Separate Sites Research Articles

A Novel Strategy to Improve Radiotherapy Effectiveness: First-in-Human MR-guided Focused Ultrasound-Stimulated Microbubbles (MRgFUS+MB) Radiation Enhancement Treatment

Background and aim: Preclinical in vitro and in vivo experiments suggest that radiation-induced tumour cell death can be enhanced 10- to 40-fold when combined with focused-ultrasound (FUS)-stimulated microbubbles (MB). The acoustic exposure of MB in the tumour volume causes vasculature perturbation, activation of the acid sphingomyelinase (ASMase) ceramide pathway, and resultant endothelial cell apoptosis. When the tumour is subsequently treated with radiation, there is increased endothelial cell death and anoxic tumour killing. Here we describe a first-in-human experience treating patients with magnetic resonance (MR)-guided FUS-stimulated MB (MRgFUS+MB) radiation enhancement. Case presentation: A head and neck cancer patient with recurrent disease underwent radiotherapy for 5 separate sites of locoregional disease followed by systemic therapy. The first consisted of a course of 45 Gy in 5 fractions alone, the second of 30 Gy in 5 fractions with hyperthermia, and the three others of 20-30 Gy in 5 fractions along with MRgFUS+MB treatment. The treatment methodology used an MR-coupled FUS-device operating at 500 KHz and 540 kPa peak negative pressure with an insonification time of 750 ms spread over 5 minutes to stimulate intravenously administered MB within tumour target. All sites treated with stimulated MB had a complete radiological response, and subsequently, the patient’s other cutaneous metastatic disease disappeared. The patient has been under surveillance for over two years without active treatment or disease progression. Discussion: MRgFUS+MB was well-tolerated with no reported treatment-related adverse events, which can be attributed to the capability of FUS to selectively stimulate MB within the tumour volume while sparing the surrounding normal tissue. Sustained local control at all target sites aligns with earlier preclinical findings suggesting the radiation enhancement potential of FUS+MB. Conclusion: MRgFUS+MB represents a novel and promising therapy for enhancing radiation efficacy and improving therapeutic index with potential improvements in disease control.

Prevalence, molecular markers, and outcome of bronchial squamous carcinoma in situ in high-risksubjects.

Bronchial squamous carcinoma in situ (CIS) is a preinvasive lesion that is thought to precede invasive carcinoma. We conducted prospective autofluorescence and white light bronchoscopy trials between 1992 and 2016 to assess the prevalence, molecular markers, and outcome of individuals with CIS and other preneoplastic bronchial lesions. Biopsies were evaluated at multiple levels and selected biopsies were tested for aneuploidy and DNA sequenced for TP53 mutation. Thirty-one individuals with CIS were identified. Twenty-two cases of CIS occurred in association with concurrent invasive carcinomas. Seven of the invasive tumors were radiographically occult. In two cases, CIS spread from the focus of invasive carcinoma into contralateral lung lobes, forming secondary invasive tumors. In nine cases, CIS occurred as isolated lesions and one progressed to invasive squamous carcinoma at the same site 40 months after discovery. In a second case, CIS was a precursor of carcinoma at a separate site in a different lobe. In seven cases CIS regressed to a lower grade or disappeared. High level chromosomal aneusomy was often associated with TP53 mutation and with invasive carcinoma. CIS most often occurs in association with invasive squamous carcinoma and may extend along the airways into distant lobes. In rare cases, CIS may be observed to directly transform into invasive carcinoma. CIS may be indicative of invasive tumor at a separate distant site. Isolated CIS may regress. Molecular changes parallel histological changes in CIS and may be used to map clonal expansion in the airways.

Characterization of cooperative PS-oligo activation of human TLR9

Single-stranded phosphorothioate oligonucleotides (PS-oligos) can activate TLR9, leading to an innate immune response. This can occur with PS-oligos containing unmethylated CpG sites, the canonical motif, or PS-oligos that do not contain those motifs (non-CpG). Structural evidence shows that TLR9 contains two PS-oligo binding sites, and recent data suggest that synergistic cooperative activation of TLR9 can be achieved by adding two separate PS-oligos to cells, each engaging with a separate site on TLR9 to enhance TLR9 activation as a pair. Here, we demonstrate and characterize this cooperativity phenomenon using PS-oligos in human cell lines, and we introduce several novel PS-oligo pairs (CpG and non-CpG pairs) that show cooperative activation. Indeed, we find that cooperative PS-oligos likely bind at different sites on TLR9. Interestingly, we find that PS-oligos that generate little TLR9 activation on their own can prime TLR9 to be activated by other PS-oligos. Finally, we determine that previous models of TLR9 activation cannot be used to fully explain data from systems using human TLR9 and PS-oligos. Overall, we reveal new details of TLR9 activation, but we also find that more work needs to be done to determine where certain PS-oligos are binding to TLR9.

