Familial congenital lower urinary tract obstruction (LUTO) suggested by screening for lower urinary tract dysfunction in parents of patients: A descriptive study.

Background: Congenital lower urinary tract obstruction (LUTO) describes a heterogeneous group of congenital malformations. Posterior urethral valves (PUV) represent the most common entity. Familial occurrence has been described, suggestive of underlying genetic factors. LUTO can occur in various degrees of severity. In severe forms, oligohydramnios, pulmonary hypoplasia, and renal damage can occur resulting in high pre- and postnatal mortality. On the contrary, mild forms may become apparent through recurrent urinary tract infections. Such high phenotypic variability has been described even within the same family. Here, we systematically screened parents of affected children for symptoms of LUTO. Methods: The study population consisted of parents of LUTO patients. Fathers over 50 years of age were excluded, to avoid inclusion of male phenocopies due to early prostatic hypertrophy. Uroflowmetry, ultrasonography for residual urine and hydronephrosis, and laboratory examination of standard renal retention parameters were assessed, and a detailed patient history was taken, including the assessment of the International Prostate Symptom Score. Results: Twenty-nine of 42 LUTO families enrolled were found eligible for the present study. Of these, we identified five families in which the father had already been diagnosed with infravesical obstruction (17%). Of the remaining families, nine agreed to participate in our study. Of these nine families, eight families had a child affected with PUV and one family had a child with urethral stenosis. Here, we found two fathers and one mother with symptoms of LUTO suggestive of mild LUTO and one family, in which the unborn male fetal brother of the affected index patient was also diagnosed prenatally with LUTO. Conclusion: Our observations suggest that LUTOs have a higher heritability than previously thought and that first-degree relatives of the affected should be clinically assessed for symptoms of LUTO.

Value of drug level concentrations of brivaracetam, lacosamide, and perampanel in care of people with epilepsy.

OBJECTIVE: The aim of this study was to determine whether clinical efficacy and reported adverse effects (AEs) of the newer antiseizure medications (ASMs) brivaracetam (BRV), lacosamide (LCM), and perampanel (PER) have been associated with plasma levels of these ASMs. We also investigated whether plasma levels outside the reference range has led to dose adjustments. METHODS: Plasma levels of 300 people with epilepsy (PWE) seen at our tertiary epilepsy center were determined by liquid chromatography-tandem mass spectrometry. PWE received BRV (n = 100), LCM (n = 100), or PER (n = 100), in most cases in polytherapy. Demographic and clinical data were retrospectively analyzed and related to plasma levels. Clinical efficacy of BRV, LCM, or PER was assessed retrospectively by comparing seizure frequency at the time of current blood draw with seizure frequency at the time of first administration. AEs were also recorded and, if reported, compared retrospectively with the time of first administration. RESULTS: No significant associations were found between plasma levels of BRV, LCM, or PER and seizure freedom (BRV, p = 1.000; LCM, p = .243; PER, p = .113) or responder status (BRV, p = .118; LCM, p = .478; PER, p = .069) at presentation. There was also no pattern between plasma levels and the occurrence of AEs. In the majority of cases, drug levels outside the reference ranges have not led to adjustments in the daily doses of BRV (93.5%), LCM (93.9%), or PER (89.1%). SIGNIFICANCE: Plasma levels at a given time point did not allow conclusions to be drawn about seizure control or the occurrence of AEs. Our findings indicate that efficacy and tolerability cannot be predicted based on averaged data from a single plasma measurement due to high interindividual variability. Instead, individual reference values should be established when sufficient clinical data are available, in line with the 2008 International League Against Epilepsy position paper on therapeutic drug monitoring.

Comparative analysis of contemporary anti-double stranded DNA antibody assays for systemic lupus erythematosus.

