A 15-million-year surface- and subsurface-integrated TEX86 temperature record from the eastern equatorial Atlantic

TEX86 is a paleothermometer based on Thaumarcheotal glycerol dialkyl glycerol tetraether (GDGT) lipids and is one of the most frequently used proxies for sea-surface temperature (SST) in warmer-than-present climates. However, GDGTs are not exclusively produced in and exported from the mixed layer, so sedimentary GDGTs may contain a depth-integrated signal that is also sensitive to local subsurface temperature variability. In addition, the correlation between TEX86 and SST is not significantly stronger than that to depth-integrated mixed-layer to subsurface temperatures. The calibration of TEX86 to SST is therefore controversial. Here we assess the influence of subsurface temperature variability on TEX86 using a downcore approach. We present a 15 Myr TEX86 record from Ocean Drilling Program Site 959 in the Gulf of Guinea and use additional proxies to elucidate the source of the recorded TEX86 variability. Relatively high GDGT[2/3] ratio values from 13.6 Ma indicate that sedimentary GDGTs were partly sourced from deeper (> 200 m) waters. Moreover, late Pliocene TEX86 variability is highly sensitive to glacial–interglacial cyclicity, as is also recorded by benthic δ18O, while the variability within dinoflagellate assemblages and surface/thermocline temperature records (Uk370 and Mg/Ca) is not primarily explained by glacial–interglacial cyclicity. Combined, these observations are best explained by TEX86 sensitivity to sub-thermocline temperature variability. We conclude that TEX86 represents a depth-integrated signal that incorporates a SST and a deeper component, which is compatible with the present-day depth distribution of Thaumarchaeota and with the GDGT[2/3] distribution in core tops. The depth-integrated TEX86 record can potentially be used to infer SST variability, because subsurface temperature variability is generally tightly linked to SST variability. Using a subsurface calibration with peak calibration weight between 100 and 350 m, we estimate that east equatorial Atlantic SST cooled by ∼ 5◦C between the Late Miocene and Pleistocene. On shorter timescales, we use the TEX86 record as a proxy for South Atlantic Central Water (SACW), which originates from surface waters in the South Atlantic Gyre and mixes at depth with Antarctic Intermediate Water (AAIW). Leads and lags around the Pliocene M2 glacial (∼ 3.3 Ma) in our record, combined with published information, suggest that the M2 glacial was marked by SACW cooling during an austral summer insolation minimum and that decreasing CO2 levels were a feedback, not the initiator, of glacial expansion

The impact of the Trauma Triage App on pre-hospital trauma triage: design and protocol of the stepped-wedge, cluster-randomized TESLA trial

Abstract Background Field triage of trauma patients is crucial to get the right patient to the right hospital within a particular time frame. Minimization of undertriage, overtriage, and interhospital transfer rates could substantially reduce mortality rates, life-long disabilities, and costs. Identification of patients in need of specialized trauma care is predominantly based on the judgment of Emergency Medical Services professionals and a pre-hospital triage protocol. The Trauma Triage App is a smartphone application that includes a prediction model to aid Emergency Medical Services professionals in the identification of patients in need of specialized trauma care. The aim of this trial is to assess the impact of this new digital approach to field triage on the primary endpoint undertriage. Methods The Trauma triage using Supervised Learning Algorithms (TESLA) trial is a stepped-wedge cluster-randomized controlled trial with eight clusters defined as Emergency Medical Services regions. These clusters are an integral part of five inclusive trauma regions. Injured patients, evaluated on-scene by an Emergency Medical Services professional, suspected of moderate to severe injuries, will be assessed for eligibility. This unidirectional crossover trial will start with a baseline period in which the default pre-hospital triage protocol is used, after which all clusters gradually implement the Trauma Triage App as an add-on to the existing triage protocol. The primary endpoint is undertriage on patient and cluster level and is defined as the transportation of a severely injured patient (Injury Severity Score ≥ 16) to a lower-level trauma center. Secondary endpoints include overtriage, hospital resource use, and a cost-utility analysis. Discussion The TESLA trial will assess the impact of the Trauma Triage App in clinical practice. This novel approach to field triage will give new and previously undiscovered insights into several isolated components of the diagnostic strategy to get the right trauma patient to the right hospital. The stepped-wedge design allows for within and between cluster comparisons. Trial registration Netherlands Trial Register, NTR7243. Registered 30 May 2018, https://www.trialregister.nl/trial/7038