Anesthetic Effect of 2% Amitriptyline Versus 2% Lidocaine: A Comparative Evaluation.

Introduction A common dental problem is the fear of pain during needle prick for giving local anesthesia (LA). The needle prick pain during dental procedures oftenvaries with sex andage. Perception of pain depends on various factors, which can be psychological and biological. This perception of pain may change the behavior of patients toward dental treatments. Traditionally, lidocaine gel formulation was utilizedbefore the parenteral dosage form. The lidocaine gel formulation is considered the drug of choice for LA in dental surgery. Currently, amitriptyline has been utilized in dental practice because of its beneficial pharmacology. Hence, the present study has been undertaken to compare the anesthetic ability of amitriptyline as an intraoral topical anesthetic agent with lidocaine gel. Methods This study was a comparative clinical study between two medications' anesthetic properties. This study included 120 patients indicated for bilateral orthodontics (the subdivision of dentistry that emphasizes identifying necessary interventions for the malocclusion of teeth) procedures. All the subjects were divided into amitriptyline and lidocaine groups. Both anesthetic gels wereapplied at separate sites before the injection of LA. The time of the onset of anesthesia was noted and analyzed. Patients were selected on the basis of inclusion and exclusion criteria. Individuals aged 18 to 30 years who were systemically healthy and orthodontically indicated for bilateral premolar extraction were included in this study. Again, patients with a history of neurological disorders and allergies to amitriptyline and lidocaine were excluded fromthe current study. Results Significant differences emerged between groups at five and 10 minutes, with amitriptyline-inducedpartial numbness (36.7% and 6.7%). At 40 and 45 minutes, both groups showed varied partial and complete numbness, with amitriptyline leading to partial recovery (23.3% and 73.3% complete numbness, 23.3% partial recovery) and lidocaine resulting in partial recovery (81.7%). When comparing the visual analog scale (VAS) scores, both groups exhibited a similar simultaneous effect at 15 minutes. Nonetheless, amitriptyline displayed significantly lower scores at 25 and 35 minutes (p < 0.001) in comparison to lidocaine. Similar observations were made when controlling for pain intensity. Conclusion It was concluded that amitriptyline holds both anesthetic and analgesic properties. Nevertheless, this study was unable to generalize the study findings because of the small sample size and being a single-center study. However, the VAS scores of anesthetic and analgesic pharmacodynamics properties of amitriptyline were statistically significantly lower than lidocaine, particularly at 25 and 35 minutes. Additionally, amitriptyline-induced anesthetic and analgesic pharmacology, especially pharmacokinetics properties, depends on the location and pattern of pain.

Prussian blue analog with separated active sites to catalyze water driven enhanced catalytic treatments

Chemodynamic therapy (CDT) uses the Fenton or Fenton-like reaction to yield toxic ‧OH following H2O2 → ‧OH for tumoral therapy. Unfortunately, H2O2 is often taken from the limited endogenous supply of H2O2 in cancer cells. A water oxidation CoFe Prussian blue (CFPB) nanoframes is presented to provide sustained, external energy-free self-supply of ‧OH from H2O to process CDT and/or photothermal therapy (PTT). Unexpectedly, the as-prepared CFPB nanocubes with no near-infrared (NIR) absorption is transformed into CFPB nanoframes with NIR absorption due to the increased Fe3+-N ≡ C-Fe2+ composition through the proposed proton-induced metal replacement reactions. Surprisingly, both the CFPB nanocubes and nanoframes provide for the self-supply of O2, H2O2, and ‧OH from H2O, with the nanoframe outperforming in the production of ‧OH. Simulation analysis indicates separated active sites in catalyzation of water oxidation, oxygen reduction, and Fenton-like reactions from CFPB. The liposome-covered CFPB nanoframes prepared for controllable water-driven CDT for male tumoral mice treatments.

A Novel AUC Maximization Imbalanced Learning Approach for Predicting Composite Outcomes in COVID-19 Hospitalized Patients.