Objective: Elevated double-stranded DNA (dsDNA) antibody levels in blood serum are considered a disease-specific marker in systemic lupus erythematosus (SLE), correlate with disease activity and the incidence of lupus nephritis, and can be detected in up to 86% of all SLE cases. Despite the high clinical relevance, the variety of dsDNA antibody testing methods with heterogenous performance in clinical use remains challenging. This study is the first to prospectively investigate the performance of two of today's most commonly applied anti-dsDNA testing methods head-to-head under real-world conditions, as well as their correlation with other clinical and serological disease parameters in SLE patients. Methods: In this prospective study, all SLE patients undergoing treatment at the Department of Rheumatology at the University Hospital Bonn within a 13-months period (n=41) and control patients without connective-tissue disease (n=51) were consecutively enrolled and examined. For all study participants' serum samples both anti-dsDNA-NcX enzyme-linked immunoassay testing EUROIMMUN, Luebeck, Germany) and the fluorescence immunoassay ELiA dsDNA (Thermo Fisher Scientific, Waltham, USA) were performed. In addition, demographic data, further laboratory values and disease activity parameters were recorded. Clinical disease activity was assessed by SLEDAI-2K. Results: Both assays showed high specificity (anti-dsDNA-NcX ELISA: 0.9, ELiA dsDNA: 0.959), but there were notable differences in sensitivity (anti-dsDNA-NcX ELISA: 0.51, ELiA dsDNA: 0.38). Pearsons's correlation yielded a positive correlation between anti-dsDNA concentrations and CRP concentrations for the anti-dsDNA-NcX ELISA (R=0.22; p=0.038) and a mild-to-moderate inverse correlation between concentrations of anti-dsDNA and complement C4 for the ELiA dsDNA test (R=-0.22; p=0.045) when SLE and control patients were considered together. Other than, no significant correlation between anti-dsDNA concentrations and clinical or laboratory findings was found for either test procedure. Conclusion: Both anti-dsDNA antibody assays represent reliable examination methods with high specificity for the diagnosis of SLE that fulfill EULAR/ACR requirements. However, the anti-dsDNA-NcX ELISA showed superior sensitivity and significant correlation with disease activity (as measured by CRP concentrations).

Method Comparison and Clinical Performance of Breast Cancer Tumor Markers on Novel Multiplex Immunoassay and Automatized LOCI Technology Platforms.

Tumor marker determinations are valuable tools for the guidance of breast cancer patients during the course of disease. They are assessed on diverse analytical platforms that may be associated with differences according to the methods applied and the clinical performance. To investigate the method dependency and clinical significance of breast cancer protein tumor markers, CEA, CA 15-3, CA 125, CA 19-9 and AFP were measured in a total of 154 biobanked samples from 77 patients with breast cancer, 10 with DCIS, 31 with benign breast diseases and 36 healthy controls using a Millipore multiplex biomarker panel (MP) and an automized version of the routinely used Vista LOCI technology. The markers were compared between methods and investigated for diagnostic performance. CEA, CA 15-3 and AFP showed good correlations between both platforms with correlation coefficients of R = 0.85, 0.85 and 0.92, respectively, in all samples, but similarly also in the various subgroups. CA 125 and CA 19-9 showed only moderate correlations (R = 0.71 and 0.56, respectively). Absolute values were significantly higher for CEA, CA 15-3, CA 125 and AFP in the Vista LOCI as compared with the MP method and vice versa for CA 19-9. The diagnostic performance for discrimination of breast cancer from healthy controls was similar for both methods with AUCs in ROC curves for CEA (MP 0.81, 95% CI 0.72-0.91; LOCI 0.81; 95% CI 0.72-0.91) and CA-15-3 (MP 0.75, 95% CI 0.65-0.86; LOCI 0.67, 95% CI 0.54-0.79). Similar results were obtained for the comparison of breast cancer with benign breast diseases regarding CEA (AUC MP 0.62, 95% CI 0.51-0.73; LOCI 0.64, 95% CI 0.53-0.74) and CA-15-3 (MP 0.70, 95% CI 0.6-0.81; LOCI 0.66, 95% CI 0.54-0.77). Both platforms show moderate to good method comparability for tumor markers with similar clinical performance. However, absolute levels in individual patients should be interpreted with care.

Hemolysis during Venovenous Extracorporeal Membrane Oxygenation in Neonates with Congenital Diaphragmatic Hernia: A Prospective Observational Study.

