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OBJECTIVE: To provide detailed guidance on the administration of systemic bevacizumab in patients with recurrent respiratory papillomatosis (RRP) based on a detailed review of the scientific literature and a consensus of experts with real-world clinical experience. METHODS: A bevacizumab consensus working group (N = 10) was composed of adult and pediatric otolaryngologists, adult and pediatric oncologists, and a representative from the RRP Foundation (RRPF), all with experience administering systemic bevacizumab in patients with RRP. After extensive review of the medical literature, a modified Delphi method-based survey series was utilized to establish consensus on the following key areas: clinical and patient characteristics ideal for treatment candidacy, patient perspective in treatment decisions, treatment access, initial dosing, monitoring, guidelines for tapering and discontinuation, and reintensifying therapy. RESULTS: Seventy-nine statements were identified across nine critical domains, and 45 reached consensus [clinical benefits of bevacizumab (3), patient and disease characteristics for treatment consideration (7), contraindications for treatment (3), shared decision-making (incorporating the patient perspective) (5), treatment access (3), initial dosing and administration (8), monitoring (7), tapering and discontinuation (6), and reintensification (3)]. CONCLUSION: This consensus statement provides the necessary guidance for clinicians to initiate systemic administration of bevacizumab and represents a potential paradigm shift toward nonsurgical treatment options for patients with RRP. LEVEL OF EVIDENCE: 5 Laryngoscope, 2024.

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Great interest exists in developing a transgenic trait that controls the economically important soybean (Glycine max) pest, soybean cyst nematode (SCN, Heterodera glycines), due to its adaptation to native resistance. Soybean plants expressing the Bacillus thuringiensis delta-endotoxin, Cry14Ab, were recently demonstrated to control SCN in both growth chamber and field testing. In that communication, ingestion of the Cry14Ab toxin by SCN second stage juveniles (J2) was demonstrated using fluorescently labeled Cry14Ab in an in vitro assay. Here, we show that consistent with expectations for a Cry toxin, Cry14Ab has a mode-of-action unique from the native resistance sources Peking and PI 88788. Further, we demonstrate in planta the ingestion and localization of the Cry14Ab toxin in the midgut of nematodes feeding on roots expressing Cry14Ab, using immunogold labeling and transmission electron microscopy. We observed immunolocalization of the toxin and resulting intestinal damage primarily in the microvillus-like (MvL)-containing region of the midgut intestine, but not in nematodes feeding on roots lacking toxin. This demonstrated that Cry14Ab was taken up by the J2 SCN, presumably through the feeding tube within the plant root cell that serves as its feeding site. This suggests that relatively large proteins can be taken up through the feeding tube. Electron microscopy showed that Cry14Ab caused lysis of the midgut MvL membrane, and eventual degradation of the MvL and the lysate, forming particulate aggregates. The accumulated electron dense aggregate in the posterior midgut intestine was not observed in SCN in non-Cry14Ab expressing plants.

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Deep infection is the second most common complication of arthroplasty following loosening of the implant. Antibiotic-loaded bone cements (ALBCs) and high concentrations of systemic broad-spectrum antibiotics are commonly used to prevent infections following injury and surgery. However, clinical data fails to show that ALBCs are effective against deep infection, and negative side effects can result following prolonged administration of antibiotics. Additionally, the rise of multidrug resistant (MDR) bacteria provides an urgent need for alternatives to broad-spectrum antibiotics. Phage therapy, or the use of bacteriophages (viruses that infect bacteria) to target pathogenic bacteria, might offer a safe alternative to combat MDR bacteria. Application of phage therapy in the setting of deep infections requires formulation strategies that would stabilize bacteriophage against chemical and thermal stress during bone-cement polymerization, that maintain bacteriophage activity for weeks or months at physiological temperatures, and that allow for sustained release of phage to combat slow-growing, persistent bacteria. Here, we demonstrate the formulation of three phages that target diverse bacterial pathogens, which includes spray-drying of the particles for enhanced thermal stability at 37 °C and above. Additionally, we use atomic layer deposition (ALD) to coat spray-dried powders with alumina to allow for delayed release of phage from the dry formulations, and potentially protect phage against chemical damage during bone cement polymerization. Together, these findings present a strategy to formulate phages that possess thermal stability and sustained release properties for use in deep infections.