The COVID-19 patient data for composite outcome pre- diction often come with class imbalance issues, i.e., only a small group of patients develop severe composite events after hospital admission while the rest do not. An ideal COVID-19 composite outcomes prediction model should seek strong imbalanced learning capability. Such a model also should have fewer tuning hyperparameters to preserve its good usability and exhibit its potential for fast incremen- tal learning. Towards this goal, by means of the classical proximal support vector machine (PSVM), this study pro- poses a novel imbalanced learning approach called Imbalanced maximizing-Area Under the Curve (AUC) Proximal Support Vector Machine (ImAUC-PSVM) to predict the hospitalized COVID-19 patients' composite outcomes within 30 days of hospitalization. ImAUC-PSVM has the following merits: (1) it incorporates the straightforward AUC maximization into the objective function and hence has fewer parameters to tune. This makes it naturally suitable for handling imbalanced COVID-19 data with a simplified training process. (2) Our theoretical derivations reveal that it has the same form of the analytical solution as PSVM. Therefore, it inherits the advantages of PSVM in dealing with incremental COVID- 19 cases using the fast incremental updating. Our proposed classifier was built and validated internally and externally on the real COVID-19 patient data retrieved from three separate sites of Mayo Clinic in the United States and also validated on the public datasets using various performance metrics. Experi- mental results demonstrate that ImAUC-PSVM outperforms in most cases, showing its potential to assist clinicians in triaging COVID-19 patients at early stage in the hospital settings.

Cross-Hole and Vadose-Zone Infiltration Tracer Test Analyses to Determine Aquifer Reactive Transport Parameters at a Former Uranium Mill Site (Grand Junction, Colorado)

The U.S. Department of Energy Office of Legacy Management is responsible for the long-term care and maintenance of former uranium mill sites in the United States. Prior predictions of site flushing times (monitored natural attenuation) are not being met due to the presence of secondary contaminant sources associated with uranium-rich sediments in the vadose zone and organic-rich sediments near the water table below and near former mill tailings (tailings have been moved to a separate disposal site). Updated sitewide modeling for future releases of contaminants (including uranium) from these secondary sources to the groundwater need appropriate input parameters. To test field techniques, two cross-hole tracer tests and one infiltration tracer test were completed at a former uranium mill site in Grand Junction, Colorado. Reactive transport modeling was completed to derive physical and geochemical parameters. The observed data from saturated zone cross-hole tracer testing was adequately simulated using PHT-USG (reactive transport model) and PEST++ (calibration routine) with reasonable estimates of hydraulic conductivity, dispersion, effective porosity, cation exchange, calcite saturation index, and uranium sorption potential. The use of multiple layering in one cross-hole model was able to capture hydraulic conductivity variations with depth, which produced a double hump in the tracer concentrations. Estimated parameter values were very similar to prior estimates from column testing and single-well push–pull testing, except for a lower uranium sorption potential in one cross-hole test. This difference is likely due to the larger scale of the cross-hole testing including pathways with a lower uranium sorption potential. The infiltration testing released constituents from the vadose zone that can contribute to ongoing groundwater contamination. Modeling simulated the immediate release of these constituents to the water table similar to downward displacement of the existing residual porewater. Delayed drainage of the infiltration water was more difficult to simulate. However, the overall contaminant release concentrations from the vadose-zone secondary sources and ongoing groundwater contamination are adequately simulated for current site purposes. Additional details on vadose-zone processes may be needed if various remedial fluids are evaluated.

Optimization of wind off-grid system for remote area: Egyptian application

Due unexpected nature of renewable energy systems, the (Wind/Diesel/Battery) (W/D/B) off-grid system has initially been investigated at a South Sinai location in Egypt for home-scale consumption. Eight different systems, each of which consists of a small wind turbine, storage batteries, and diesel generator, are investigated in accordance with the varying needs of the power loads and seasonal weather data. The major goal is to investigate how adding wind power as an energy source will affect the price of electricity generated while taking into account the cost of reducing CO2 emissions as an external benefit of the wind turbine, which emits no pollutants during operation. In order to compare a Taguchi OA design to a two-level full factorial design to evaluate the systems at two separate sites (South Sinai and the Western Desert in Egypt), a design evaluation tool in DOE++ will be used. To pinpoint the crucial variables and analyze the impact of six different factors on eight different sets, Taguchi OA is used. The proportion of power shortfall is a production indicator, while the net present cost (NPC) and cost of energy (COE) are used as economic indicators. The simulation results demonstrate that W/D/B systems are economically viable for the hypothetical community site when using HOMER software, with electricity generated at a cost of about 0.285$/kWh without accounting for external benefits and 0.221$/kWh if CO2 emissions are competitive with diesel-only systems, where COE is 0.432$/kWh. As a new evaluation approach, the Box-Cox transformation calculated the best λ is about −2 at the two locations, indicating similar technique behaviors, and the fitted probability shows, meaning that the significant impact of system components are wind turbines. Regression model of CO2 emission is demonstrated to be successful for estimates at the Western Desert location than the South Sinai region

Poster 190: Utilization of Distal Clavicle Bone Grafting in the Treatment of a Mobile Mesoacromion: Rationale and Technique

