Association between prenatal glucocorticoid exposure and adolescent neurodevelopment: An observational follow-up study.

INTRODUCTION: Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long-lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8-9 years. This follow-up study aimed to examine whether these findings persisted into adolescence. MATERIAL AND METHODS: Prospective observational follow-up study involving twenty-one 14- to 15-year-old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37+4 gestational weeks). Thirty-five children not exposed to betamethasone served as the reference group (median 37+6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention-deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus-pituitary-adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm. RESULTS: No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 versus references 105.9, mean difference -2.0, 95% confidence interval [CI]: -7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress-induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency-adjusted means: 16.0 Hz versus 17.8 Hz, mean difference -1.83 Hz, 95% CI: -3.21 to -0.45, p = 0.01). CONCLUSIONS: In 14- to 15-year-old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow-up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions.

Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8- to 9-year-old children: A prospective observational study.

INTRODUCTION: Glucocorticoid (GC) -induced fetal programming of the activity of the hypothalamus-pituitary-adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood. MATERIAL AND METHODS: Prospective observational study in 31 children whose mothers received single (n = 19) or multiple (n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+6  weeks of gestation) compared with 38 non-exposed, age-matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention-deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG). RESULTS: There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM-exposed children had lower IQ scores than the unexposed group. BM-exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose-response relation between BM exposure and activity of the ANS and IQ was estimated in post-hoc analyses. CONCLUSIONS: Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life-saving therapy, but its prescription may warrant a well-balanced risk-benefit assessment.

Combined assessment of 3q26 amplification and promoter methylation in patients with high grade cervical lesions show age specific differences.

A considerable proportion of high grade cervical intraepithelial lesions (CIN2/3) are known to resolve on their own especially among young women. However, since reliable prognostic markers are still lacking, the diagnosis "CIN3" is still an indication for surgery which may result in overtreatment. It is conceivable that a combination of different, ideally independent molecular markers may provide more reliable results. In the present cross-sectional study two established triage markers, 3q26 amplification and a methylation signature, were evaluated in an age-dependent manner. The patient cohort comprised 60 patients with histologically confirmed CIN2/3 in two equally sized age groups (<30 years, ≥30 years). Cervical scrapes were analyzed by interphase fluorescence in situ hybridization for 3q26 amplification and methylation specific PCR (GynTect®) for six different genome regions. Both assays showed a significantly different pattern of test outcome independent of age (P = .001). Moreover, the combination of both assays differed significantly for double positive and double negative cases when comparing the two age groups: In patients <30 years there were clearly less cases with positive methylation signature and amplification of 3q26 as in women ≥30 years (23% vs 63%, Bonferroni adjusted P = .016). Of particular interest is the finding that double negative results were exclusive for the young age group (0% vs 27%, Bonferroni adjusted P = .020). Since regression of CIN2/3 characteristically occurs among young women it is tempting to speculate that a double negative test result could be prognostic for regression of CIN2/3. This will have to be investigated further in a prospective longitudinal intervention study.

Impact of sleep disordered breathing on short-term post-operative outcome after elective coronary artery bypass graft surgery: a prospective observational study.

Sleep disordered breathing (SDB) is common in patients with coronary disease, but its impact on post-operative recovery after coronary artery bypass graft surgery (CABG) is unclear. We therefore determined the effects of SDB on post-operative outcome after elective CABG.In this prospective two-centre study, 219 patients due to receive elective CABG underwent cardiorespiratory polygraphy for SDB prior to surgery and were monitored for post-operative complications. The primary end-point was a composite of 30-day mortality or major post-operative complications (cardiac, respiratory, surgical, infectious, acute renal failure or stroke). Key secondary end-points were single components of the primary end-point.SDB was present in 69% and moderate/severe SDB in 43% of the CABG patients. There was no difference in the composite of 30-day mortality or major postoperative complications between patients with and without SDB (OR 0.97, 95% CI 0.49-1.96) and between patients with moderate/severe SDB and no/mild SDB (OR 1.07, 95% CI 0.55-2.06). However, moderate/severe SDB was associated with higher rates of mortality (crude OR 10.1, 95% CI 1.22-83.5), sepsis (OR 2.96, 95% CI 1.17-7.50) and respiratory complications (OR 2.85, 95% CI 1.46-5.55).Although SDB was not associated with higher overall morbidity/mortality, moderate/severe SDB may increase the risk of death, and septic and respiratory complications, after elective CABG.

