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The inhibition of intracellular protein‐protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co‐activator protein and oncogene β‐catenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high‐affinity binders comprise only large molecular weight inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α‐helical β‐catenin‐binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a β‐catenin inhibitor with single‐digit micromolar activity in a cell‐based assay. This study sheds light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity. [ABSTRACT FROM AUTHOR]

Background: The distance traveled by the positron before annihilation with an electron, the so‐called positron range, negatively effects the positron emission tomography (PET) image quality for radionuclides emitting high‐energy positrons such as Gallium‐68 (68Ga). Purpose: In this study, the effect of a tissue‐independent positron range correction for Gallium‐68 (68Ga‐PRC) was investigated based on phantom measurements. The effect of the 68Ga‐PRC was also explored in four patients. Methods: The positron range distribution profile of 68Ga in water was generated via Monte Carlo simulation. That profile was mapped to a spatially invariant 3D convolution kernel which was incorporated in the OSEM and Q.Clear reconstruction algorithms to perform the 68Ga‐PRC. In addition, each reconstruction method included point spread function (PSF) modeling and time‐of‐flight information. For both Fluorine‐18 (18F) and 68Ga, the NEMA IQ phantom was filled with a sphere‐to‐background ratio of 10:1 and scanned with the GE Discovery MI 5R PET/CT system. Standard non‐positron range correction (PRC) reconstructions were performed for both radionuclides, while also PRC reconstructions were performed for 68Ga. Reconstructions parameters (OSEM: number of updates, Q.Clear: beta value) were adapted to achieve similar noise levels between the corresponding reconstructions. The effect of 68Ga‐PRC was assessed for both OSEM and Q.Clear reconstructions and compared to non‐PRC reconstructions for 68Ga and 18F in terms of image contrast, noise, recovery coefficient (RC), and spatial resolution. For the clinical validation, 68Ga‐labeled prostate‐specific membrane antigen (68Ga‐PSMA) and 68Ga‐DOTATOC PET scans were included of two patients each. For each PET scan, patients were injected with 1.5 MBq/kg of 68Ga‐PSMA or 68Ga‐DOTATOC and the contrast‐to‐noise ratio (CNR) was calculated and compared to the non‐PRC reconstructions. Results: For OSEM reconstructions, including the 68Ga‐PRC improved the RC by 9.4% (3.7%–19.3%) and spatial resolution by 21.7% (4.6 mm vs. 3.6 mm) for similar noise levels. For Q.Clear reconstructions, 68Ga‐PRC modeling improved the RC by 6.7% (2.8%–10.5%) and spatial resolution by 15.3% (5.9 mm vs. 5.0 mm) while obtaining similar noise levels. In the patient data, the use of 68Ga‐PRC enhanced the CNR by 13.2%. Conclusions: Including 68Ga‐PRC in the PET reconstruction enhanced the image quality of 68Ga PET data compared to the standard non‐PRC reconstructions for similar noise levels. Limited patient results also supported this improvement. [ABSTRACT FROM AUTHOR]

The world in which we live is homochiral. The ribose units that form the backbone of DNA and RNA are all D‐configured and the encoded amino acids that comprise the proteins of all living species feature an all‐L‐configuration at the α‐carbon atoms. The homochirality of α‐amino acids is essential for folding of the peptides into well‐defined and functional 3D structures and the homochirality of D‐ribose is crucial for helix formation and base‐pairing. The question of why nature uses only encoded L‐α‐amino acids is not understood. Herein, we show that an RNA‐peptide world, in which peptides grow on RNAs constructed from D‐ribose, leads to the self‐selection of homo‐L‐peptides, which provides a possible explanation for the homo‐D‐ribose and homo‐L‐amino acid combination seen in nature. [ABSTRACT FROM AUTHOR]

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Resident memory T (TRM) cells have been recently established as an important subset of memory T cells that provide early and essential protection against reinfection in the absence of circulating memory T cells. Recent findings showing that TRM expand in vivo after repeated antigenic stimulation indicate that these memory T cells are not terminally differentiated. This suggests an opportunity for in vitro TRM expansion to apply in an immunotherapy setting. However, it has also been shown that TRM may not maintain their identity and form circulating memory T cells after in vivo restimulation. Therefore, we set out to determine how TRM respond to antigenic activation in culture. Using Listeria monocytogenes and LCMV infection models, we found that TRM from the intraepithelial compartment of the small intestine expand in vitro after antigenic stimulation and subsequent resting in homeostatic cytokines. A large fraction of the expanded TRM retained their phenotype, including the expression of key TRM markers CD69 and CD103 (ITGAE). The optimal culture of TRM required low O2 pressure to maintain the expression of these and other TRM‐associated molecules. Expanded TRM retained their effector capacity to produce cytokines after restimulation, but did not acquire a highly glycolytic profile indicative of effector T cells. The proteomic analysis confirmed TRM profile retention, including expression of TRM‐related transcription factors, tissue retention factors, adhesion molecules, and enzymes involved in fatty acid metabolism. Collectively, our data indicate that limiting oxygen conditions supports in vitro expansion of TRM cells that maintain their TRM phenotype, at least in part, suggesting an opportunity for therapeutic strategies that require in vitro expansion of TRM. [ABSTRACT FROM AUTHOR]

Global challenges call for timely social--ecological transformation. There is a substantial amount of literature on social--ecological transformation, increasingly replacing and going beyond 'sustainability'. However, the concept itself is used very inconsistently. This paper aims at identifying and systematizing the strains of argumentation that encompass the social--ecological transformation. Adding German-speaking literature to the Anglophone debate, we systematize as we follow the concept's genesis to its varieties of use within context-based (spatial, temporal, and societal) disciplinary, interdisciplinary, and transdisciplinary debates. Building on the various strands of contemporary use, this paper aims at contouring the epistemologies of the concept. Lastly, we illustrate the roles of geographical research approaches and the assigned methodology. We argue that the strands tend to drift apart and cannot be seen nor used as a singular uniform approach. We identify the key dimensions of how scholars use social--ecological transformation, unearthing underlying epistemologies. To conclude, we delineate key elements that geographical research on social--ecological transformation must address, laying the foundation for further scholarly debate. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter of the global adult population. A key event in the pathophysiology of MASLD is the development of metabolic‐associated steatohepatitis (MASH), which greatly increases the chances of developing cirrhosis and hepatocellular carcinoma. The underlying cause of MASH is multifactorial, but accumulating evidence indicates that the inflammatory process in the hepatic microenvironment typically follows a pattern that can be roughly divided into three stages: (1) Detection of hepatocyte stress by tissue‐resident immune cells including γδ T cells and CD4−CD8− double‐negative T cells, followed by their secretion of pro‐inflammatory mediators, most notably IL‐17A. (2) Recruitment of pro‐inflammatory cells, mostly of the myeloid lineage, and initiation of inflammation through secretion of effector‐type cytokines such as TNF, TGF‐β, and IL‐1β. (3) Escalation of the inflammatory response by recruitment of lymphocytes including Th17, CD8 T, and B cells leading to chronic inflammation, hepatic stellate cell activation, and fibrosis. Here we will discuss these three stages and how they are consecutively linked like falling domino tiles to the pathophysiology of MASH. Moreover, we will highlight the clinical potential of inflammation as a biomarker and therapeutic target for the treatment of MASLD. [ABSTRACT FROM AUTHOR]