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BACKGROUND: Asthma, the most common chronic disease of childhood, can affect a child's physical and mental health and social and emotional development. OBJECTIVE: The aim of this study was to identify factors associated with emergency department (ED) return visits for asthma exacerbations within 14 days of an initial visit. METHODS: This was a retrospective review from Cerner Real-World Data for patients aged from 5 to 18 years and seen at an ED for an asthma exacerbation and discharged home at the index ED visit. Asthma visits were defined as encounters in which a patient was diagnosed with asthma and a beta agonist, anticholinergic, or systemic steroid was ordered or prescribed at that encounter. Return visits were ED visits for asthma within 14 days of an index ED visit. Data, including demographic characteristics, ED evaluation and treatment, health care utilization, and medical history, were collected. Data were analyzed via logistic regression mixed effects model. RESULTS: A total of 80,434 index visits and 17,443 return visits met inclusion criteria. Prior ED return visits in the past year were associated with increased odds of a return visit (odds ratio [OR] 2.12; 95% CI 2.07-2.16). History of pneumonia, a concomitant diagnosis of pneumonia, and fever were associated with increased odds of a return visit (OR 1.19; 95% CI 1.10-1.29; OR 1.15; 95% CI 1.04-1.28; OR 1.20; 95% CI 1.11-1.30, respectively). CONCLUSIONS: Several variables seem to be associated with statistically significant increased odds of ED return visits. These findings indicate a potentially identifiable population of at-risk patients who may benefit from additional evaluation, planning, or education prior to discharge.

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Cell-based medicinal products (CBMPs) are a growing class of therapeutics that promise new treatments for complex and rare diseases. Given the inherent complexity of the whole human cells comprising CBMPs, there is a need for robust and fast analytical methods for characterization, process monitoring, and quality control (QC) testing during their manufacture. Existing techniques to evaluate and monitor cell quality typically constitute labor-intensive, expensive, and highly specific staining assays. In this work, we combine image-based deep learning with flow imaging microscopy (FIM) to predict cell health metrics using cellular morphology "fingerprints" extracted from images of unstained Jurkat cells (immortalized human T-lymphocyte cells). A supervised (i.e., algorithm trained with human-generated labels for images) fingerprinting algorithm, trained on images of unstained healthy and dead cells, provides a robust stain-free, non-invasive, and non-destructive method for determining cell viability. Results from the stain-free method are in good agreement with traditional stain-based cytometric viability measurements. Additionally, when trained with images of healthy cells, dead cells and cells undergoing chemically induced apoptosis, the supervised fingerprinting algorithm is able to distinguish between the three cell states, and the results are independent of specific treatments or signaling pathways. We then show that an unsupervised variational autoencoder (VAE) algorithm trained on the same images, but without human-generated labels, is able to distinguish between samples of healthy, dead and apoptotic cells along with cellular debris based on learned morphological features and without human input. With this, we demonstrate that VAEs are a powerful exploratory technique that can be used as a process monitoring analytical tool.

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BACKGROUND: Paediatric laceration repair procedures are common in the ED; however, post-discharge recovery remains understudied. Perioperative research demonstrates that children exhibit maladaptive behavioural changes following stressful and painful medical procedures. This study examined post-discharge recovery following paediatric laceration repair in the ED. METHODS: This prospective observational study included a convenience sample of 173 children 2-12 years old undergoing laceration repair in a paediatric ED in Orange, California, USA between April 2022 and August 2023. Demographics, laceration and treatment data (eg, anxiolytic medication), and caregiver-reported child pre-procedural and procedural pain (Numerical Rating Scale (NRS)) were collected. On days 1, 3, 7 and 14 post-discharge, caregivers reported children's pain and new-onset maladaptive behavioural changes (eg, separation anxiety) via the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery. Univariate and logistic regression analyses were conducted to identify variables associated with the incidence of post-discharge maladaptive behavioural change. RESULTS: Post-discharge maladaptive behavioural changes were reported in 43.9% (n=69) of children. At 1 week post-discharge, approximately 20% (n=27) of children exhibited maladaptive behavioural changes and 10% (n=13) displayed behavioural changes 2 weeks post-discharge. Mild levels of pain (NRS ≥2) were reported in 46.7% (n=70) of children on post-discharge day 1, 10.3% (n=14) on day 7 and 3.1% (n=4) on day 14. An extremity laceration (p=0.029), pre-procedural midazolam (p=0.020), longer length of stay (p=0.043) and post-discharge pain on day 1 (p<0.001) were associated with incidence of maladaptive behavioural changes. Higher pain on post-discharge day 1 was the only variable independently associated with an increased likelihood of maladaptive behavioural change (OR=1.32 (95% CI 1.08 to 1.61), p=0.001). CONCLUSION: Over 40% of children exhibited maladaptive behavioural changes after ED discharge. Although the incidence declined over time, 10% of children continued to exhibit behavioural changes 2 weeks post-discharge. Pain on the day following discharge emerged as a key predictor, highlighting the potential critical role of proactive post-procedural pain management in mitigating adverse behavioural changes.

