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Accurate and rapid point-of-care tissue and microbiome sampling is critical for early detection of cancers and infectious diseases and often result in effective early intervention and prevention of disease spread. In particular, the low prevalence of Barrett's and gastric premalignancy in the Western world makes population-based endoscopic screening unfeasible and cost-ineffective. Herein, we report a method that may be useful for prescreening the general population in a minimally invasive way using a swallowable, re-expandable, ultra-absorbable, and retrievable nanofiber cuboid and sphere produced by electrospinning, gas-foaming, coating, and crosslinking. The water absorption capacity of the cuboid- and sphere-shaped nanofiber objects is shown ∼6000% and ∼2000% of their dry mass. In contrast, unexpanded semicircular and square nanofiber membranes showed500% of their dry mass. Moreover, the swallowable sphere and cuboid were able to collect and release more bacteria, viruses, and cells/tissues from solutions as compared with unexpanded scaffolds. In addition to that, an expanded sphere shows higher cell collection capacity from the esophagus inner wall as compared with the unexpanded nanofiber membrane. Taken together, the nanofiber capsules developed in this study could provide a minimally invasive method of collecting biological samples from the duodenal, gastric, esophagus, and oropharyngeal sites, potentially leading to timely and accurate diagnosis of many diseases. STATEMENT OF SIGNIFICANCE: Recently, minimally invasive technologies have gained much attention in tissue engineering and disease diagnosis. In this study, we engineered a swallowable and retrievable electrospun nanofiber capsule serving as collection device to collect specimens from internal organs in a minimally invasive manner. The sample collection device could be an alternative endoscopy to collect the samples from internal organs like jejunum, stomach, esophagus, and oropharynx without any sedation. The newly engineered nanofiber capsule could be used to collect, bacteria, virus, fluids, and cells from the abovementioned internal organs. In addition, the biocompatible and biodegradable nanofiber capsule on a string could exhibit a great sample collection capacity for the primary screening of Barret Esophagus, acid reflux, SARS-COVID-19, Helicobacter pylori, and gastric cancer.

How does banking competition affect credit provision and growth? How does it affect financial stability? In order to identify the causal effects of banking competition, we exploit a discontinuity in bank capital requirements during the 19th century National Banking Era. We show that banks operating in markets with lower entry barriers extend more credit. The resulting local credit boom, in turn, is associated with an expansion in real economic activity. However, banks in markets with lower entry barriers also take more risk and are also more likely to default. Thus, we provide causal evidence that banking competition can cause both growth and financial instability.

Burden transfer, when veterinary client caregiver burden underlies stressful encounters with providers, elevates risk for occupational distress in veterinary medicine. To date, burden transfer has been primarily examined in veterinarians working in general practice, using methods that are time consuming. The current work validates an abbreviated Burden Transfer Inventory (BTI-A) and explores burden transfer across positions of employment and veterinary settings.Participants completed online measures of burden transfer, stress and burnout. A BTI-A with items representing each BTI domain was created with an initial validation sample (The BTI-A correlated with the full-length BTI (The BTI-A can be used in place of the original measure when brevity is important. Use of the BTI-A may help guide allied mental health professionals in providing support for wellbeing in veterinary healthcare team members.

Due to their biomimetic properties, electrospun nanofibers have shown great potential in many biomedical fields. However, traditionally‐produced nanofibers are typically two‐dimensional (2D) membranes limiting their applications. Herein, we report a large‐scale synthesis of compressible and re‐expandable three‐dimensional (3D) nanofiber matrices for potential biomedical applications. The reproducible mass production of such matrices is achieved using a multiple‐emitter electrospinning machine with a controlled environment (e.g., temperature, humidity, and air flow rate) followed by an innovative gas‐foaming expansion. The modified 20‐emitter circular array with 3D‐printed needle caps is capable of maintaining stable Taylor cones under extremely high flow rates. The introduction of such an emitter array allows for the production rate of 3D nanofiber matrices to increase by over 800 times while retaining the desired morphological, mechanical, and absorptive properties when compared to ones generated by a single‐nozzle electrospinning setup. Taken together, a feasible, optimized method has been demonstrated for scaling up production of shape‐recoverable, expansile nanofiber matrices, representing a step towards translating such materials into preclinical, large animal testing, clinical trials, and eventually clinical applications.

The 5-year survival of pancreatic cancer (PC) remains low. Murine models may not adequately mimic human PC and can be too small for medical device development. A large-animal PC model could address these issues. We induced and characterized pancreatic tumors in Oncopigs (transgenic swine containing KRASG12D and TP53R167H). The oncopigs underwent injection of adenovirus expressing Cre recombinase (AdCre) into one of the main pancreatic ducts. Resultant tumors were characterized by histology, cytokine expression, exome sequencing and transcriptome analysis. Ten of 14 Oncopigs (71%) had gross tumor within 3 weeks. At necropsy, all of these subjects had gastric outlet obstruction secondary to pancreatic tumor and phlegmon. Oncopigs with injections without Cre recombinase and wild-type pigs with AdCre injection did not show notable effect. Exome and transcriptome analysis of the porcine pancreatic tumors revealed similarity to the molecular signatures and pathways of human PC. Although further optimization and validation of this porcine PC model would be beneficial, it is anticipated that this model will be useful for focused research and development of diagnostic and therapeutic technologies for PC. This article has an associated First Person interview with the joint first authors of the paper.