Intravenous S-ketamine does not inhibit alveolar fluid clearance in a septic rat model

We previously demonstrated that intratracheally administered S-ketamine inhibits alveolar fluid clearance (AFC), whereas an intravenous (i.v.) bolus injection had no effect. The aim of the present study was to characterize whether continuous i.v. infusion of S-ketamine, yielding clinically relevant plasma concentrations, inhibits AFC and whether its effect is enhanced in acute lung injury (ALI) which might favor the appearance of i.v. S-ketamine at the alveolar surface. AFC was measured in fluid-instilled rat lungs. S-ketamine was administered i.v. over 6 h (loading dose: 20 mg/kg, followed by 20 mg/kg/h), or intratracheally by addition to the instillate (75 µg/ml). ALI was induced by i.v. lipopolysaccharide (LPS; 7 mg/kg). Interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant (CINC)-3 were measured by ELISA in plasma and bronchoalveolar lavage fluid. Isolated rat alveolar type-II cells were exposed to S-ketamine (75 µg/ml) and/or LPS (1 mg/ml) for 6 h, and transepithelial ion transport was measured as short circuit current (ISC). AFC was 27±5% (mean±SD) over 60 min in control rats and was unaffected by i.v. S-ketamine. Tracheal S-ketamine reduced AFC to 18±9%. In LPS-treated rats, AFC decreased to 16±6%. This effect was not enhanced by i.v. S-ketamine. LPS increased IL-6 and CINC-3 in plasma and bronchoalveolar lavage fluid. In alveolar type-II cells, S-ketamine reduced ISC by 37% via a decrease in amiloride-inhibitable sodium transport. Continuous administration of i.v. S-ketamine does not affect rat AFC even in endotoxin-induced ALI. Tracheal application with direct exposure of alveolar epithelial cells to S-ketamine decreases AFC by inhibition of amiloride-inhibitable sodium transpor

Central and local arterial stiffness in White Europeans compared to age-, sex-, and BMI-matched South Asians

BackgroundEthnicity impacts cardiovascular disease (CVD) risk, and South Asians demonstrate a higher risk than White Europeans. Arterial stiffness is known to contribute to CVD, and differences in arterial stiffness between ethnicities could explain the disparity in CVD risk. We compared central and local arterial stiffness between White Europeans and South Asians and investigated which factors are associated with arterial stiffness.MethodsData were collected from cohorts of White Europeans (the Netherlands) and South Asians (India). We matched cohorts on individual level using age, sex, and body mass index (BMI). Arterial stiffness was measured with ARTSENS® Plus. Central stiffness was expressed as carotid-femoral pulse wave velocity (cf-PWV, m/s), and local carotid stiffness was quantified using the carotid stiffness index (Beta) and pressure-strain elastic modulus (Epsilon, kPa). We compared arterial stiffness between cohorts and used multivariable linear regression to identify factors related to stiffness.ResultsWe included n = 121 participants per cohort (age 53±10 years, 55% male, BMI 24 kg/m2). Cf-PWV was lower in White Europeans compared to South Asians (6.8±1.9 vs. 8.2±1.8 m/s, p0.05 for interaction). Systolic blood pressure was associated with carotid stiffness in both cohorts, whereas age was associated to carotid stiffness only in South Asians and BMI only in White Europeans.ConclusionEthnicity is associated with central but not local arterial stiffness. Conversely, ethnicity seems to modify associations between CVD risk factors and local but not central arterial stiffness. This suggests that ethnicity interacts with arterial stiffness measures and the association of these measures with CVD risk factors

Central and local arterial stiffness in White Europeans compared to age-, sex-, and BMI-matched South Asians

