Bayesian methods: a potential path forward for sepsis trials.

BACKGROUND: Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. METHODS: We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. RESULTS: In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. CONCLUSIONS: Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.

Amplification of nonlinear polariton pulses in waveguides.

Using a sub-millimeter exciton-polariton waveguide suitable for integrated photonics, we experimentally demonstrate nonlinear modulation of pico-Joule pulses at the same time as amplification sufficient to compensate the system losses. By comparison with a numerical model we explain the observed interplay of gain and nonlinearity as amplification of the interacting polariton field by stimulated scattering from an incoherent continuous-wave reservoir that is depleted by the pulses. This combination of gain and giant ultrafast nonlinearity operating on picosecond pulses has the potential to open up new directions in low-power all-optical information processing and nonlinear photonic simulation of conservative and driven-dissipative systems.

Polarization-resolved strong light-matter coupling in planar GaAs/AlGaAs waveguides.

We study the influence of optical selection rules and polarization splittings on properties of exciton polaritons in a planar AlGaAs waveguide containing embedded GaAs quantum wells. We demonstrate that transverse electric and transverse magnetic modes couple differently with light- and heavy-hole quantum well excitons, which leads to distinct polarization splittings of the resulting polariton modes. The experimental data are in good agreement with modeling based on theoretical data for the optical selection rules for quantum well excitons.

Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.

Importance: Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes. Objective: To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity. Design, Setting, and Participants: Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017. Interventions: Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients). Main Outcomes and Measures: The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9. Results: Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, -5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group). Conclusions and Relevance: Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT01046669.

A novel alternative to classify tissues from T 1 and T 2 relaxation times for prostate MRI.

OBJECTIVE: To segment and classify the different attenuation regions from MRI at the pelvis level using the T 1 and T 2 relaxation times and anatomical knowledge as a first step towards the creation of PET/MR attenuation maps. MATERIALS AND METHODS: Relaxation times were calculated by fitting the pixel-wise intensities of acquired T 1- and T 2-weighted images from eight men with inversion-recovery and multi-echo multi-slice spin-echo sequences. A decision binary tree based on relaxation times was implemented to segment and classify fat, muscle, prostate, and air (within the body). Connected component analysis and an anatomical knowledge-based procedure were implemented to localize the background and bone. RESULTS: Relaxation times at 3 T are reported for fat (T 1 = 385 ms, T 2 = 121 ms), muscle (T 1 = 1295 ms, T 2 = 40 ms), and prostate (T 1 = 1700 ms, T 2 = 80 ms). The relaxation times allowed the segmentation-classification of fat, prostate, muscle, and air, and combined with anatomical knowledge, they allowed classification of bone. The good segmentation-classification of prostate [mean Dice similarity score (mDSC) = 0.70] suggests a viable implementation in oncology and that of fat (mDSC = 0.99), muscle (mDSC = 0.99), and bone (mDSCs = 0.78) advocates for its implementation in PET/MR attenuation correction. CONCLUSION: Our method allows the segmentation and classification of the attenuation-relevant structures required for the generation of the attenuation map of PET/MR systems in prostate imaging: air, background, bone, fat, muscle, and prostate.

Endotoxin removal: bringing the mission to North America.

The EUPHRATES trial (Evaluating Use of Polymyxin B Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock) is the first biomarker-driven trial in sepsis. This unique trial is being run in a blinded manner, further contributing to the robustness of its design. This paper will describe the implementation of the EUPHRATES trial focusing on 3 pertinent features: (1) managing (and maintaining) the blinding of a medical device trial; (2) impact of the use of a diagnostic test where eligible subjects with septic shock must also have high levels of endotoxin (≥ 0.60 EAA units), and (3) managing enrolment in a complicated trial design where two medical teams are involved (the intensivist as the blinded caregiver and nephrologists as the unblinded performers of the intervention). The study is nearing the halfway mark and is currently experiencing excellent recruitment success.

Low-heat, mild alkaline pretreatment of switchgrass for anaerobic digestion.