While many Bayesian state‐space models for infectious disease processes focus on population infection dynamics (eg, compartmental models), in this work we examine the evolution of infection processes and the complexities of the immune responses within the host using these techniques. We present a joint Bayesian state‐space model to better understand how the immune system contributes to the control of Leishmania infantum infections over the disease course. We use longitudinal molecular diagnostic and clinical data of a cohort of dogs to describe population progression rates and present evidence for important drivers of clinical disease. Among these results, we find evidence for the importance of co‐infection in disease progression. We also show that as dogs progress through the infection, parasite load is influenced by their age, ectoparasiticide treatment status, and serology. Furthermore, we present evidence that pathogen load information from an earlier point in time influences its future value and that the size of this effect varies depending on the clinical stage of the dog. In addition to characterizing the processes driving disease progression, we predict individual and aggregate patterns of Canine Leishmaniasis progression. Both our findings and the application to individual‐level predictions are of direct clinical relevance, presenting possible opportunities for application in veterinary practice and motivating lines of additional investigation to better understand and predict disease progression. Finally, as an important zoonotic human pathogen, these results may support future efforts to prevent and treat human Leishmaniosis. [ABSTRACT FROM AUTHOR]

Background: Canine prostheses have been commercially available for many years but are still in early stages of research, development, and clinical application. Objective: To prospectively investigate mid‐term clinical outcomes of partial limb amputation with a socket prosthesis (PLASP) in canine patients via a descriptive prospective clinical case series and to describe a clinical protocol for PLASP. Methods: Client‐owned dogs (n = 12) with distal limb pathology for which total limb amputation was recommended were enrolled. Partial limb amputation was performed and a socket prosthesis was moulded and fitted to the limb. Complications, clinical follow‐up, and objective gait analysis (OGA) were recorded for at least 6 months. An online survey was completed by owners after study completion. Results: Ten dogs with thoracic limb pathology and two with pelvic limb pathology were included. The most common site of amputation was mid‐radius (n = 5). Eleven of 12 dogs demonstrated quadrupedal gait on OGA with mean per cent body weight distribution (%BWD) of 26% on thoracic limb prostheses and a %BWD of 16% for the one pelvic limb prosthesis that OGA data were available for. Complications included prosthesis suspension difficulties (n = 5), pressure sores (4), bursitis (4), postoperative infection (3), prosthesis aversion (2), dermatitis (1), and owner noncompliance (1). Two owners elected to discontinue prosthesis use. Conclusions: PLASP allowed restoration of quadrupedal gait patterns in most patients. Owners reported overall positive satisfaction, though a high complication rate was observed. PLASP should be considered in select cases as an alternative to total limb amputation for dogs with distal limb pathology. [ABSTRACT FROM AUTHOR]

The natural instability of an inverted pendulum and its dynamics richness, in terms of nonlinearity, provide a nice apparatus to reproduce behaviors of analogous systems. In this way, it is useful to perform benchmark tests for new control approaches developed. In this paper, we address the main inverted pendulum problems: pendulum stabilization, tracking, and catching swing‐up control. We show how robust recursive, control and filtering, techniques improve the system performance. They are developed to solve stochastic problems based on deterministic approaches, in order to decrease the worst influence of uncertainties. Experimental results of the proposed robust approach provide robust stability and performance despite parametric uncertainties, disturbances, and noise effects. [ABSTRACT FROM AUTHOR]

RNA is a molecule that can both store genetic information and perform catalytic reactions. This observed dualism places RNA into the limelight of concepts about the origin of life. The RNA world concept argues that life started from self‐replicating RNA molecules, which evolved toward increasingly complex structures. Recently, we demonstrated that RNA, with the help of conserved non‐canonical nucleosides, which are also putative relics of an early RNA world, had the ability to grow peptides covalently connected to RNA nucleobases, creating RNA‐peptide chimeras. It is conceivable that such molecules, which combined the information‐coding properties of RNA with the catalytic potential of amino acid side chains, were once the structures from which life emerged. Herein, we report prebiotic chemistry that enabled the loading of both nucleosides and RNAs with amino acids as the first step toward RNA‐based peptide synthesis in a putative RNA‐peptide world. [ABSTRACT FROM AUTHOR]

Die RNA ist ein Molekül, das sowohl genetische Informationen speichern als auch katalytische Reaktionen ausführen kann. Dieser beobachtete Dualismus rückt die RNA ins Rampenlicht der Konzepte über den Ursprung des Lebens. Die RNA‐Welt‐Hypothese geht davon aus, dass das Leben aus selbst replizierenden RNA‐Molekülen entstand, die sich zu immer komplexeren Strukturen entwickelten. Vor kurzem haben wir gezeigt, dass RNA mit Hilfe erhaltener nicht‐kanonischer Nukleoside, die potenzielle Relikte einer frühen RNA‐Welt sind, in der Lage ist, Peptide zu bilden, die kovalent an Nukleobasen der RNA gebunden sind, wodurch RNA‐Peptid‐Chimären entstehen. Es ist denkbar, dass solche Moleküle, welche die informationskodierenden Eigenschaften der RNA mit dem katalytischen Potenzial von Aminosäureseitenketten kombinieren können, einst die Strukturen waren, aus denen das Leben entstand. In diesem Artikel berichten wir über präbiotische Chemie, die es ermöglicht sowohl Nukleoside als auch RNA mit Aminosäuren zu beladen, was einen ersten Schritt zu einer RNA‐basierten Peptidsynthese in einer mutmaßlichen RNA‐Peptid‐Welt darstellt. [ABSTRACT FROM AUTHOR]