OBJECTIVE: To investigate the incidence of hemolysis and its association with outcome in neonates with congenital diaphragmatic hernia (CDH) requiring venovenous extracorporeal membrane oxygenation (ECMO) treatment using a Medos Deltastream circuit with a DP3 pump, a hilite 800 LT oxygenator system, and a »' tubing. STUDY DESIGN: Plasma free hemoglobin (PFH) was prospectively measured once daily during ECMO using spectrophotometric testing. Patients (n = 62) were allocated into two groups according to presence or absence of hemolysis. Hemolysis was defined as PFH ≥ 50 mg/dL on at least 2 consecutive days during ECMO treatment. Hemolysis was classified as either moderate with a maximum PFH of 50-100 mg/dL or severe with a maximum PFH >100 mg/dL. RESULTS: Hemolysis was detected in 14 patients (22.6%). Mortality was 100% in neonates with hemolysis compared with 31.1% in neonates without hemolysis (P < .001). In 21.4% hemolysis was moderate and in 78.6% severe. Using multivariable analysis, hemolysis (hazard ratio: 6.8; 95%CI: 1.86-24.86) and suprasystemic pulmonary hypertension (PH) (hazard ratio: 3.07; 95%CI: 1.01-9.32) were independently associated with mortality. Hemolysis occurred significantly more often using 8 French (Fr) cannulae than 13 Fr cannulae (43% vs 17%; P = .039). Cutoff for relative ECMO flow to predict hemolysis were 115 ml/kg/ minute for patients with 8 Fr cannulae (Area under the curve [AUC] 0.786, P = .042) and 100 ml/kg/ minute for patients with 13 Fr cannulae (AUC 0.840, P < .001). CONCLUSIONS: Hemolysis in CDH neonates receiving venovenous ECMO is independently associated with mortality.

NT-proBNP and Zlog-transformed NT-proBNP values predict extubation failure in critically ill neonates with pulmonary hypertension and ventricular dysfunction.

OBJECTIVES: Critically ill neonates with a history of pulmonary hypertension (PH) or ventricular dysfunction are at risk to experience an extubation failure (EF) after liberation from mechanical ventilation (MV). Due to insufficient data from neonatal cohorts, it remains unclear whether NT-proBNP is an appropriate biomarker to predict EF in this cohort. The Zlog-transformation of NT-proBNP (further named NT-proBNPZlog ) is an additional tool to optimize the interpretation of NT-proBNP since absolute NT-proBNP values are varying with the age of these infants. PATIENTS AND METHODS: This was a retrospective single-center analysis at the University Children's Hospital, Bonn, Germany, during the study period from January 2020 until December 2021. Forty-three neonates met the inclusion criteria and were screened for study participation. INCLUSION CRITERIA: prolonged (>24 h) MV with at least one extubation attempt, with a history of PH and/or ventricular dysfunction in the echocardiographic assessment at admission to the neonatal intensive care unit or during the period of MV, NT-proBNP measurements before (max. 24 h, baseline) and after (max. 24 h, follow-up) the first extubation attempt. The primary clinical endpoint was defined as EF with need for reintubation (0-72 h). Neonates with an EF were allocated to group A and neonates with successful liberation from MV to group B. MAIN RESULTS: The primary clinical endpoint (EF) was reached in 21% (nine infants). Absolute mean NT-proBNP values (NT-proBNPabs ) at baseline did not differ significantly in infants of group A and B (6931 vs. 7136 pg/ml, p = 0.227). NT-proBNPZlog values at baseline (2.35 vs. 1.57, p = 0.073) tended to higher values in group A. NT-proBNPabs values measured at follow-up were significantly higher in infants allocated to group A (11120 vs. 7570 pg/ml, p = 0.027). Likewise, NT-proBNPZlog values at follow-up were significantly higher in infants allocated to group A (3.05 vs. 1.93, p = 0.009). NT-proBNPabs values at follow-up and NT-proBNPZlog values at baseline correlated significantly with the severity of PH. Regarding the receiver operating characteristic-analysis, a NT-proBNPabs value at follow-up of ≥4622 pg/ml was calculated as optimal cut-off value for the prediction of EF (area under the curve [AUC] 0.742, p = 0.001). A NT-proBNPZlog value at baseline of ≥1.63 and at follow-up of ≥2.14 was calculated as optimal cut-off for the prediction of EF (AUC: 0.690/p = 0.027, and 0.781/p = 0.000, respectively). CONCLUSION: NT-proBNPabs and NT-proBNPZlog might be valuable biomarkers for the prediction of EF in critically ill neonates. The Zlog-transformation of NT-proBNP allows an age-independent interpretation of NT-proBNP and should be considered for clinical routine.