This study examines the effectiveness of alkaline pretreatment under mild heat conditions (100°C or 212°F) on the anaerobic co-digestion of switchgrass. The effects of alkaline concentration, types of alkaline, heating time and rinsing were evaluated. In addition to batch studies, continuous-feed studies were performed in triplicate to identify potential digester operational problems caused by switchgrass co-digestion while accounting for uncertainty due to digester variability. Few studies have examined anaerobic digestion of switchgrass or the effects of mild heating to enhance alkaline pretreatment prior to biomass digestion. Results indicate that pretreatment can significantly enhance digestion of coarse-ground (≤ 0.78 cm particle size) switchgrass. Energy conversion efficiency as high as 63% was observed, and was comparable or superior to fine-grinding as a pretreatment method. The optimal NaOH concentration was found to be 5.5% (wt/wt alkaline/biomass) with a 91.7% moisture level. No evidence of operational problems such as solids build-up, poor mixing, or floating materials were observed. These results suggest the use of waste heat from a generator could reduce the concentration of alkaline required to adequately pretreat lignocellulosic feedstock prior to anaerobic digestion.

Endotoxemic Shock: A Molecular Phenotype in Sepsis.

BACKGROUND: Marked heterogeneity exists among patients with sepsis, both in terms of distribution of organ dysfunction and its severity. Such heterogeneity could be explained by the presence of multiple subtypes of sepsis that may have important implications for treatment. METHODS: Narrative review of published literature involving endotoxin from 1970 to 2022. RESULTS: In humans, endotoxemia is most consistently associated with a specific pattern of organ failure including shock, endothelial dysfunction, acute kidney injury, and hepatic dysfunction. This pattern is consistent with complement activation and uncontrolled inflammation, two features of endotoxemia. Unbiased discovery using artificial intelligence also identifies a subtype of sepsis which features these same organ failures. CONCLUSION: Endotoxin appears to represent an important molecular phenotype of sepsis with unique clinical features and high mortality.

Adsorption of Endotoxin and Mitigation of Sepsis.

In the fields of sepsis and systemic inflammation, endotoxin might be the most studied molecule since the term was coined by Richard Pfeiffer in 1892. Paradoxically measuring endotoxin in humans and finding an effective treatment for endotoxemia have remained challenging. While advances have been made in understanding the mechanisms of how this simple molecule can trigger an intense immune cascade, there is an ever growing need to develop better treatments. Studies measuring endotoxin levels in patients with septic shock have consistently demonstrated that there is a dose-response relationship between endotoxin levels and adverse outcomes. A rapid assay to measure endotoxin activity has been available for more than a decade, but few studies have synergized the assay with a therapeutic. Polymyxin B hemoperfusion (PMX-HP) leverages a molecule with high affinity for endotoxin with a technique to eliminate exposure. Polymyxin is bound and immobilized to fibers within a cartridge and administered as an extracorporeal therapy via veno-venous hemoperfusion. Clinical evidence of its use is plentiful yet inconsistent in studies based on an outcome for mortality at 28 days. Herein, we describe targeted patient selection using the endotoxin activity assay and clinical phenotyping followed by adsorption of endotoxin using the PMX-HP for endotoxemic sepsis.

Observation of Zitterbewegung in photonic microcavities.

We present and experimentally study the effects of the photonic spin-orbit coupling on the real space propagation of polariton wavepackets in planar semiconductor microcavities and polaritonic analogues of graphene. In particular, we demonstrate the appearance of an analogue Zitterbewegung effect, a term which translates as 'trembling motion' in English, which was originally proposed for relativistic Dirac electrons and consisted of the oscillations of the centre of mass of a wavepacket in the direction perpendicular to its propagation. For a planar microcavity, we observe regular Zitterbewegung oscillations whose amplitude and period depend on the wavevector of the polaritons. We then extend these results to a honeycomb lattice of coupled microcavity resonators. Compared to the planar cavity, such lattices are inherently more tuneable and versatile, allowing simulation of the Hamiltonians of a wide range of important physical systems. We observe an oscillation pattern related to the presence of the spin-split Dirac cones in the dispersion. In both cases, the experimentally observed oscillations are in good agreement with theoretical modelling and independently measured bandstructure parameters, providing strong evidence for the observation of Zitterbewegung.