Background Ethnicity impacts cardiovascular disease (CVD) risk, and South Asians demonstrate a higher risk than White Europeans. Arterial stiffness is known to contribute to CVD, and differences in arterial stiffness between ethnicities could explain the disparity in CVD risk. We compared central and local arterial stiffness between White Europeans and South Asians and investigated which factors are associated with arterial stiffness. Methods Data were collected from cohorts of White Europeans (the Netherlands) and South Asians (India). We matched cohorts on individual level using age, sex, and body mass index (BMI). Arterial stiffness was measured with ARTSENS® Plus. Central stiffness was expressed as carotid-femoral pulse wave velocity (cf-PWV, m/s), and local carotid stiffness was quantified using the carotid stiffness index (Beta) and pressure-strain elastic modulus (Epsilon, kPa). We compared arterial stiffness between cohorts and used multivariable linear regression to identify factors related to stiffness. Results We included n = 121 participants per cohort (age 53±10 years, 55% male, BMI 24 kg/m2). Cf-PWV was lower in White Europeans compared to South Asians (6.8±1.9 vs. 8.2±1.8 m/s, p0.05 for interaction). Systolic blood pressure was associated with carotid stiffness in both cohorts, whereas age was associated to carotid stiffness only in South Asians and BMI only in White Europeans. Conclusion Ethnicity is associated with central but not local arterial stiffness. Conversely, ethnicity seems to modify associations between CVD risk factors and local but not central arterial stiffness. This suggests that ethnicity interacts with arterial stiffness measures and the association of these measures with CVD risk factors

Effects on coagulation and fibrinolysis induced by influenza in mice with a reduced capacity to generate activated protein C and a deficiency in plasminogen activator inhibitor type 1

Influenza infections increase the risk of diseases associated with a prothrombotic state, such as venous thrombosis and atherothrombotic diseases. However, it is unclear whether influenza leads to a prothrombotic state in vivo. To determine whether influenza activates coagulation, we measured coagulation and fibrinolysis in influenza-infected C57BL/6 mice. We found that influenza increased thrombin generation, fibrin deposition, and fibrinolysis. In addition, we used various anti- and prothrombotic models to study pathways involved in the influenza-induced prothrombotic state. A reduced capacity to generate activated protein C in TM(pro/pro) mice increased thrombin generation and fibrinolysis, whereas treatment with heparin decreased thrombin generation in influenza-infected C57Bl/6 mice. Thrombin generation was not changed in hyperfibrinolytic mice, deficient in plasminogen activator inhibitor type-1 (PAI-1(-/-)); however, increased fibrin degradation was seen. Treatment with tranexamic acid reduced fibrinolysis, but thrombin generation was unchanged. We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin. The fibrinolytic system appears not to be important for thrombin generation. These findings suggest that influenza leads to a prothrombotic state by coagulation activation. Heparin treatment reduces the influenza induced prothrombotic stat

Traumatic Brain Injury in Rats Induces Lung Injury and Systemic Immune Suppression

<p>Traumatic brain injury (TBI) is frequently complicated by acute lung injury, which is predictive for poor outcome. However, it is unclear whether lung injury develops independently or as a result of mechanical ventilation after TBI. Further, TBI is strongly associated with the development of pneumonia, suggesting a specific vulnerability for the development of nosocomial infections in the lung after TBI. In this study, we evaluated whether indeed pulmonary injury and immune suppression develop spontaneously in an animal model of mild TBI (mTBI). TBI was induced in male PVG rats by closed-head trauma using a weight-drop device. Subsequently, we evaluated the effects of this on the lungs as well as on the excitability of the systemic immune system. Finally, we performed an experiment in which TBI was followed by induction of pneumonitis and evaluated whether TBI affects the severity of subsequent pneumonitis induced by intratracheal instillation of heat-killed Staphylococcus aureus. mTBI resulted in significant lung injury, as evidenced by pulmonary edema, protein leakage to the alveolar compartment, and increased concentrations of interleukin-1 and -6 in broncho alveolar lavage fluid (all p0.05), suggesting that systemic immune suppression is not translated toward the pulmonary compartment in this specific model. We here show that during mild experimental TBI, acute pulmonary injury, as well as a decrease in the excitability of the systemic immune system, can be observed.</p>