CA125: a novel cardiac biomarker for infants with congenital diaphragmatic hernia.

BACKGROUND: The carbohydrate antigen 125 (CA125) was proven as a robust biomarker for risk stratification in adults with heart failure. This is the first study analyzing CA125 in a cohort of infants with congenital diaphragmatic hernia (CDH). METHODS: Sixty-eight infants with CDH, treated at the University Children's Hospital Bonn (Germany), between January 2018 and February 2021, were prospectively enrolled for analysis. CA125 values were measured at the following timepoints: 6,12, 24, 48 h, and during ECMO daily from day 1 to day 7. RESULTS: In infants not surviving to discharge, CA125 values were significantly higher at day 1 (6, 12, and 24 h). Infants with subsequent need for ECMO presented significantly higher CA125 values at 12 h of life. During ECMO, CA125 values measured at day 1 were significantly higher in infants not surviving to discharge. In the ROC analysis, a CA125 value of ≥10 U/ml was calculated as optimal cut-off for the prediction of ECMO and in-hospital mortality. CA125 values correlated significantly with the severity of PH and ventricular dysfunction. CONCLUSIONS: CA125 values correlate significantly with echocardiographic markers of PH and ventricular dysfunction and correlate significantly with parameters of disease severity (need for ECMO, mortality). IMPACT: CA125 was proven as robust cardiac biomarker in adult cohorts. Information about the utility as a biomarker in neonatal cohorts is lacking. This is the first study analyzing CA125 as a cardiac biomarker in a cohort of infants with congenital diaphragmatic hernia (CDH). CA125 correlates significantly with markers of echocardiographic assessment (PH and ventricular dysfunction) in infants with CDH and helps to identify infants at high risk for ECMO and in-hospital mortality. The results underline the need for the inclusion of cardiac biomarkers in the clinical routine in neonates at risk for cardiopulmonary failure.

High maternal BMI and low maternal blood BDNF may determine the limit of detection of amniotic fluid BDNF throughout gestation: Analysis of mother-fetus trios and literature review.

OBJECTIVE: An increasing number of studies show the importance of brain-derived neurotrophic factor (BDNF) acting at the feto-placental interface, however, only a few studies describe BDNF levels in amniotic fluid (AF). METHODS: In this cross-sectional, prospective study, 109 maternal blood-amniotic fluid pairs (including 66 maternal blood-fetal-blood-amniotic fluid trios) were analyzed. BDNF concentrations were measured with a commercially available immunoassay. RESULTS: In 71 AF from 109 samples, AF-BDNF concentrations were below the lowest limit of Quantitation (LLoQ) of 1.19 pg/ml (group A), leaving 38 samples with measurable BDNF concentrations (group B). Patients in group A showed significantly higher maternal BMI before pregnancy (mean±SD 26.3± 6.7 (kg/m2) vs. 23.8 ±4.5 (kg/m2) p = 0.04) and lower maternal blood BDNF concentrations than the other group (mean±SD 510.6 ± 554.7 pg/ml vs. mean±SD 910.1± 690.1 pg/ml; p<0.0001). Spearman correlation showed a negative correlation between maternal BMI before pregnancy and maternal BDNF concentrations (r = -0.25, p = 0.01). CONCLUSION: Our study is the first to correlate AF-BDNF samples with the corresponding maternal and fetal blood-BDNF samples. The significant negative correlation between maternal BMI before pregnancy and maternal BDNF and AF-BDNF concentrations below the limit of detection has to be evaluated in further studies.

Autoantibodies to dense-fine-speckled 70 (DFS70) do not necessarily rule out connective tissue diseases.