Surgery remains the only potentially curative treatment option for pancreatic cancer, but resections are made more difficult by infiltrative disease, proximity of critical vasculature, peritumoral inflammation, and dense stroma. Surgeons are limited to tactile and visual cues to differentiate cancerous tissue from normal tissue. Furthermore, translating preoperative images to the intraoperative setting poses additional challenges for tumor detection, and can result in undetected and unresected lesions. Thus, PDAC has high rates of incomplete resections, and subsequently, disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to improve intraoperative detection of cancer and ultimately improve surgical outcomes. Initial clinical trials have demonstrated feasibility of FGS for PDAC, but there are limited targeted probes under investigation for this disease, highlighting the need for development of additional novel biomarkers to reflect the PDAC heterogeneity. MUCIN16 (MUC16) is a glycoprotein that is overexpressed in 60-80% of PDAC. In our previous work, we developed a MUC16-targeted murine antibody near-infrared conjugate, termed AR9.6-IRDye800, that showed efficacy in detecting pancreatic cancer. To build on the translational potential of this imaging probe, a humanized variant of the AR9.6 fluorescent conjugate was developed and investigated herein. This conjugate, termed huAR9.6-IRDye800, showed equivalent binding properties to its murine counterpart. Using an optimized dye:protein ratio of 1:1, in vivo studies demonstrated high tumor to background ratios in MUC16-expressing tumor models, and delineation of tumors in a patient-derived xenograft model. Safety, biodistribution, and toxicity studies were conducted. These studies demonstrated that huAR9.6-IRDye800 was safe, did not yield evidence of histological toxicity, and was well tolerated in vivo. The results from this work suggest that AR9.6-IRDye800 is an efficacious and safe imaging agent for identifying pancreatic cancer intraoperatively through fluorescence-guided surgery.

Minimally invasive procedures are becoming increasingly more common in surgery. However, the biomaterials capable of delivering biomimetic, three-dimensional (3D) functional tissues in a minimally invasive manner and exhibiting ordered structures after delivery are lacking. Herein, we reported the fabrication of gelatin methacryloyl (GelMA)-coated, 3D expanded nanofiber scaffolds, and their potential applications in minimally invasive delivery of 3D functional tissue constructs with ordered structures and clinically appropriate sizes (4 cm × 2 cm × 1.5 mm). GelMA-coated, expanded 3D nanofiber scaffolds produced by combining electrospinning, gas-foaming expansion, hydrogel coating, and cross-linking are extremely shape recoverable after release of compressive strain, displaying a superelastic property. Such scaffolds can be seeded with various types of cells, including dermal fibroblasts, bone marrow-derived mesenchymal stem cells, and human neural stem/precursor cells to form 3D complex tissue constructs. Importantly, the developed 3D tissue constructs can be compressed and loaded into a 4 mm diameter glass tube for minimally invasive delivery without compromising the cell viability. Taken together, the method developed in this study could hold great promise for transplantation of biomimetic, 3D functional tissue constructs with well-organized structures for tissue repair and regeneration using minimally invasive procedures like laparoscopy and thoracoscopy.

Peripheral arterial disease (PAD) is a progressive atherosclerotic disorder characterized by narrowing and occlusion of arteries supplying the lower extremities. Approximately 200 million people worldwide are affected by PAD. The current standard of operative care is open or endovascular revascularization in which blood flow restoration is the goal. However, many patients are not appropriate candidates for these treatments and are subject to continuous ischemia of their lower limbs. Current research in the therapy of PAD involves developing modalities that induce angiogenesis, but the results of simple cell transplantation or growth factor delivery have been found to be relatively poor mainly due to difficulties in stem cell retention and survival and rapid diffusion and enzymolysis of growth factors following injection of these agents in the affected tissues. Biomaterials, including hydrogels, have the capability to protect stem cells during injection and to support cell survival. Hydrogels can also provide a sustained release of growth factors at the injection site. This review will focus on biomaterial systems currently being investigated as carriers for cell and growth factor delivery, and will also discuss biomaterials as a potential stand-alone method for the treatment of PAD. Finally, the challenges of development and use of biomaterials systems for PAD treatment will be reviewed., Graphical abstract Image 1, Highlights • Biomaterial systems investigated as carriers for cell and growth factor delivery for PAD are overviewed. • Biomaterials as a potential stand-alone method for the treatment of PAD are discussed. • The challenges of development and use of biomaterials systems for PAD treatment are commented.

