Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, ...which may delay appropriate cause-specific treatment.
To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission.
The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission.
Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients.
CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).
Breast hypoplasia and impaired lactation are poorly studied sequelae of chest radiation therapy (RT) in children. The Pediatric Normal Tissue Effects in the Clinic female breast task force aimed to ...quantitate the radiation dose-volume effects on these endpoints.
A literature search was conducted of peer-reviewed manuscripts evaluating breast hypoplasia and lactation after chest RT in children, yielding 789 abstracts. Only 2 studies on children irradiated at <4 years of age for angioma of the breast provided dosimetric data correlated with breast hypoplasia. For patients who received brachytherapy, the dose was converted to external beam RT in equivalent 2 Gy fractions (D
), although the limitations of this type of mathematical conversion need to be recognized. We calculated relative risks (RR) and 95% confidence intervals (95% CIs) based on these data. Only 1 study was relevant to the lactation endpoint, in which patients were given RT for Hodgkin lymphoma at age 14 to 40 years.
The 3 studies involved 206 patients in total. In patients <4 years old at the time of RT, the prevalence of patient-perceived breast hypoplasia was 38% (RR 2.5; 95% CI, 1.3-4.6) after D
of <0.34 Gy, 61% (RR 4.0; 95% CI, 2.1-7.4) after D
0.34-0.97 Gy, and 97% (RR 6.3; 95% CI, 3.6-10.8) after D
≥0.97 Gy to the breast anlage. A simple linear regression model (r = 0.72; P < .001) showed that the treated breast was smaller than the untreated breast by 13% at D
= 0.5 Gy, 20% at D
= 1 Gy, 32% at D
= 2 Gy, 51% at D
= 4 Gy, 66% at D
= 6 Gy, 79% at D
= 8 Gy, and 90% at D
= 10 Gy. The risk of unsuccessful breastfeeding was 39% after a median mediastinal dose of 41 Gy, compared with 21% in a sibling control group (P = .04). RT dose of ≥42 Gy was not associated with less breastfeeding success compared with <42 Gy, and data on lower doses were unavailable.
Based on extremely limited data, young adults exposed to thoracic RT as children seem to be at significant risk of breast hypoplasia and impaired lactation. Doses as low as 0.3 Gy to immature breasts can cause breast hypoplasia. Additional studies are needed to quantify dose and technique effects with modern RT indications. Prospective collection of clinical outcomes and dosimetric factors would enhance our understanding of RT-induced breast hypoplasia and impaired lactation.
Multimodality reporter gene imaging combines the sensitivity, resolution and translational potential of two or more signals. The approach has not been widely adopted by the animal imaging community, ...mainly because its utility in this area is unproven. We developed a new complementation-based reporter gene system where the large component of split NanoLuc luciferase (LgBiT) presented on the surface of cells (TM-LgBiT) interacts with a radiotracer consisting of the high-affinity complementary HiBiT peptide labeled with a radionuclide. Radiotracer uptake could be imaged in mice using SPECT/CT and bioluminescence within two hours of implanting reporter-gene-expressing cells. Imaging data were validated by ex vivo biodistribution studies. Following the demonstration of complementation between the TM-LgBiT protein and HiBiT radiotracer, we validated the use of the technology in the highly specific in vivo multimodal imaging of cells. These findings highlight the potential of this new approach to facilitate the advancement of cell and gene therapies from bench to clinic.
Blood dilution after transfusion fluids leads to diminished coagulant activity monitored by rotational thromboelastometry, assessing elastic fibrin clot formation, or by thrombin generation testing. ...We aimed to determine the contributions of blood cells (platelets, red blood cells) and plasma factors (fibrinogen, prothrombin complex concentrate) to fibrin clot formation under conditions of haemodilution in vitro or in vivo.Whole blood or plasma diluted in vitro was supplemented with platelets, red cells, fibrinogen or prothrombin complex concentrate (PCC). Thromboelastometry was measured in whole blood as well as plasma; thrombin generation was determined in parallel. Similar tests were performed with blood from 48 patients, obtained before and after massive fluid infusion during cardiothoracic surgery.Addition of platelets or fibrinogen, in additive and independent ways, reversed the impaired fibrin clot formation (thromboelastometry) in diluted whole blood. In contrast, supplementation of red blood cells or prothrombin complex concentrate was ineffective. Platelets and fibrinogen independently restored clot formation in diluted plasma, resulting in thromboelastometry curves approaching those in whole blood. In whole blood from patients undergoing dilution during surgery, elastic clot formation was determined by both the platelet count and the fibrinogen level. Thrombin generation in diluted (patient) plasma was not changed by fibrinogen, but improved markedly by prothrombin complex concentrate. In conclusion, in dilutional coagulopathy, platelets and fibrinogen, but not red blood cells or vitamin K-dependent coagulation factors, independently determine thromboelastometry parameters measured in whole blood and plasma. Clinical decisions for transfusion based on thromboelastometry should take into account the platelet concentration.