Biomechanical properties of 3D printable material usable for synthetic personalized healthy human aorta.

With the development of three-dimensional (3D) printing, 3D-printed products have been widely used in medical fields, such as plastic surgery, orthopedics, dentistry, etc. In cardiovascular research, 3D-printed models are becoming more realistic in shape. However, from a biomechanical point of view, only a few studies have explored printable materials that can represent the properties of the human aorta. This study focuses on 3D-printed materials that might simulate the stiffness of human aortic tissue. First, the biomechanical properties of a healthy human aorta were defined and used as reference. The main objective of this study was to identify 3D printable materials that possess similar properties to the human aorta. Three synthetic materials, NinjaFlex (Fenner Inc., Manheim, USA), FilasticTM (Filastic Inc., Jardim Paulistano, Brazil), and RGD450+TangoPlus (Stratasys Ltd.©, Rehovot, Israel), were printed in different thicknesses. Uniaxial and biaxial tensile tests were performed to compute several biomechanical properties, such as thickness, stress, strain, and stiffness. We found that with the mixed material RGD450+TangoPlus, it was possible to achieve a similar stiffness to healthy human aorta. Moreover, the 50-shore-hardness RGD450+TangoPlus had similar thickness and stiffness to the human aorta.

Aortic local biomechanical properties in ascending aortic aneurysms.

Ascending aortic aneurysm (AsAA) is a high-risk cardiovascular disease with an increased incidence over years. In this study, we compared different risk factors based on the pre-failure behavior (from a biomechanical point of view) obtained ex-vivo from an equi-biaxial tensile test. A total of 100 patients (63 ± 12 years, 72 males) with AsAA replacement, were recruited. Equi-biaxial tensile tests of AsAA walls were performed on freshly sampled aortic wall tissue after ascending aortic replacement. The aneurysmal aortic walls were divided into four quadrants (medial, anterior, lateral, and posterior) and two directions (longitudinal and circumferential) were considered. The stiffness was represented by the maximum Young modulus (MYM). Based on patient information, the following subgroups were considered: age, gender, hypertension, obesity, dyslipidemia, diabetes, smoking history, aortic insufficiency, aortic stenosis, coronary artery disease, aortic diameter and aortic valve type. In general, when the aortic diameter increased, the aortic wall became thicker. In terms of the MYM, the longitudinal direction was significantly higher than that in the circumferential direction. In the multivariant analysis, the impact factors of age (p = 0.07), smoking (p = 0.05), diabetes (p = 0.03), aortic stenosis (p = 0.02), coronary artery disease (p < 10-3), and aortic diameters (p = 0.02) were significantly influencing the MYM. There was no significant MYM difference when the patients presented arterial hypertension, dyslipidemia, obesity, or bicuspid aortic valve. To conclude, the pre-failure aortic stiffness is multi-factorial, according to our population of 100 patients with AsAA. STATEMENT OF SIGNIFICANCE: Our research on the topic of "Aortic local biomechanical properties in case of ascending aortic aneurysms" is about the biomechanical properties on one hundred aortic samples according to the aortic wall quadrants and the direction. More than ten factors and risks which may impact ascending aortic aneurysms have been studied. According to our knowledge, so far, this article involved the largest population on this topic. It will be our pleasure to share this information with all the readers.

Nonlinear polaritons in a monolayer semiconductor coupled to optical bound states in the continuum.