Background: Systemic immunity can be regulated via transient interactions of non-colonizing bacteria and immune cells in the small intestinal mucosa. The potential to harness these interactions for IO treatment was first described by Sivan in 2015. EDP1503 is a non-colonizing preparation of a single strain of Bifidobacterium animalis lactis that, when administered orally, in preclinical models, invokes an anti-tumor immune response by activation of innate and adaptive immune mechanisms. The pleiotropic effects of EDP1503 are initiated in the small intestine and mediated by interactions with multiple pattern-recognition receptors inducing a proinflammatory signature in human PBMCs, activating CD8 and NK cell IFNγ production and cytolytic activity. Preclinically, EDP1503 inhibits tumor growth as a monotherapy and in combination with anti-PD-1/L1. Single agent PD-1/L1 therapies have showed limited clinical benefit in previously treated triple-negative breast cancer (TNBC) patients. Here, we report the safety, tolerability, and efficacy of EDP1503 in combination with pembrolizumab in patients with TNBC (NCT03775850). Methods: EDP1503-101 is an open label Phase 1/2 study of EDP1503 in combination with pembrolizumab. TNBC subjects who had received ≥ 1 treatment regimen for metastatic disease were enrolled. Prior anti-PD-1/L1 treatment was permitted. Subjects initially receive 14 days of EDP1503 monotherapy orally twice a day (b.i.d) and then EDP1503 b.i.d. in combination with pembrolizumab 200 mg iv every 3 weeks. The initial 3 subjects received 2 capsules of EDP1503 b.i.d. All other subjects received 4 capsules b.i.d. Safety and tolerability were assessed using CTCAE v5.0. Evidence of anti-tumor activity was based on investigator-assessed objective response (OR), by RECIST v1.1 and iRECIST, and disease control rate defined as OR and/or stable disease (SD) after 4 cycles of therapy. Paired biopsies at baseline and day 14 were used to establish PD-L1 status and investigate pharmacodynamic biomarker changes. Results: As of 1 October 2020, 15 TNBC subjects had been treated (median age of 52, median of 2 prior lines of therapy and ECOG of 0-1). Additional subjects are being recruited, up to a maximum of 30. EDP1503 was well-tolerated as monotherapy and in combination with pembrolizumab. 53% of subjects experienced treatment-related adverse events (TRAEs). Most common TRAEs were GI-related: abdominal distension (20%), decreased appetite (20%), diarrhea (13%), flatulence (13%). No Grade 4-5 TRAEs were observed. 1 Grade 3 TRAE (diarrhea) leading to treatment discontinuation was reported. In 12 subjects receiving the 4 capsules b.i.d dose, 2 partial responses (PR) and 1 SD were observed, giving an objective response rate (ORR) of 18% and a disease control rate (DCR) of 27% in evaluable patients (n=11). Both responders had tumor burden reductions of >65% by RECIST. One responder had 4 prior lines of therapy for metastatic disease, including a PD-L1 inhibitor combination, has a PD-L1 combined positive score (CPS) of 30 and has been on study treatment for 192 days with a 66% reduction in target lesions. The only residual lesion is 6 mm which is PET-negative. The other responder had 2 prior lines of therapy for metastatic disease, was checkpoint inhibitor naive, has a PD-L1 CPS of 2 and remained on study treatment for 275 days with a 73% reduction in target lesions before discontinuing due to treatment-related AEs. The patient with SD had also previously relapsed on a PD-L1 inhibitor and was on study treatment for 226 days before progressing. Conclusions: EDP1503 administered with pembrolizumab is safe and well-tolerated with no Grade 4-5 TRAEs or SAEs. Clinical benefit was observed in a subset of TNBC patients treated with the combination of EDP1503 and pembrolizumab. This study is continuing to recruit TNBC patients at the high dose of EDP1503. Citation Format: Loise Francisco-Anderson, Shamira Shariffudin, Humphrey Gardner, Peter Sandy, Michael Goldberg, Shubhra Kashyap, Mary Abdou, Maria Sizova, Valeria Kravitz, Holly Ponichtera, Mark Carlson, Shannon Argueta, Chris Davitt, Pooja Parameswaran, Michael Chisamore, Mark Bodmer, Duncan McHale. A phase I/II clinical trial of EDP1503 with pembrolizumab for triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-27.

Plasma fibrinogen (F1) and fibronectin (pFN) polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing. About 90% of plasma F1 has a homodimeric pair of γ chains (γγF1), and 10% has a heterodimeric pair of γ and more acidic γ′ chains (γγ′F1). We have synthesized a novel fibrin matrix exclusively from a 1:1 (molar ratio) complex of γγ′F1 and pFN in the presence of highly active thrombin and recombinant Factor XIII (rFXIIIa). In this matrix, the fibrin nanofibers were decorated with pFN nanoclusters (termed γγ′F1:pFN fibrin). In contrast, fibrin made from 1:1 mixture of γγF1 and pFN formed a sporadic distribution of “pFN droplets” (termed γγF1+pFN fibrin). The γγ′F1:pFN fibrin enhanced the adhesion of primary human umbilical vein endothelium cells (HUVECs) relative to the γγF1+FN fibrin. Three dimensional (3D) culturing showed that the γγ′F1:pFN complex fibrin matrix enhanced the proliferation of both HUVECs and primary human fibroblasts. HUVECs in the 3D γγ′F1:pFN fibrin exhibited a starkly enhanced vascular morphogenesis while an apoptotic growth profile was observed in the γγF1+pFN fibrin. Relative to γγF1+pFN fibrin, mouse dermal wounds that were sealed by γγ′F1:pFN fibrin exhibited accelerated and enhanced healing. This study suggests that a 3D pFN presentation on a fibrin matrix promotes wound healing., Graphical abstract The novel fibrin sealant forms a 3D matrix at the wound bed. Nanoscale fibronectin clusters are formed on the fibrin nanofibers. These nanoclusters can stimulate the pro-healing cells such as endothelial cells, fibroblasts and keratinocytes and promote their migration, survival, proliferation and function, resulting in faster and better wound healing.Image 1, Highlights • A novel fibrin matrix exclusively from a 1:1 (molar ratio) complex of γγ’F1 and pFN was made. • In this new matrix, fibrin nanofibers were decorated with nano-scale pFN clusters (termed γγ’F1:pFN fibrin). • This matrix significantly enhances mouse skin wound healing. • This study suggests that a 3D pFN nanoclusters presented on a fibrin matrix can promote wound healing.

