morbidity and mortality rates and affects millions of patients. Telemedicine, defined as the exchange of medical information via electronic communication, improves the outcome of patients with sepsis and decreases the mortality rate and length of stay in the intensive care unit (ICU). Additional telemedicine rounds could be an effective component of performance-improvement programs for sepsis, especially in underserved rural areas and hospitals without ready access to critical care physicians. OBJECTIVE: Our aim was to evaluate the impact of additional daily telemedicine rounds on adherence to sepsis bundles. We hypothesized that additional telemedicine support may increase adherence to sepsis guidelines and improve the detection rates of sepsis and septic shock. METHODS: We conducted a retrospective, observational, multicenter study between January 2014 and July 2015 with one tele-ICU center and three ICUs in Germany. We implemented telemedicine as part of standard care and collected data continuously during the study. During the daily telemedicine rounds, routine screening for sepsis was conducted and adherence to the Surviving Sepsis Campaign's 3-hour and 6-hour sepsis bundles were evaluated. RESULTS: In total, 1168 patients were included in this study, of which 196 were positive for severe sepsis and septic shock. We found that additional telemedicine rounds improved adherence to the 3-hour (Quarter 1, 35% vs Quarter 6, 76.2%; P=.01) and 6-hour (Quarter 1, 50% vs Quarter 6, 95.2%; P=.001) sepsis bundles. In addition, we noted an increase in adherence to the item "Administration of fluids when hypotension" (Quarter 1, 80% vs Quarter 6, 100%; P=.049) of the 3-hour bundle and the item "Remeasurement of lactate" (Quarter 1, 65% vs Quarter 6, 100%, P=.003) of the 6-hour bundle. The ICU length of stay after diagnosis of severe sepsis and septic shock remained unchanged over the observation period. Due to a higher number of patients with sepsis in Quarter 5 (N=60) than in other quarters, we observed stronger effects of the additional rounds on mortality in this quarter (Quarter 1, 50% vs Quarter 5, 23.33%, P=.046). CONCLUSIONS: Additional telemedicine rounds are an effective component of and should be included in performance-improvement programs for sepsis management.

Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy.

The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m2: 6-month corticosteroid monotherapy; GFR=30-59 ml/min per 1.73 m2: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m2 during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; P=0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively; P=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m2 did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.

Intensive Supportive Care plus Immunosuppression in IgA Nephropathy.

BACKGROUND: The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain. METHODS: We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio <0.2 [with both protein and creatinine measured in grams] and a decrease in the estimated glomerular filtration rate [eGFR] of <5 ml per minute per 1.73 m(2) of body-surface area from baseline) and a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) at the end of the trial. The primary end points were analyzed with the use of logistic-regression models. RESULTS: The run-in phase was completed by 309 of 337 patients. The proteinuria level decreased to less than 0.75 g of urinary protein excretion per day in 94 patients. Of the remaining 162 patients who consented to undergo randomization, 80 were assigned to the supportive-care group, and 82 to the immunosuppression group. After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the immunosuppression group, had a full clinical remission (P=0.01). A total of 22 patients (28%) in the supportive-care group and 21 (26%) in the immunosuppression group had a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) (P=0.75). There was no significant difference in the annual decline in eGFR between the two groups. More patients in the immunosuppression group than in the supportive-care group had severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment. One patient in the immunosuppression group died of sepsis. CONCLUSIONS: The addition of immunosuppressive therapy to intensive supportive care in patients with high-risk IgA nephropathy did not significantly improve the outcome, and during the 3-year study phase, more adverse effects were observed among the patients who received immunosuppressive therapy, with no change in the rate of decrease in the eGFR. (Funded by the German Federal Ministry of Education and Research; STOP-IgAN ClinicalTrials.gov number, NCT00554502.).

Urinary Biomarkers in the Prediction of Prognosis and Treatment Response in IgA Nephropathy.