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BACKGROUND: Despite improvements over the past decade, children continue to experience significant pain and distress surrounding invasive procedures in the emergency department (ED). To assess the impact of newly developed interventions, we must create more reliable and valid behavioral assessment tools that have been validated for the unique settings of pediatric EDs. OBJECTIVE: This study aimed to create and test the Emergency Department Child Behavior Coding System (ED-CBCS) for the assessment of child distress and nondistress behaviors surrounding pediatric ED procedures. METHODS: Via an iterative process, a multidisciplinary expert panel developed the ED-CBCS, an advanced time-based behavioral coding measure. Inter-rater reliability and concurrent validity were examined using 38 videos of children aged from 2 to 12 years undergoing laceration procedures. Face, Legs, Activity, Cry, Consolability (FLACC) scale scores were used to examine concurrent validity. RESULTS: The final ED-CBCS included 27 child distress and nondistress behaviors. Time-unit κ values from 0.64 to 0.98 and event alignment κ values from 0.62 to 1.00 indicated good to excellent inter-rater reliability for all but one of the individual codes. ED-CBCS distress (B = 1.26; p < 0.001) and nondistress behaviors (B = -0.69, p = 0.025) were independently significantly associated with FLACC scores, indicating concurrent validity. CONCLUSIONS: We developed a psychometrically sound tool tailored for pediatric ED procedures. Future work could use this measure to better identify behavioral targets and test the effects of interventions to relieve pediatric ED pain and distress.

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Pore-forming toxins (PFTs) are proteins that form lesions in biological membranes. Better understanding of the structure and function of these proteins will be beneficial in a number of biotechnological applications, including the development of new pest control methods in agriculture. When searching for new pore formers, existing sequence homology-based methods fail to discover truly novel proteins with low sequence identity to known proteins. Search methodologies based on protein structures would help us move beyond this limitation. As the number of known structures for PFTs is very limited, it's quite challenging to identify new proteins having similar structures using computational approaches like deep learning. In this article, we therefore propose a sample-efficient graphical model, where a protein structure graph is first constructed according to consensus secondary structures. A semi-Markov conditional random fields model is then developed to perform protein sequence segmentation. We demonstrate that our method is able to distinguish structurally similar proteins even in the absence of sequence similarity (pairwise sequence identity < 0.4)-a feat not achievable by traditional approaches like HMMs. To extract proteins of interest from a genome-wide protein database for further study, we also develop an efficient framework for UniRef50 with 43 million proteins.

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Enveloped viruses are attractive candidates for use as gene- and immunotherapeutic agents due to their efficacy at infecting host cells and delivering genetic information. They have also been used in vaccines as potent antigens to generate strong immune responses, often requiring fewer doses than other vaccine platforms as well as eliminating the need for adjuvants. However, virus instability in liquid formulations may limit their shelf life and require that these products be transported and stored under stringently controlled temperature conditions, contributing to high cost and limiting patient access. In this work, spray-drying and lyophilization were used to embed an infectious enveloped virus within dry, glassy polysaccharide matrices. No loss of viral titer was observed following either spray-drying (at multiple drying gas temperatures) or lyophilization. Furthermore, viruses embedded in the glassy formulations showed enhanced thermal stability, retaining infectivity after exposure to elevated temperatures as high as 85 °C for up to one hour, and for up to 10 weeks at temperatures as high as 30 °C. In comparison, viruses in liquid formulations lost infectivity within an hour at temperatures above 40 °C, or after incubation at 25 °C for longer periods of time.