During the 2008 financial crisis, the Federal Reserve established two emergency facilities for broker-dealers: one provided collateralized loans; the other, collateral upgrades. These facilities alleviated dealers’ funding pressures when access to repos backed by illiquid collateral deteriorated. The ability to upgrade collateral allowed dealers to continue funding their own illiquid inventories (avoiding potential firesales) and to provide better bond market liquidity. It also helped sustain dealers’ credit to hedge fund clients, which in turn posted relatively better returns.

This paper considers various ways of using balance sheet policy (BSP) to provide monetary policy stimulus, including the BSPs put in place by the Federal Reserve in the wake of the Global Financial Crisis, the choice between fixed-size and flow-based asset purchase programs, policies targeting interest rate levels rather than the quantity of asset purchases, and programs aimed at increasing more direct lending to households and firms. For each of these BSP options, we evaluate benefits and costs. We conclude by observing that BSPs’ relative effectiveness and thus optimal configuration will depend on the shocks affecting the economy. Consequently, it would be valuable for the Federal Reserve to keep a variety of tools at its disposal and employ the ones that best fit the situation that it faces.

End-of-life decision making for a companion animal relies on the veterinarian acting as educator and counselor. However, little research has been conducted to understand client variables in this context. The current study examined potential client-related contributors to steps taken toward a euthanasia decision. Caregiver burden, anticipatory grief, depression, stress, and income all correlated positively with this outcome. However, when client factors were examined in a regression model controlling for animal quality of life, only caregiver burden and income emerged as significant predictors. All 3 caregiver burden factors: general strain, affective/relational discomfort, and guilt/uncertainty were significantly related to consideration of euthanasia.