Viral-Cellular DNA Junctions as Molecular Markers for Assessing Intra-Tumor Heterogeneity in Cervical Cancer and for the Detection of Circulating Tumor DNA.

The development of cervical cancer is frequently accompanied by the integration of human papillomaviruses (HPV) DNA into the host genome. Viral-cellular junction sequences, which arise in consequence, are highly tumor specific. By using these fragments as markers for tumor cell origin, we examined cervical cancer clonality in the context of intra-tumor heterogeneity. Moreover, we assessed the potential of these fragments as molecular tumor markers and analyzed their suitability for the detection of circulating tumor DNA in sera of cervical cancer patients. For intra-tumor heterogeneity analyses tumors of 8 patients with up to 5 integration sites per tumor were included. Tumor islands were micro-dissected from cryosections of several tissue blocks representing different regions of the tumor. Each micro-dissected tumor area served as template for a single junction-specific PCR. For the detection of circulating tumor-DNA (ctDNA) junction-specific PCR-assays were applied to sera of 21 patients. Samples were collected preoperatively and during the course of disease. In 7 of 8 tumors the integration site(s) were shown to be homogenously distributed throughout different tumor regions. Only one tumor displayed intra-tumor heterogeneity. In 5 of 21 analyzed preoperative serum samples we specifically detected junction fragments. Junction-based detection of ctDNA was significantly associated with reduced recurrence-free survival. Our study provides evidence that HPV-DNA integration is as an early step in cervical carcinogenesis. Clonality with respect to HPV integration opens new perspectives for the application of viral-cellular junction sites as molecular biomarkers in a clinical setting such as disease monitoring.

Intensified colonisation screening according to the recommendations of the German Commission for Hospital Hygiene and Infectious Diseases Prevention (KRINKO): identification and containment of a Serratia marcescens outbreak in the neonatal intensive care unit, Jena, Germany, 2013-2014.

PURPOSE: In 2013, the German Commission for Hospital Hygiene and Infectious Disease Prevention (KRINKO) stated that extending weekly colonisation screening from very low birth weight (VLBW) infants (<1500 g) to all patients in the Neonatal Intensive Care Unit (NICU) might be useful. METHODS: After implementing this recommendation, we detected a previously unnoticed cluster of Serratia marcescens. Strains were typed by Pulsed Field Gel Electrophoresis (PFGE). RESULTS: Over 6 months, 19 out of 159 infants acquired S. marcescens. Twelve of the nineteen patients with S. marcescens were non-VLBW infants, and they were colonised significantly earlier than were VLBW infants (median 17 vs. 28 days; p < 0.01). Molecular typing revealed a polyclonal outbreak with multiple strain types leading to one or two transmissions each and a dominating outbreak strains being involved in an explosive outbreak involving eight neonates. CONCLUSION: The revised KRINKO recommendation may help identify unnoticed outbreaks. Colonised non-VLBW patients may be an underestimated source of S. marcescens.

End-of-life care in the intensive care unit: a patient-based questionnaire of intensive care unit staff perception and relatives' psychological response.

BACKGROUND: Communication is a hallmark of end-of-life care in the intensive care unit. It may influence the impact of end-of-life care on patients' relatives. We aimed to assess end-of-life care and communication from the perspective of intensive care unit staff and relate it to relatives' psychological symptoms. DESIGN: Prospective observational study based on consecutive patients with severe sepsis receiving end-of-life care; trial registration NCT01247792. SETTING/PARTICIPANTS: Four interdisciplinary intensive care units of a German University hospital. Responsible health personnel (attendings, residents and nurses) were questioned on the day of the first end-of-life decision (to withdraw or withhold life-supporting therapies) and after patients had died or were discharged. Relatives were interviewed by phone after 90 days. RESULTS: Overall, 145 patients, 610 caregiver responses (92% response) and 84 relative interviews (70% response) were analysed. Most (86%) end-of-life decisions were initiated by attendings and only 2% by nurses; 41% of nurses did not know enough about end-of-life decisions to communicate with relatives. Discomfort with end-of-life decisions was low. Relatives reported high satisfaction with decision-making and care, 87% thought their degree of involvement had been just right. However, 51%, 48% or 33% of relatives had symptoms of post-traumatic stress disorder, anxiety or depression, respectively. Predictors for depression and post-traumatic stress disorder were patient age and relatives' gender. Relatives' satisfaction with medical care and communication predicted less anxiety (p = 0.025). CONCLUSION: Communication should be improved within the intensive care unit caregiver team to strengthen the involvement of nurses in end-of-life care. Improved communication between caregivers and the family might lessen relatives' long-term anxiety.