A 15-million-year surface- and subsurface-integrated TEX86 temperature record from the eastern equatorial Atlantic

TEX86 is a paleothermometer based on Thaumarcheotal glycerol dialkyl glycerol tetraether (GDGT) lipids and is one of the most frequently used proxies for sea-surface temperature (SST) in warmer-than-present climates. However, GDGTs are not exclusively produced in and exported from the mixed layer, so sedimentary GDGTs may contain a depth-integrated signal that is also sensitive to local subsurface temperature variability. In addition, the correlation between TEX86 and SST is not significantly stronger than that to depth-integrated mixed-layer to subsurface temperatures. The calibration of TEX86 to SST is therefore controversial. Here we assess the influence of subsurface temperature variability on TEX86 using a downcore approach. We present a 15 Myr TEX86 record from Ocean Drilling Program Site 959 in the Gulf of Guinea and use additional proxies to elucidate the source of the recorded TEX86 variability. Relatively high GDGT[2/3] ratio values from 13.6 Ma indicate that sedimentary GDGTs were partly sourced from deeper (> 200 m) waters. Moreover, late Pliocene TEX86 variability is highly sensitive to glacial–interglacial cyclicity, as is also recorded by benthic δ18O, while the variability within dinoflagellate assemblages and surface/thermocline temperature records (Uk370 and Mg/Ca) is not primarily explained by glacial–interglacial cyclicity. Combined, these observations are best explained by TEX86 sensitivity to sub-thermocline temperature variability. We conclude that TEX86 represents a depth-integrated signal that incorporates a SST and a deeper component, which is compatible with the present-day depth distribution of Thaumarchaeota and with the GDGT[2/3] distribution in core tops. The depth-integrated TEX86 record can potentially be used to infer SST variability, because subsurface temperature variability is generally tightly linked to SST variability. Using a subsurface calibration with peak calibration weight between 100 and 350 m, we estimate that east equatorial Atlantic SST cooled by ∼ 5◦C between the Late Miocene and Pleistocene. On shorter timescales, we use the TEX86 record as a proxy for South Atlantic Central Water (SACW), which originates from surface waters in the South Atlantic Gyre and mixes at depth with Antarctic Intermediate Water (AAIW). Leads and lags around the Pliocene M2 glacial (∼ 3.3 Ma) in our record, combined with published information, suggest that the M2 glacial was marked by SACW cooling during an austral summer insolation minimum and that decreasing CO2 levels were a feedback, not the initiator, of glacial expansion

Saponin-based adjuvants enhance antigen cross-presentation in human CD11c+ CD1c+ CD5− CD163+ conventional type 2 dendritic cells

Background Adjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition to antibody responses. Recent preclinical studies revealed that SBAs induced cross-presentation and lipid bodies in otherwise poorly cross-presenting CD11b+ murine dendritic cells (DCs).Method Here, we investigated the response of human DC subsets to SBAs with RNA sequencing and pathway analyses, lipid body induction visualized by laser scanning microscopy, antigen translocation to the cytosol, and antigen cross-presentation to CD8+ T cells.Results RNA sequencing of SBA-treated conventional type 1 DC (cDC1) and type 2 DC (cDC2) subsets uncovered that SBAs upregulated lipid-related pathways in CD11c+ CD1c+ cDC2s, especially in the CD5− CD163+ CD14+ cDC2 subset. Moreover, SBAs induced lipid bodies and enhanced endosomal antigen translocation into the cytosol in this particular cDC2 subset. Finally, SBAs enhanced cross-presentation only in cDC2s, which requires the CD163+ CD14+ cDC2 subset.Conclusions These data thus identify the CD163+ CD14+ cDC2 subset as the main SBA-responsive DC subset in humans and imply new strategies to optimize the application of saponin-based adjuvants in a potent cancer vaccine