Increasing complexity of treatment plans is associated with higher levels of caregiver burden in owners of dogs with skin disease. It is possible that elevated caregiver burden resulting from treatment complexity could, in turn, affect the veterinarian-client relationship.We expected that treatment complexity, caregiver burden, and the client's perception of the veterinarian-client relationship would be related to each other. We also expected an indirect effect of caregiver burden on the cross-sectional association between treatment complexity and the veterinarian-client relationship, and that this effect would be robust to adjustment for the dog's skin disease course and severity.Participants were 349 owners of dogs with skin disease recruited through online consumer panels.Cross-sectional online assessments were completed for caregiver burden, treatment plan complexity, veterinarian-client relationship, and skin disease course and severity. Demographic information also was collected.The indirect effect of caregiver burden on the relationship between treatment complexity and veterinarian-client relationship was statistically significant, accounting for 42.76% of the variance in the model. After controlling for disease severity and course, that effect remained statistically significant, accounting for 37.76% of the variance.Findings support the notion that greater treatment complexity is related to the owner's perception of the veterinarian-client relationship via caregiver burden. Efforts to reduce caregiver burden by using the simplest effective treatment may benefit the veterinarian-client relationship.背景-治疗计划的复杂性增加,会增加皮肤病患犬主人的护理者负担水平。治疗的复杂性导致护理人员负担增加可能反过来影响兽医-客户关系。 假设/目的-我们预期治疗复杂性、护理人员负担和客户对兽医-客户关系的看法有相互关联。我们还预期护理人员负担对治疗复杂性和兽医-客户关系之间横向关联具有调解作用, 并且该作用将对调整犬的皮肤病病程和严重程度具有稳健性。 参与者-参与者是通过在线消费者小组招募的349名皮肤病患犬的主人。 材料和方法-完成护理人员负担、治疗计划复杂性、兽医-客户关系以及皮肤病病程和严重程度的横向在线评估。还收集了人口统计学信息。 结果-照顾者负担对治疗复杂性与兽医-客户关系关系的间接影响有统计学意义, 占模型方差的42.76%。在控制了疾病严重程度和病程后, 该效应仍具有统计学显著性, 占方差的37.76%。 结论和临床重要性-研究结果支持这样一种观点, 即较高的治疗复杂性与主人对兽医与客户关系的看法, 与照顾者负担有关。通过使用最简单有效的治疗来减轻看护者负担的努力,可能有利于兽医与客户的关系。.Contexte - La complexité croissante des plans de traitement est associée à des niveaux plus élevés de fardeau pour les soignants propriétaires de chiens atteints de maladies de peau. Il est possible que le fardeau élevé des soignants résultant de la complexité du traitement pourrait, à son tour, affecter la relation vétérinaire-client. Hypothèses/Objectifs - Nous nous attendions à ce que la complexité du traitement, le fardeau des soignants et la perception du client de la relation vétérinaire-client seraient liés les uns aux autres. Nous nous attendions également à un effet indirect de le fardeau du soignant sur l'association transversale entre la complexité du traitement et le vétérinaire-client relation, et que cet effet serait robuste à l'ajustement de l'évolution et de la gravité de la maladie de peau du chien. Participants - Les participants étaient 349 propriétaires de chiens atteints de maladies de la peau recrutés par le biais de consommateurs en ligne panneaux. Matériels et méthodes - Des évaluations transversales en ligne ont été réalisées pour le fardeau des soignants, le traitement la complexité du plan, la relation vétérinaire-client et l'évolution et la gravité des maladies de la peau. Informations démographiques a également été collecté. Résultats - L'effet indirect du fardeau des soignants sur la relation entre la complexité du traitement et le vétérinaire-la relation client était statistiquement significative, représentant 42,76 % de la variance du modèle. Après contrôle pour la gravité et l'évolution de la maladie, cet effet est resté statistiquement significatif, représentant 37,76 % des la variance. Conclusions et importance clinique - Les résultats appuient l'idée qu'une plus grande complexité du traitement est liée à la perception du propriétaire de la relation vétérinaire-client via le fardeau des soignants. Efforts pour réduire le soignant fardeau en utilisant le traitement efficace le plus simple peut être bénéfique pour la relation vétérinaire-client.Hintergrund - Eine zunehmende Komplexität von Behandlungsplänen geht mit einer größeren Pflegebelastung für die BesitzerInnen von Hunden mit Hauterkrankungen einher. Es ist möglich, dass eine größere Pflegebelastung aufgrund komplexerer Behandlungen, in Zukunft die Beziehung zwischen dem Tierarzt/der Tierärztin und den BesitzerInnen beeinträchtigen könnte. Hypothese/Ziele - Wir erwarteten, dass die Komplexität der Behandlung, die Belastung der Pflegenden, sowie die Wahrnehmung der Beziehung zwischen den VeterinärmedizinerInnen/KundInnen durch die KundInnen voneinander abhängig waren. Wir erwarteten auch einen Mediationseffekt der Belastung durch die Pflegenden auf den durchschnittlichen Zusammenhang zwischen Behandlungskomplexität und die Beziehung zwischen den VeterinärmedizinerInnen/KundInnen und dass diese Auswirkung bei Anpassungen in Bezug auf die Hauterkrankung des Hundes und ihren Schweregrad beständig sein würde. Teilnehmende - Es nahmen 349 BesitzerInnen von Hunden mit Hauterkrankungen teil, die durch Online KonsumentInnen Gruppen rekrutiert wurden. Materialien und Methoden - Querschnittsbewertungen wurden durchgeführt und Fragen bezüglich Belastung durch Pflegende, Komplexität von Behandlungsplänen, Beziehung der VeterinärmedizinerInnen und KundInnen, sowie der Verlauf und Schweregrad der Hauterkrankung beantwortet. Es wurden demografische Informationen gesammelt. Ergebnisse - Die indirekte Wirkung der Belastung für die Pflegenden auf den Zusammenhang der Komplexität der Behandlung und der Beziehung der VeterinärmedizinerInnen und KundInnen war statistisch signifikant, was für eine 42,76%ige Varianz in diesem Modell stand. Nach einer Kontrolle der Schwere der Krankheit und ihrem Verlauf, blieb diese Auswirkung statistisch signifikant, was für eine 37,76%ige Varianz stand. Schlussfolgerungen und klinische Bedeutung - Diese Ergebnisse unterstützen die Vorstellung, dass eine größere Behandlungskomplexität aufgrund der erhöhten Pflegeleistung die Wahrnehmung der BesitzerInnen ihrer Beziehung zu den VeterinärmedizinerInnen im Zusammenhang steht. Bemühungen, die Pflegebelastung durch Einsatz einfachster wirksamer Behandlungen zu reduzieren, könnte dem Verhältnis der VeterinärmedizinerInnen und ihren KundInnen dienlich sein.背景 - 治療計画の複雑化は、皮膚疾患を持つ犬の飼い主の介護負担の増加につながっている。治療の複雑化に伴う介護者の負担の増大は、ひいては獣医師とクライアントの関係に影響を与える可能性がある。 仮説・目的 - 治療の複雑さ、介護者の負担、および獣医師・クライアント関係に対するクライアントの認識は相互に関連すると予想した。また、治療の複雑さと獣医師とクライアント関係の横断的関連に介護者の負担が媒介効果を及ぼすこと、そしてこの効果は犬の皮膚病の経過と重症度の調整に対して強力であることも予想された。 参加者 - 参加者は、オンライン消費者パネルで募集した皮膚病の犬の飼い主349名であった。 材料と方法 - 介護者の負担、治療計画の複雑さ、獣医師とクライアントの関係、および皮膚病の経過と重症度について、オンラインで横断的な評価が行われた。また、人口統計学的情報も収集した。 結果 - 治療の複雑さと獣医師・クライアント関係との関係に対する介護者の負担の間接効果は統計的に有意であり、モデルの分散の 42.76%を占めた。疾患の重症度と経過を考慮しても、この効果は統計的に有意であり、分散の37.76%を占めた。 結論と臨床的重要性 - 調査結果は、治療の複雑さが、介護者の負担を通じて獣医師とクライアントとの関係に対する飼い主の認識と関連しているという考え方を支持している。最もシンプルで効果的な治療法を用いて介護者の負担を軽減する努力は、獣医師とクライアントの関係に利益をもたらすかもしれない。.Contexto - O aumento da complexidade dos planos de tratamento está associado a altos níveis de sobrecarga do cuidador de cães com doenças de pele. É possível que a sobrecarga do cuidador elevada resultante da complexidade da terapia possa, desta forma, afetar a relação veterinário-cliente. Hipótese/Objetivos - Nós imaginamos que a complexidade do tratamento, a sobrecarga do cuidador, e a percepção do cliente da relação veterinário-cliente estariam relacionadas. Nós também imaginamos que poderia uma mediação da sobrecarga do cuidador na associação transversal entre a complexidade do tratamento e a relação veterinário-cliente, e que este efeito seria robusto para ajustar o curso e a gravidade da doença de pele do cão. Participantes - Os participantes foram 349 tutores de cães com doença de pele recrutados através de formulários online. Materiais e métodos - Avaliações transversais online foram preenchidas para sobrecarga do cuidador, complexidade do plano de tratamento, relação veterinário-cliente, e curso da doença de pele e gravidade. Dados demográficos também foram coletados. Resultados - O efeito indireto da sobrecarga do cuidador na relação entre a complexidade do tratamento e a relação veterinário-cliente foi significativamente significativa, sendo responsável por 42,76% da variância no modelo. Após controlar para gravidade da doença e curso, esse efeito permaneceu estatisticamente significativo, respondendo por 37,76% da variância. Conclusões e importância clínica - Os achados corroboram com a ideia de que a complexidade do tratamento está relacionada à percepção do tutor sobre a relação veterinário-cliente pela sobrecarga do cuidador. Esforços para reduzir a sobrecarga do cuidador utilizando planos terapêuticos mais simples podem beneficiar a relação veterinário-cliente.Introducción- el aumento de la complejidad de los planes de tratamiento se asocia a mayores niveles de responsabilidad de los propietarios de perros con enfermedades de la piel. Es posible que esta mayor carga para el propietario resultante de la complejidad del tratamiento pueda, a su vez, afectar a la relación veterinario-cliente. Hipótesis/Objetivos- esperábamos que la complejidad del tratamiento, la mayor responsabilidad para cuidadores y la percepción de los propietarios de la relación veterinario-cliente estuvieran relacionadas entre sí. También esperábamos un efecto de mediación de la mayor carga del cuidador en la asociación transversal entre la complejidad del tratamiento y la relación veterinario-cliente, y que este efecto sería sólido para el ajuste del curso y la gravedad de la enfermedad de la piel del perro. Participantes- los participantes fueron 349 propietarios de perros con enfermedades de la piel reclutados a través de paneles de consumidores vía telemática. Materiales y métodos- se completaron evaluaciones transversales en línea sobre la carga del cuidador, la complejidad del plan de tratamiento, la relación veterinario-cliente y el curso y la gravedad de la enfermedad de la piel. También se recopiló información demográfica. Resultados - El efecto indirecto de la carga del cuidador sobre la relación entre la complejidad del tratamiento y la relación veterinario-cliente fue estadísticamente significativo, explicando el 42,76% de la varianza del modelo. Después de controlar la gravedad y el curso de la enfermedad, ese efecto siguió siendo estadísticamente significativo y representó el 37,76 % de la varianza. Conclusiones e importancia clínica- los hallazgos respaldan la noción de que una mayor complejidad del tratamiento está relacionada con la percepción del propietario de la relación veterinario-cliente mediante una mayor carga del cuidador. Esfuerzos para reducir la carga del cuidador mediante el uso de tratamientos efectivos más simples pueden beneficiar a la relación veterinario-cliente.