Study protocol: prediction of stroke associated infections by markers of autonomic control.

BACKGROUND: Infection is the most important complication after acute stroke. This is substantially based on a stroke-induced immunosuppression. Heart rate variability (HRV) represents the autonomic nervous system activity in connection with stroke-induced immunomodulation and infections. We demonstrated in a feasibility study that HRV indices obtained in patients without acute post-stroke infections can predict infections in the subsequent sub-acute phase. METHODS/DESIGN: The study PRED-SEP is a prospective observational study. Adult patients with acute ischemic infarction in the territory of the middle cerebral artery and severe neurological deficit (National Institutes of Health Stroke Scale: NIHSS ≥ 8) are recruited. Primary endpoint is the development of infections, secondary endpoints are SIRS and severe sepsis in the sub-acute phase (day 3-5) after stroke and the functional outcome after 3 months. Infection is defined according to the PANTHERIS study and comprises pneumonia, urinary tract infection and infections without determined focus. SIRS and severe sepsis are defined according to German Sepsis Society guidelines. Functional outcome is measured by lethality and neurological scores (modified Rankin Scale, Barthel Index). Prognostic factors are HRV risk indices calculated from selected intervals of 24 h ECG measurements within 48 hours after symptom onset. It is planned to recruit 240 patients.HRV risk indices (predictors) will be calculated according to standards and procedures previously developed and published by the authors. The predictive effects of HRV indices on infections will be estimated by fitting logistic regression models and estimating odds ratios with 95% confidence intervals. A prespecified modelling procedure will be applied to estimate unadjusted and confounder adjusted odds ratios. Secondary endpoints will be analysed in the same way. The functional outcome scales will be dichotomized. The association between HRV indices and pro- and anti-inflammatory markers will be quantified by calculating the appropriate correlation coefficients according to scale (Person or Spearman). DISCUSSION: Since a general prophylactic antibiotic treatment after stroke is not recommended, results of this study could have essential implications for an early identification and hence, timely appropriate treating of stroke-induced infections. TRIAL REGISTRATION: Prädiktoren für die Sepsis - Pred Sep, German Clinical Trials Register: DRKS00003392.

Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study.

INTRODUCTION: Current sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome. METHODS: In a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality. RESULTS: Median time to AT was 2.1 (IQR 0.8 - 6.0) hours and 3 hours (-0.1 - 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001). CONCLUSIONS: A delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality.

The PRAISE study: a prospective, multi-center, randomized, double blinded, placebo-controlled study for the evaluation of iloprost in the early postoperative period after liver transplantation (ISRCTN12622749).

BACKGROUND: Liver graft dysfunction can deteriorate to complete organ failure and increases perioperative morbidity and mortality after liver transplantation. Therapeutic strategies reducing the rate of graft dysfunction are of current clinical relevance. One approach is the systemic application of prostaglandins, which were demonstrated to be beneficial in reducing ischemia-reperfusion injury. Preliminary data indicate a positive effect of prostacyclin analogue iloprost on allograft viability after liver transplantation. The objective of the study is to evaluate the impact of iloprost in a multi-center trial. METHODS/DESIGN: A prospective, double-blinded, randomized, placebo-controlled multicenter study in a total of 365 liver transplant recipients was designed to assess the effect of intravenous iloprost after liver transplantation. Primary endpoint will be the primary graft dysfunction characterized as presentation of one or more of the following criteria: ALAT or ASAT level>2000 IU/ml within the first 7 postoperative days, bilirubine ≥ 10 mg/dl on postoperative day 7; INR ≥ 1.6 on postoperative day 7 or initial non-function. Secondary endpoints are parameters of post-transplant morbidity, like rates of infections, biliary complications, need of clotting factors or renal replacement therapy and the graft and patient survival. DISCUSSION: A well-established treatment concept to avoid graft dysfunction after liver transplantation does not exist at the moment. If the data of this research project confirm prior findings, iloprost would improve the general outcome after liver transplantation. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00003514. Current Controlled Trials Register: ISRCTN12622749.