Nanoparticles are used as carriers for the delivery of drugs and imaging agents. Proteins are safer than synthetic nanocarriers due to their greater biocompatibility and the absence of toxic degradation products. In this context, ferritin has the additional benefit of inherently targeting the membrane receptor transferrin 1, which is overexpressed by most cancer cells. Furthermore, this self‐assembling multimeric protein can be loaded with more than 2000 iron atoms, as well as drugs, contrast agents, and other cargos. However, recombinant ferritin currently costs ~3.5 million € g−1, presumably because the limited number of producers cannot meet demand, making it generally unaffordable as a nanocarrier. Because plants can produce proteins at very‐large‐scale, we developed a simple, proof‐of‐concept process for the production of the human ferritin heavy chain by transient expression in Nicotiana benthamiana. We optimized the protein yields by screening different compartments and 5′‐untranslated regions in PCPs, and selected the best‐performing construct for production in differentiated plants. We then established a rapid and scalable purification protocol by combining pH and heat treatment before extraction, followed by an ultrafiltration/diafiltration size‐based separation process. The optimized process achieved ferritin levels of ~40 mg kg−1 fresh biomass although depth filtration limited product recovery to ~7%. The purity of the recombinant product was >90% at costs ~3% of the current sales price. Our method therefore allows the production of affordable ferritin heavy chain as a carrier for therapeutic and diagnostic agents, which is suitable for further stability and functionality testing in vitro and in vivo. [ABSTRACT FROM AUTHOR]

[18F]FTC‐146 was introduced as a very potent and selective sigma‐1 receptor radioligand, which has shown promising application as an imaging agent for neuropathic pain with positron emission tomography. In line with a multi‐laboratory project on animal welfare, we chose this radioligand to investigate its potential for detecting neuropathic pain and tissue damage in tumor‐bearing animals. However, the radiochemical yield (RCY) of around 4–7% was not satisfactory to us, and efforts were made to improve it. Herein, we describe an improved approach for the radiosynthesis of [18F]FTC‐146 resulting in a RCY, which is sevenfold higher than that previously reported. A tosylate precursor was synthesized and radio‐fluorination experiments were performed via aliphatic nucleophilic substitution reactions using either K[18F]F‐Kryptofix®222 (K2.2.2)‐carbonate system or tetra‐n‐butylammonium [18F]fluoride ([18F]TBAF). Several parameters affecting the radiolabeling reaction such as solvent, 18F‐fluorination agent with the corresponding amount of base, labeling time, and temperature were investigated. Best labeling reaction conditions were found to be [18F]TBAF and acetonitrile as solvent at 100°C. The new protocol was then translated to an automated procedure using a FX2 N synthesis module. Finally, the radiotracer reproducibly obtained with RCYs of 41.7 ± 4.4% in high radiochemical purity (>98%) and molar activities up to 171 GBq/μmol. [ABSTRACT FROM AUTHOR]

Protein–protein interactions (PPI) are involved in all cellular processes and many represent attractive therapeutic targets. However, the frequently rather flat and large interaction areas render the identification of small molecular PPI inhibitors very challenging. As an alternative, peptide interaction motifs derived from a PPI interface can serve as starting points for the development of inhibitors. However, certain proteins remain challenging targets when applying inhibitors with a competitive mode of action. For that reason, peptide‐based ligands with an irreversible binding mode have gained attention in recent years. This review summarizes examples of covalent inhibitors that employ peptidic binders and have been tested in a biological context. [ABSTRACT FROM AUTHOR]

The diversity of El Niño events is commonly described by two distinct flavors, the Eastern Pacific (EP) and Central Pacific (CP) type. While the remote impacts, that is, teleconnections, of EP and CP events have been studied for different regions individually, a global picture of their structure is still lacking. Here, we use Forman‐Ricci curvature applied on climate networks constructed from surface air temperature data to distinguish regional links from teleconnections. Our results confirm that both El Niño types influence the teleconnection patterns, however, with different spatial manifestations. Our analysis suggests that EP El Niños alter the general circulation which changes the teleconnection structure to primarily tropical teleconnections. In contrast, the teleconnection pattern of CP El Niños show only subtle changes to normal conditions. Moreover, this work identifies the dynamics of the Eastern Pacific as a proxy for the remote impact of both El Niño types. Plain Language Summary: El Niño events, characterized by anomalous sea surface temperatures (SSTs) in the Tropical Pacific, come in two flavors; Eastern Pacific (EP) and Central Pacific (CP) types, depending on the longitudinal location of the strongest SST anomalies. Their remote impacts, known as teleconnections, differ. Although there are many studies investigating teleconnections of EP and CP events for individual target regions, a global analysis of the spatial distribution of their teleconnections is still lacking. In this study, we use the theory of complex networks to study EP and CP El Niño teleconnections. We construct "climate networks" from global surface air temperature data and use the notion of "curvature" of a network link to uncover their spatial organization. We show that the most negatively curved links highlight important teleconnection patterns that differ depending on the El Niño type. EP events change the teleconnection structure to the tropics while CP and Normal year conditions reveal teleconnections to all latitudes. Interestingly, the Central Pacific does not show many teleconnections, even during CP El Niño events which we attribute to the varying location of warm water anomalies in the Central Pacific. The Eastern Pacific changes more consistently allowing identifying remote impacts of both El Niños types. Key Points: Ricci curvature of boreal winter climate networks reveals long‐range teleconnection structureEastern Pacific (EP) El Niños show primarily teleconnections in tropical while Central Pacific El Niños teleconnections on all latitudesThe EP contains robust teleconnections for both El Niño types [ABSTRACT FROM AUTHOR]