Optical bound states in the continuum (BICs) provide a way to engineer very narrow resonances in photonic crystals. The extended interaction time in these systems is particularly promising for the enhancement of nonlinear optical processes and the development of the next generation of active optical devices. However, the achievable interaction strength is limited by the purely photonic character of optical BICs. Here, we mix the optical BIC in a photonic crystal slab with excitons in the atomically thin semiconductor MoSe2 to form nonlinear exciton-polaritons with a Rabi splitting of 27 meV, exhibiting large interaction-induced spectral blueshifts. The asymptotic BIC-like suppression of polariton radiation into the far field toward the BIC wavevector, in combination with effective reduction of the excitonic disorder through motional narrowing, results in small polariton linewidths below 3 meV. Together with a strongly wavevector-dependent Q-factor, this provides for the enhancement and control of polariton-polariton interactions and the resulting nonlinear optical effects, paving the way toward tuneable BIC-based polaritonic devices for sensing, lasing, and nonlinear optics.

Major prognostic impact of persistent microvascular obstruction as assessed by contrast-enhanced cardiac magnetic resonance in reperfused acute myocardial infarction.

The aim of this study was to compare the prognostic significance of microvascular obstruction (MO) and persistent microvascular obstruction (PMO) as assessed by cardiac magnetic resonance (CMR) in patients with acute myocardial infarction (AMI). CMR was performed in 184 patients within the week following successfully reperfused first AMI. First-pass images were performed to evaluate extent of MO and late gadolinium-enhanced images to assess PMO and infarct size (IS). Major adverse cardiac events (MACE) were collected at 1-year follow-up. MO and PMO were found in 127 (69%) and 87 (47%) patients, respectively. By using univariate logistic regression analysis, high Global Registry of Acute Coronary Events (GRACE) risk score (odds ratio [OR] 95% confidence interval [CI]: 3.6 [1.8-7.4], p < 0.001), IS greater than 10% (OR [95% CI]: 2.7 [1.1-6.9], p = 0.036), left ventricular ejection fraction less than 40% (OR [95% CI]: 2.4 [1.1-5.2], p = 0.027), presence of MO (OR [95% CI]: 3.1 [1.3-7.3], p = 0.004) and presence of PMO (OR [95% CI]:10 [4.1-23.9], p < 0.001) were shown to be significantly associated with the outcome. By using multivariate analysis, presence of MO (OR [95% CI]: 2.5 [1.0-6.2], p = 0.045) or of PMO (OR [95% CI]: 8.7 [3.6-21.1], p < 0.001), associated with GRACE score, were predictors of MACE. Presence of microvascular obstruction and persistent microvascular obstruction is very common in AMI patients even after successful reperfusion and is associated with a dramatically higher risk of subsequent cardiovascular events, beyond established prognostic markers. Moreover, our data suggest that the prognostic impact of PMO might be superior to MO.

Spatiotemporal continuum generation in polariton waveguides.

We demonstrate the generation of a spatiotemporal optical continuum in a highly nonlinear exciton-polariton waveguide using extremely low excitation powers (2-ps, 100-W peak power pulses) and a submillimeter device suitable for integrated optics applications. We observe contributions from several mechanisms over a range of powers and demonstrate that the strong light-matter coupling significantly modifies the physics involved in all of them. The experimental data are well understood in combination with theoretical modeling. The results are applicable to a wide range of systems with linear coupling between nonlinear oscillators and particularly to emerging polariton devices that incorporate materials, such as gallium nitride and transition metal dichalcogenide monolayers that exhibit large light-matter coupling at room temperature. These open the door to low-power experimental studies of spatiotemporal nonlinear optics in submillimeter waveguide devices.

N-acetylaspartate/creatine and choline/creatine ratios in the thalami, insular cortex and white matter as markers of hypertension and cognitive impairment in the elderly.