Evaluation of CIN2/3 Lesion Regression in GynTect® DNA Methylation-Marker-Negative Patients in a Longitudinal Study.

Cervical intraepithelial neoplasia (CIN) grade 2/3 has a high spontaneous regression rate, especially among women ≤29 years of age. To reduce overtreatment, reliable prognostic biomarkers would be helpful. The main aim of this study was to analyze the negative predictive value of the methylation marker panel GynTect® for lesion regression. In this prospective, multicenter, longitudinal observational proof-of-concept study, women aged ≤29 years with histologically confirmed CIN2 (n = 24) or CIN3 (n = 36) were closely monitored without treatment for up to 24 or 12 months, respectively. The outcome was either regression, persistence, or progression of the lesion. For each patient, a single baseline sample (V0) for cytology, hrHPV detection and methylation analysis was taken. In a primary analysis, the negative predictive value (NPV) of a GynTect®-negative test result at V0 for regression was determined. We tested the null hypothesis NPV ≤ 70% against the alternative hypothesis NPV ≥ 90%. Twelve of the eighteen GynTect®-negative CIN2 patients showed regression (NPV = 67%, 90% CI 44-85%, p = 0.53). Of the 27 GynTect®-negative CIN3 lesions, 15 regressed (NPV = 56%, 90% CI 38-72%, p = 0.92). Although the majority of GynTect®-negative lesions regressed, the postulated NPV of ≥90% was not observed. Thus, the clinical relevance for an implementation of the GynTect® assay for patients undergoing watchful waiting remains questionable. Further studies with longer observation periods should be undertaken.

Impact of stable PGI2 analog iloprost on early graft viability after liver transplantation: a pilot study.

BACKGROUND: Ischemia/reperfusion injury after liver transplantation (LT) may be associated with primary graft dysfunction (PDF) or non-function. Prostaglandins were demonstrated to be beneficial in reducing ischemic injury by improving microcirculation and protecting endothelial cells. The aim of this study was to analyze the effect of the continuously administered prostaglandin I(2) analog iloprost on allograft function after LT. METHODS: Eighty patients were prospectively randomized and assigned to two groups. Patients in the treatment group received iloprost for seven d after transplantation, and those in the control group did not. The primary end point was graft dysfunction. RESULTS: The incidence of PDF was 20% (n = 8) in the control group and 5% (n = 2) in the treatment group, respectively (p = 0.087). Four patients in the control group underwent re-transplantation for initial non-function (INF). There was no evidence for INF in the treatment group. Iloprost was associated with improved allograft function. Clinical course and outcome were comparable. CONCLUSIONS: We suggest iloprost to be beneficial for early post-transplant liver function. If the rate of PDF can be significantly reduced with this treatment concept, it should be analyzed in a larger number of patients (ISRCTN95672167).

Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance.

PURPOSE: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. METHODS: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients' individual HPV-integration sites (vcj-PCR on the basis of NGS). RESULTS: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6-34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8-27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7-20.7%) and predicted ten of fourteen recurrences at six months. CONCLUSIONS: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.

Prevalence of antibodies to swine influenza viruses in humans with occupational exposure to pigs, Thuringia, Germany, 2008-2009.