Objectives: The treatment of symptomatic unstable os acromiale can be fraught with challenges. It is estimated that between 3-5% of the population has an unfused mesoacromion, but only a small fraction of those shoulders develop a painful, mobile mesoacromion that requires treatment. The variety of concomitant shoulder pathology and overlapping symptoms can make diagnosis and treatment difficult. Furthermore, there remains no consensus for the optimal surgical treatment when conservative methods fail. Surgical options include fragment excision, acromioplasty, and open reduction internal fixation (ORIF) with or without bone grafting. A variety of arthroscopic and open techniques have been described with a large amount of heterogeneity in the literature making comparison of these techniques difficult. Biomechanical forces through the clavicle and acromioclavicular (AC) joint throughout shoulder range of motion have been described in the literature. These forces have theoretical implications on the relationship between the distal clavicle and mesoacromion. Shear, rotational, translational and compression forces imparted against the acromion, by the clavicle and the acromioclavicular ligaments, impart those same forces on the mesoacromial defect via the linkage of the AC joint. There are currently no studies describing the utility in using the distal clavicle as a bone graft source during ORIF of symptomatic mesoacromion. The cross sectional shape and surface area of the distal clavicle is remarkably similar to that of the acromial process. We describe a surgical technique utilizing the distal clavicle as a bone grafting source and present a case series of 8 patients with 100% union rate. Methods: A retrospective analysis was done on 8 patients from 2001-2016 who underwent open reduction internal fixation (ORIF) with distal clavicle bone grafting of a symptomatic, mobile mesoacromion by a single surgeon. The technique utilizes a saber type incision for exposure of the acromion, AC joint, and distal clavicle. Small splits in the anterior and posterior deltoid are utilized to palpate the anterior and posterior aspect of the acromion. Two parallel Kirschner wires (K wires) are placed from anterior to posterior through the acromion crossing the mesoacromion site. The proximal and distal aspects of the site are prepared and rasped. The distal clavicle is skeletonized and 9mm of distal clavicle is removed using a micro saw. The distal clavicle is sliced to 2-3 mm thickness creating a "wafer" of local bone graft. Two narrow slots are placed into the wafer using a small rongeur. These slots are spaced at the exact distance of the parallel K wires. The wafer of bone graft is then placed into the prepared mesoacromion defect and allowed to straddle the K wires via the slots. The acromion is then clamped from front to back using a bone clamp and cannulated screws are placed over the K-wires. Supplemental tension band fixation was used for the earlier portion of the senior author’s practice. Over the course of the technique, with the development of modern screws, the supplemental tension band was felt to be unnecessary. Soft tissues were closed in a standard fashion. Results: The median patient age was 52.5 (range, 41-59) with 75% male and 87.5% Caucasian. The median body mass index (BMI) was 29.4 (range, 23.9-39.2), 62.5% were non-smokers, 25% were type 2 diabetics, 37.5% had hypertension and 25% had no comorbidities. The patients who underwent this procedure with a median follow-up of 6 years (range 2-18). All procedures were done utilizing the distal clavicle bone graft technique described above with fixation reinforced by tension band in 6 of the 8 patients. Seven of 8 patients had concomitant shoulder pathology which included either partial or full rotator cuff tears (n=6), AC arthritis (n=4), glenohumeral (GH) arthritis (n=2) and biceps injury (n=2). Six of 8 patients underwent additional procedures during the index mesoacromion ORIF including rotator cuff repair (n=3), biceps tenodesis (n=4), and AC or GH debridement (n=5). One patient had an acute superficial postoperative infection successfully treated with irrigation and debridement. Otherwise, there were no complications related to the index procedure. Postoperatively all patients had symptomatic relief and went on to radiographic union of the mesoacromion. Conclusions: There remains a paucity of literature to help guide surgical treatment of symptomatic mesoacromion. Studies are largely limited to retrospective reviews and case series with various surgical techniques utilized. Therefore, the importance of relying on surgical experience and expert opinion cannot be overemphasized. This is the first study describing the use of the distal clavicle as bone graft for ORIF of the mesoacromion. Use of a distal clavicle bone graft obviates the need for a separate bone graft harvest site. Furthermore, it reduces abutment, translational and rotational forces on the mobile mesoacromion, maintains acromion length, and increases surface area for bony union. This evolved technique resulted in 100% union rate in our series of 8 patients with a median 6 year follow-up.

Tissue Engineering: Current Technology for Facial Reconstruction.