OBJECTIVES: In some patients with antinuclear antibodies (ANA), a pattern called anti-dense-fine-speckled-70 antibody (anti-DFS70) can be detected. Presence of anti-DFS70 is less frequently observed in patients with connective tissue diseases (CTD) and is therefore used as an exclusion criterion by some rheumatologists. To date, however, it is unclear as to what extent the presence of an anti-DFS70 can reliably rule out CTDs. METHODS: Data of 460 patients who were tested for the presence of anti-DFS70 at University Hospital Bonn, Germany, were analyzed. Patients were examined with regard to clinical symptoms and signs, type of disease, type of CTD, fulfillment of the classification criteria, presence of anti-DFS70, other systemic autoantibodies and ANA titers by indirect immunofluorescence (IIF) assays and line immunoassays. Differences in DFS70 antibody status between patients with CTD were examined. In addition, specificity, sensitivity, and positive predictive values for different ANA titers were calculated. RESULTS: In 182 of the 460 patients (of whom 79.8% were female), CTD was diagnosed. 354 patients (77.0%) tested negative, 81 (17.6%) positive and 25 (5.4%) borderline for anti-DFS70. Twenty-one patients (25.9%) with a positive result had CTD. No significant differences were observed between anti-DFS70 positive and anti-DFS70 negative patients with CTD concerning age, gender, symptoms, clinical signs, and other disease-specific antibodies. However, of these 21 patients, only one patient showed the monospecific appearance of anti-DFS70. Anti-DFS70 had a sensitivity and a specificity of 26.9% and 86.8%, respectively, with a positive predictive value of 68.2% at an ANA titer of ≥1:160 with respect to the absence of CTD. CONCLUSIONS: Autoantibodies to DFS70 seem to be prevalent in CTD patients and are thus not a good exclusion criterion. The monospecific occurrence of anti-DFS70 can, however, be helpful in ambiguous situations.

Comparison of Perioperative High-Sensitive Troponin T and Troponin I Assays in Cardiac Surgery.

BACKGROUND: Troponin measurements are among the standard parameters for monitoring perioperative myocardial ischaemia after cardiosurgical procedures. As high-sensitive assays continue to replace older analytic parameters with lower sensitivity, this study aimed to compare perioperative profiles of a high-sensitive troponin T assay (hsTnT, Roche Diagnostics, Mannheim, Germany) with a troponin I assay (sTnI, Siemens Healthcare Diagnostics, Eschborn, Germany). METHODS: A total of 287 consecutive patients undergoing a typical spectrum of cardiac procedures from August 2017 to March 2018 monitored with the hsTnT assay were compared with a propensity-matched collective analysed with the sTnI assay. For side-by side comparison, the peak troponin (Tmax) values were scaled to a z-score distribution before comparison. RESULTS: Despite absolute postoperative hsTnT and sTnI values differing by an order of magnitude, parameters could be scaled to a common distribution with kernel density curves overlapping 92%. Both parameters showed equal behaviour in subgroup analyses regarding relevant perioperative factors, such as type of procedure, cross-clamping time, and type of cardioplegic solution. However, there were some differences regarding pre-existing renal impairment between both parameters. In both groups, renal failure patients with chronic kidney disease stages IV or V as well as patients on haemodialysis exhibited a marked Tmax increase of >100% compared with normal kidney function (hsTnT, +121%; 2,383.5 vs 1,078.8 ng/L; p=0.0006; and sTnI, +149%; 27.3 ng/mL vs 11.0 ng/mL; p=0.009). However, in patients with moderately impaired renal function, those in the hsTnT group, but not in the sTnI cohort, showed significantly increased Tmax values (CKD stages II or III, 1,233.5 ng/L [+14%] and 1,314.1 ng/L [+22%] vs 1,078.8 ng/L; p=0.01 and p=0.03). In these patients, the postoperative interval until Tmax was reached was also significantly increased (14.4 and 19.0 hrs vs 12.4 hrs for chronic kidney disease stages II and III; p=0.0038 and p<0.001), indicating a higher rate of accumulation in the hsTnT parameter. CONCLUSION: In the context of cardiac surgery, this study found that both parameters behaved in a similar manner under most relevant circumstances. Despite significant difference in the absolute serum concentration, hsTnT and sTnI can be scaled to virtually identical distributions. However, renal impairment did affect both parameters differently with troponin T but not troponin I, showing evidence of accumulation in moderately impaired renal disease.

Correlation between a quantitative anti-SARS-CoV-2 IgG ELISA and neutralization activity.