The Eurasian lineages of swine influenza viruses are different genetically from classical swine H1N1 influenza viruses and comprise avian-like H1N1 and human-like H1N2 and H3N2 subtypes. Although sporadic isolation of such viruses from human specimens has been reported, the prevalence of human infections is not known. In the present study, the seroprevalence against Eurasian swine influenza viruses was investigated. Sera were collected in Thuringia, Germany, from December 2007 to April 2009. The study group comprised 118 professionals with occupational exposure to pigs (50 pig slaughterers/meat inspectors, 46 pig farmers, 22 veterinarians caring for pig herds). The control group included 118 age- and gender-matched blood donors from Thuringia. As a result, 18 sera of the study group were identified with raised hemagglutination-inhibition titers against a panel of nine swine influenza viruses (three strains/ subtype). For 17/18 sera this finding was confirmed in the neutralization assay. For 11/18 sera the raise of titers was significant, that is, a fourfold increase of hemagglutination-inhibition titers was observed. No gender-specific bias of the high titer sera was observed. Twelve sera of the control group showed increased hemagglutination-inhibition titers against swine influenza viruses. Hemagglutination-inhibition titers of 2/12 control sera were raised fourfold but did not exhibit a significant increase of neutralization titers. All increased hemagglutination-inhibition titers of the control group may be explained by cross-reactivity with seasonal influenza virus strains, as all these sera also reacted with human strains.

Triage of hrHPV-positive women: comparison of two commercial methylation-specific PCR assays.

AIM: High-risk human papillomavirus (hrHPV)-based screening is becoming increasingly important, either by supplementing or replacing the traditional cytology-based cervical Pap smear. However, hrHPV screening lacks specificity, because it cannot differentiate between transient virus infection and clinically relevant hrHPV-induced disease. Therefore, reliable triage methods are needed for the identification of HPV-positive women with cervical intraepithelial neoplasia (CIN) in need of treatment. Promising tools discussed for the triage of these patients are molecular diagnostic tests based on epigenetic markers. Here, we compare the performance of two commercially available DNA methylation-based diagnostic assays-GynTect® and the QIAsure Methylation Test-in physician-taken cervical scrapes from 195 subjects. FINDINGS: Both GynTect® and the QIAsure Methylation Test detected all cervical carcinoma and carcinoma in situ (CIS). The differences observed in the detection rates between both assays for the different grades of cervical lesions (QIAsure Methylation Test: CIN1 26.7%, CIN2 27.8% and CIN3 74.3%; GynTect®: CIN1 13.3%, CIN2 33.3% and CIN3 60%) were not significant. Concerning the false-positive rates, significant differences were evident. For the healthy (NILM) hrHPV-positive group, the false-positive rates were 5.7% for GynTect® and 26.4% for QIAsure Methylation Test (p = 0.003) and for the NILM hrHPV-negative group 2.2% vs. 23.9% (p = 0.006), respectively. When considering hrHPV-positive samples only for comparison (n = 149), GynTect® delivered significantly higher specificity compared to the QIAsure Methylation Test for CIN2 + (87.6% vs. 67.4% (p < 0.001)) and CIN3 + (84.1% vs. 68.2% (p = 0.002)). Overall our findings suggest that DNA methylation-based tests are suitable for the triage of hrHPV-positive women. With the goal to provide a triage test that complements the limited specificity of HPV testing in HPV-based screening, GynTect® may be preferable, due to its higher specificity for CIN2+ or CIN3+ .

Very Low Frequency Heart Rate Variability Predicts the Development of Post-Stroke Infections.

Stroke-induced immunodepression is a major risk factor for severe infectious complications in the immediate post-stroke period. We investigated the predictive value of heart rate variability (HRV) to identify patients at risk of post-stroke infection, systemic inflammatory response syndrome, or severe sepsis during the post-acute interval from days 3 to 5 after stroke onset. A prospective, observational monocentric cohort study was conducted in a university hospital stroke unit of patients with ischemic infarction in the territory of the middle cerebral artery without an ongoing infection at admission. Standard HRV indices were processed from Holter ECG. Recording started within the first day after the onset of stroke. Infection (primary endpoint: pneumonia, urinary tract, unknown localization) was assessed between days 3 and 5. The predictive value of HRV adjusted for clinical data was analyzed by logistic regression models and area under the receiver operating characteristic curve (AUC). From 287 eligible patients, data of 89 patients without event before completion of 24-h Holter ECG were appropriate for prediction of infection (34 events). HRV was significantly associated with incident infection even after adjusting for clinical covariates. Very low frequency (VLF) band power adjusted for both, the National Institutes of Health Stroke Scale (NIHSS) at admission and diabetes predicted infection with AUC = 0.80 (cross-validation AUC = 0.74). A model with clinical data (diabetes, NIHSS at admission, involvement of the insular cortex) performed similarly well (AUC = 0.78, cross-validation AUC = 0.71). Very low frequency HRV, an index of integrative autonomic-humoral control, predicts the development of infectious complications in the immediate post-stroke period. However, the additional predictive value of VLF band power over clinical risk factors such as stroke severity and insular involvement was marginal. The continuous HRV monitoring starting immediately after admission might probably increase the predictive performance of VLF band power. That needs to be clarified in further investigations.

Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam to improve outcome in patients with sepsis (TARGET): a prospective, multi-centre, randomised controlled trial.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection with a hospital mortality in excess of 40%. Along with insufficient and delayed empirical antimicrobial therapy, inappropriate antimicrobial exposure has been identified to negatively affect patient outcomes. Receipt of prolonged infusion (i.e. extended or continuous infusion) of piperacillin/tazobactam (TZP) improves antimicrobial exposure and is associated with reduced mortality in patients with sepsis. Using therapeutic drug monitoring (TDM) with dosing tailored to the altered pharmacokinetics of the individual patient to avoid under- and overdosing may be a further strategy to improve patient outcomes. This current trial will address the question whether a TDM-guided therapy with TZP administered by continuous infusion will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion of the total daily dose of TZP without TDM. METHODS: The study is an investigator-initiated, multi-centre, parallel-group, single-blinded, randomised controlled trial. The trial will be conducted in several centres across Germany. Adult patients (aged ≥ 18 years) with severe sepsis or septic shock will be eligible for study participation. Participants will be randomly assigned to receive either TZP by continuous infusion guided by daily TDM of piperacillin (experimental group) or by continuous infusion without TDM guidance (total daily dose in normal renal function 13.5 g TZP) (control group). The pharmacokinetic (PK)/pharmacodynamic (PD) target will be 100% f T>4MIC (percentage of time during a dosing interval that the free [f] drug concentration exceeds 4 times the minimum inhibitory concentration). The primary efficacy endpoint is the change in mean total Sequential Organ Failure Assessment score from day 1 after randomisation until day 10 or discharge from the intensive care unit or death, whichever comes first. Secondary outcomes include mortality, clinical cure, microbiological cure, overall antibiotic use, individual components of the primary outcome, adverse events and analysis of PK and (PD) indices. DISCUSSION: This trial will assess for the first time whether continuous infusion of TZP guided by daily TDM in patients with sepsis will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion without TDM. TRIAL REGISTRATION: German Clinical Trials Register (GermanCTR), DRKS00011159 . Registered on 10 October 2016.

Characterisation of the interaction between circulating and in vitro cultivated endothelial progenitor cells and the endothelial barrier.

In vitro cultured endothelial progenitor cells (cEPC) are used for intracoronary cell therapy in cardiac regeneration. The aim of this study was to investigate whether cEPC and circulating mononuclear cells (MNC), which include a small number of in vivo circulating EPC, are able to transmigrate through the endothelial barrier into the cardiac tissue. MNC and EPC were isolated from the peripheral blood from healthy male volunteers (n = 13, 25+/-6 years) and stained with a fluorescent marker. The cells were perfused in vitro through organs with endothelial layers of different phenotypes (rat aorta, human umbilical vein, isolated mouse heart). The endothelium and the basal lamina were then stained by immunofluorescence and the cryo-sections analysed using a confocal laser scanning microscope. After perfusion through the rat aorta, an adhesion/integration of MNC was observed at the endothelial layer and the basal lamina beneath endothelial cells. However, no migration of MNC over the endothelial barrier was found. This remained true even when the cell numbers were increased (from 0.5 to 10 million cells/h), when the time of perfusion was prolonged (1.5-4 h) and when the aorta was cultivated for 24 h. In the Langendorff-perfused mouse heart with intact endothelium, no migration of MNC (1 x 10(7)) or cEPC (1 x 10(6)) was observed after 0.5 and 2 h. In conclusion, MNC and cEPC do not possess any capacity to transmigrate the endothelial barrier. In the context of stem cell therapy, these cells may therefore serve as endothelial regenerators but not as cardiomyocyte substitutes.