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Subvisible particles may be encountered throughout the processing of therapeutic protein formulations. Flow imaging microscopy (FIM) and backgrounded membrane imaging (BMI) are techniques commonly used to record digital images of these particles, which may be analyzed to provide particle size distributions, concentrations, and identities. Although both techniques record digital images of particles within a sample, FIM analyzes particles suspended in flowing liquids, whereas BMI records images of dry particles after collection by filtration onto a membrane. This study compared the performance of convolutional neural networks (CNNs) in classifying images of subvisible particles recorded by both imaging techniques. Initially, CNNs trained on BMI images appeared to provide higher classification accuracies than those trained on FIM images. However, attribution analyses showed that classification predictions from CNNs trained on BMI images relied on features contributed by the membrane background, whereas predictions from CNNs trained on FIM features were based largely on features of the particles. Segmenting images to minimize the contributions from image backgrounds reduced the apparent accuracy of CNNs trained on BMI images but caused minimal reduction in the accuracy of CNNs trained on FIM images. Thus, the seemingly superior classification accuracy of CNNs trained on BMI images compared to FIM images was an artifact caused by subtle features in the backgrounds of BMI images. Our findings emphasize the importance of examining machine learning algorithms for image analysis with attribution methods to ensure the robustness of trained models and to mitigate potential influence of artifacts within training data sets.

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Suspensions of protein antigens adsorbed to aluminum-salt adjuvants are used in many vaccines and require mixing during vial filling operations to prevent sedimentation. However, the mixing of vaccine formulations may generate undesirable particles that are difficult to detect against the background of suspended adjuvant particles. We simulated the mixing of a suspension containing a protein antigen adsorbed to an aluminum-salt adjuvant using a recirculating peristaltic pump and used flow imaging microscopy to record images of particles within the pumped suspensions. Supervised convolutional neural networks (CNNs) were used to analyze the images and create "fingerprints" of particle morphology distributions, allowing detection of new particles generated during pumping. These results were compared to those obtained from an unsupervised machine learning algorithm relying on variational autoencoders (VAEs) that were also used to detect new particles generated during pumping. Analyses of images conducted by applying both supervised CNNs and VAEs found that rates of generation of new particles were higher in aluminum-salt adjuvant suspensions containing protein antigen than placebo suspensions containing only adjuvant. Finally, front-face fluorescence measurements of the vaccine suspensions indicated changes in solvent exposure of tryptophan residues in the protein that occurred concomitantly with new particle generation during pumping.

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Normal absolute neutrophil count (ANC) variations, as seen with Duffy-null associated neutrophil count (DANC), are not accounted for in trial eligibility, which may contribute to racial enrollment disparities. We describe ANC eligibility for pediatric oncology phase I/II clinical trials according to primary sponsorship from 2010 to 2023 using ClinicalTrials.gov. Out of 438 trials, 20% were industry-sponsored. Total 17% of trials required ANC ≥1500 cells/µL for enrollment; however, industry-sponsored trials were significantly more likely to require ANC ≥1500 cells/µL than non-industry-sponsored trials (odds ratio 2.53, 95% confidence interval: 1.39-4.62; p < .001). These data suggest laboratory exclusion criteria are one possible mechanism for pediatric clinical trial enrollment disparities.

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Objective: Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. Approach: We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results: MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. Significance: These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

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Many countries are considering nuclear power as a means of reducing greenhouse gas emissions, and the IAEA (IAEA, 2022) has forecasted nuclear power growth rates up to 224% of the 2021 level by 2050. Nuclear power plants release trace quantities of radioxenon, an inert gas that is also monitored because it is released during nuclear explosive tests. To better understand how nuclear energy growth (and resulting Xe emissions) could affect a global nonproliferation architecture, we modeled daily releases of radioxenon isotopes used for nuclear explosion detection in the International Monitoring System (IMS) that is part of the Comprehensive Nuclear Test-Ban Treaty: 131mXe, 133Xe, 133mXe, and 135Xe to examine the change in the number of potential radioxenon detections as compared to the 2021 detection levels. If a 40-station IMS network is used, the potential detections of 133Xe in 2050 would range from 82% for the low-power scenario to 195% for the high-power scenario, compared to the detections in 2021. If an 80-station IMS network is used, the potential detections of 133Xe in 2050 would range from 83% of the 2021 detection rate for the low-power scenario to 209% for the high-power scenario. Essentially no detections of 131mXe and 133mXe are expected. The high growth scenario could lead to a 2.5-fold increase in 135Xe detections, but the total number of detections is still small (on the order of 1 detection per day in the entire network). The higher releases do not pose a health issue, but better automated methods to discriminate between radioactive xenon released from industrial sources and nuclear explosions will be needed to offset the higher workload for people who perform the monitoring.