Before the 2008 financial crisis, the Federal Reserve (Fed) regularly conducted repurchase agreements (repos) in a fairly modest size with primary dealers to adjust the supply of reserves in the banking system and to keep the federal funds rate at the target set by the FOMC. During the economic downturn that followed the financial crisis, the Fed engaged in large scale asset purchases in order to provide additional monetary accommodation, and those purchases significantly increased the supply of reserves and eliminated the need for the Fed to engage in repo operations to increase reserves in the system.

We describe our initial studies in the development of an orthotopic, genetically defined, large animal model of pancreatic cancer. Primary pancreatic epithelial cells were isolated from pancreatic duct of domestic pigs. A transformed cell line was generated from these primary cells with oncogenic KRAS and SV40T. The transformed cell lines outperformed the primary and SV40T immortalized cells in terms of proliferation, population doubling time, soft agar growth, transwell migration and invasion. The transformed cell line grew tumors when injected subcutaneously in nude mice, forming glandular structures and staining for epithelial markers. Future work will include implantation studies of these tumorigenic porcine pancreatic cell lines into the pancreas of allogeneic and autologous pigs. The resultant large animal model of pancreatic cancer could be utilized for preclinical research on diagnostic, interventional, and therapeutic technologies.

BackgroundIn patients with short bowel syndrome, an elevated pre-resection Body Mass Index may be protective of post-resection body composition. We hypothesized that rats with diet-induced obesity would lose less lean body mass after undergoing massive small bowel resection compared to non-obese rats.MethodsRats (CD®IGS; age = 2 mo; N = 80) were randomly assigned to either a high-fat (obese rats) or a low-fat diet (non-obese rats), and fed ad lib for six months. Each diet group then was randomized to either underwent a 75% distal small bowel resection (massive resection) or small bowel transection with re-anastomosis (sham resection). All rats then were fed ad lib with an intermediate-fat diet (25% of total calories) for two months. Body weight and quantitative magnetic resonance-determined body composition were monitored.ResultsPreoperative body weight was 884 ± 95 vs. 741 ± 75 g, and preoperative percent body fat was 35.8 ± 3.9 vs. 24.9 ± 4.6%; high-fat vs. low fat diet, respectively (p < 0.0001); preoperative diet type had no effect on lean mass. Regarding total body weight, massive resection produced an 18% vs. 5% decrease in high-fat vs. low-fat rats respectively, while sham resection produced a 2% decrease vs. a 7% increase, respectively (p < 0.0001, preoperative vs. necropsy data). Sham resection had no effect on lean mass; after massive resection, both high-fat and low-fat rats lost lean mass, but these changes were not different between the latter two rat groups.ConclusionThe high-fat diet and low-fat diet induced obesity and marginal obesity, respectively. The massive resection produced greater weight loss in high-fat rats compared to low-fat rats. The type of dietary preconditioning had no effect on lean mass loss after massive resection. A protective effect of pre-existing obesity on lean mass after massive intestinal resection was not demonstrated.

