Long-Term Renal Function in Liver Transplant Recipients After Conversion From Calcineurin Inhibitors to mTOR Inhibitors

BACKGROUND: Renal dysfunction often occurs in liver transplant (LT) recipients receiving calcineurin inhibitor (CNI)-based immunosuppressive regimens, increasing morbidity and mortality rates. Replacement of CNIs by mTOR inhibitor-based immunosuppressive protocols may prevent renal impairment in LT recipients. MATERIAL AND METHODS: Outcomes in patients who underwent LT between 1996 and 2010 at our center and who were switched from CNI-based to mTOR inhibitor-based immunosuppression were retrospectively analyzed. Renal course, hyperlipidemia, and graft rejection were assessed in patients maintained on this CNI-free regimen for at least 24 months. RESULTS: Of the 85 patients switched from CNI-based to mTOR inhibitor-based, CNI-free immunosuppression, 78 met the inclusion criteria. Within the first 6 weeks after switching, the covariable adjusted estimated glomerular filtration rate (eGFR) increased 5.6 mL/min [95% confidence interval 2.6–8.7 mL/min, p<0.001], but there were no further statistically noticeable changes in eGFR. Concentrations of cholesterol and triglycerides increased statistically, noticeable within the first 12 months after drug conversion. Histologically proven graft rejection was observed in 4 patients (5.1%) after conversion. CONCLUSIONS: Conversion from CNI-based to CNI-free, mTOR inhibitor-based immunosuppression after LT is safe and can result in significant renal recovery. CNI-free, mTOR inhibitor-based immunosuppression is a potential option for patients with contraindications for CNIs and for LT recipients with rapid reduction in kidney function due to CNIs

A phase 1 study evaluating rovalpituzumab tesirine in frontline treatment of patients with extensive-stage SCLC

INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC. METHODS: One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3). RESULTS: A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T-related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%). CONCLUSIONS: Lower Rova-T doses may be associated with lower incidence of some Rova-T-related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE

Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems

Cardiopulmonary bypass (CPB) is often necessary for congenital cardiac surgery, but CPB can alter drug pharmacokinetic parameters resulting in underdosing. Inadequate plasma levels of antibiotics could lead to postoperative infections with increased morbidity. The influence of pediatric CPB systems on cefazolin and clindamycin plasma levels is not kn

In Vitro Recovery of Sufentanil, Midazolam, Propofol, and Methylprednisolone in Pediatric Cardiopulmonary Bypass Systems

Objectives: To evaluate in vitro drug recovery in cardiopulmonary bypass (CPB) systems used for pediatric cardiac surgery. Design: Observational in vitro study. Setting: Single-center university hospital. Participants: In vitro CPB systems used for pediatric cardiac surgery. Interventions: Three full neonatal, infant, and pediatric CPB systems were primed according to hospital protocol and kept running for 6 hours. Midazolam, propofol, sufentanil, and methylprednisolone were added to the venous side of the systems in doses commonly used for induction of general anesthesia. Blood samples were taken from the postoxygenator side of the circuit immediately after injection of the drugs and after 2, 5, 7, 10, 30, 60, 180, and 300 minutes. Measurements and Main Results: Linear mixed model analyses were performed to assess the relationship between log-transformed drug concentration (dependent variable) and type of CPB system and sample time point (independent variables). The mean percentage of drug recovery after 60 and 180 minutes compared with T1 was 41.7% (95% confidence interval [CI] 35.9-47.4) and 23.0% (95% CI 9.2-36.8) for sufentanil, 87.3% (95% CI 64.9-109.7) and 82.0% (95% CI 64.6-99.4) for midazolam, 41.3% (95% CI 15.5-67.2) and 25.0% (95% CI 4.7-45.3) for propofol, and 119.3% (95% CI 101.89-136.78) and 162.0% (95% CI 114.09-209.91) for methylprednisolone, respectively. Conclusions: The present in vitro experiment with neonatal, infant, and pediatric CPB systems shows a variable recovery of routinely used drugs with significant differences between drugs, but not between system categories (with the exception of propofol). The decreased recovery of mainly sufentanil and propofol could lead to suboptimal dosing of patients during cardiac surgery with CPB

Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project

The European Human Biomonitoring Initiative (HBM4EU) is coordinating and advancing human biomonitoring (HBM). For this purpose, a network of laboratories delivering reliable analytical data on human exposure is fundamental. The analytical comparability and accuracy of laboratories analysing flame retardants (FRs) in serum and urine were investigated by a quality assurance/quality control (QA/QC) scheme comprising interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs). This paper presents the evaluation process and discusses the results of four ICI/EQUAS rounds performed from 2018 to 2020 for the determination of ten halogenated flame retardants (HFRs) represented by three congeners of polybrominated diphenyl ethers (BDE-47, BDE-153 and BDE-209), two isomers of hexabromocyclododecane (α-HBCD and γ-HBCD), two dechloranes (anti-DP and syn-DP), tetrabromobisphenol A (TBBPA), decabromodiphenylethane (DBDPE), and 2,4,6-tribromophenol (2,4,6-TBP) in serum, and four metabolites of organophosphorus flame retardants (OPFRs) in urine, at two concentration levels. The number of satisfactory results reported by laboratories increased during the four rounds. In the case of HFRs, the scope of the participating laboratories varied substantially (from two to ten) and in most cases did not cover the entire target spectrum of chemicals. The highest participation rate was reached for BDE-47 and BDE-153. The majority of participants achieved more than 70% satisfactory results for these two compounds over all rounds. For other HFRs, the percentage of successful laboratories varied from 44 to 100%. The evaluation of TBBPA, DBDPE, and 2,4,6-TBP was not possible because the number of participating laboratories was too small. Only seven laboratories participated in the ICI/EQUAS scheme for OPFR metabolites and five of them were successful for at least two biomarkers. Nevertheless, the evaluation of laboratory performance using Z-scores in the first three rounds required an alternative approach compared to HFRs because of the small number of participants and the high variability of experts' results. The obtained results within the ICI/EQUAS programme showed a significant core network of comparable European laboratories for HBM of BDE-47, BDE-153, BDE-209, α-HBCD, γ-HBCD, anti-DP, and syn-DP. On the other hand, the data revealed a critically low analytical capacity in Europe for HBM of TBBPA, DBDPE, and 2,4,6-TBP as well as for the OPFR biomarkers.We gratefully acknowledge funding by the European Union's Horizon 2020 research and innovation programme under the grant agreement No. 733032.S

Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project

The European Human Biomonitoring Initiative (HBM4EU) is coordinating and advancing human biomonitoring (HBM). For this purpose, a network of laboratories delivering reliable analytical data on human exposure is fundamental. The analytical comparability and accuracy of laboratories analysing flame retardants (FRs) in serum and urine were investigated by a quality assurance/quality control (QA/QC) scheme comprising interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs). This paper presents the evaluation process and discusses the results of four ICI/EQUAS rounds performed from 2018 to 2020 for the determination of ten halogenated flame retardants (HFRs) represented by three congeners of polybrominated diphenyl ethers (BDE-47, BDE-153 and BDE-209), two isomers of hexabromocyclododecane (α-HBCD and γ-HBCD), two dechloranes (anti-DP and syn-DP), tetrabromobisphenol A (TBBPA), decabromodiphenylethane (DBDPE), and 2,4,6-tribromophenol (2,4,6-TBP) in serum, and four metabolites of organophosphorus flame retardants (OPFRs) in urine, at two concentration levels. The number of satisfactory results reported by laboratories increased during the four rounds. In the case of HFRs, the scope of the participating laboratories varied substantially (from two to ten) and in most cases did not cover the entire target spectrum of chemicals. The highest participation rate was reached for BDE-47 and BDE-153. The majority of participants achieved more than 70% satisfactory results for these two compounds over all rounds. For other HFRs, the percentage of successful laboratories varied from 44 to 100%. The evaluation of TBBPA, DBDPE, and 2,4,6-TBP was not possible because the number of participating laboratories was too small. Only seven laboratories participated in the ICI/EQUAS scheme for OPFR metabolites and five of them were successful for at least two biomarkers. Nevertheless, the evaluation of laboratory performance using Z-scores in the first three rounds required an alternative approach compared to HFRs because of the small number of participants and the high variability of experts' results. The obtained results within the ICI/EQUAS programme showed a significant core network of comparable European laboratories for HBM of BDE-47, BDE-153, BDE-209, α-HBCD, γ-HBCD, anti-DP, and syn-DP. On the other hand, the data revealed a critically low analytical capacity in Europe for HBM of TBBPA, DBDPE, and 2,4,6-TBP as well as for the OPFR biomarkers.We gratefully acknowledge funding by the European Union's Horizon 2020 research and innovation programme under the grant agreement No. 733032.S