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This note reports on eight observations of inverted swimming behavior by species of ceratioid whipnose anglerfishes in the genus Gigantactis, from the Caribbean, tropical east Atlantic, tropical western Indian Ocean, the north-east and north-west Pacific and south-west Pacific. It covers four putative species and strongly suggests that this is the normal behavior for the genus. A possible reason is briefly discussed. In addition, a new depth record of 5866 m for the ceratioid anglerfish is recorded.

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Treatment with tisagenlecleucel (tisa-cel) achieves excellent complete remission rates in children and young adults with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL), but approximately 50% maintain long-term remission. Consolidative hematopoietic stem cell transplantation (cHSCT) is a potential strategy to reduce relapse risk, but it carries substantial short- and long-term toxicities. Additionally, several strategies for management of B cell recovery (BCR) and next-generation sequencing (NGS) positivity post-tisa-cel exist, without an accepted standard. We hypothesized that practice preferences surrounding cHSCT, as well as management of BCR and NGS positivity, varies across tisa-cel-prescribing physicians and sought to characterize current practice preferences. A survey focusing on preferences regarding the use of cHSCT, management of BCR, and NGS positivity was distributed to physicians who prescribe tisa-cel for children and young adults with B-ALL. Responses were collected from August 2022 to April 2023. Fifty-nine unique responses were collected across 43 institutions. All respondents prescribed tisa-cel for children and young adults. The clinical focus of respondents was HSCT in 71%, followed by leukemia/lymphoma in 24%. For HSCT-naive patients receiving tisa-cel, 57% of respondents indicated they made individualized decisions for cHSCT based on patient factors, whereas 22% indicated they would avoid cHSCT and 21% indicated they would pursue cHSCT when feasible. Certain factors influenced >50% of respondents towards recommending cHSCT (either an increased likelihood of recommending or always recommending), including preinfusion disease burden >25%, primary refractory B-ALL, M3 bone marrow following reinduction for relapse, KMT2A-rearranged B-ALL, history of blinatumomab nonresponse, and HSCT-naive status. Most respondents indicated they would pursue HSCT for HSCT-naive, total body irradiation (TBI) recipients with BCR before 6 months post-tisa-cel or with NGS positivity at 1 or 3 months post-tisa-cel, although there was variability in responses regarding whether to proceed to HSCT directly or provide intervening therapy prior to HSCT. Fewer respondents recommended HSCT for BCR or NGS positivity in patients with a history of HSCT, in noncandidates for TBI, and in patients with trisomy 21. The results of this survey indicate there exists significant practice variability regarding the use of cHSCT, as well as interventions for post-tisa-cel BCR or NGS positivity. These results highlight areas in which ongoing clinical trials could inform more standardized practice.

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Identification of the mechanisms by which viruses lose activity during droplet formation and drying is of great importance to understanding the spread of infectious diseases by virus-containing respiratory droplets and to developing thermally stable spray dried live or inactivated viral vaccines. In this study, we exposed suspensions of baculovirus, an enveloped virus, to isolated mechanical stresses similar to those experienced during respiratory droplet formation and spray drying: fluid shear forces, osmotic pressure forces, and surface tension forces at interfaces. DNA released from mechanically stressed virions was measured by SYBR Gold staining to quantify viral capsid disruption. Theoretical estimates of the force exerted by fluid shear, osmotic pressures and interfacial tension forces during respiratory droplet formation and spray drying suggest that osmotic and interfacial stresses have greater potential to mechanically destabilize viral capsids than forces associated with shear stresses. Experimental results confirmed that rapid changes in osmotic pressure, such as those associated with drying of virus-containing droplets, caused significant viral capsid disruption, whereas the effect of fluid shear forces was negligible. Surface tension forces were sufficient to provoke DNA release from virions adsorbed at air-water interfaces, but the extent of this disruption was limited by the time required for virions to diffuse to interfaces. These results demonstrate the effect of isolated mechanical stresses on virus particles during droplet formation and drying.

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