Facial reconstruction is a complex surgical process that requires intricate three-dimensional (3D) concepts for optimal functional and aesthetic outcomes. Conventional reconstruction of structural facial anomalies, such as those including cartilage or bony defects, typically rely on hand-carving autologous constructs harvested from a separate donor site, and shaping that cartilage or bone into a new structural framework. Tissue engineering has emerged in recent decades as a potential approach to mitigate the need for donor site morbidity while improving precision in the design of reconstructive construct. Computer-aided design and computer-aided manufacturing have allowed for a digital 3D workflow to digitally execute the planned reconstruction in virtual space. 3D printing and other manufacturing techniques can then be utilized to create custom-fabricated scaffolds and guides to improve the reconstructive efficiency. Tissue engineering can be paired with custom 3D-manufactured scaffolds to theoretically create an ideal framework for structural reconstruction. In the past decade, there have been several compelling preclinical studies demonstrating the capacity to induce chondrogenesis or osteogenesis in a custom scaffold. However, to date, these preclinical data have not yet translated into significant clinical experience. This translation has been hindered by a lack of consensus on the ideal materials and cellular progenitors to be utilized in these constructs and a lack of regulatory guidance and control to enable clinical application. In this review, we highlight the current state of tissue engineering in facial reconstruction and exciting potential for future applications as the field continues to advance.

Isothermal Titration Calorimetry binding properties of Cibacron Blue F3GA in complex with Human Serum Albumin.

Binding interactions between cibacron blue-F3GA (CB-F3GA) and human serum albumin (HSA, at physiologically ten-fold lower concentration) was studied by isothermal titration calorimetry (ITC) and in-silico docking computations. ITC experiments revealed two separate binding sites on HSA with different binding affinities for CB-F3GA. The high-affinity binding site (PBS-II) on HSA binds CB-F3GA at nanomolar scale (KD1 =118±107 nM) with favorable binding enthalpy (ΔHo 1 = - 6.47±0.44 kcal/mol) and entropy (-TΔSo 1 = -2.98 kcal/mol) energies. CB-F3GA binds to the low-affinity binding site (PBS-I) at μM scale (KD2 = 31.20±18.40 μM) with favorable binding enthalpy (ΔHo 1 = - 5.03±3.86x10-2 kcal/mol) and entropy (-TΔSo 1 = -1.12 kcal/mol) energies. ITC binding data strongly suggest that CB-F3GA binding to PBS-II site increases the formation of dimeric-HSA clusters (N1 = 2.43 ± 0.50), while binding to PBS-I leads to tetrameric-HSA clusters (N2 = 4.61 ± 0.90). These results suggest that a higher degree of HSA aggregation upon drug binding may be expected under physiological conditions, a notion that should be further investigated for the delivery and toxicity of drug.HSA interactions. This article is protected by copyright. All rights reserved.

Setting a reference for wetland carbon: the importance of accounting for hydrology, topography, and natural variability

Wetland soils are a key global sink for organic carbon (C) and a focal point for C management and accounting efforts. The ongoing push for wetland restoration presents an opportunity for climate mitigation, but C storage expectations are poorly defined due to a lack of reference information and an incomplete understanding of what drives natural variability among wetlands. We sought to address these shortcomings by (1) quantifying the range of variability in wetland soil organic C (SOC) stocks on a depressional landscape (Delmarva Peninsula, USA) and (2) investigating the role of hydrology and relative topography in explaining variability among wetlands. We found a high degree of variability within individual wetlands and among wetlands with similar vegetation and hydrogeomorphic characteristics. This suggests that uncertainty should be presented explicitly when inferring ecosystem processes from wetland types or land cover classes. Differences in hydrologic regimes, particularly the rate of water level recession, explained some of the variability among wetlands, but relationships between SOC stocks and some hydrologic metrics were eclipsed by factors associated with separate study sites. Relative topography accounted for a similar portion of SOC stock variability as hydrology, indicating that it could be an effective substitute in large-scale analyses. As wetlands worldwide are restored and focus increases on quantifying C benefits, the importance of appropriately defining and assessing reference systems is paramount. Our results highlight the current uncertainty in this process, but suggest that incorporating landscape heterogeneity and drivers of natural variability into reference information may improve how wetland restoration is implemented and evaluated.