We describe our initial studies in the development of an orthotopic, genetically-defined, large animal model of breast cancer, using immunocompetent pigs. Primary mammary epithelial cells were isolated from the porcine gland. Primary mammary cells were immortalized with hTERT, and then transformed cell lines were generated from these immortalized cells with oncogenic KRAS and dominant negative p53. The transformed cell lines outperformed the primary cells in terms proliferation, population doubling time, soft agar growth, 2D migration, and Matrigel invasion. Three transformed cell lines were selected based on in vitro performance, and were able to grow tumors when injected subcutaneously in nude mice, with undifferentiated morphology. Tumorigenic porcine mammary cell lines were generated in this report.

Electrostatic flocking, a textile engineering technique, uses Coulombic driving forces to propel conductive microfibers towards an adhesive-coated substrate, leaving a forest of aligned fibers. Though an easy way to induce anisotropy along a surface, this technique is limited to microfibers capable of charge transfer and accumulation from charging surfaces to microfibers. This study reports a novel method, utilizing principles from the percolation theory, to make electrically-insulative polymeric microfibers flockable. A variety of well-mixed conductive materials are added to multiple insulative and biodegradable polymer microfibers during wet spinning, which enables nearly all types of polymer microfibers to accumulate sufficient charges required for flocking. Biphasic, biodegradable scaffolds are fabricated by flocking silver nanoparticle (AgNP)-filled poly(ε-caprolactone) (PCL) microfibers onto substrates made from three-dimensional (3D) printing, electrospinning, and thin-film casting. The incorporation of AgNP into PCL fibers and use of chitosan-based adhesive enables antimicrobial activity against methicillin-resistant Staphylococcus aureus. The fabricated scaffolds demonstrated both favorable in vitro cell response and new tissue formation after subcutaneous implantation in rats as evidenct by new blood vessels and infiltrated cells. This technology opens many doors for using once unflockable polymer microfibers as surface modifiers or standalone structures in many engineering fields.

During early March 2020, amid rapidly spreading restrictions associated with preventing the spread of COVID-19, financial markets came under immense strain. These strains ultimately spilled over to funding markets and to institutions that are highly dependent on such markets.

Background Caregiver burden is present in many clients managing illness in a companion animal, but current assessment tools are time‐consuming and lack normative reference values. Objectives Statistical reduction of items in a measure of caregiver burden to create an abbreviated version, validation of the abbreviated version, and calculation of reference values. Animals None. Methods This study was conducted using observational methods. Owners of an ill cat or dog were recruited through social media (n = 429). Veterinary clients with an ill (n = 459) or healthy (n = 961) cat or dog were recruited through a general veterinary and an academic hospital with multiple specialties. The study was conducted in 3 stages: (a) reduction of the Zarit Burden Interview (ZBI) adapted for use in pets via factor and item analyses, (b) psychometric validation of the abbreviated instrument, and (c) standardization of the abbreviated (7 items) and full (18 items) measures. Results A 7‐item measure showed high correlations with the full measure (r = 0.88‐0.93) and good internal consistency (α = .71‐.75) across samples of veterinary clients with an ill cat or dog. This abbreviated measure correlated significantly (P

This paper studies the incentives of large, sophisticated creditors to withdraw funds during a run on a systemically important financial institution—specifically the famous run on Continental Illinois in 1984. Surprisingly, we find that creditors with relatively liquid balance sheets initially withdrew more than other creditors. As time went on, institutions with relative large exposures were more likely to withdraw, despite government support which included a broad guarantee of all creditors. These findings have important implications for the design of facilities to resolve systemically important institutions in the future.

Biofilms of multidrug-resistant bacteria in chronic wounds pose a great challenge in wound care. Herein, we report the topical delivery of molecularly engineered antimicrobial peptides using electrospun nanofiber dressings as a carrier for the treatment of biofilms of multidrug-resistant bacteria in diabetic wounds. Molecularly engineered human cathelicidin peptide 17BIPHE2 was successfully encapsulated in the core of pluronic F127/17BIPHE2-PCL core-shell nanofibers. The in vitro release profiles of 17BIPHE2 showed an in initial burst followed by a sustained release over 4 weeks. The peptide nanofiber formulations effectively killed methicillin-resistant Staphylococcus aureus (MRSA) USA300. Similarly, the 17BIPHE2 peptide containing nanofibers could also effectively kill other bacteria including Klebsiella pneumoniae (104 to 106 CFU) and Acinetobacter baumannii (104 to 107 CFU) clinical strains in vitro without showing evident cytotoxicity to skin cells and monocytes. Importantly, 17BIPHE2-containing nanofiber dressings without debridement caused five-magnitude decreases of the MRSA USA300 CFU in a biofilm-containing chronic wound model based on type II diabetic mice. In combination with debridement, 17BIPHE2-containing nanofiber dressings could completely eliminate the biofilms, providing one possible solution to chronic wound treatment. Taken together, the biodegradable nanofiber-based wound dressings developed in this study can be utilized to effectively deliver molecularly engineered peptides to treat biofilm-containing chronic wounds.