In the current COVID-19 pandemic, a better understanding of the relationship between merely binding and functionally neutralizing antibodies is necessary to characterize protective antiviral immunity following infection or vaccination. This study analyzes the level of correlation between the novel quantitative EUROIMMUN Anti-SARS-CoV-2 QuantiVac ELISA (IgG) and a microneutralization assay. A panel of 123 plasma samples from a COVID-19 outbreak study population, preselected by semiquantitative anti-SARS-CoV-2 IgG testing, was used to assess the relationship between the novel quantitative ELISA (IgG) and a microneutralization assay. Binding IgG targeting the S1 antigen was detected in 106 (86.2%) samples using the QuantiVac ELISA, while 89 (72.4%) samples showed neutralizing antibody activity. Spearman's correlation analysis demonstrated a strong positive relationship between anti-S1 IgG levels and neutralizing antibody titers (rs = 0.819, p < 0.0001). High and low anti-S1 IgG levels were associated with a positive predictive value of 72.0% for high-titer neutralizing antibodies and a negative predictive value of 90.8% for low-titer neutralizing antibodies, respectively. These results substantiate the implementation of the QuantiVac ELISA to assess protective immunity following infection or vaccination.

Extrahepatic Surgery in Cirrhosis Significantly Increases Portal Pressure in Preclinical Animal Models.

Background: Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model. Methods: Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured in-vivo. Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed. Results: Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model. Conclusion: In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis.

Resistin in pregnancy: Analysis of determinants in pairs of umbilical cord blood and maternal serum.

OBJECTIVE: Despite intensive research on the cytokine resistin only few studies investigated mother-newborn-pairs during healthy pregnancy and reported about interactions with clinical obstetric variables or other cytokines. Comparison of existing studies is difficult due to differences between assays, sample collection, gestational age, definition of healthy controls and patient characteristics. Furthermore, differences between rodent models and humans do not allow for a direct comparison. METHODS: In this cross-sectional, prospective study 109 healthy mother-newborn pairs were analyzed. Maternal venous blood samples were taken on admission to the labor ward; newborn venous blood samples were drawn from the placental part of the umbilical cord (UC), immediately after clamping. Resistin, leptin, adiponectin, TNF-α, IL-6 and brain derived neurotrophic factor (BDNF) serum concentrations were measured with commercially available immunoassays. Determinants of maternal and newborn resistin levels were analyzed using simple and multiple linear regression. RESULTS: UC resistin levels were higher than maternal concentrations (median 17.69 ng/mL, IQR 7.36 vs. median 8.04 ng/mL, IQR 4.30). Correlation between UC and maternal resistin levels was moderate (R = 0.503, p < 0.01). In multiple regression analysis levels of maternal resistin and newborn TNF-α remained significant determining factors for UC resistin levels. Gestational age and maternal BDNF-levels remained significant factors for maternal resistin levels. CONCLUSION: In healthy, term newborns and their respective mothers a positive correlation between maternal and newborn levels and an association with gestational age around term can be found and point to a placental source of resistin. Further investigations are needed to clarify the possible contribution of transplacental transport of resistin into the fetal circulation. Except for gestational age most of the clinical obstetric variables tested do not seem to be determining factors for fetal or maternal resistin. Interactions of resistin with other cytokines like TNF-α and BDNF could be the missing link for the conflicting results in literature.

Memory B cells targeting SARS-CoV-2 spike protein and their dependence on CD4+ T cell help.

Memory B cells seem to be more durable than antibodies and thus crucial for the long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here we investigate SARS-CoV-2 spike-specific memory B cells and their dependence on CD4+ T cell help in different settings of coronavirus disease 2019 (COVID-19). Compared with severely ill individuals, those who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals. The increased activation and exhaustion of memory B cells observed during COVID-19 correlates with CD4+ T cell functions. Intriguingly, CD4+ T cells recognizing membrane protein show a stronger association with spike-specific memory B cells than those recognizing spike or nucleocapsid proteins. Overall, we identify CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection.

Rapid diagnostic test negative Plasmodium falciparum malaria in a traveller returning from Ethiopia.

