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Angioembolization is an important adjunct in the non-operative management of adult trauma patients with splenic injury. Multiple studies have shown that angioembolization may increase the non-operative splenic salvage rate for patients with high-grade splenic injuries. We performed a systematic review and developed evidence-based recommendations regarding the need for post-splenectomy vaccinations after splenic embolization in trauma patients.A systematic review and meta-analysis of currently available evidence were performed utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.Nine studies were identified and analyzed. A total of 240 embolization patients were compared to 443 control patients who neither underwent splenectomy nor were embolized. There was no statistical difference between the splenic immune function of embolized and control patients. In addition, a total of 3974 splenectomy patients was compared with 686 embolization patients. Embolization patients had fewer infectious complications and a greater degree of preserved splenic immune function.In adult trauma patients who have undergone splenic angioembolization, we conditionally recommend against routine post-splenectomy vaccinations.systematic review/meta-analysis Level of evidence: level III.

Current Opinion.Level V, Expert Opinion.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.

Narrative practice (NP) is a psychotherapy approach that helps people identify subordinated storylines and reimagine their lives. The concept of intervention fidelity (IF) refers to the extent to which an intervention is implemented as planned, and it is an essential component in rigorous intervention research. However, it is challenging to assess IF in NP, because NP cannot be simply seen as standardized procedures. This study used the idea of scaffolding suggested in White (2007) to analyze White's conversations and develop a method assessing whether his conversations adhered to his stated principles. Results revealed potential indicators, such as progression, synchrony, and proportion of conversation utterances. These indicators are far from comprehensive and they do not represent any absolute standards. Nonetheless, they open the discussion about how we can rationalize intervention fidelity in NP.

Underrepresented minorities in medicine (URiMs) are disproportionally represented in surgery training programs. Rates of URiMs applying to and completing General Surgery residency remain low. We hypothesized that the patterns of URiMs disparities would persist into surgical critical care (SCC) fellowship applicants, matriculants, and graduates.We performed a retrospective analysis of SCC applicants, matriculants, and graduates from 2005 to 2020 using the graduate medical education resident survey and analyzed applicant characteristics using the Surgical Critical Care and Acute Care Surgery Fellowship Application Service from 2018 to 2020. The data were stratified by race/ethnicity and sex. Indicator variables were created for Asian, Hispanic, White, and Black trainees. Yearly proportions for each race/ethnicity and sex categories completing or enrolling in a program were calculated and plotted over time with Loess smoothing lines and overlying 95% confidence bands. The yearly rate and statistical significance of change over time were tested with linear regression models with race/ethnicity and sex proportion as the dependent variables and year as the explanatory variable.From 2005 to 2020, there were a total of 2,481 graduates. Black men accounted for 4.7% of male graduates with a significant decline of 0.3% per year for the study period of those completing the fellowship (p = 0.02). Black women comprised 6.4% of female graduates and had a 0.6% decline each year (p0.01). A similar trend was seen with Hispanic men, who comprised 3.2% of male graduates and had a 0.3% annual decline (p = 0.02). White men had a significant increase in both matriculation to and graduation from SCC fellowships during the same interval. Similarly, Black and Hispanic applicants declined from 2019 to 2020, while the percentage of White applicants increased.Disparities in URiMs representation remain omnipresent in surgery and extend from residency training to SCC fellowship. Efforts to enhance the recruitment and retention of URiMs in SCC training are warranted.Prognostic and Epidemiologic; level IV.