BACKGROUND/AIMS: The addition of immunosuppression to supportive care reduces proteinuria in a subset of patients with IgA nephropathy (IgAN) but is associated with an increased rate of adverse events. The present work investigates whether urinary biomarkers are able to identify subjects who benefit from immunosuppression and to predict the progression of disease in a sub-cohort of the STOP-IgAN trial. METHODS: Urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), calprotectin, and the product of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 (TIMP2•IGFBP7) were measured in all available urine samples obtained at the time point of enrollment in the STOP-IgAN trial (n=113). RESULTS: Biomarker concentrations in both the overall study population and the subgroup with additional immunosuppression did not differ in subjects reaching vs. not reaching full clinical remission, eGFR loss ≥ 15, or 30 ml/min/1.73 m2 over the 3-year trial phase (p> 0.05 each). Receiver-operating characteristic curves showed a poor predictive accuracy of each biomarker for the above-mentioned parameters in the overall study population (areas under the curve ≤0.611). Accordingly, there was neither a significant correlation of any biomarker and adverse outcome in linear regression analysis, nor between biomarker concentrations at enrollment and change in the eGFR over the 3-year observation period. CONCLUSION: NGAL, KIM-1, calprotectin, and [TIMP-2]•[IGFBP7] had neither a prognostic value for the progression of IgAN, nor for the response to immunosuppression in the present sub-cohort of the STOP-IgAN trial. The search for appropriate biomarkers for an individualized treatment strategy in IgAN continues.

CTLA-4 Polymorphisms in Patients with IgA Nephropathy Correlate with Proteinuria.

BACKGROUND/AIMS: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and still constitutes one of the most important causes of end-stage renal disease. Abnormal T cell responses may play a role in IgAN pathogenesis. Co-stimulatory molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are important for naive T cells to initiate and terminate immune responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 gene locus are associated with several autoimmune diseases. METHODS: We aimed to investigate the occurrence of the SNPs -318C/T, +49A/G and CT60 G/A within the CTLA4 locus in healthy blood donors (n=455) and IgAN patients (n=252) recruited from the recently published STOP-IgAN trial. The presence of these SNPs was then associated with baseline proteinuria in IgAN patients. RESULTS: We observed a significantly increased frequency of the CTLA4 -318C/T genotype in IgAN patients as compared to controls (CC vs. CT+TT: OR 1.65, 95%-CI 1.03-2.65, p=0.035). No significant associations, neither with the +49A/G nor for the CT60 G/A SNP, were detected. However, when we stratified for proteinuria at time of inclusion into the STOP-IgAN trial (<1 g/day vs. >1 g/day), we observed significant differences in the frequencies of the CT60 G/A genotype, i.e. a significantly increased risk for higher proteinuria in patients carrying the G allele (OR 2.81, 95%-CI 1.03-7.64, p=0.042). CONCLUSION: The CTLA4 -318/C/T SNP was associated with an increased risk to develop IgAN, while the CT60 G/A genotype significantly associated with the risk for higher proteinuria suggesting a possible role for CTLA-4 in IgAN.

Renal outcomes of STOP-IgAN trial patients in relation to baseline histology (MEST-C scores).