Purpose: To assess surgical success and the post‐operative development of intraocular pressure between XEN45® gelstent, Preserflo® MicroShunt and trabeculectomy with mitomycin C. Methods: Data from 105 eyes from 105 patients of matched cases with refractory open‐angle glaucoma, who underwent surgery between January 2019, and August 2020, were evaluated. Patients underwent either stand‐alone XEN gelstent insertion with Mitomycin C, stand‐alone Preserflo with Mitomycin C or trabeculectomy with Mitomycin C. The primary outcome was the proportion of complete surgical success at 6 months post‐operatively (i.e. intraocular pressure between 5mmHg and 18mmHg, no revision surgery, no loss of light perception and no post‐operative pharmaceutical antiglaucomatous treatment). The reduction of intraocular pressure after 6 months, the classes of antiglaucomatous medication used post‐operatively, best‐corrected visual acuity, spherical refractive errors and astigmatism were assessed as secondary outcomes. Results: We included 35 eyes in each group. After 6‐month follow‐up, complete success was 73.5% [95%‐CI: 57.9%–89.2%] in the trabeculectomy group, 51.4% [95%‐CI: 34.0%–68.8%] in the XEN group and 74.2% [95%‐CI: 57.9%–90.5%] in the Preserflo group (p = 0.08). Regarding secondary outcomes, the reduction of intraocular pressure was 12.1 ± 7.9 mmHg in the trabeculectomy group and was thereby 5.8 [95%‐CI: 2.2–9.6] mmHg greater compared with the XEN group (p < 0.001) and 4.8 [95%‐CI: 0.9–8.7] mmHg higher than the Preserflo group (p = 0.01). Conclusions: No statistically significant differences were found between trabeculectomy, XEN45® gelstent implantation and Preserflo® MicroShunt implantation regarding surgical success after 6 months. Yet reduction in intraocular pressure was significantly higher in the trabeculectomy group. However, all three interventions resulted in sufficiently low post‐operative intraocular pressure and may therefore be considered individually for glaucoma treatment. [ABSTRACT FROM AUTHOR]

Light‐induced charge separation is at the very heart of many solar harvesting technologies. The reduction of energetic barriers to charge separation and transfer increases the rate of separation and the overall efficiency of these technologies. Here we report that the internal reorganization energy of the redox acceptor, the movement of the atoms with changing charge, has a profound effect on the charge transfer rates from donor quantum dots. We experimentally studied and modelled with Marcus Theory charge transfer to cobalt complexes that have similar redox potentials covering 350 mV, but vastly different reorganization energies spanning 2 eV. While the driving force does influence the electron transfer rates, the reorganization energies had a far more profound effect, increasing charge transfer rates by several orders of magnitude. Our studies suggest that careful design of redox mediators to minimize reorganization energy is an untapped route to drastically increase the efficiency of quantum dot applications that feature charge transfer. [ABSTRACT FROM AUTHOR]

Tissue‐resident memory T cells (Trm) are retained in peripheral tissues after infection for enhanced protection against secondary encounter with the same pathogen. We have previously shown that the transcription factor Hobit and its homolog Blimp‐1 drive Trm development after viral infection, but how and when these transcription factors mediate Trm formation remains poorly understood. In particular, the major impact of Blimp‐1 in regulating several aspects of effector T‐cell differentiation impairs study of its specific role in Trm development. Here, we used the restricted expression of Hobit in the Trm lineage to develop mice with a conditional deletion of Blimp‐1 in Trm, allowing us to specifically investigate the role of both transcription factors in Trm differentiation. We found that Hobit and Blimp‐1 were required for the upregulation of CD69 and suppression of CCR7 and S1PR1 on virus‐specific Trm precursors after LCMV infection, underlining a role in their retention within tissues. The early impact of Hobit and Blimp‐1 favored Trm formation and prevented the development of circulating memory T cells. Thus, our findings highlight a role of Hobit and Blimp‐1 at the branching point of circulating and resident memory lineages by suppressing tissue egress of Trm precursors early during infection. [ABSTRACT FROM AUTHOR]

Peptide receptor radionuclide therapy is used to treat solid tumors by locally delivering radiation. However, due to nephro‐ and hepato‐toxicity, it is limited by its dosage. To amplify radiation damage to tumor cells, radiolabeled nanogels can be used. We show that by tuning the mechanical properties of nanogels significant enhancement in circulation half‐life of the gel could be achieved. We demonstrate why and how small changes in the mechanical properties of the nanogels influence its cellular fate. Nanogels with a storage modulus of 37 kPa were minimally phagocytosed by monocytes and macrophages compared to nanogels with 93 kPa modulus. Using PET/CT a significant difference in the blood circulation time of the nanogels was shown. Computer simulations affirmed the results and predicted the mechanism of cellular uptake of the nanogels. Altogether, this work emphasizes the important role of elasticity even for particles that are inherently soft such as nano‐ or microgels. [ABSTRACT FROM AUTHOR]

For several authorities, benchmark dose (BMD) methodology has become the recommended approach by which to derive reference values for risk assessment. However, in practice, the BMD approach is not standard use in risk assessment for pesticides where the no observed adverse effect level, lowest observed adverse effect level and effective dose (ED50 or EDx) prevail. Regression‐based BMD and the benchmark dose lower confidence limit (BMDL) have several advantages, such as utilizing more information from the generated data and being less dependent on tested dose levels. However, the BMD approach requires some degree of expert knowledge for defining an appropriate risk level for estimating the BMD and using more sophisticated statistical methods to calculate BMD and BMDL. The BMD approach is one way to move away from p value‐based binary decision‐making towards putting the weight on effect sizes. We review the advantages and disadvantages of focusing on the BMD approach for risk assessment of pesticides. Further, we discuss potential applications in efficacy trials for pest management purposes. © 2021 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

This study describes the charge‐state evolution of relativistic lead ions passing through a thin aluminum stripper foil. It is motivated by the Gamma Factory project at CERN, where optical laser pulses will be converted into intense gamma‐ray beams with energies up to a few hundred MeV, achieved via excitation of atomic transitions in few‐electron heavy‐ions at highly relativistic velocities. The recently developed BREIT code is employed together with theoretical cross‐sections for single‐electron loss and capture of the projectile ions. All charge‐states starting from Pb54 + up to bare ions are considered at kinetic projectile energies of 4.2 and 5.9 GeV u−1. During recent Gamma Factory beam tests, the calculated preparatory predictions allow to effectively produce Pb80 + and Pb81 + ions from Pb54 + in the transfer beam line between the PS and SPS synchrotron accelerators at CERN and consequently, to store partially stripped ions in the LHC for the very first time. Reasonable agreement is found between the calculations and the very few experimental data available. The study lays the groundwork to optimize the yields of charge states of interest for experiments within the future Gamma Factory project, including the upcoming Gamma Factory Proof‐of‐Principle experiment for which predictions for the production of Pb79 + are presented. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate long‐term results of glaucoma surgery in newborn and infants with glaucoma. Methods: Seventy‐nine eyes of 52 children (age: 3 weeks–15.3 years) with primary congenital or secondary glaucoma treated between 2015 and 2017 were included. The median follow‐up time was 3.9 years. Conventional probe trabeculotomy, 360° catheter‐assisted trabeculotomy, filtering and cyclodestructive surgery were compared. Strict criteria for surgical success were applied: Complete surgical success (IOP below target IOP, no further surgery) and incomplete surgical success (additional surgery allowed) were analyzed, and IOP at baseline and last follow‐up was compared. Results: Intraocular pressure (IOP) was significantly reduced in primary congenital (preoperative IOP: 27.8 ± 7.5 mmHg vs. postoperative IOP: 14.2 ± 4.5 mmHg) and secondary glaucoma (preoperative IOP: 29.2 ± 9.1 mmHg vs. postoperative IOP: 16.6 ± 4.7 mmHg). 90% of all eyes reached target IOP with or without medication allowing for additional surgeries. As first surgery, 360° catheter‐assisted trabeculotomy had a tendency to higher surgical success than other surgical approaches, while cyclodestructive procedures had lowest. Conclusions: We found very promising surgical results in our childhood glaucoma patient group. Surgical success in both congenital and secondary glaucoma was high. [ABSTRACT FROM AUTHOR]