295 Topical Tranexamic Acid in Burn Surgery – A Randomized Controlled Trial

Abstract Introduction Early excision and grafting of large burn wounds can result in considerable bleeding. Systemic use of tranexamic acid (TXA) generally reduces surgical bleeding by 30-40%, but its safety in burn surgery has not been studied. Topical use may provide a sufficient wound concentration with negligible risk of systemic adverse events. However, it is unclear whether topical use may delay wound re-epithelialization. This pilot double-blinded randomized controlled trial aimed to evaluate the therapeutic potential of topical TXA for reducing blood loss and the effect on wound re-epithelialization in burn surgery. Methods Between Jan 2021 – April 2022, burn patients at a single national burn center who needed at least two separate donor sites for split-thickness skin grafting were included. In total, 36 wound pairs in similar anatomical areas were made in 23 patients. Donor sites were infiltrated with tumescence containing epinephrine before harvesting. Paired wounds were randomized to topical application of standard epinephrine solution, with or without added TXA 25 mg/ml, before coverage with vaseline and dry gauze. Endpoints were time to re-epithelialization and surrogate bleeding estimates defined as net weight gain of dressings per cm2 wound area, bloodstain area per wound area, and visual rating of the amount of blood in dressings on the first postoperative day. Results There was no difference in healing time between wounds. The results trended towards less increase in dressing weight gain per cm2 of wound area in the TXA group, though not significant (p=0.12). However, when dividing the results in two at the median bleeding volume, there was a significant reduction in bleeding in the high-bleed group (p=0.012). Similar observations were made for the other two bleeding endpoints, but the differences did not reach statistical significance. Conclusions Moistening a superficial wound surface with TXA 25 mg/ml does not impair wound re-epithelialization. Topical TXA may reduce bleeding from graft donor sites with low risk of systemic complications. Applicability of Research to Practice This pilot study suggests that topical TXA is of value in reducing bleeding in burn surgery without delaying donor site healing. The effect may be larger in wounds not prepared with epinephrine infiltration. More research is warranted regarding the optimal mode of topical drug delivery and systemic concentrations after topical application in burns. Furthermore, it remains to investigate whether topical TXA affects graft take.

Time and event-specific deep learning for personalized risk assessment after cardiac perfusion imaging

Standard clinical interpretation of myocardial perfusion imaging (MPI) has proven prognostic value for predicting major adverse cardiovascular events (MACE). However, personalizing predictions to a specific event type and time interval is more challenging. We demonstrate an explainable deep learning model that predicts the time-specific risk separately for all-cause death, acute coronary syndrome (ACS), and revascularization directly from MPI and 15 clinical features. We train and test the model internally using 10-fold hold-out cross-validation (n = 20,418) and externally validate it in three separate sites (n = 13,988) with MACE follow-ups for a median of 3.1 years (interquartile range [IQR]: 1.6, 3.6). We evaluate the model using the cumulative dynamic area under receiver operating curve (cAUC). The best model performance in the external cohort is observed for short-term prediction – in the first six months after the scan, mean cAUC for ACS and all-cause death reaches 0.76 (95% confidence interval [CI]: 0.75, 0.77) and 0.78 (95% CI: 0.78, 0.79), respectively. The model outperforms conventional perfusion abnormality measures at all time points for the prediction of death in both internal and external validations, with improvement increasing gradually over time. Individualized patient explanations are visualized using waterfall plots, which highlight the contribution degree and direction for each feature. This approach allows the derivation of individual event probability as a function of time as well as patient- and event-specific risk explanations that may help draw attention to modifiable risk factors. Such a method could help present post-scan risk assessments to the patient and foster shared decision-making.

Automated radiosynthesis of [89Zr]Zr-DFOSq-Durvalumab for imaging of PD-L1 expressing tumours in vivo

Objectives89Zr-labelled proteins are gaining importance in clinical research in a variety of diseases. To date, no clinical study has been reported that utilizes an automated approach for radiosynthesis of 89Zr-labelled radiopharmaceuticals. We aim to develop an automated method for the clinical production of 89Zr-labelled proteins and apply this method to Durvalumab, a monoclonal antibody targeting PD-L1 immune-checkpoint protein. PD-L1 expression is poorly understood and can be up-regulated over the course of chemo- and radiotherapy treatment. The ImmunoPET multicentre study aims to examine the dynamics of PD-L1 expression via 89Zr-Durvalumab PET imaging before, during, and after chemoradiotherapy. The developed automated technique will enable reproducible clinical production of [89Zr]Zr-DFOSq-Durvalumab for this study at three different sites. MethodsConjugation of Durvalumab to H3DFOSqOEt was optimized for optimal chelator-to-antibody ratio. Automated radiolabelling of H3DFOSq-Durvalumab with zirconium-89 was optimized on the disposable cassette based iPHASE technologies MultiSyn radiosynthesizer using a modified cassette. Activity losses were tracked using a dose calibrator and minimized by optimizing fluid transfers, reaction buffer, antibody formulation additives and pH. The biological profile of the radiolabelled antibody was confirmed in vivo in PD-L1+ (HCC827) and PD-L1- (A549) murine xenografts. Clinical process validation and quality control were performed at three separate study sites to satisfy clinical release criteria. ResultsH3DFOSq-Durvalumab with an average CAR of 3.02 was obtained. Radiolabelling kinetics in succinate (20 mM, pH 6) were significantly faster when compared to HEPES (0.5 M, pH 7.2) with >90 % conversion observed after 15 min. Residual radioactivity in the 89Zr isotope vial was reduced from 24 % to 0.44 % ± 0.18 % (n = 7) and losses in the reactor vial were reduced from 36 % ± 6 % (n = 4) to 0.82 % ± 0.75 % (n = 4) by including a surfactant in the reaction and formulation buffers. Overall process yield was 75 % ± 6 % (n = 5) and process time was 40 min. Typically, 165 MBq of [89Zr]Zr-DFOSq-Durvalumab with an apparent specific activity of 315 MBq/mg ± 34 MBq/mg (EOS) was obtained in a volume of 3.0 mL. At end-of-synthesis (EOS), radiochemical purity and protein integrity were always >99 % and >96 %, respectively, and dropped to 98 % and 65 % after incubation in human serum for 7 days at 37 °C. Immunoreactive fraction in HEK293/PD-L1 cells was 83.3 ± 9.0 (EOS). Preclinical in vivo data at 144 h p.i. showed excellent SUVmax in PD-L1+ tumour (8.32 ± 0.59) with a tumour-background ratio of 17.17 ± 3.96. [89Zr]Zr-DFOSq-Durvalumab passed all clinical release criteria at each study site and was deemed suitable for administration in a multicentre imaging trial. ConclusionFully automated production of [89Zr]Zr-DFOSq-Durvalumab for clinical use was achieved with minimal exposure to the operator. The cassette-based approach allows for consecutive productions on the same day and offers an alternative to currently used manual protocols. The method should be broadly applicable to other proteins and has the potential for clinical impact considering the growing number of clinical trials investigating 89Zr-labelled antibodies.