BACKGROUND: The Oxford classification of IgA nephropathy (IgAN) defines histologic criteria (MEST-C) that provide prognostic information based on the kidney biopsy. There are few data on the predictive impact of this classification in randomized clinical trial settings. METHODS: We performed an exploratory analysis of MEST-C scores in 70 available renal biopsies from 162 randomized STOP-IgAN trial participants and correlated the results with clinical outcomes. Analyses were performed by researchers blinded to the clinical outcome of the patients. Biopsies had been obtained 6.5 to 95 (median 9.4) months prior to randomization. RESULTS: Mesangial hypercellularity (M1) associated with higher annual eGFR-loss during the 3-year trial (M1: - 5.06 ± 5.17 ml/min/1.73 m2, M0: - 0.79 ± 4.50 ml/min/1.73 m2, p = 0.002). An M0-score additionally showed a weak association with full clinical remission, whereas the percentage of patients losing ≥15 ml/min/1.73 m2 over the 3-year trial phase was higher among those scored as M1. Among patients with additional immunosuppression, ESRD occurred more frequently in patients when tubulointerstitial fibrosis (T1/2) was present (T1/2 = 33%, T0 = 0%, p = 0.008). In patients receiving supportive care only, ESRD frequencies were similar (T1/2 = 18%, T0 = 7%, p = 0.603). At randomization, eGFR was significantly lower when tubulointerstitial fibrosis was present (T1/2: 45.2 ± 15.7 ml/min/1.73 m2, T0: 74.6 ± 28.2 ml/min/1.73 m2, p < 0.0001). Endocapillary hypercellularity (E), and glomerular segmental sclerosis (S) were not associated with any clinical outcome parameter. In the analyzed cohort, patients with glomerular crescents (C1/2 scores) in their biopsies were more likely to develop ESRD during the 3-year trial phase, but this trend was only significant in patients under supportive care. CONCLUSIONS: This secondary analysis of STOP-IgAN biopsies indicates that M1, T1/2 and C1/2 scores associate with worse renal outcomes.

Con: STOP immunosuppression in IgA nephropathy.

A comprehensive supportive therapy approach constitutes the mainstay treatment of IgA nephropathy (IgAN) patients. In our recent Supportive versus immunosuppressive Therapy Of Progressive IgA Nephropathy (STOP-IgAN) trial, we systematically selected for patients at high risk of a progressive disease course and evaluated the effect of immunosuppression, combined with supportive care, on renal end points in these patients. There was a higher rate of full clinical remission and transient proteinuria reduction in immunosuppressed patients. However, deterioration of renal function (i.e. number of patients with an estimated glomerular filtration rate (eGFR) decrease of at least 15 mL/min over the 3-year trial phase) was remarkably slow in both groups, compared with previous studies, and was not slowed further by adding immunosuppression to supportive care. Here, we address several concerns raised on the design and interpretation of our trial. In our randomized patients, we confirmed a lower baseline proteinuria to be predictive of clinical remission in IgAN. However, the observed transient drop in proteinuria in the immunosuppressed patients did not translate into an improved overall renal outcome in these patients. Although longer follow-up would be desirable, there was not even a trend for the eGFR course to diverge between our two treatment arms during the trial phase. Finally, it is important to note that we excluded specific infrequent patient groups during our run-in phase. Therefore, IgAN patients with a rapidly progressing course and those with persistent proteinuria >3.5 g/day would require further evaluation regarding potential benefits of immunosuppressive therapies.

Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury.

Despite increasing use of prothrombin complex concentrate (PCC) to treat hemorrhage-associated coagulopathy, few studies have investigated PCC in trauma, and there is a particular lack of safety data. This study was performed to evaluate PCC therapy in a porcine model of coagulopathy with blunt liver injury. Coagulopathy was induced in 27 anesthetized pigs by replacing approximately 70% blood volume with hydroxyethyl starch 130/0.4 and Ringer's lactate solution; erythrocytes were collected and retransfused. Ten minutes after trauma, animals randomly received PCC (35 or 50 IU/kg) or saline. Coagulation parameters including thromboelastometry, thrombin generation, and blood loss were monitored for 2 hours. Internal organs were examined macroscopically and histologically to determine the presence of emboli and assess liver injury. Total blood loss was significantly lower and survival was higher in both PCC groups versus the control group (P < .05). These outcomes appeared to be dose-independent. Thromboembolism was found in all animals treated with 50 IU/kg PCC; 44% also showed signs of disseminated intravascular coagulation. Liver injury was similar in all animals. In conclusion, 35 IU/kg PCC safely improved coagulation and attenuated blood loss. However, the higher dose of PCC (50 IU/kg) appeared to increase the risk of thromboembolism and disseminated intravascular coagulation.

Maternal and fetal cord blood lipids in intrauterine growth restriction.