One of the deadliest diseases is skin cancer, especially melanoma. The high resemblance between different skin lesions such as melanoma and nevus in the skin colour images increases the complexity of identification and diagnosis. An efficient automated early detection system for skin cancer detection is essential in order to save human lives, time, and effort. In this article, an automatic skin lesion classification system using a pretrained deep learning network and transfer learning was proposed. Here, diagnosing melanoma in premature stages, a detection system has been designed which contains the following digital image processing techniques. First, dermoscopy images of skin were taken and this is subjected to a preprocessing step for noise removal and postprocessing step for image enhancement. Then the processed image undergoes image segmentation using k-means and modified k-means clustering. Second, using feature extraction technology, Gray Level Co-occurrence Matrix, and first order statistics, characteristics are extracted. Features are selected on the basis of Harris Hawks optimization (HHO). Finally, various classifiers are used for predicting the stages and efficiency of the proposed work. Measures of well-known quantities, sensitivity, precision, accuracy, and specificity are used in assessing the efficiency of the suggested method, where higher values were obtained. Compared to the current methods, it is found that the classification rate exceeded the output of the current approaches in the performance of the proposed approach. [ABSTRACT FROM AUTHOR]

We propose benchmark dose estimation for event-time data, using a two-step approach. This approach avoids estimation of complex models and has been previously shown to give robust results for summarizing relevant parameters for risk assessment. In the first step, the probability of the event of interest to occur (in a certain time interval) is described as a function of time, resulting in an event-time model; such a model is fitted allowing an individual curve for each dose, and relevant estimates are extracted. In the second step, a dose--response model is fitted to the estimates of t50 obtained from the event-time model in the first step. Given a predefined benchmark response, the benchmark dose is then estimated from the resulting model. This novel approach is demonstrated in two examples. Our application of the time-to-event model showed a gain in power compared to the traditional analysis of end-of-study summary data. [ABSTRACT FROM AUTHOR]

18F‐fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is now an integral part of lymphoma staging and management. Because of its greater accuracy compared with CT alone, PET/CT is currently routinely performed for staging and for response assessment at the end of treatment in the vast majority of FDG‐avid lymphomas and is the cornerstone of response classification for these lymphomas according to the Lugano classification. Interim PET/CT, typically performed after 2 to 4 of 6 to 8 chemotherapy/chemoimmunotherapy cycles with or without radiation, is commonly performed for prognostication and potential treatment escalation or de‐escalation early in the course of therapy, a concept known as response‐adapted or risk‐adapted treatment. Quantitative PET is an area of growing interest. Metrics, such as the standardized uptake value, changes (Δ) in the standardized uptake value, metabolic tumor volume, and total lesion glycolysis, are being investigated as more reproducible and potentially more accurate predictors of response and prognosis. Despite the progress made in standardizing the use of PET/CT in lymphoma, challenges remain, particularly with respect to its limited positive predictive value, emphasizing the need for more specific molecular probes. This review highlights the most relevant applications of PET/CT in Hodgkin and B‐cell non‐Hodgkin lymphoma, its strengths and limitations, as well as recent efforts at implementing PET/CT‐based metrics as promising tools for precision medicine. This review highlights the most relevant applications of positron emission tomography/computed tomography in lymphoma, their strengths and limitations, and recent efforts at implementing positron emission tomography‐based and computed tomography‐based metrics as potential tools of precision medicine in lymphoma. [ABSTRACT FROM AUTHOR]

While numerous reference electrodes suitable for aqueous electrolytes exist, there is no well‐defined standard for non‐aqueous electrolytes. Furthermore, reference electrodes are often large and do not meet the size requirements for small cells. In this work, we present a simple method for fabricating stable 3D‐printed micro‐reference electrodes. The prints are made from polyvinylidene fluoride, which is chemically inert in strong acids, bases, and commonly used non‐aqueous solvents. We chose six different reference systems based on Ag, Cu, Zn, and Na, including three aqueous and three non‐aqueous systems to demonstrate the versatility of the approach. Subsequently, we conducted cyclic voltammetry experiments and measured the potential difference between the aqueous homemade reference electrodes and a commercial Ag/AgCl‐electrode. For the non‐aqueous reference electrodes, we chose the ferrocene redox couple as an internal standard. From these measurements, we deduced that this new class of micro‐reference electrodes is leak‐tight and shows a stable electrode potential. [ABSTRACT FROM AUTHOR]

Purpose: To examine multi-component relaxation modelling for quantification of on-and off-resonance relaxation signals in multi-echo ultra-short echo time (UTE) data of human Achilles tendon (AT) and compare bias and dispersion errors of model parameters to that of the bi-component model. Theory and Methods: Multi-component modelling is demonstrated for quantitative multi-echo UTE analysis of AT and supported using a novel method for determining number of MR-visible off-resonance components, UTE data from six healthy volunteers, and analysis of proton NMR measurements from ex vivo bovine AT. Cramer-Rao lower bound expressions are presented for multi-and bi-component models and parameter estimate variances are compared. Bias error in bi-component estimates is characterized numerically. Results: Two off-resonance components were consistently detected in all six volunteers and in bovine AT data. Multi-component model exhibited superior quality of fit, with a marginal increase in estimate variance, when compared to the bi-component model. Bi-component estimates exhibited notable bias particularly in R2.1* in the presence of off-resonance components. Conclusion: Multi-component modelling more reliably quantifies tendon matrix water components while also providing quantitation of additional non-water matrix constituents. Further work is needed to interpret the origin of the observed offresonance signals with preliminary assignments made to chemical groups in lipids and proteoglycans. [ABSTRACT FROM AUTHOR]