BACKGROUND: Plasmodium falciparum strains with mutations/deletions of the genes encoding the histidine-rich proteins 2/3 (pfhrp2/3) have emerged during the last 10 years leading to false-negative results in HRP2-based rapid diagnostic tests (RDTs). This can lead to unrecognized infections in individuals and to setbacks in malaria control in endemic countries where RDTs are the backbone of malaria diagnostics and control. CASE DESCRIPTION: Here the detection of a pfhrp2/3-negative P. falciparum infection acquired in Ethiopia by a 63-year old female traveller is presented. After onset of symptoms during travel, she was first tested negative for malaria, most probably by RDT, at a local hospital in Harar, Ethiopia. Falciparum malaria was finally diagnosed microscopically upon her return to Germany, over 4 weeks after infection. At a parasite density of approximately 5387 parasites/µl, two different high-quality RDTs: Palutop + 4 OPTIMA, NADALRMalaria PF/pan Ag 4 Species, did not respond at their respective P. falciparum test lines. pfhrp2/3 deletion was confirmed by multiplex-PCR. The patient recovered after a complete course of atovaquone and proguanil. According to the travel route, malaria was acquired most likely in the Awash region, Central Ethiopia. This is the first case of imported P. falciparum with confirmed pfhrp2/3 deletion from Ethiopia. CONCLUSION: HRP2-negative P. falciparum strains may not be recognized by the presently available HRP2-based RDTs. When malaria is suspected, confirmation by microscopy and/or qPCR is necessary in order to detect falciparum malaria, which requires immediate treatment. This case of imported P. falciparum, non-reactive to HRP2-based RDT, possibly underlines the necessity for standardized, nationwide investigations in Ethiopia and should alert clinicians from non-endemic countries to the possibility of false-negative RDT results which may increase in returning travellers with potentially life-threatening infections.

Testosterone serum levels are not predictive of maternal virilization in hyperreactio luteinalis.

BACKGROUND: Elevated concentrations of circulating testosterone are present in hyperreactio luteinalis (HL), a pregnancy-specific, self-limited condition. HL is associated with maternal virilization in about 30% of cases. The correlation between testosterone levels and maternal virilization has not yet been quantified. Our aim was to identify a testosterone cut-off level which may allow to predict maternal virilization. METHODS: A literature research was performed. Publications were chosen if serum testosterone concentrations and presence or absence of maternal virilization was mentioned. Additionally, we report serial levels of steroids analyzed by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) in one case of HL managed at our institution. RESULTS: In all, 31 cases fulfilled the search criteria. We found significant overlap between testosterone levels in asymptomatic women and women with signs of virilization (range 6.2-37.3 nmol/l and 13.7-197.5 nmol/l, respectively). The method applied for testosterone analysis was mentioned in three reports only. Peak serum testosterone concentration in our case was 120.3 nmol/l. CONCLUSION: From the available data, maternal virilization in HL cannot be predicted by the level of circulating testosterone. However, comparability of results is hampered by the analytical methods applied. LC-MS/MS should preferably be used for reporting concentrations of circulating testosterone.

Infection fatality rate of SARS-CoV2 in a super-spreading event in Germany.

A SARS-CoV2 super-spreading event occurred during carnival in a small town in Germany. Due to the rapidly imposed lockdown and its relatively closed community, this town was seen as an ideal model to investigate the infection fatality rate (IFR). Here, a 7-day seroepidemiological observational study was performed to collect information and biomaterials from a random, household-based study population. The number of infections was determined by IgG analyses and PCR testing. We found that of the 919 individuals with evaluable infection status, 15.5% (95% CI:[12.3%; 19.0%]) were infected. This is a fivefold higher rate than the reported cases for this community (3.1%). 22.2% of all infected individuals were asymptomatic. The estimated IFR was 0.36% (95% CI:[0.29%; 0.45%]) for the community and 0.35% [0.28%; 0.45%] when age-standardized to the population of the community. Participation in carnival increased both infection rate (21.3% versus 9.5%, p < 0.001) and number of symptoms (estimated relative mean increase 1.6, p = 0.007). While the infection rate here is not representative for Germany, the IFR is useful to estimate the consequences of the pandemic in places with similar healthcare systems and population characteristics. Whether the super-spreading event not only increases the infection rate but also affects the IFR requires further investigation.

Changes in PUFA and eicosanoid metabolism during/after apnea diving: a prospective single-center study.