Estimating vital rate variation to assess early success of scrub mint translocations

AbstractSpecies translocations are increasingly common in rare plant conservation. Wild populations can provide basic ecological knowledge to improve their chance of success. In the heavily fragmented Florida scrub, USA, many listed species require translocations to persist, including Dicerandra christmanii. In 1994, we began monitoring the only protected population of D. christmanii growing both in gaps (open areas) within the shrub matrix and on roadsides. In 2010, we augmented this population by adding plants and seeds to unoccupied gaps. In 2012, we introduced plants to a separate protected site to create a new population. We evaluated early translocation success using generalized linear mixed‐effect models of vital rate variation among habitat types. Survival probability increased with size, peaking at 0.6–0.8, and was lowest in augmentations and highest in introductions. Growth increased with plant size across all habitat types, except for the largest adults which experienced senescence. Naturally recruited plants in gaps showed the highest reproduction probability and fecundity at smaller sizes, but larger plants in translocations had the highest fecundity. Yearling recruitment was higher in translocated plants relative to naturally recruited plants in gaps during the initial years following outplanting. Experimental components of translocations also affected outplanting performance with positive effects of fire. These analyses suggest a high potential for translocations to become established and contribute to species recovery.

Sub-nanometer Pt2In3 intermetallics as ultra-stable catalyst for propane dehydrogenation

Pt-based catalysts are the typical industrial catalysts for propane dehydrogenation (PDH), which still suffer from insufficient long-term durability due to the structural instability and coke deposition. A commercial γ-Al2O3 supported thermally robust sub-nanometer Pt2In3 intermetallic catalyst with atomically ordered structure and rigorously separated Pt single atoms was fabricated, which showed outstanding robustness in 240 h long-term operation at 600 °C with the deactivation rate constant kd as low as 0.00078 h−1, ranking among the lowest reported values. Based on various in situ characterizations and theoretical calculations, it was proved that the catalyst stability not only resulted from the separated Pt single-atom sites but also significantly affected by the distance of adjacent Pt atoms. An increasing distance to 3.25 Å in the Pt2In3 could induce a weak π-adsorption configuration of propylene on Pt sites, which facilitated the desorption of propylene and restrained the side reactions like coking.

Separating broad-band site response from single-station seismograms

SUMMARY In this paper, we explore the use of seismicity data on a single-station basis in site response characterization. We train a supervised deep-learning model, SeismAmp, to recognize and separate seismic site response with reference to seismological bedrock (VS = 3.45 km s−1) in a broad frequency range (0.2–20 Hz) directly from single-station earthquake recordings (features) in Japan. Ground-truth data are homogeneously created using a classical multistation approach—generalized spectral inversion at a total number of 1725 sites. We demonstrate that site response can be reliably separated from single-station seismograms in an end-to-end approach. When SeismAmp is tested at new sites in both Japan (in-domain) and Europe (cross-domain), it achieves the lowest standard deviation among all tested single-station techniques. We also find that horizontal-to-vertical spectral ratio (HVSR) is not the optimal use of single-station recordings. The individual components of each record carry salient information on site response, especially at high frequencies. However, part of the information is lost in HVSR. SeismAmp could lead to improved site-specific earthquake hazard prediction in cases where recordings are available or can be collected at target sites. It is also a convenient tool to remove repeatable site effects from ground motions, which may benefit other applications, for example, improving the retrieval of seismic source parameters. Finally, SeismAmp is trained on data from Japan, future studies could explore transfer learning for practical applications in other regions.