In this statement we describe which scientific considerations should guide vaccination strategies, what the limitations of vaccination are, how this should be communicated to the public and how we should proceed as our knowledge on the SARS-CoV-2 virus and its vaccines increases. The perspective method of assessing safety issues renders vaccination campaigns against COVID-19 mandatory to identify the level of acceptability by people of immunization as well as the level of accessibility of people to vaccines. The vector and mRNA-based vaccines typically use the SARS-CoV-2 spike protein as antigen to induce host immunity, with promising results with regards to induction of neutralizing antibodies. For some of the currently developed vaccines there is also evidence for vaccine-induced Th1 and CD8 SP + sp T-cell immunity and our basis of knowledge on these topics is rapidly increasing [7]. [Extracted from the article]

Magnetic field sensors that exploit quantum effects have shown that they can outperform classical sensors in terms of sensitivity enabling a range of novel applications in future, such as a brain machine interface. Negatively charged nitrogen‐vacancy (NV) centers in diamond have emerged as a promising high sensitivity platform for measuring magnetic fields at room temperature. Transferring this technology from laboratory setups into products and applications, the total size of the sensor, the overall power consumption, and the costs need to be reduced and optimized. Here, a fiber‐based NV magnetometer featuring a complete integration of all functional components is demonstrated without using any bulky laboratory equipment. This integrated prototype allows portable measurement of magnetic fields with a sensitivity of 344 pT Hz−1/2. [ABSTRACT FROM AUTHOR]

Tissue‐resident memory CD8+ T cells (TRM) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (TCM) and effector memory CD8+ T cells (TEM) also contribute to tissue recall responses, but their potential to form mucosal TRM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of TCM and TEM at mucosal sites. Donor TCM and TEM exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue‐homing and ‐retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF‐β stimulation. Upon pathogen clearance, TCM and TEM readily gave rise to secondary TEM. TCM also formed secondary central memory in lymphoid tissues and TRM in internal tissues, for example, the liver. Both TCM and TEM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal TRM, but not liver TRM, efficiently reformed CD103+ TRM. Our findings demonstrate that circulating TCM and TEM are limited in generating mucosal TRM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8+ T cells for protection at mucosal sites. [ABSTRACT FROM AUTHOR]

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy with a growing incidence worldwide. The initial conventional management is surgery, followed by consideration of 131I treatment that includes three options. These are termed remnant ablation (targeting benign thyroid remnant), adjuvant (targeting presumed microscopic DTC) and known disease (targeting macroscopic DTC) treatments. Some experts mostly rely on clinicopathologic assessment for recurrence risk to select patients for the 131I treatment. Others, in addition, apply radioiodine imaging to guide their treatment planning, termed theranostics (aka theragnostics or radiotheragnostics). In patients with low‐risk DTC, remnant ablation rather than adjuvant treatment is generally recommended and, in this setting, the ATA recommends a low 131I activity. 131I adjuvant treatment is universally recommended in patients with high‐risk DTC (a primary tumor of any size with gross extrathyroidal extension) and is generally recommended in intermediate‐risk DTC (primary tumor >4 cm in diameter, locoregional metastases, microscopic extrathyroidal extension, aggressive histology or vascular invasion). The optimal amount of 131I activity for adjuvant treatment is controversial, but experts reached a consensus that the 131I activity should be greater than that for remnant ablation. The main obstacles to establishing timely evidence through randomized clinical trials for 131I therapy include years‐to‐decades delay in recurrence and low disease‐specific mortality. This mini‐review is intended to update oncologists on the most recent clinical, pathologic, laboratory and imaging variables, as well as on the current 131I therapy‐related definitions and management paradigms, which should optimally equip them for individualized patient guidance and treatment. [ABSTRACT FROM AUTHOR]

Invariant natural killer T cells (iNKT) constitute up to 50% of liver lymphocytes and contribute to immunosurveillance as well as pathogenesis of the liver. Systemic activation of iNKT cells induces acute immune‐mediated liver injury. However, how tissue damage events regulate iNKT cell function and homeostasis remains unclear. We found that specifically tissue‐resident iNKT cells in liver and spleen express the tissue‐damage receptor P2RX7 and the P2RX7‐activating ectoenzyme ARTC2. P2RX7 expression restricted formation of iNKT cells in the liver suggesting that liver iNKT cells are actively restrained under homeostatic conditions. Deliberate activation of P2RX7 in vivo by exogenous NAD resulted in a nearly complete iNKT cell ablation in liver and spleen in a P2RX7‐dependent manner. Tissue damage generated by acetaminophen‐induced liver injury reduced the number of iNKT cells in the liver. The tissue‐damage‐induced iNKT cell depletion was driven by P2RX7 and localized to the site of injury, as iNKT cells in the spleen remained intact. The depleted liver iNKT cells reconstituted only slowly compared to other lymphocytes such as regulatory T cells. These findings suggest that tissue‐damage‐mediated depletion of iNKT cells acts as a feedback mechanism to limit iNKT cell‐induced pathology resulting in the establishment of a tolerogenic environment. [ABSTRACT FROM AUTHOR]

Stripe‐like patterns of surface wave arrival angle deviations have been observed by several seismological studies around the world, but this phenomenon has not been explained so far. Here we test the hypothesis that systematic arrival angle deviations observed at the AlpArray broadband seismic network in Europe are interference patterns caused by diffraction of surface waves at single small‐scaled velocity anomalies. We use the observed pattern of Rayleigh waves from two earthquakes under the Southern Atlantic Ocean, and we fit this pattern with theoretical arrival angles derived by a simple modeling approach describing the interaction of a seismic wavefield with small anomalies. A grid search inversion scheme is implemented, which indicates that the anomaly is located in Central Africa, with its head under Cameroon. Moreover, the inversion enables the characterization of the anomaly: The anomaly is inferred to be between 320 and 420 km wide, matching in length the 2,500 km long upper mantle low‐velocity region under the volcano‐capped swells of the Cameroon volcanic line. We show that this approach can be generally used for studying the upper mantle anomalies worldwide. Key Points: Arrival angle deviations of surface waves are explained by interference of diffracted wavefronts after passing a distant anomalyWe find a strong, elongated low‐velocity region in the upper mantle under the Cameroon volcanic lineThese findings can help for understanding the nature of small‐scale convection in the upper mantle [ABSTRACT FROM AUTHOR]