Our objective was to investigate the influence of hypertension on N-acetylaspartate (NAA) and choline (Cho) ratios in brain tissues in a community-dwelling elderly population. Brain flexibility was also evaluated with regard to the same metabolite ratios. Proton magnetic resonance spectroscopy (MRS) and the Trail Making Test (TMT) were performed in 80 subjects (75.7+/-4 years old) from the Three-City Study. Fifty-eight participants had hypertension. The NAA/creatine (Cr) and Cho/Cr ratios were obtained in the insular cortex, the thalami and the deep periventricular white matter. In addition, the B-A score of the TMT was evaluated. Uni- and multi-variate analyses were performed in order to examine the relationships among these data. In the insula and the thalami of the hypertensive group, NAA/Cr ratios were significantly lower (1.39+/-0.23 and 1.52+/-0.23, respectively; p=0.01) than those in the normotensive control group (1.52+/-0.25 and 1.70+/-0.19, respectively; p<0.0001), whereas no such reduction was observed in the periventricular white matter of older hypertensive brains. Moreover, the NAA or Cho ratios were significantly correlated with the TMT B-A scores at the level of the thalami, insula and periventricular white matter. These statistical results were confirmed by the multivariate analysis. In an elderly population, hypertension leads to a reduction in NAA/Cr ratios in the insula and the thalami, possibly due to a decrease in blood flow through small perforating and cortical arteries. The TMT B-A test appears to be relevant not only for the frontal areas but also for more remote areas such as the thalami, the insula and the deep periventricular white matter.

Utility of Cardiac Magnetic Resonance to assess association between admission hyperglycemia and myocardial damage in patients with reperfused ST-segment elevation myocardial infarction.

AIMS: to investigate the association between admission hyperglycemia and myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI) using Cardiac Magnetic Resonance (CMR). METHODS: We analyzed 113 patients with STEMI treated with successful primary percutaneous coronary intervention. Admission hyperglycemia was defined as a glucose level >/= 7.8 mmol/l. Contrast-enhanced CMR was performed between 3 and 7 days after reperfusion to evaluate left ventricular function and perfusion data after injection of gadolinium-DTPA. First-pass images (FP), providing assessment of microvascular obstruction and Late Gadolinium Enhanced images (DE), reflecting the extent of infarction, were investigated and the extent of transmural tissue damage was determined by visual scores. RESULTS: Patients with a supramedian FP and DE scores more frequently had left anterior descending culprit artery (p = 0.02 and <0.001), multivessel disease (p = 0.02 for both) and hyperglycemia (p < 0.001). Moreover, they were characterized by higher levels of HbA1c (p = 0.01 and 0.04), peak plasma Creatine Kinase (p < 0.001), left ventricular end-systolic volume (p = 0.005 and <0.001), and lower left ventricular ejection fraction (p = 0.001 and <0.001). In a multivariate model, admission hyperglycemia remains independently associated with increased FP and DE scores. CONCLUSION: Our results show the existence of a strong relationship between glucose metabolism impairment and myocardial damage in patients with STEMI. Further studies are needed to show if aggressive glucose control improves myocardial perfusion, which could be assessed using CMR.

Evaluation of pulverized trommel fines for use as a soil amendment.

Pulverized trommel fines collected from the City of Chicago's municipal solid waste were applied as a soil amendment over a 2-year period to evaluate: (1) their effects on soil quality by measuring soil elemental concentrations, pH, organic matter and cation exchange capacity; (2) their potential for pathogen transfer. A secondary objective was to examine crop growth, yield and productivity. Total and fecal coliform, Enterococci, Escherichia coli, Staphylococci and Salmonella were below minimum detection limits in trommel fines. Trommel fines contained 894.5+/-171.4 mg/kg Pb, and when applied at a rate equivalent to 9.95 mt/ha dry wt, resulted in a soil Pb concentration increase of 18.80 mg/kg, thereby limiting lifetime trommel fine application to 15.9 years before reaching the 300 ppm IEPA (USEPA) regulatory limit. Trommel fines were subjected to a shake extraction procedure and resulting leachate Pb samples were 88.7% below the IEPA (USEPA) regulatory limit (5 mg/l). For the first year, corn yield was significantly higher on soil amended with trommel fines than soil amended with inorganic nitrogen fertilizer. During the second year, soybean yield was significantly lower on soil amended with trommel fines than on soil amended with inorganic fertilizer due to lower plant population. Results of this study suggest that trommel fines can be land applied as a soil amendment if best management practices are followed.