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.

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.

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.

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.

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.

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.

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.

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.

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.

What are normal relaxation times of tissues at 3 T?

The T1 and T2 relaxation times are the basic parameters behind magnetic resonance imaging. The accurate knowledge of the T1 and T2 values of tissues allows to perform quantitative imaging and to develop and optimize magnetic resonance sequences. A vast extent of methods and sequences has been developed to calculate the T1 and T2 relaxation times of different tissues in diverse centers. Surprisingly, a wide range of values has been reported for similar tissues (e.g. T1 of white matter from 699 to 1735ms and T2 of fat from 41 to 371ms), and the true values that represent each specific tissue are still unclear, which have deterred their common use in clinical diagnostic imaging. This article presents a comprehensive review of the reported relaxation times in the literature in vivo at 3T for a large span of tissues. It gives a detailed analysis of the different methods and sequences used to calculate the relaxation times, and it explains the reasons of the spread of reported relaxation times values in the literature.

Absolute volume of the rectum and AUC from rectal DVH between 25Gy and 50Gy predict acute gastrointestinal toxicity with IG-IMRT in prostate cancer.

BACKGROUND: To determine whether dose/volume specific endpoints (DVSE) or Area under the rectal DVH curve (rAUC) better predict acute gastrointestinal (GI) toxicity in prostate cancer patients treated with IMRT in the era of daily image guidance (IG-IMRT). METHODS: A set of DVSE was recorded from V25 to V75 (increments of 5Gy) (both in % and in cc) for 180 men. The rAUC was calculated for doses ranging between 25Gy and 50Gy (rAUC25-50). Univariate and multivariate logistic regressions were performed to determine the relationship between DVSE or rAUC25-50 and the appearance of any acute GI toxicity. RESULTS: The rates of acute grade 1 (G1), G2 and G3 GI toxicities were 53.3 %, 10.6 % and 1.1 %, respectively. No G4+ toxicity was observed. Rectal V25 to V75 expressed in % were not predictive of G ≥ 1 GI toxicity (p ≥ 0.12) whereas rectal V25 to V50 expressed in cc did correlate with GI toxicity G ≥ 1 (p ≤ 0.04). rAUC25-50 expressed in cc. Gy correlated significantly with the occurrence of any acute GI toxicity G ≥ 1 (p = 0.027). CONCLUSIONS: The absolute volume of the rectum between 25Gy and 50Gy and rAUC25-50 could significantly predict any acute rectal toxicity in prostate cancer patients treated with daily IG-IMRT.

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.

ProstateAnalyzer: Web-based medical application for the management of prostate cancer using multiparametric MR imaging.

OBJECTIVES: In this paper, we present ProstateAnalyzer, a new web-based medical tool for prostate cancer diagnosis. ProstateAnalyzer allows the visualization and analysis of magnetic resonance images (MRI) in a single framework. METHODS: ProstateAnalyzer recovers the data from a PACS server and displays all the associated MRI images in the same framework, usually consisting of 3D T2-weighted imaging for anatomy, dynamic contrast-enhanced MRI for perfusion, diffusion-weighted imaging in the form of an apparent diffusion coefficient (ADC) map and MR Spectroscopy. ProstateAnalyzer allows annotating regions of interest in a sequence and propagates them to the others. RESULTS: From a representative case, the results using the four visualization platforms are fully detailed, showing the interaction among them. The tool has been implemented as a Java-based applet application to facilitate the portability of the tool to the different computer architectures and software and allowing the possibility to work remotely via the web. CONCLUSION: ProstateAnalyzer enables experts to manage prostate cancer patient data set more efficiently. The tool allows delineating annotations by experts and displays all the required information for use in diagnosis. According to the current European Society of Urogenital Radiology guidelines, it also includes the PI-RADS structured reporting scheme.

Computer-Aided Detection and diagnosis for prostate cancer based on mono and multi-parametric MRI: a review.

Prostate cancer is the second most diagnosed cancer of men all over the world. In the last few decades, new imaging techniques based on Magnetic Resonance Imaging (MRI) have been developed to improve diagnosis. In practise, diagnosis can be affected by multiple factors such as observer variability and visibility and complexity of the lesions. In this regard, computer-aided detection and computer-aided diagnosis systems have been designed to help radiologists in their clinical practice. Research on computer-aided systems specifically focused for prostate cancer is a young technology and has been part of a dynamic field of research for the last 10 years. This survey aims to provide a comprehensive review of the state-of-the-art in this lapse of time, focusing on the different stages composing the work-flow of a computer-aided system. We also provide a comparison between studies and a discussion about the potential avenues for future research. In addition, this paper presents a new public online dataset which is made available to the research community with the aim of providing a common evaluation framework to overcome some of the current limitations identified in this survey.

The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial.

BACKGROUND: Septic shock is common and has unacceptably high morbidity, mortality, and associated cost with numerous failed attempts at developing effective therapies. Endotoxin, one of the most potent mediators of sepsis, is found in high levels in approximately 50% of patients with septic shock. Polymyxin B (PMX) hemoperfusion has been shown in numerous studies to successfully remove endotoxin and potentially improve outcomes. EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock) is a theragnostic trial (matching blood measurement to treatment capability) of PMX hemoperfusion in patients with septic shock and confirmed endotoxemia as measured by the endotoxin activity assay (EAA). METHODS: EUPHRATES is a pivotal regulatory trial that is multi-centered, placebo-controlled and blinded. The trial is being conducted in fifty ICUs in the United States and Canada and is powered to enroll 360 patients. Patients with persistent septic shock despite adequate fluid resuscitation on vasopressors for more than 2 and less than 30 hours are eligible for measurement of the EAA. Those with EAA ≥0.60 are eligible to be randomized to treatment with two sessions of PMX hemoperfusion 24 hours apart. The primary endpoint for the trial is 28-day all-cause mortality. DISCUSSION: Unique features of the trial include absence of systemic inflammatory response (SIRS) criteria as a requirement for inclusion, use of the EAA to confirm endotoxemia as a requisite for treatment, and use of a detailed "façade" hemoperfusion event as a blinding mechanism. The outcomes of the second interim analysis included a resizing of the trial to 650 patients and the addition of an exclusion criterion of subjects with multiple organ dysfunction score (MODS) ≤ 9. Results are anticipated in 2016. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01046669. Registered: January 8, 2010.

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.