BackgroundThe COVID-19 pandemic forced postgraduate interview processes to move to a virtual platform. There are no studies on the opinions of faculty and applicants regarding this format. The aim of this study was to assess the opinions of surgical critical care (SCC) applicants and program directors regarding the virtual versus in-person interview process.MethodsAn anonymous survey of the SCC Program Director’s Society members and applicants to the 2019 (in-person) and 2020 (virtual) interview cycles was done. Demographic data and Likert scale based responses were collected using Research Electronic Data Capture.ResultsFellowship and program director responses rates were 25% (137/550) and 58% (83/143), respectively. Applicants in the 2020 application cycle attended more interviews. The majority of applicants (57%) and program faculty (67%) strongly liked/liked the virtual interview format but felt an in-person format allows better assessment of the curriculum and culture of the program. Both groups felt that an in-person format allows applicants and faculty to establish rapport better. Only 9% and 16% of SCC program directors wanted a purely virtual or purely in-person interview process, respectively. Applicants were nearly evenly split between preferring a purely in-person versus virtual interviews in the future.DiscussionThe virtual interview format allows applicants and program directors to screen a larger number of programs and applications. However, the virtual format is less useful than an in-person interview format for describing unique aspects of a training program and for allowing faculty and applicants to establish rapport. Future strategies using both formats may be optimal, but such an approach requires further study.Level of evidenceEpidemiologic level IV