Introduction: The chromatin factor BRD9 is a genetic dependency in some cancers, often referred to as SMARCB1-perturbed cancers. Two types of genetic alterations result in SMARCB1 perturbation: SS18-SSX gene fusion and SMARCB1 loss-of-function mutations. In synovial sarcoma, a rare and aggressive soft tissue malignancy comprising approximately 10% of all soft tissue sarcomas, the presence of the SS18-SSX fusion gene drives the disruption of SMARCB1 function and leads to a synthetic lethal dependence on BRD9. In SMARCB1-null solid tumors, for example malignant rhabdoid tumors (MRT), poorly differentiated chordomas, and epithelioid sarcomas, the absence of SMARCB1 protein results in a similar BRD9 dependence. Thus, in SMARCB1-perturbed cancers, including synovial sarcoma and SMARCB1-null cancers, degradation of BRD9 is hypothesized to result in an anticancer effect. CFT8634 is an orally bioavailable heterobifunctional degrader that induces ternary complex formation with BRD9 and an E3 ligase, leading to the ubiquitination of BRD9 and its subsequent degradation by the proteasome. Results: Here we describe the chemical structure of CFT8634 and an overview of the medicinal chemistry path leading to its discovery. In vitro, CFT8634 promotes rapid, potent, deep, and selective degradation of BRD9 with a half-maximal degradation concentration (DC50) of 2 nM in a synovial sarcoma cell line. In long-term growth assays, CFT8634 is effective at impairing cell growth in a concentration-dependent manner specifically in SMARCB1-perturbed contexts. In vivo, oral dosing of CFT8634 in xenograft models of SMARCB1-perturbed cancers leads to robust and dose-dependent degradation of BRD9, which translates to significant and dose-dependent inhibition of tumor growth in preclinical xenograft models. Conclusion: The preclinical data presented herein support the clinical development of CFT8634 for the treatment of synovial sarcoma and SMARCB1-null tumors. Citation Format: Katrina L. Jackson, Roman V. Agafonov, Mark W. Carlson, Prasoon Chaturvedi, David Cocozziello, Kyle Cole, Richard Deibler, Scott J. Eron, Andrew Good, Ashley A. Hart, Minsheng He, Christina S. Henderson, Hongwei Huang, Marta Isasa, R. Jason Kirby, Linda Lee, Michelle Mahler, Moses Moustakim, Christopher G. Nasveschuk, Michael Palmer, Laura L. Poling, Roy M. Pollock, Matthew Schnaderbeck, Stan Spence, Gesine K. Veits, Jeremy L. Yap, Ning Yin, Rhamy Zeid, Adam S. Crystal, Andrew J. Phillips, Stewart L. Fisher. The discovery and characterization of CFT8634: A potent and selective degrader of BRD9 for the treatment of SMARCB1-perturbed cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND09.

Human plasma fibronectin (FN) enhances fibrin polymer strength and is typically present at

We analyze whether the Federal Reserve's Paycheck Protection Program Liquidity Facility (PPPLF) was successful in bolstering the ability of commercial banks to provide credit to small businesses under the Small Business Administration's Paycheck Protection Program (PPP). Using an instrumental variables approach, we find a causal effect of the facility boosting PPP lending. On average, commercial banks that used the PPPLF extended over twice as many PPP loans, relative to their total assets, as banks that did not use the PPPLF. Our instrument is a measure of banks' familiarity with the operation of the Federal Reserve’s discount window; this measure is strongly related to both the propensity to sign up for and to utilize the PPPLF. Further, using a similar instrumental variables approach, we find evidence that the availability of the facility as a backstop source of funds may also have supported bank PPP lending, especially for larger banks.

We describe our initial studies in the development of an orthotopic, genetically-defined, large animal model of pancreatic cancer. Primary pancreatic epithelial cells were isolated from pancreatic duct of domestic pigs. A transformed cell line was generated from these primary cells with oncogenic KRAS and SV40T. The transformed cell lines outperformed the primary and SV40T immortalized cells in terms of proliferation, population doubling time, soft agar growth, transwell migration and invasion. The transformed cell line grew tumors when injected subcutaneously in nude mice, forming glandular structures and staining for epithelial markers. Future work will include implantation studies of these tumorigenic porcine pancreatic cell lines into the pancreas of allogeneic and autologous pigs. The resultant large animal model of pancreatic cancer could be utilized for preclinical research on diagnostic, interventional, and therapeutic technologies.

The Pigskin architecture and physiology are similar to these of humans. Thus, the pig model is valuable for studying skin biology and testing therapeutics for skin diseases. The single-cell RNA sequencing technology allows quantitatively analyzing cell types, cell states, signaling, and receptor-ligand interactome at single-cell resolution and at high throughput. scRNA-Seq has been used to study mouse and human skins. However, studying pigskin with scRNA-Seq is still rare. Here we described a robust method for isolating and cryo-preserving pig single cells for scRNA-Seq. We showed that pigskin could be efficiently dissociated into single cells with high cell viability using the Miltenyi Human Whole Skin Dissociation kit and the Miltenyi gentleMACS Dissociator. Also, we showed that the subsequent single cells could be cryopreserved using DMSO without causing additional cell death, cell aggregation, or changes in gene expression profiles. Using the developed protocol, we were able to identify all the major skin cell types. The protocol and results from this study will be very valuable for the skin research scientific community.