Crystal formation in Eu3+ - Doped oxyfluorophosphate glass-ceramics for luminescence thermometry

Eu3+ doped-Oxyfluorophosphate glasses with a general composition 75 NaPO3 - (25-x) CaO – x CaF2 (with x ranging from 0 to 25 mol%) were prepared and their spectroscopic changes induced by the addition of fluorine and when applying a thermal treatment in order to grow crystals in the glasses were investigated. The addition of CaF2 at the expense of CaO reduces Ω2 and Ω4 parameters indicating that the Eu3+ ions are located in less covalent and well separated sites in oxyfluorophosphate glasses. An increase in the CaF2 content at the expense of CaO also leads to an increase in the absolute thermometric sensitivity from (4.2 × 10−4) K−1 to (17.6 × 10−4) K−1 at 523 K while decreasing the relative thermometric sensitivity from 3.0% to 1.4%.The heat treatment leads to the precipitation of crystals, the composition of crystal phase depends on the glass composition. For the glasses with x = 0 and 10, the thermal treatment increases Ω6 while reducing Ω4, as a result of an enhanced stiffness and reduced covalency of dopant's environment due to the precipitation of various crystals. As Ω2 remains unchanged, the Eu3+ are suspected to remain mainly in the amorphous part of the glass-ceramics in agreement with the lack of sharp peaks in the emission spectrum. For the glasses with x = 20 and 25, Ω2 increases indicating a change in the site symmetry of Eu3+ resulting from the dopant entering the CaF2 crystalline phase. Due to the changes in the Eu3+ sites in the heat treated glasses, the heat treatment of the glass increases the absolute thermal sensitivity, but reduces the relative thermal sensitivity. The oxyfluorophosphate glass-ceramic with x = 25 exhibits high absolute thermometric sensitivity compared to oxyfluorophosphate glass, but also comparatively low relative sensitivity of 0.5% K−1.

Stereotactic Radiosurgery vs Conventional Radiotherapy for Localized Vertebral Metastases of the Spine

Spine metastasis can be treated with high-dose radiation therapy with advanced delivery technology for long-term tumor and pain control. To assess whether patient-reported pain relief was improved with stereotactic radiosurgery (SRS) as compared with conventional external beam radiotherapy (cEBRT) for patients with 1 to 3 sites of vertebral metastases. In this randomized clinical trial, patients with 1 to 3 vertebral metastases were randomized 2:1 to the SRS or cEBRT groups. This NRG 0631 phase 3 study was performed as multi-institutional enrollment within NRG Oncology. Eligibility criteria included the following: (1) solitary vertebral metastasis, (2) 2 contiguous vertebral levels involved, or (3) maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients enrolled in the trial, and 339 patients were analyzed. This analysis includes data extracted on March 9, 2020. Patients randomized to the SRS group were treated with a single dose of 16 or 18 Gy (to convert to rad, multiply by 100) given to the involved vertebral level(s) only, not including any additional spine levels. Patients assigned to cEBRT were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below. The primary end point was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale (NRPS) without worsening in pain at the secondary site(s) or the use of pain medication. Secondary end points included treatment-related toxic effects, quality of life, and long-term effects on vertebral bone and spinal cord. A total of 339 patients (mean [SD] age of SRS group vs cEBRT group, respectively, 61.9 [13.1] years vs 63.7 [11.9] years; 114 [54.5%] male in SRS group vs 70 [53.8%] male in cEBRT group) were analyzed. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the SRS group and 5.88 (2.41) in the cEBRT group. The primary end point of pain response at 3 months favored cEBRT (41.3% for SRS vs 60.5% for cEBRT; difference, -19 percentage points; 95% CI, -32.9 to -5.5; 1-sided P = .99; 2-sided P = .01). Zubrod score (a measure of performance status ranging from 0 to 4, with 0 being fully functional and asymptomatic, and 4 being bedridden) was the significant factor influencing pain response. There were no differences in the proportion of acute or late adverse effects. Vertebral compression fracture at 24 months was 19.5% with SRS and 21.6% with cEBRT (P = .59). There were no spinal cord complications reported at 24 months. In this randomized clinical trial, superiority of SRS for the primary end point of patient-reported pain response at 3 months was not found, and there were no spinal cord complications at 2 years after SRS. This finding may inform further investigation of using spine radiosurgery in the setting of oligometastases, where durability of cancer control is essential. ClinicalTrials.gov Identifier: NCT00922974.