Ambulatory assessment for physical activity research. State of the science, best practices and future directions

Technological and digital progress benefits physical activity (PA) research. Here we compiled expert knowledge on how Ambulatory Assessment (AA) is utilized to advance PA research, i.e., we present results of the 2nd International CAPA Workshop 2019 "Physical Activity Assessment - State of the Science, Best Practices, Future Directions" where invited researchers with experience in PA assessment, evaluation, technology and application participated. First, we provide readers with the state of the AA science, then we give best practice recommendations on how to measure PA via AA and shed light on methodological frontiers, and we furthermore discuss future directions. AA encompasses a class of methods that allows the study of PA and its behavioral, biological and physiological correlates as they unfold in everyday life. AA includes monitoring of movement (e.g., via accelerometry), physiological function (e.g., via mobile electrocardiogram), contextual information (e.g., via geolocation-tracking), and ecological momentary assessment (EMA; e.g., electronic diaries) to capture self-reported information. The strengths of AA are data assessment that near real-time, which minimizes retrospective biases in real-world settings, consequentially enabling ecological valid findings. Importantly, AA enables multiple assessments across time within subjects resulting in intensive longitudinal data (ILD), which allows unraveling within-person determinants of PA in everyday life. In this paper, we show how AA methods such as triggered e-diaries and geolocation-tracking can be used to measure PA and its correlates, and furthermore how these findings may translate into real-life interventions. In sum, AA provides numerous possibilities for PA research, especially the opportunity to tackle within-subject antecedents, concomitants, and consequences of PA as they unfold in everyday life. In-depth insights on determinants of PA could help us design and deliver impactful interventions in real-world contexts, thus enabling us to solve critical health issues in the 21st century such as insufficient PA and high levels of sedentary behavior. (DIPF/Orig.

The epidemiology of pertussis in Germany: past and present

<p>Abstract</p> <p>Background</p> <p>Current and past pertussis epidemiology in the two parts of Germany is compared in the context of different histories of vaccination recommendations and coverage to better understand patterns of disease transmission.</p> <p>Methods</p> <p>Available regional pertussis surveillance and vaccination coverage data, supplemented by a literature search for published surveys as well as official national hospital and mortality statistics, were analyzed in the context of respective vaccination recommendations from 1964 onwards.</p> <p>Results</p> <p>Routine childhood pertussis vaccination was recommended in the German Democratic Republic (GDR) from 1964 and in former West German states (FWG) from 1969, but withdrawn from 1974–1991 in FWG. Pertussis incidence declined to <1 case/100.000 inhabitants in GDR prior to reunification in 1991, while in FWG, where pertussis was not notifiable after 1961, incidence was estimated at 160–180 cases/100.000 inhabitants in the 1970s-1980s. Despite recommendations for universal childhood immunization in 1991, vaccination coverage decreased in former East German States (FEG) and increased only slowly in FWG. After introduction of acellular pertussis vaccines in 1995, vaccination coverage increased markedly among younger children, but remains low in adolescents, especially in FWG, despite introduction of a booster vaccination for 9–17 year olds in 2000. Reported pertussis incidence increased in FEG to 39.3 cases/100.000 inhabitants in 2007, with the proportion of adults increasing from 20% in 1995 to 68% in 2007. From 2004–2007, incidence was highest among 5–14 year-old children, with a high proportion fully vaccinated according to official recommendations, which did not include a preschool booster until 2006. Hospital discharge statistics revealed a ~2-fold higher pertussis morbidity among infants in FWG than FEG.</p> <p>Conclusion</p> <p>The shift in pertussis morbidity to older age groups observed in FEG is similar to reports from other countries with longstanding vaccination programs and suggests that additional booster vaccination may be necessary beyond adolescence. The high proportion of fully vaccinated cases in older children in FEG suggests waning immunity 5–10 years after primary immunisation in infancy. The higher incidence of pertussis hospitalisations in infants suggests a stronger force of infection in FWG than FEG. Nationwide pertussis reporting is required for better evaluation of transmission patterns and vaccination policy in both parts of Germany.</p