AIM: Small for gestational age neonates (SGA) could be subdivided into two groups according to the underlying causes leading to low birth weight. Intrauterine growth restriction (IUGR) is a pathologic condition with diminished growth velocity and fetal compromised well-being, while non-growth restricted SGA neonates are constitutionally (genetically determined) small. Antenatal sonographic measurements are used to differentiate these two subgroups. Maternal metabolic changes contribute to the pathogenesis of IUGR. A disturbed lipid metabolism and cholesterol supply might affect the fetus, with consequences for fetal programming of cardiovascular diseases. We evaluated fetal serum lipids and hypothesized a more atherogenic lipoprotein profile in IUGR fetuses. METHODS: Umbilical cord serum lipids and oxidative modified, low-density lipoprotein (oxLDL) concentrations were measured by colorimetric enzymatic measurements, or by ELISA. Values of IUGR (n=36) and constitutionally small for gestational age neonates (SGA, n=22) were compared with those of healthy, adequate for gestational age, born neonates (CN, n=97). SAS-statistic software was used and two-way ANOVA was adjusted for gestational age at delivery. RESULTS: Fetal high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) concentrations were found to be lower in the IUGR compared to the CN and SGA groups (HDL-C: P<0.001, TC: P<0.01). Atherogenic indices, including the oxLDL/LDL-C ratio, were increased in the IUGR compared to the CN group (oxLDL/LDL-C ratio: P<0.001). CONCLUSION: Our results support the hypothesis of a disturbed cholesterol supply in IUGR fetuses. Born SGA has been shown to be a risk factor for developing cardiovascular disease later in life. Since HDL-C has anti-inflammatory properties, a reduced HDL-C during fetal development, and an increase in atherogenic indices, might provide a link to this observation in IUGR fetuses.

High-dose supplementation of selenium in left ventricular assist device implant surgery: A double-blinded, randomized controlled pilot trial.

BACKGROUND: Systemic inflammation and oxidative stress remain the main causes of complications in patients with heart failure receiving a left ventricular assist device (LVAD). Selenoproteins are a cornerstone of antioxidant defense mechanisms for improving inflammatory conditions. METHODS: In a monocentric, double-blinded pilot trial patients scheduled for LVAD implantation were randomized to receive 300 mcg of selenium orally the evening before surgery, followed by a high-dose of intravenous selenium supplementation (3000 mcg after anesthesia induction, 1000 mcg upon intensive care unit [ICU] admission, and 1000 mcg daily in the ICU for a maximum of 14 days) or placebo. The main outcomes were feasibility and effectiveness in restoring serum selenium concentrations. RESULTS: Twenty patients were included in the analysis. The average duration of study intervention was 12.6 days (7-14), with 97.7% dose compliance. No patient received open-label selenium. The supplementation strategy was effective in compensating low serum selenium concentrations (before surgery: control, 63.5 ± 11.9 mcg/L vs intervention, 65.8 ± 16.5 mcg/L; ICU admission: control, 49.0 ± 9.8 mcg/L vs intervention, 144.2 ± 45.4 mcg/L). Serum selenium concentrations in the intervention group were significantly higher during the observation period (baseline: mean of placebo (MoP), 63.1 vs mean of selenium (MoS), 64.0; ICU admission: MoP, 49.0 vs MoS, 144.6; day 1-13: MoP, 43.6-48.5 vs MoS, 100.4-131.0). CONCLUSION: Selenium supplementation in patients receiving LVAD implantation is feasible and effective to compensate a selenium deficiency.

Predicting experimental success: a retrospective case-control study using the rat intraluminal thread model of stroke.