Introduction: Peripheral T-cell lymphomas (PTCLs) include heterogeneous entities of rare and aggressive neoplasms. The improved understanding of the biological/molecular mechanisms driving T-cell transformation and tumor maintenance has powerfully propelled new therapeutic programs. However, despite this progress, PTCLs remain an unmet medical need. Recurrent aberrations and the deregulated activation of distinct signaling pathways have been mapped and linked to selective subtypes. The JAK/STAT signaling pathway's deregulated activation plays a pathogenetic role in PTCL, including ALCL subtypes. STATs regulate the differentiation/phenotype, survival and cell-growth, metabolism, and drug resistance of T-cell lymphomas as well as host immunosuppressive microenvironments. Although many drugs' discovery programs were launched, a plethora of compounds has failed. Methods: We have discovered heterobifunctional molecules by an iterative medicinal chemistry SAR campaign that potently and selectively degrade STAT3 in a proteasome-dependent manner. Conventional PTCL cell lines and Patient Derived Tumor Xenograft (PDTX) and/or derived cell lines (PDTX-CL), carrying either WT- or mutated-STAT3, were exposed to increasing amounts (50nM⇒5µM) of STAT3-degraders. Proteins and mRNA transcripts (2⇒144hrs) were assessed by deep-proteomics and paired-end RNA sequencing, combined with WB/flow cytometry and qRT-PCR. Cell-titer-glo, cell titer blue, Annexin-V and S-cell cycle analyses were used as readouts. Chromatin accessibility, STAT3 DNA binding, 3D chromosomal architecture reorganization and 5-hmC profiling were assessed by ATACseq, CHIPseq and Hi-C and H3K27ac Hi-CHIP and mass-spectrometry. Drug testing/discovery combinations (96-well-plate) were performed using a semi-automated flow-cytometry. A battery of PTCL PDTX models were tested in pre-clinical trials. Results: Treatment of ALK+ ALCL (SU-DHL1) led to the rapid (~6hrs.) and profound down-regulation of STAT3 followed by the loss of canonical STAT3-regulated proteins (SOCS3, MYC, Granzyme B, GAS1, and IL2RA), without appreciable changes for other STAT family members (STAT1, STAT5b). In vitro, cytoplasmic, nuclear, and mitochondrial STAT3 downregulation was maintained up to 144 hrs. Loss of STAT3 in ALK+/- ALCL and BIA-ALCL cells was associated with major transcriptional changes (7116-10615 and 15114 DEGs in ALK- and ALK+ ALCL, respectively), underscoring public/shared as well as private time-dependent signatures. Main down-regulated pathways included JAK-STAT, MAPK, NF-kB, PI3K, TGFb, and TNFa. Comparison of STAT3 shRNA (ALK+ ALCL) and STAT3 degrader (ALK-/ALK+ ALCL) signatures demonstrated a substantial and concordant gene modulation (24hrs) among all models with the highest overlaps between ALK+ ALCL (Figure 3). To identify direct STAT3 gene targets, we analyzed CHIPseq peaks and predicted bindings sites, demonstrating that canonical genes, i.e., SOCS3, Granzyme B, GAS1, IL2RA, STAT3, and CD30, were significantly downregulated. Conversely, CD58, CD274, and MCH-I/II were upregulated at late time points. By mapping the STAT3 binding sites in ALK+ and ALK- ALCL, we have identified 1077 and 2763 STAT3 peaks within promoter/5'-/3'- and distant intergenic regions, corresponding to both coding and non-coding genes. Therapeutically, in vitro treatments led to cell cycle arrest and profound growth inhibition, and over time increased cell death of PTCL cells, including ALCL. Accordingly, growth inhibition of ALCL xenograft and PDTX tumors was also achieved (Figure 2). To identify drugs that could synergize withSTAT3-degrader activity, we tested a compound library (40) targeting pro-tumorigenic PTCL pathways as well as FDA-approved compounds. Ongoing studies are in progress. Conclusion: We have discovered selective STAT3 degraders which control PTCL growth. STAT3 degraders are powerful tools to define the STAT3 pathogenetic mechanisms and dissect genes/pathways to be targeted for T-cell lymphoma eradication. These data provide additional rationale for testing STAT3 degraders in the clinic for the treatment of aggressive malignancies including PTCL/ALCL. Figure 1 Figure 1. Disclosures Yang: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dey: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karnik: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Elemento: Owkin: Consultancy, Other: Current equity holder; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; Johnson and Johnson: Research Funding; Eli Lilly: Research Funding; Janssen: Research Funding; Champions Oncology: Consultancy; Freenome: Consultancy, Other: Current equity holder in a privately-held company; One Three Biotech: Consultancy, Other: Current equity holder; AstraZeneca: Research Funding. Horwitz: Affimed: Research Funding; Aileron: Research Funding; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. DeSavi: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Introduction: Immunotherapy is a promising therapeutic intervention for cancer treatment. Activation of the immune system via checkpoint blockade has been shown to produce antitumor responses in patients with both solid and hematological tumors. However, many patients do not respond to checkpoint inhibitors, and additional therapies are needed to treat these patients. Testing immunotherapies requires a functional human immune system; thus, it is difficult to evaluate their effectiveness using conventional experimental models. For this reason, establishing in vivo models that closely reproduce not only human tumors, but also their interactions with the human immune system, has become mandatory. Methods: We developed a humanized mouse model and combined it with a patient-derived tumor xenograft (PDTX). Humanized mice (HuMice) were generated by transplantation of cord blood or mobilized peripheral blood CD34+ hematopoietic stem and progenitor cells into preconditioned immunodeficient mice. We compared human engraftment in 3 different mouse strains: NSG (NOD.Cg-Prkdc scidIl2rg tm1Wjl/SzJ), NSGS (NOD.Cg-Prkdc scidIl2rg tm1Wjl Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ) and NBSGW (NOD.Cg-Kit W-41J Tyr + Prkdc scid Il2rg tm1Wjl/ThomJ). Immune cell profiling and distribution was performed using flow cytometry and immunohistochemistry. The B cell receptor (BCR) repertoire was evaluated using an RNA-based NGS assay. To evaluate the maturation and functionality of T cells developing in HuMice we performed proliferation, degranulation and intracellular cytokine staining. Results: Two months after CD34+ cell transplantation, we observed high levels of human hematopoietic chimerism in all the 3 strains. NSGS mice supported high-level chimerism as early as 1 month after transplantation, with more than 25% of human CD45+ cells in the blood. In all mice the majority of human circulating leukocytes were CD19+ B cells. An early appearance of CD3+ human T cells was detected in NSGS mice as compared to the other strains. Notably, the T cell expansion correlated with a decrease in relative B cell abundance while the myeloid cell contribution to the graft remained steady. We documented the differentiation of CD4+ and CD8+ human T cells at a 2:1 ratio. The characterization of the T cell subsets revealed that the majority was represented by CD45RA-CCR7- effector memory cells in both the spleen and the blood of HuMice. Nevertheless, recipient mice did not exhibit overt signs of graft-versus-host disease. We also evaluated the cytotoxic potential of T cells isolated from the spleen of HuMice: ex vivo peptide antigen (i.e. EBV) presentation let to generation of effective and specific cytotoxic T-cells. After assessing a functional human immune system reconstitution in HuMice, we challenged them in vivo with low-passage tumor fragments from a diffuse large B cell lymphoma (DLBCL) PDTX. All tumor implants were successfully engrafted in both HuMice and non-humanized controls. Remarkably, all the 3 HuMice strains showed a significant reduction in the tumor volume and/or eradication compared to matched non-humanized controls. Flow cytometry analysis of the peripheral blood of humanized PDTX revealed that the tumor engraftment elicited a significant expansion of CD3+ T cells and cytotoxic CD8+ lymphocytes. Moreover, tumors developing in HuMice exhibited intermediate to high levels of tumor infiltrating T lymphocytes commingling with the neoplastic B cells, as determined by immunohistochemistry. Large areas of necrosis were often observed in PDTX of HuMice. Infiltrating CD3+ cells were TIGIT, PD-1 and Lag-3 positive, and did not efficiently proliferate ex vivo: all features consistent with an exhaustion phenotype. PDTX of HuMice often displayed larger areas of necrosis. Conclusions: Collectively, our data demonstrate that a robust reconstitution can be achieved in different strains of immunocompromised mice and that HuMice elicit effective anti-lymphoma responses. PDTX HuMice represent a powerful platform to study host-tumor interactions, and to test novel immune-based strategies (CAR-T, bifunctional Abs) and new pharmacological approaches to counteract T-cell exhaustion. Figure 1 Figure 1. Disclosures Scandura: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; MPN-RF (Foundation): Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees . Roth: Janssen: Consultancy; Merck: Consultancy.