Optic edge design as long-term factor for posterior capsular opacification rates.

OBJECTIVE: To compare the difference in posterior capsular opacification (PCO) between highly refractive silicone and hydrophobic acrylic foldable intraocular lenses (IOLs) with sharp and round edge designs 3 years after in-the-bag IOL implantation in subjects undergoing bilateral cataract surgery. DESIGN: Open-label, prospective, randomized, multicenter clinical trial. PARTICIPANTS: Two hundred and eighty-eight patients with bilateral surgery for senile cataract operated in German university clinics, eye hospitals, and private ophthalmic surgical centers (Aachen, Ahaus, Bad Hersfeld, Frankfurt/Main, Jena, Rosenheim, and Sulzbach/Saar). INTERVENTIONS: At each center, a highly refractive index silicone IOL with a sharp optic edge (CeeOn) was intraindividually compared either with a high-refractive index silicone IOL with a round optic edge (PhacoFlex) in 108 patients or with an acrylic IOL with a sharp optic edge (AcrySof) in 139 patients. All patients received standard phacoemulsification with IOL implantation in the bag in both eyes from the same surgeon. A morphological evaluation of PCO was performed by the Evaluation of the Posterior Capsule Opacification (EPCO) system 1 to 2 weeks and 11 to 14 and 35 to 37 months after surgery. The blinded digital pictures were evaluated by an independent investigator. Posterior capsular opacification was statistically evaluated by paired comparisons of 3-year cumulative incidences of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser treatment and EPCO scores. MAIN OUTCOME MEASURES: Posterior capsular opacification. RESULTS: The 3-year cumulative incidences of Nd:YAG laser capsulotomy were 2.1% (CeeOn), compared with 2.1% (AcrySof) (risk difference, 0%; 90% confidence interval, -3.4% to 3.4%), and 5.7% (CeeOn), compared with 17.0% (PhacoFlex) (risk difference, -11.4%; 90% confidence interval, -18.1% to -4.7%). In patients without Nd:YAG laser treatment, medians of the total area EPCO score were 0.0005 (CeeOn) versus 0.0440 (AcrySof) and 0 (CeeOn) versus 0.0700 (PhacoFlex) at 3 years. Functional results, safety, and handling did not significantly differ for the 3 lenses. CONCLUSIONS: Our results suggest that modern foldable IOLs have a low incidence of PCO after 3 years. There is less PCO for sharp optic edge designs independent of IOL material.

Number of genomic imbalances correlates with the overall survival for adrenocortical cancer in childhood.

BACKGROUND: Adrenocortical tumours (ACT) in children are rare and, if malignant, often associated with poor prognosis. Relevant cytogenetic factors for prognosis are hardly available. PROCEDURES: We analysed 14 adrenocortical cancers (ACC) of children by comparative genomic hybridisation (CGH). RESULTS: The total number of genomic imbalances ranged from 1 to 17 in individual tumour samples. The most common imbalances were +1q (57%), +12p (50%), +12q (50%), +1p (43%), +7q (42%), +9q (42%), +15q (42%), and -4q (57%), -11q (57%), -4p (42%), and -16q (42%). The median number of genomic changes was 5.5 (n = 8) in pT1-pT2 and 15.5 (n = 6) in pT3-pT4 tumours. The median number was 4 in the eight patients, who remain in remission more than 51 months and 15.5 in the six patients, who have died from the disease within 44 months. Moreover, all seven patients with less than 10 individual imbalances were in remission (median follow-up 72 months), while all but one patient with 10 and more individual imbalances (n = 7) have died from the disease (median survival time 30 months). Comparison of the data from children and adults revealed characteristic differences. Gain of 1p and loss of 4p, 4q and 16q are frequent in childhood and rare in adults. Inversely, loss of 1p is rare in childhood but frequent in adult ACT. CONCLUSION: The number of CGH imbalances appeared to have a predictive value for overall survival in paediatric ACC.