Analysis of shotgun metagenomic data generated from next generation sequencing platforms can be done through a variety of bioinformatic pipelines. These pipelines employ different sets of sophisticated bioinformatics algorithms which may affect the results of this analysis. In this study, we compared two commonly used pipelines for shotgun metagenomic analysis: MG-RAST and Kraken 2, in terms of taxonomic classification, diversity analysis, and usability using their primarily default parameters. Overall, the two pipelines detected similar abundance distributions in the three most abundant taxa Proteobacteria, Firmicutes, and Bacteroidetes. Within bacterial domain, 497 genera were identified by both pipelines, while an additional 694 and 98 genera were solely identified by Kraken 2 and MG-RAST, respectively. 933 species were detected by the two algorithms. Kraken 2 solely detected 3550 species, while MG-RAST identified 557 species uniquely. For archaea, Kraken 2 generated 105 and 236 genera and species, respectively, while MG-RAST detected 60 genera and 88 species. 54 genera and 72 species were commonly detected by the two methods. Kraken 2 had a quicker analysis time (~4 hours) while MG-RAST took approximately 2 days per sample. This study revealed that Kraken 2 and MG-RAST generate comparable results and that a reliable high-level overview of sample is generated irrespective of the pipeline selected. However, Kraken 2 generated a more accurate taxonomic identification given the higher number of "Unclassified" reads in MG-RAST. The observed variations at the genus level show that a main restriction is using different databases for classification of the metagenomic data. The results of this research indicate that a more inclusive and representative classification of microbiomes may be achieved through creation of the combined pipelines. [ABSTRACT FROM AUTHOR]

The potential of carbonyl sulfide (COS) flux measurements as an additional constraint for estimating the gross primary production depends, among other preconditions, on our understanding of the soil COS exchange and its contribution to the overall net ecosystem COS flux. We conducted soil chamber measurements of COS, with transparent chambers, in three different ecosystems across Europe. The in situ measurements were followed by laboratory measurements of soil samples collected at the study sites. The soil samples were exposed to UV radiation to investigate the role of photo‐degradation for COS exchange. In situ and laboratory measurements revealed pronounced intersite and intrasite variability of COS exchange. In situ COS fluxes were primarily governed by radiation in the savannah‐like grassland (SAV), soil temperature and intrasite heterogeneity in the deciduous broadleaf forest, and soil water content and intrasite heterogeneity in the evergreen needleleaf forest. The soil of the ecosystem with the highest light intensity incident on the soil surface, SAV, was a net source for COS, while the soils of the other two ecosystems were COS sinks. UV radiation increased COS emissions and/or reduced COS uptake from all soil samples under laboratory conditions. The impact of UV on the COS flux differed between soil samples, with a tendency toward a stronger response of the COS flux to UV radiation exposure in samples with higher soil organic matter content. Our results emphasize the importance of photo‐degradation for the soil COS flux and stress the substantial spatial variability of soil COS exchange in ecosystems. Key Points: COS emissions increased after UV exposure of soil samples from three European soilsPrimary abiotic driver of COS cycling differs between three European soils [ABSTRACT FROM AUTHOR]

Background: [18F]‐2‐fluoro‐2‐deoxy‐D‐glucose (FDG) positron emission tomography (PET) is applied to delineate cerebral glucose metabolic patterns in Alzheimer's disease (AD). Sodium MR imaging (23Na‐MRI) can reveal alterations in tissue sodium concentration (TSC) in the brain, potentially reflecting mitochondrial dysfunction and impaired cellular energy state. This initial study aims at investigating disease‐specific topographical associations between glucose metabolism assessed via FDG‐PET and regional TSC from 23Na‐MRI, thus improving our understanding of neuroenergetics alteration in AD. Method: 20 patients with a biological biomarker‐based diagnosis of prodromal/mild AD (mean age 68±7.5; 8 females; CDR 0.75±0.57, MMSE 23.9±4.2) received an FDG‐PET, 23Na‐MRI and 1H‐MRI at 3T magnetic field (Siemens Prisma). A variable flip angle method was used to obtain TSC maps (Coste et al., 2019). To control for inter‐individual differences, FDG‐PET and TSC images were intensity‐normalized to the brainstem to create normalized glucose metabolism (nFDG) and normalized TSC maps (nTSC) (de Souza et al., 2011; Nugent et al., 2020), respectively. The Hammersmith and VolBrain Segmentation atlases were applied for region‐of‐interest analysis and to create correlation matrices between nFDG, nTSC and normalized local brain volume. Result: Regional nTSC negatively correlated with nFDG in AD patients mainly in temporal lobe structures and superior frontal gyri, indicating that decreased glucose metabolism was associated with increased TSC and vice versa. As expected, regional volume was positively correlated with nFDG in regions of the temporal lobe. When performing partial correlation controlling for volume, negative correlation clusters between nTSC and nFDG remained significant for superior frontal gyri and the anterior temporal lobes (Figure 1). Conclusion: For the first time, the association between local glucose consumption rates and sodium concentrations were investigated in AD using combined FDG‐PET and 23Na‐MRI at 3T. Consistently to our recent findings of increased TSC in AD patients (Haeger et al., 2021), the negative correlations between nTSC and nFDG values in temporal and frontal brain regions, are confirming the interplay between reduced energy metabolism and sodium increase in AD, the exact nature of which remains to be determined. References: Coste [...]. Magnetic Resonance Imaging 2019. Haeger [...]. Alzheimer's & Dementia 2021. Nugent [...]. Scientific Reports 2020. de Souza [...]. Brain 2011. [ABSTRACT FROM AUTHOR]

In this review, recent methodological developments for the benchmark dose (BMD) methodology are summarized. Specifically, we introduce the advances for the main steps in BMD derivation: selecting the procedure for defining a BMD from a predefined benchmark response (BMR), setting a BMR, selecting a dose–response model, and estimating the corresponding BMD lower limit (BMDL). Although the last decade has shown major progress in the development of BMD methodology, there is still room for improvement. Remaining challenges are the implementation of new statistical methods in user‐friendly software and the lack of consensus about how to derive the BMDL. [ABSTRACT FROM AUTHOR]

Hypothyroidism is common, with an extreme manifestation of myxedema coma if untreated. Hematologic consequences of myxedema coma include mild leukopenia and anemia, rarely pancytopenia. We present a patient with typical symptoms of myxedema coma, but found to be pancytopenic, with sustained response to levothyroxine and blood transfusion for anemia. [ABSTRACT FROM AUTHOR]

