Increased circulating cytokeratin 19 fragment levels in preterm neonates receiving mechanical ventilation are associated with poor outcome.

Invasive mechanical ventilation and oxygen toxicity are postnatal contributors to chronic lung disease of prematurity, also known as bronchopulmonary dysplasia (BPD). Cyfra 21-1 is a soluble fragment of cytokeratin 19, which belongs to the cytoskeleton stabilizing epithelial intermediate filaments. As a biomarker of structural integrity, Cyfra 21-1 might be associated with airway injury and lung hypoplasia in neonates. Serum Cyfra 21-1 concentrations for 80 preterm and 80 healthy term newborns were measured within 48 h after birth. Preterm infants with the combined endpoint BPD/mortality had significantly higher Cyfra 21-1 levels compared with those without fulfilling BPD/mortality criteria (P = 0.01). Also, severe RDS (>grade III) was associated with higher Cyfra levels (P = 0.01). Total duration of oxygen therapy was more than five times longer in neonates with high Cyfra 21-1 levels (P = 0.01). Infants with higher Cyfra 21-1 values were more likely to receive mechanical ventilation (50% vs. 17.5%). However, the duration of mechanical ventilation was similar between groups. The median Cyfra value was 1.93 ng/mL (IQR: 1.68-2.53 ng/mL) in healthy term neonates and 8.5 ng/mL (IQR: 3.6-16.0 ng/mL) in preterm infants. Using ROC analysis, we calculated a Cyfra cutoff > 8.5 ng/mL to predict BPD/death with an AUC of 0.795 (P = 0.004), a sensitivity of 88.9%, and a specificity of 55%. Mortality was predicted with a cutoff > 17.4 ng/mL (AUC: 0.94; P = 0.001), a sensitivity of 100%, and a specificity of 84%. These findings suggest that Cyfra 21-1 concentration might be useful to predict poor outcome in premature infants.

[Toxicity after chimeric antigen receptor T-cell therapy : Overview and management of early and late onset side effects]. / Toxizitäten nach Chimärer-Antigenrezeptor-T-Zell-Therapie : Übersicht und Management früher und verzögerter Nebenwirkungen.

BACKGROUND: The transfusion of chimeric antigen receptor (CAR) T­cells has become established as a new treatment option in oncology; however, this is regularly associated with immune-mediated side effects, which can also run a severe course and necessitate a specific treatment and intensive medical treatment. MATERIAL AND METHODS: A literature review was carried out on CAR T-cell therapy, toxicities and the management of side effects. RESULTS: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) regularly occur shortly after CAR T-cell treatment. The symptoms of CRS can range from mild flu-like symptoms to multiorgan failure. In addition to mild symptoms, such as disorientation and aphasia, ICANS can also lead to convulsive seizures and brain edema. The management of CRS and ICANS is based on the severity according to the grading of the American Society for Transplantation and Cellular Therapy (ASTCT). Tocilizumab and corticosteroids are recommended for CRS and corticosteroids are used for ICANS. In the further course persisting hypogammaglobulinemia and cytopenia are frequent even months after the initial treatment and promote infections even months after CAR T­cell therapy. DISCUSSION: Potentially severe complications regularly occur after CAR T-cell therapy. An interdisciplinary cooperation between intensive care physicians, hematologists, neurologists and specialists in other disciplines is of decisive importance for the optimal care of patients after CAR T­cell therapy.

Expression of soluble receptor for advanced glycation end products is associated with disease severity in congenital diaphragmatic hernia.

Pulmonary hypertension (PH) and lung hypoplasia are major contributors to morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). The soluble receptor for advanced glycation end products (sRAGE) is a marker of endothelial function and might be associated with disease severity in CDH newborns. In a cohort of 30 CDH newborns and 20 healthy control newborns, sRAGE concentration was measured at birth and at 6 h, 12 h, 24 h, 48 h, and 7-10 days. In healthy newborns, sRAGE was significantly higher at birth and at 48 h compared with CDH newborns (both P < 0.001). Among CDH newborns, sRAGE was significantly lower at birth (P = 0.033) and at 7-10 days (P = 0.035) in patients receiving extracorporeal membrane oxygenation (ECMO) compared with patients not receiving ECMO. In contrast, CDH newborns receiving ECMO had significantly higher values at 6 h (P = 0.001), 12 h (P = 0.004), and 48 h (0.032). Additionally, sRAGE correlated significantly with PH severity, intensity and duration of mechanical ventilation, and prenatally assessed markers of CDH severity (lung size, liver herniation). The probability to receive ECMO therapy was five times higher in CDH newborns with sRAGE concentrations below the calculated cutoff of 650 pg/ml at birth (P = 0.002) and nine times higher in CDH newborns with sRAGE concentrations above the cutoff of 3,500 pg/ml at 6 h (P = 0.001). These findings suggest a potential involvement of sRAGE in the pathophysiology of CDH and may act as a therapeutic target in future treatment approaches.