Background: The popularity of apneic diving is continually growing. As apnea diving substantially burdens the cardiovascular system, special focus is warranted. Regarding inflammation processes and associated inflammatory-related diseases (e.g., cardiovascular diseases), eicosanoids play an important role. This study aims to investigate polyunsaturated fatty acids (PUFAs) and eicosanoids in voluntary apnea divers, and so to further improve understanding of pathophysiological processes focusing on proinflammatory effects of temporarily hypercapnic hypoxia.. Methods: The concentration of PUFAs and eicosanoids were investigated in EDTA plasma in apnea divers (n=10) before and immediately after apnea, 0.5 hour and four hours later, applying liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Mean age was 41±10 years, and divers performed a mean breath-hold time of 317±111 seconds. PUFAs, eicosanoids and related lipids could be classified in four different kinetical reaction groups following apnea. The first group (e.g., Ω-6 and Ω-3-PUFAs) showed an immediate concentration increase followed by a decrease below baseline four hours after apnea. The second group (e.g., thromboxane B2) showed a slower increase, with its maximum concentration 0.5 hour post-apnea followed by a decrease four hours post-apnea. Group 3 (9- and 13-hydroxyoctadecadienoic acid) is characterized by two concentration increase peaks directly after apnea and four hours afterward compared to baseline. Group 4 (e.g., prostaglandin D2) shows no clear response. Conclusion: Changes in the PUFA metabolism after even a single apnea revealed different kinetics of pro- and anti-inflammatory regulations and changes for oxidative stress levels. Due to the importance of these mediators, apnea diving should be evaluated carefully and be performed only with great caution against the background of cardiovascular diseases and inflammation processes.

Hematologic changes after short term hypoxia in non-elite apnea divers under voluntary dry apnea conditions.

PURPOSE: This study investigated the acute changes in full spectrum differential blood cell count including reticulocytes and immature reticulocytes after a voluntary maximal dry apnea in non-elite divers. Aim of the present study is to obtain information on important regulatory compensation mechanisms and to provide insights into apneic regulatory processes. METHODS: Ten apnea divers performed a voluntary dry mean apnea time of 317 sec [SD ±111 sec]. Differential blood cell count including reticulocytes was measured before and immediately after a single maximal breath-hold. To evaluate kinetics, blood samples were also taken after 30 min and 4 h. Value distributions are presented with dot plots. P-values were calculated using a mixed linear model for time dependency. Four difference values were compared to baseline values with Dunnett's procedure. RESULTS: Significant changes were found in red blood cell parameters for erythrocytes, red cell distribution width, hematocrit, hemoglobin, MCV, reticulocytes and immature reticulocytes, and in white blood cell parameters for leucocytes, lymphocytes, immature granulocytes, monocytes, basophile granulocytes, neutrophil granulocytes and eosinophil granulocytes and for thrombocytes. CONCLUSION: Adaptive mechanisms regarding cell counts in elite apnea divers are not readily transferable to non-elite recreational sportspersons. Divers and physicians should be aware of the limited adaptive performance of humans in the case of extended apnea.

High-Sensitivity Troponin T Testing: Consequences on Daily Clinical Practice and Effects on Diagnosis of Myocardial Infarction.

It remains unclear how introduction of high-sensitivity troponin T testing, as opposed to conventional troponin testing, has affected the diagnosis of acute myocardial infarction (AMI) and resource utilization in unselected hospitalized patients. In this retrospective analysis, we include all consecutive cases from our center during two corresponding time frames (10/2016-04/2017 and 10/2017-04/2018) for which different troponin tests were performed: conventional troponin I (cTnI) and high-sensitivity troponin T (hs-TnT) assays. Testing was performed in 18,025 cases. The incidence of troponin levels above the 99th percentile was significantly higher in cases tested using hs-TnT. This was not associated with increased utilization of echocardiography, coronary angiography, or percutaneous coronary intervention. Although there were no changes in local standard operating procedures, study site personnel, or national coding guidelines, the number of coded AMI significantly decreased after introduction of hs-TnT. In this single-center retrospective study comprising 18,025 mixed medical and surgical cases with troponin testing, the introduction of hs-TnT was not associated with changes in resource utilization among the general cohort, but instead, led to a decrease in the international classification of diseases (ICD)-10 coded diagnosis of AMI.