The immune and endocrine systems ensure two vital functions in the body. The immune system protects us from lethal pathogens, whereas the endocrine system ensures proper metabolic function of peripheral organs by regulating systemic homeostasis. These two systems were long thought to operate independently. The immune system uses cytokines and immune receptors, whereas the endocrine system uses hormones to regulate metabolism. However, recent findings show that the immune and endocrine systems closely interact, especially regarding regulation of glucose metabolism. In response to pathogen encounter, cytokines modify responsiveness of peripheral organs to endocrine signals, resulting in altered levels of blood hormones such as insulin, which promotes the ability of the body to fight infection. Here we provide an overview of recent literature describing various mechanisms, which the immune system utilizes to modify endocrine regulation of systemic metabolism. Moreover, we will describe how these immune–endocrine interactions derail in the context of obesity. From a clinical perspective we will elaborate how infection and obesity aggravate the development of metabolic diseases such as diabetes mellitus type 2 in humans. In summary, this review provides a comprehensive overview of immune‐induced changes in systemic metabolism following infection, with a focus on regulation of glucose metabolism. [ABSTRACT FROM AUTHOR]

The National Chip Processing Trial is a collaborative effort between public breeding programs and the potato (Solanum tuberosum L.) industry to identify new clones with broad adaptation. The objective of this study was to investigate the genetic covariance of trial locations, based on 337 clones evaluated in 10 states from 2011 to 2016. Three models were considered: (I) assuming a uniform genetic correlation between locations within a year, (II) using a factor-analytic (FA) model of the total genetic covariance of environments (location--year combinations), and (III) using a FA model of the additive genetic covariance based on 5278 single-nucleotide polymorphism (SNP) markers. With Model I, the genetic correlation between locations was 0.50 for vine maturity, 0.54 for tuber yield, and 0.72 for specific gravity. The Akaike information criterion decreased as model complexity increased, from Models I to II to III, for maturity and yield but not specific gravity. Of the 10 states in the dataset, Florida stood out for having environments with substantial (up to 88%) genetic variance unexplained by the latent factors. Linear discriminants (LD) of the factor loadings were used to visualize the genetic correlation between locations. For vine maturity, LD1 separated Florida from the other locations, and LD2 separated the remaining southern locations from the northern ones. For yield, LD1 separated Texas from the other locations. This study has created a foundation for the design of more efficient trialing and selection programs for the US potato community. [ABSTRACT FROM AUTHOR]

Abstract: CD8 T cells acquire cytotoxic molecules including granzyme B during effector differentiation. Both tissue‐resident memory CD8 T cells (Trm) and circulating CD45RA+ effector‐type T cells (Temra) cells have the ability to retain granzyme B protein expression into the memory phase, but it is unclear how this persistence of cytolytic activity is regulated during steady state. Previously, we have described that the transcriptional regulators Hobit and Blimp‐1 have overlapping target genes that include granzyme B, but their impact on the regulation of cytotoxicity in Trm and Temra cells during homeostasis has remained unclear. We examined the expression regulation of Hobit and Blimp‐1 in murine and human CD8 T‐cells to determine their timeframe of activity. While Blimp‐1 mRNA was expressed throughout effector and memory T cells, Blimp‐1 protein, was only transiently expressed during the effector stage. In contrast, Hobit mRNA and protein expression was stably maintained during quiescence, but downregulated after activation. Notably, Blimp‐1 was required for expression of granzyme B in murine effector T cells and Trm, while Hobit specifically regulated granzyme B in murine Trm during the memory phase. These findings suggest that Blimp‐1 initiates cytotoxic effector function and that Hobit maintains cytotoxicity in a deployment‐ready modus in Trm. [ABSTRACT FROM AUTHOR]

Objective To examine the impact of treatment setting and demographic factors on oropharyngeal and laryngeal cancer time to treatment initiation (TTI). Study Design Retrospective case series. Setting Safety net hospital and adjacent private academic hospital. Subjects and Methods Demographic, staging, and treatment details were retrospectively collected for 239 patients treated from January 1, 2014, to June 30, 2016. TTI was defined as days between diagnostic biopsy and initiation of curative treatment (defined as first day of radiotherapy [RT], surgery, or chemotherapy). Results On multivariable analysis, safety net hospital treatment (vs private academic hospital treatment), initial diagnosis at outside hospital, and oropharyngeal cancer (vs laryngeal cancer) were all associated with increased TTI. Surgical treatment, severe comorbidity, and both N1 and N2 status were associated with decreased TTI. Conclusion Safety net hospital treatment was associated with increased TTI. No differences in TTI were found when language spoken and socioeconomic status were examined in the overall cohort. [ABSTRACT FROM AUTHOR]

Abstract: Small randomized trials have not shown an overall survival (OS) difference among local treatment modalities for patients with extremity soft‐tissue sarcomas (E‐STS) but were underpowered for OS. We examine the impact of local treatment modalities on OS and sarcoma mortality (SM) using two national registries. The National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program were analyzed separately to identify patients with stage II‐III, high‐grade E‐STS diagnosed between 2004 and 2013 and treated with (1) amputation alone, (2) limb‐sparing surgery (LSS) alone, (3) preoperative radiation therapy (RT) and LSS, or (4) LSS and postoperative RT. Multivariable analyses (MVAs) and 1:1 matched pair analyses (MPAs) examined treatment impacts on OS (both databases) and SM (SEER only). From the NCDB and SEER, 7828 and 2937 patients were included. On MVAs, amputation was associated with inferior OS and SM. Relative to LSS alone, both preoperative RT and LSS (HR, 0.70; 95% CI: 0.62‐0.78) and LSS and postoperative RT (HR, 0.69; 95% CI: 0.63‐0.75) improved OS in NCDB analyses with confirmation by SEER. Estimated median survivals from MPA utilizing NCDB data were 7.2 years with LSS alone (95% CI: 6.5‐8.9 years) vs 9.8 years (95% CI: 9.0‐11.2 years) with LSS and postoperative RT. A MPA comparing preoperative RT and LSS to LSS alone found median survivals of 8.9 years (95% CI: 7.9‐not estimable) and 6.6 years (95% CI: 5.4‐7.8 years). Optimal high‐grade E‐STS management includes LSS with preoperative or postoperative RT as evidenced by superior OS and SM. [ABSTRACT FROM AUTHOR]