Clinical Course and Outcome of Patients with SARS-CoV-2 Alpha Variant Infection Compared to Patients with SARS-CoV-2 Wild-Type Infection Admitted to the ICU.

The alpha variant of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is associated with higher transmissibility and possibly higher mortality compared with wild-type SARS-CoV-2. However, few data are available on the clinical course of infections with the alpha variant compared with wild-type SARS-CoV-2 in critically ill patients in intensive care units (ICUs). Therefore, we retrospectively analyzed patients admitted to our ICU due to SARS-CoV-2 Alpha variant infection and compared characteristics and course to patients with SARS-CoV-2 wild-type infection. The median age of patients with Alpha variant infections was 57 years compared to 62 years in the wild-type group. ICU survival was 41/80 (51%) in the Alpha variant group and 35/80 (44%) in the wild-type group (p = 0.429). Results of a matched-pair analysis based on age and sex illustrated that 45/58 patients (77.6%) in the Alpha variant group and 38/58 (65.5%) patients in the wild-type group required mechanical ventilation (p = 0.217). ICU survival was documented for 28/58 patients (48.3%) in the Alpha variant group and 27/58 patients (46.6%) in the wild-type group (p = 1). Thus, ICU mortality among patients with SARS-CoV-2 infections remains high. Although the Alpha variant group included younger patients requiring mechanical ventilation, no significant differences between patients with the SARS-CoV-2 Alpha variant and the SARS-CoV-2 wild-type, respectively, were detected with respect to clinical course and ICU mortality. For future VOCs, we believe it would be important to obtain valid and rapid data on the clinical course of critically ill patients who test positive for COVID-19 in order to perform appropriate epidemiological planning of intensive care capacity.

Early postnatal changes of circulating N-terminal-pro-B-type natriuretic peptide in neonates with congenital diaphragmatic hernia.

BACKGROUND: Severity of lung hypoplasia, pulmonary hypertension (PH) and cardiac dysfunction are major contributors to mortality in congenital diaphragmatic hernia (CDH). Therefore, early assessment and management is important to improve outcome. NT-proBNP is an established cardiac biomarker with only limited data for early postnatal risk assessment in CDH newborns. AIMS: To investigate the correlation of NT-proBNP at birth, 6 h, 12 h, 24 h, and 48 h with PH and cardiac dysfunction and the prognostic information of NT-proBNP for the use of ECMO support or mortality. SUBJECTS: 44 CDH newborns treated at our institution (December 2014-October 2017) were prospectively enrolled. OUTCOME MEASURES: Primary clinical endpoint was either need for ECMO or death within the first 48 h (group A). Infants not receiving ECMO support were allocated to group B. Mortality was tested as secondary endpoint. RESULTS: NT-proBNP levels measured at 6 h, 12 h, 24 h and 48 h postpartum correlated significantly with PH severity following NICU admission and at 24 h, and with severity of cardiac dysfunction at birth, 24 h, 48 h and after 7 days of life. There was no difference in NT-proBNP levels between survivors and non-survivors. NT-proBNP levels were significantly higher in group A at 6 h (p = 0.007), 12 h (p = 0.036), and 24 h (p = 0.007), but not at birth (p = 0.785) or 48 h (p = 0.15) compared to group B. CONCLUSION: NT-proBNP analysis in the first 48 h of life may be useful to assess PH and cardiac dysfunction in CDH newborns and to predict the need for ECMO support.

Suppressed competitive exclusion enabled the proliferation of Permian/Triassic boundary microbialites.