The poor translational success rate of preclinical stroke research may partly be due to inaccurate modelling of the disease. We provide data on transient middle cerebral artery occlusion (tMCAO) experiments, including detailed intraoperative monitoring to elaborate predictors indicating experimental success (ischemia without occurrence of confounding pathologies). The tMCAO monitoring data (bilateral cerebral blood flow, CBF; heart rate, HR; and mean arterial pressure, MAP) of 16 animals with an 'ideal' outcome (MCA-ischemia), and 48 animals with additional or other pathologies (subdural haematoma or subarachnoid haemorrhage), were checked for their prognostic performance (receiver operating characteristic curve and area under the curve, AUC). Animals showing a decrease in the contralateral CBF at the time of MCA occlusion suffered from unintended pathologies. Implementation of baseline MAP, in addition to baseline HR (AUC, 0.83, 95% c.i. 0.68 to 0.97), increased prognostic relevance (AUC, 0.89, 95% c.i. 0.79 to 0.98). Prediction performance improved when two additional predictors referring to differences in left and right CBF were considered (AUC, 1.00, 95% c.i. 1.0 to 1.0). Our data underline the importance of peri-interventional monitoring to verify a successful experimental performance in order to ensure a disease model as homogeneous as possible.

Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy.

BACKGROUND: Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial. METHODS: STOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models. RESULTS: Among the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies. CONCLUSION: In the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.

Perioperative Vitamin C and E levels in Cardiac Surgery Patients and Their Clinical Significance.

BACKGROUND: Oxidative stress contributes to organ dysfunction after cardiac surgery and still represents a major problem. Antioxidants, such as vitamins C and E might be organ protective. METHODS: The primary objective of this prospective observational study was the description to evaluate the perioperative vitamin C and E levels in 56 patients undergoing cardiac surgery with the use of cardiopulmonary bypass. The association of vitamin C with inflammatory reaction, oxidative stress, organ dysfunctions, and clinical outcomes were evaluated in an explorative approach. RESULTS: Vitamin C levels decreased significantly from 6.5 (3.5-11.5) mg/L before surgery to 2.8 (2.0-3.9) mg/L 48 h after surgery (p < 0.0001). Fifty-six percent of patients had a suboptimal vitamin C status even before surgery. In protein-denaturized probes, significantly higher vitamin C concentrations were detected (p = 0.0008). Vitamin E levels decreased significantly from preoperative level 11.6 (9.5-13.2) mg/L to 7.1 (5.5-7.4) mg/L, (p = 0.0002) at the end of cardiopulmonary bypass, remained low during the first day on ICU and recovered to 8.2 (7.1-9.3) mg/L 48 h after surgery. No patient was vitamin E deficient before surgery. Analysis showed no statistically significant association of vitamin C with inflammation, oxidative stress or organ dysfunction levels in patients with previously suboptimal vitamin C status or patients with a perioperative decrease of ≥50% vitamin C after surgery. Patients with higher vitamin C levels had a shorter ICU stay than those who were vitamin C depleted, which was not statistically significant (72 versus 135 h, p = 0.1990). CONCLUSION: Vitamin C and E levels significantly declined intraoperatively and remained significantly reduced low for 2 days after cardiac surgery. The influence of reduced serum levels on the inflammatory reaction and clinical outcome of the patients remain unclear in this small observational study and need to be investigated further. Given vitamin C´s pleiotropic role in the human defense mechanisms, further trials are encouraged to evaluate the clinical significance of Vitamin C in cardiac surgery patients.

Regional variations in serotype distribution and vaccination status in children under six years of age with invasive pneumococcal disease in Germany.