Present literature seems to support the nonoperative management of penetrating renal trauma although data remain limited. We conducted a nine-year retrospective review of nonoperative

Necrotizing soft tissue infection of the perineum, or Fournier's gangrene (FG), is a morbid and mortal diagnosis. Despite the severity of FG, the optimal definitive wound closure strategy is unknown, as are long-term wound outcomes. A retrospective review was performed over a 3-year period at a single trauma center. Patients were managed according to our institutional approach focusing on primary wound closure and secondary intention healing in residual wounds. Overall 168 patients were included. Complete primary wound closure was accomplished in 39.9 per cent of patients. Patients undergoing primary wound closure were primarily male (89.6 vs 64.4%, P0.001), had lower mean sequential organ failure assessment (SOFA) scores (1.70 ± 2.30 vs 2.98 ± 3.36, P = 0.004), more often had perineum-limited FG (67.2 vs 42.6%, P = 0.003), and required fewer debridements (2.40 vs 2.79, P = 0.02). On logistic regression, predictors of primary closure included gender (odds ratio 4.643, 95% confidence interval 1.885-11.437, P = 0.001) and SOFA score (odds ratio 0.834, 95% confidence interval 0.727-0.957, P = 0.01). Wound healing rates increased over time, to an 82.1 per cent wound healing rate without further intervention at greater than six months of follow-up. Wounds healed with secondary intention ranged from 70 to 9520 cm3 and primary closure ranged from 126 to 6912 cm3, whereas wounds requiring skin grafts ranged from 405 to 16,170 cm3. Complete primary wound closure is often achievable in FG patients. Using this standardized approach to FG wound management, even large wounds and wounds undergoing secondary intention healing will often close with long-term wound care and do not require flap creation or early skin grafting.