During the earliest Triassic microbial mats flourished in the photic zones of marginal seas, generating widespread microbialites. It has been suggested that anoxic conditions in shallow marine environments, linked to the end-Permian mass extinction, limited mat-inhibiting metazoans allowing for this microbialite expansion. The presence of a diverse suite of proxies indicating oxygenated shallow sea-water conditions (metazoan fossils, biomarkers and redox proxies) from microbialite successions have, however, challenged the inference of anoxic conditions. Here, the distribution and faunal composition of Griesbachian microbialites from China, Iran, Turkey, Armenia, Slovenia and Hungary are investigated to determine the factors that allowed microbialite-forming microbial mats to flourish following the end-Permian crisis. The results presented here show that Neotethyan microbial buildups record a unique faunal association due to the presence of keratose sponges, while the Palaeotethyan buildups have a higher proportion of molluscs and the foraminifera Earlandia. The distribution of the faunal components within the microbial fabrics suggests that, except for the keratose sponges and some microconchids, most of the metazoans were transported into the microbial framework via wave currents. The presence of both microbialites and metazoan associations were limited to oxygenated settings, suggesting that a factor other than anoxia resulted in a relaxation of ecological constraints following the mass extinction event. It is inferred that the end-Permian mass extinction event decreased the diversity and abundance of metazoans to the point of significantly reducing competition, allowing photosynthesis-based microbial mats to flourish in shallow water settings and resulting in the formation of widespread microbialites.

Constraining the formation of authigenic carbonates in a seepage-affected cold-water coral mound by lipid biomarkers.

Cold-water coral (CWC) mounds are build-ups comprised of coral-dominated intervals alternating with a mixed carbonate-siliciclastic matrix. At some locations, CWC mounds are influenced by methane seepage, but the impact of methane on CWC mounds is poorly understood. To constrain the potential impact of methane on CWC mound growth, lipid biomarker investigations were combined with mineralogical and petrographic analyses to investigate the anaerobic oxidation of methane (AOM) and authigenic carbonate formation in sediment from a seep-affected CWC mound in the Gulf of Cadiz. The occurrence of AOM was confirmed by characteristic lipids found within a semi-lithified zone (SLZ) consisting of authigenic aragonite, high-magnesium calcite and calcium-excess dolomite. The formation of high-Mg calcite is attributed to AOM, acting as a lithifying agent. Aragonite is only a minor phase. Ca-excess dolomite in the SLZ and upper parts may be formed by organoclastic sulphate reduction, favouring precipitation by increased alkalinity. The AOM biomarkers in the SLZ include isoprenoid-based archaeal membrane lipids, such as abundant glycerol dibiphytanyl glycerol tetraethers (GDGTs) dominated by GDGT-2. The δ13 C values of GDGT-2, measured as ether-cleaved monocyclic biphytanes, are as low as -100‰ versus V-PDB. Further, bacterial dialkyl glycerol diethers with two anteiso-C15 alkyl chains and δ13 C values of -81‰ are interpreted as biomarkers of sulphate-reducing bacteria. The lipid biomarker signatures and mineralogical patterns suggest that anaerobic methane-oxidizing archaea of the ANME-1 group thrived in the subsurface at times of slow and diffusive methane seepage. Petrographic analyses revealed that the SLZ was exhumed at some point (e.g. signs of bioerosion of the semi-lithified sediment), providing a hard substrate for CWC larval settlement. In addition, this work reveals that AOM-induced semi-lithification likely played a role in mound stabilization. Lipid biomarker analysis proves to be a powerful tool to disentangle early diagenetic processes induced by microbial metabolisms.

Continuous intravenous sildenafil as an early treatment in neonates with congenital diaphragmatic hernia.

BACKGROUND: Pulmonary hypertension (PH) is an important contributor of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). Treatment options are limited, but sildenafil might improve oxygenation and PH in neonates with CDH. OBJECTIVE: Aim of this study is to assess effects of intravenous sildenafil on oxygenation and PH in neonates with CDH. METHODS: A retrospective chart review was performed in all neonates with CDH born in our institution between September 2012 and December 2014. Indication for sildenafil was an OI > 15, PH > 2/3 systemic pressure, or a difference in pre- and postductal oxygen saturation (≥8%). A sildenafil bolus was administered followed by a maintenance infusion of 1.6 mg/kg/d. Primary outcome was improved oxygenation after starting sildenafil. Patients were compared according to improvement in oxygenation (responder vs non-responder). RESULTS: A total of 26 of 44 neonates were treated with intravenous sildenafil and in all sildenafil were initiated within the first 24 h of life (median age 3.1 h). Improved oxygenation was observed in 11 infants (42.3%). Among the 15 non-responders (57.6%) ECMO was started in 13 and two infants died without ECMO. Vasopressor support increased significantly during the first hours after commencing sildenafil in responders and non-responders. Echocardiographic indices demonstrated an effect on pulmonary arterial pressure within the first 24 h after starting sildenafil. CONCLUSIONS: Treatment of neonates with intravenous sildenafil during the first day of life was associated with acute improvement in oxygenation in more than 40% of patients. However, a significant increase in vasopressor support was observed.