OVERVIEW: The protective effect of infant pneumococcal conjugate vaccine (PCV) recommendation can be seen in Germany as a whole and in smaller regional groups. Comparisons between population-normalized geographic regions of Germany show different serotype distributions after program implementation, particularly in non-vaccine serotypes. The prior distinct differences in serotype distribution in children between the former East and former West German federal states have vanished. Children under six remain a vulnerable group, but the occurrence of vaccine-type (VT) invasive pneumococcal disease (IPD) in children correctly vaccinated (using a three-dose primary series plus one booster dose) with PCV13 was low (9 out of 374 cases, 2.4%). However, only 18.4% of children in Germany with IPD were correctly vaccinated with PCV13 according to the recommended schedule. Continued surveillance and better schedule adherence are essential to definitively establish the most effective PCV administration schedule. VACCINATION EFFECTS: For all PCV products used in Germany (PCV7, PCV10, and PCV13), vaccination status was the most common statistically significant predictor of infection with a particular serotype: Unvaccinated children old enough to have received at least one dose of vaccine in the PCV7 group had significantly higher odds (OR: 6.84, 95%CI: 2.66-22.06, adjusted for per capita income and residence in the northeastern federal states) of contracting VT IPD. In the PCV10 group, VT IPD had an OR of 4.52 (95% CI: 1.60-15.62, adjusted for year of infection, median household size, and residence in the southern federal states) in unvaccinated children, and in the PCV13 group, unvaccinated children continued to have higher odds (OR: 6.21, 95%CI: 3.45-11.36, adjusted for year of infection, age of child, per capita income, residence in the southern federal states, and percentage of children using public daycare) of getting vaccine-type IPD. Being unvaccinated was the most frequent significant indicator for infection with vaccine-type serotypes for each analysis group, while geographic groupings showed more limited potential to predict serotype of infection in early childhood IPD in Germany.

Evaluation to improve the quality of medication preparation and administration in pediatric and adult intensive care units.

PURPOSE: To determine the type, frequency, and factors associated with medication preparation and administration errors in adult intensive care units (ICUs) and neonatal ICUs (NICUs)/pediatric ICUs (PICUs). PATIENTS AND METHODS: We conducted a prospective direct observation study in an adult ICU and NICU/PICU in a tertiary university hospital. Between June 2012 and June 2013, a clinical pharmacist and medical student observed the nursing care staff on weekdays during the preparation and administration of intravenous drugs. We analyzed the frequency and type of preparation and administration errors and factors associated with errors. RESULTS: Six hundred and three preparations in the adult ICU and 281 in the NICU/PICU were observed. Three hundred and eighty-five errors occurred in the adult ICU and 38 in the NICU/PICU. There were 5,040 and 2,514 error opportunities, with overall error rates of 7.6% and 1.5%, respectively. The total opportunities for error meant each single step of preparation and administration that was relevant for the drug. Most errors applied to the category "uniform mixing" (adult ICU: n=227, 59%; NICU/PICU: n=14, 37%). The multivariate logistic regression results showed a significantly different influence of the "preparation type" for the adult ICU compared with the NICU/PICU with regard to the occurrence of an error. Preparations for adult patients of the LCD type (liquid concentrate with diluent into syringe or infusion bag) were more often associated with errors than the P (powder in a glass vial that must be reconstituted and diluted if necessary), P=0.012, and LC (liquid concentrate into syringe), P=0.002 type. CONCLUSION: "Uniform mixing" was the most erroneous preparation step in intravenous drug preparations in two ICUs. Improvement of nurse training and the preparation of prefilled syringes in the pharmacy might reduce errors and improve the quality and safety of drug therapy.

Secretory Leukocyte Protease Inhibitor (SLPI)-A Novel Predictive Biomarker of Acute Kidney Injury after Cardiac Surgery: A Prospective Observational Study.

Acute kidney injury (AKI) is one of the most frequent complications after cardiac surgery and is associated with poor outcomes. Biomarkers of AKI are crucial for the early diagnosis of this condition. Secretory leukocyte protease inhibitor (SLPI) is an alarm anti-protease that has been implicated in the pathogenesis of AKI but has not yet been studied as a diagnostic biomarker of AKI. Using two independent cohorts (development cohort (DC), n = 60; validation cohort (VC), n = 148), we investigated the performance of SLPI as a diagnostic marker of AKI after cardiac surgery. Serum and urinary levels of SLPI were quantified by ELISA. SLPI was significantly elevated in AKI patients compared with non-AKI patients (6 h, DC: 102.1 vs. 64.9 ng/mL, p < 0.001). The area under the receiver operating characteristic curve of serum SLPI 6 h after surgery was 0.87 ((0.76-0.97); DC). The addition of SLPI to standard clinical predictors significantly improved the predictive accuracy of AKI (24 h, VC: odds ratio (OR) = 3.91 (1.44-12.13)). In a subgroup, the increase in serum SLPI was evident before AKI was diagnosed on the basis of serum creatinine or urine output (24 h, VC: OR = 4.89 (1.54-19.92)). In this study, SLPI was identified as a novel candidate biomarker for the early diagnosis of AKI after cardiac surgery.