The spectrum of a segment of InAs nanowire, confined between two superconducting leads, was measured as function of gate voltage and superconducting phase difference using a third normal-metal tunnel ...probe. Subgap resonances for odd electron occupancy-interpreted as bound states involving a confined electron and a quasiparticle from the superconducting leads, reminiscent of Yu-Shiba-Rusinov states-evolve into Kondo-related resonances at higher magnetic fields. An additional zero-bias peak of unknown origin is observed to coexist with the quasiparticle bound states.
Preclinical studies suggest that hospitalized patients are susceptible to infections caused by nosocomial respiratory pathogens at least in part because of immune suppression caused by the condition ...for which they were admitted.
We aimed to characterize the systemic host response in hospital-acquired pneumonia (HAP) when compared with community-acquired pneumonia (CAP).
We performed a prospective study in two intensive care units (ICUs) in 453 patients with HAP (n = 222) or CAP (n = 231). Immune responses were determined on ICU admission by measuring 19 plasma biomarkers reflecting organ systems implicated in infection pathogenesis (in 192 patients with HAP and 183 patients with CAP) and by applying genome-wide blood gene expression profiling (in 111 patients with HAP and 110 patients with CAP).
Patients with HAP and CAP presented with similar disease severities and mortality rates did not differ up to 1 year after admission. Plasma proteome analysis revealed largely similar responses, including systemic inflammatory and cytokine responses, and activation of coagulation and the vascular endothelium. The blood leukocyte genomic response was greater than 75% common in patients with HAP and CAP, comprising proinflammatory, antiinflammatory, T-cell signaling, and metabolic pathway gene sets. Patients with HAP showed overexpression of genes involved in cell-cell junction remodeling, adhesion, and diapedesis, which corresponded with lower plasma levels of matrix metalloproteinase-8 and soluble E-selectin. In addition, patients with HAP demonstrated underexpression of a type-I interferon signaling gene signature.
Patients with HAP and CAP present with a largely similar host response at ICU admission.
Aesthetic preference is intricately linked to learning and creativity. Previous studies have largely examined the perception of novelty in terms of pleasantness and the generation of novelty via ...creativity separately. The current study examines the connection between perception and generation of novelty in music; specifically, we investigated how pleasantness judgements and brain responses to musical notes of varying probability (estimated by a computational model of auditory expectation) are linked to learning and creativity. To facilitate learning de novo, 40 non-musicians were trained on an unfamiliar artificial music grammar. After learning, participants evaluated the pleasantness of the final notes of melodies, which varied in probability, while their EEG was recorded. They also composed their own musical pieces using the learned grammar which were subsequently assessed by experts. As expected, there was an inverted U-shaped relationship between liking and probability: participants were more likely to rate the notes with intermediate probabilities as pleasant. Further, intermediate probability notes elicited larger N100 and P200 at posterior and frontal sites, respectively, associated with prediction error processing. Crucially, individuals who produced less creative compositions preferred higher probability notes, whereas individuals who composed more creative pieces preferred notes with intermediate probability. Finally, evoked brain responses to note probability were relatively independent of learning and creativity, suggesting that these higher-level processes are not mediated by brain responses related to performance monitoring. Overall, our findings shed light on the relationship between perception and generation of novelty, offering new insights into aesthetic preference and its neural correlates.
Recent experiments have demonstrated superconducting transmon qubits with semiconductor nanowire Josephson junctions. These hybrid gatemon qubits utilize field effect tunability characteristic of ...semiconductors to allow complete qubit control using gate voltages, potentially a technological advantage over conventional flux-controlled transmons. Here, we present experiments with a two-qubit gatemon circuit. We characterize qubit coherence and stability and use randomized benchmarking to demonstrate single-qubit gate errors below 0.7% for all gates, including voltage-controlled Z rotations. We show coherent capacitive coupling between two gatemons and coherent swap operations. Finally, we perform a two-qubit controlled-phase gate with an estimated fidelity of 91%, demonstrating the potential of gatemon qubits for building scalable quantum processors.
We present conductance-matrix measurements in long, three-terminal hybrid superconductor-semiconductor nanowires, and compare with theoretical predictions of a magnetic-field-driven, topological ...quantum phase transition. By examining the nonlocal conductance, we identify the closure of the excitation gap in the bulk of the semiconductor before the emergence of zero-bias peaks, ruling out spurious gap-closure signatures from localized states. We observe that after the gap closes, nonlocal signals and zero-bias peaks fluctuate strongly at both ends, inconsistent with a simple picture of clean topological superconductivity.
We investigate transmon qubits made from semiconductor nanowires with a fully surrounding superconducting shell. In the regime of reentrant superconductivity associated with the destructive ...Little-Parks effect, numerous coherent transitions are observed in the first reentrant lobe, where the shell carries 2π winding of superconducting phase, and are absent in the zeroth lobe. As junction density was increased by gate voltage, qubit coherence was suppressed then lost in the first lobe. These observations and numerical simulations highlight the role of winding-induced Andreev states in the junction.
PDF