Nodal/TGFβ signaling regulates diverse biological responses. By combining RNA-seq on Foxh1 and Nodal signaling loss-of-function embryos with ChIP-seq of Foxh1 and Smad2/3, we report a comprehensive genome-wide interaction between Foxh1 and Smad2/3 in mediating Nodal signaling during vertebrate mesendoderm development. This study significantly increases the total number of Nodal target genes regulated by Foxh1 and Smad2/3, and reinforces the notion that Foxh1-Smad2/3-mediated Nodal signaling directly coordinates the expression of a cohort of genes involved in the control of gene transcription, signaling pathway modulation and tissue morphogenesis during gastrulation. We also show that Foxh1 may function independently of Nodal signaling, in addition to its role as a transcription factor mediating Nodal signaling via Smad2/3. Finally, we propose an evolutionarily conserved interaction between Foxh1 and PouV, a mechanism observed in Pou5f1-mediated regulation of pluripotency in human embryonic stem and epiblast cells.

Gene regulatory networks (GRNs) involve highly combinatorial interactions between transcription factors and short sequence motifs in cis-regulatory modules of target genes to control cellular phenotypes. The GRNs specifying most cell types are largely unknown and are the subject of wide interest. A catalog of transcription factors is a valuable tool toward obtaining a deeper understanding of the role of these critical effectors in any biological setting. Here we present a comprehensive catalog of the transcription factors for the diploid frog Xenopus tropicalis. We identify 1235 genes encoding DNA-binding transcription factors, comparable to the numbers found in typical mammalian species. In detail, the repertoire of X. tropicalis transcription factor genes is nearly identical to human and mouse, with the exception of zinc finger family members, and a small number of species/lineage-specific gene duplications and losses relative to the mammalian repertoires. We applied this resource to the identification of transcription factors differentially expressed in the early gastrula stage embryo. We find transcription factor enrichment in Spemann's organizer, the ventral mesoderm, ectoderm and endoderm, and report 218 TFs that show regionalized expression patterns at this stage. Many of these have not been previously reported as expressed in the early embryo, suggesting thus far unappreciated roles for many transcription factors in the GRNs regulating early development. We expect our transcription factor catalog will facilitate myriad studies using Xenopus as a model system to understand basic biology and human disease.

The purpose of this study is to evaluate the performance of multidetector computed tomography (MDCT) in diagnosing arterioportal fistulas (APF) in high-grade liver injury. A retrospective analysis of catheter-based hepatic angiograms performed for major penetrating and blunt liver injuries identified 11 patients with APFs. Using the trauma registry, two additional demographically matched groups with and without liver injury were formed. A randomized qualitative consensus review of 33 MDCTs was performed by three trauma radiologists for the following MDCT findings of APF: transient hepatic parenchymal attenuation differences (THPAD), early increased attenuation of a peripheral or central portal vein compared with the main portal vein, and the "double-barrel" or "rail tract" signs. THPAD was the most sensitive finding and also had a high specificity for diagnosing APF. Both the early increased attenuation of a peripheral or central portal vein compared with the main portal vein and the double-barrel or rail tract signs had a100% specificity and a sensitivity of 64% and 36%, respectively. Measurement of differences in attenuation values between the APF and the contralateral central portal vein was most sensitive and specific in diagnosing APF. Traumatic APF of the liver can be optimally diagnosed with arterial phase imaging of solid organ using MDCT.

We contribute to a greater understanding of political psychology by 1) collecting data in a more systematic way for the intellectual community, 2) sensitizing students to the extent to which any intellectual discipline is socially constructed and is a work in progress, 3) heightening awareness of the political aspects of intellectual life, 4) exposing readers to the wide variety of diverse approaches and methodologies utilized by political psychologists, and 5) suggesting the range of topics that political psychology can address successfully and the range of techniques it can utilize.