The relevance of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentration for postoperative infections and postoperative organ dysfunctions in cardiac surgery patients: The eVIDenCe study.

BACKGROUND & AIMS: Recent studies indicate that vitamin D deficiency is associated with increased morbidity and mortality in critically ill patients. Knowledge about the functional role and clinical relevance of vitamin D for patients undergoing cardiac surgery is sparse. Therefore, we investigated the clinical significance of vitamin D levels on outcome of cardiac surgery patients. METHODS: 92 patients undergoing elective cardiac surgery with cardiopulmonary arrest were included in this prospective observational pilot study. 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured prior to surgery, immediately postoperatively as well as 6, 12 and 24 h after surgery. We assessed postoperative organ dysfunctions, infections and death until hospital discharge. RESULTS: The serum concentration of 1,25(OH)2D significantly decreased intraoperatively by 29.3% (p < 0.001) and was significantly lower at any postoperative time point compared to baseline values, whereas 25OHD levels did not show significant changes during the observation period. Coronary artery bypass graft (CABG) patients had significant higher baseline 1,25(OH)2D values than patients with valve surgery (39.7 ± 13.9 ng/l vs. 30.1 ± 14.1 ng/l, p = 0.010) or CABG + valve surgery (39.7 ± 13.9 ng/l vs. 32.6 ± 11.8 ng/l, p = 0.044). Our data showed a significant odds ratio to develop postoperative organ dysfunction (OR 0.95; p = 0.009) and PCT levels ≥5 µg/l (OR 0.94; p = 0.046) for every ng/l increment in 1,25(OH)2D, when performing multivariable analysis and after adjusting for preoperative illness and demographics. In addition, multivariable-adjusted statistical analyses revealed that patients stayed significantly shorter on ICU (-0.21 h; p = 0.001) and in hospital (-2.6 days; p = 0.009) for every ng/l increment in 1,25(OH)2D. CONCLUSION: Our data highlight important evidence about the clinical significance of 1,25(OH)2D levels in cardiac surgery patients. Higher levels were associated with significantly less postoperative organ dysfunctions, elevated PCT levels, death and prolonged hospital stay. 1,25(OH)2D levels decreased significantly intra- and postoperatively, while serum levels of 25OHD did not. TRIAL REGISTRATION: clinicaltrials.gov (NCT02488876), registered May 1, 2015.

Epidemiology and distribution of 10 superantigens among invasive Streptococcus pyogenes disease in Germany from 2009 to 2014.

A nationwide laboratory-based surveillance study of invasive S. pyogenes infections was conducted in Germany. Invasive isolates (n = 719) were obtained between 2009 and 2014. Most isolates were obtained from blood (92.1%). The proportions of isolates from cerebrospinal fluid, pleural fluid, synovial fluid and peritoneal fluid were 3.9%, 1.8%, 1.7% and 0.6%, respectively. The most common emm types were emm 1 (31.8%), emm 28 (15.4%) and emm 89 (14.5%). The most common superantigen genes (speA, speC, speG, speH, speI, speJ, speK, speL, speM, ssa) identified from S. pyogenes were speG (92.1%), speJ (50.9%), and speC (42.0%). Significant associations of superantigen genes with underlying conditions or risks were observed in speG, speH, speJ, and speK. Significant associations between emm types or superantigen genes with clinical complications were observed in emm type 3 and in superantigen gene speA 1-3. Most frequent clinical manifestations included sepsis 59.4%, STSS 6.3%, meningitis 5.4%, and necrotizing fasciitis 5.0% (significantly associated with emm1).