The Intelligent adaptive tunnel lighting system is a design approach in which the tunnel interior lighting system adapts to the real time roadway environment conditions. The level of tunnel lighting can be reduced or dimmed when the intensity of tunnel exterior daylight is decreased. Moreover, it can also be reduced when traffic on access road to the tunnel is absent. Dimming the luminaries to meet the minimum requirements would save on power consumption as well as maintenance costs. An adaptive tunnel lighting system is developed with the purpose of providing sufficient tunnel interior luminance so that motorist can access and exit the tunnel conveniently. Three levels were developed with integration of motion and light sensors. The results indicate that average of 22.1 % of power consumption can be reduced by using this system. Furthermore, LED is highly recommended to be use in the system due to its luminous efficiency and long lifecycle.

The combination of liquid biopsies and ultra-sensitive next-generation sequencing (NGS) holds tremendous promise in oncology for the detection and surveillance of somatic mutations that correlate with diagnosis, prognosis, response prediction, resistance monitoring and tumor burden. We have developed a capture-based NGS workflow that provides ultra-sensitive detection of 4 mutation classes - single nucleotide variants (SNVs), insertions/deletions, copy number amplifications (CNAs) and fusions - from low input cell-free DNA isolated from plasma. Sensitivity and specificity of 2 different AVENIO ctDNA Analysis Kits (for Research Use Only) across 3 sites for 48 samples that included contrived DNA blends with known mutations validated by digital PCR and normal reference plasma samples were assessed. The AVENIO ctDNA Targeted Kit (Targeted) was designed to detect mutations in 17 genes, across 80kb, included in NCCN Guidelines for solid tumors plus additional variants relevant for therapy selection. The AVENIO ctDNA Expanded Kit (Expanded) was designed to detect mutations in 77 genes, across 200kb, associated with solid tumor including variants relevant for clinical trial research. Testing sites achieved 100% sensitivity for SNVs and fusions at 0.5% and 1% allelic frequency, respectively, from 30 ng of input DNA for both kits. Median coverage of 4,200-6,400X was greater with the Targeted kit relative to that of 2,700-3,800X with the Expanded kit. Specificity was 100% for the Targeted kit either by sample or variant. The Expanded kit had a specificity of 91.7-100% by sample and 99.7-100% by variant. At an expected 5X or 8X copy number amplification for multiple genes, both the Targeted and Expanded kits were 100% sensitive and 93.1-98.4% specific per gene. The specificity for fusion detection was 100% for both kits down to 1% mutant allele frequency. The AVENIO ctDNA Analysis Kits for plasma and NGS applications provide exquisite sensitivity and specificity for the simultaneous detection of 4 different mutation classes. Citation Format: Stephanie Yaung, Alex Lovejoy, Dan Klass, Fergal Casey, Aruna Arcot, Melissa Loyzer, William Chiu, Nabil Azhar, Sophie Beckert, Maria Lange, Sandra Siemann, Sebastian Froehler, Shelly Gunn, John F. Palma. Inter-site comparison of performance of an ultra-sensitive sequencing technology for circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2744. doi:10.1158/1538-7445.AM2017-2744

Background During embryogenesis, signaling molecules produced by one cell population direct gene regulatory changes in neighboring cells and influence their developmental fates and spatial organization. One of the earliest events in the development of the vertebrate embryo is the establishment of three germ layers, consisting of the ectoderm, mesoderm and endoderm. Attempts to measure gene expression in vivo in different germ layers and cell types are typically complicated by the heterogeneity of cell types within biological samples (i.e., embryos), as the responses of individual cell types are intermingled into an aggregate observation of heterogeneous cell types. Here, we propose a novel method to elucidate gene regulatory circuits from these aggregate measurements in embryos of the frog Xenopus tropicalis using gene network inference algorithms and then test the ability of the inferred networks to predict spatial gene expression patterns. Results We use two inference models with different underlying assumptions that incorporate existing network information, an ODE model for steady-state data and a Markov model for time series data, and contrast the performance of the two models. We apply our method to both control and knockdown embryos at multiple time points to reconstruct the core mesoderm and endoderm regulatory circuits. Those inferred networks are then used in combination with known dorsal-ventral spatial expression patterns of a subset of genes to predict spatial expression patterns for other genes. Both models are able to predict spatial expression patterns for some of the core mesoderm and endoderm genes, but interestingly of different gene subsets, suggesting that neither model is sufficient to recapitulate all of the spatial patterns, yet they are complementary for the patterns that they do capture. Conclusion The presented methodology of gene network inference combined with spatial pattern prediction provides an additional layer of validation to elucidate the regulatory circuits controlling the spatial-temporal dynamics in embryonic development.

Indium-111-oxine labeled leukocyte ((111)In-WBC) scintigraphy is well known for its ability to localize in areas of active infection, but not in areas of lymphomatous involvement. We present a case of Ki-1-positive anaplastic large-cell lymphoma that was initially thought to be a case of multifocal osteomyelitis because of positive uptake on a (111)In-WBC scan. The areas of abnormal uptake on the indium scan were demonstrated histopathologically to be sites of lymphomatous involvement in bone.

This chapter explores how, through various steps and missteps, international norms governing refugees and asylum-seekers have evolved in response to events and crises of the 20th century. The two great wars of the 20th century triggered crucial rounds of normative development. The debates over what to do with refugees created by World War I and the Russian Revolution led to ad hoc measures and an emerging norm of care for refugees. The Holocaust triggered a new cycle of norm change, out of which emerged international organizations (UNHCR) and treaties (the 1951 Convention and its 1967 Protocol) designed to ensure basic rights for refugees and asylum-seekers. In subsequent refugee crises, states have sought to limit their international responsibilities toward refugees.

The purpose of this study is to review demographics and examine and stratify risk factors related to the outcome of operatively treated iliac vascular injuries. We conducted a retrospective review of 78 cases of iliac vessel injury. Patients with blunt and penetrating injury had statistically similar length of hospital stay and intensive care unit stay, incidence of shock, and mortality. Shock on admission and bleeding hematoma are linked, and shock increased mortality with an odds ratio of 5.2 ( P = 0.002). A review of operative technique and outcome demonstrated a low mortality of 25 per cent in arterial bypass of an isolated arterial injury versus a mortality of 83 per cent in the combined injury group. Patients treated with primary repair of venous injuries had a lower incidence of shock and mortality compared with patients treated with venous ligation. We conclude that, if matched for severity of injury and physiologic instability, the mechanism of injury does not affect mortality. Shock is the most significant prognostic factor for mortality. Operative management must be based on presence of shock.

As the demand for current cellular voice-oriented networks to include other services such as data and video applications is increasing rapidly, the reliability of information transmission over the mobile radio environment is important. Performance evaluation in terms of the bit error rate (BER) and block (packet) error rate (BKER) of modulation schemes in such an environment is of considerable research interest. In this thesis, we study the BER as well as the BKER performance of Gaussian-filtered Minimum Shift Keying (GMSK) modulation, currently used in the Global System for Mobile Communication (GSM) standard, in additive white Gaussian noise (AWGN) as well as flat and frequency selective Rayleigh fading. 1-bit and 2-bit differential detectors are used for demodulation. A detailed analysis is carried out to examine the IF filtering effect on the BER performance over the fading channels. The BKER performance is mainly studied through simulations. Since the premodulation Gaussian filter at the GMSK transmitter introduces significant Intersymbol Interference (ISI), we also examine the performance of a decision feedback (DF) scheme which partially removes the ISI, over such channels. The BER results in both flat and frequency selective (FS) Rayleigh fading show that 2-bit conventional (with no decision feedback) GMSK performs slightly better than 1-bit conventional GMSK when Eb/NQ < 25 dB. Above this value, the latter performs better and has a lower irreducible error. Results also show that 2-bit conventional GMSK is more sensitive to the IF filtering distortion than 1-bit conventional GMSK in Rayleigh fading. The percentage improvement in BKER of 1-bit DF GMSK over 1-bit conventional GMSK is almost equal to that of the corresponding BERs. In the case of 2-bit DF GMSK, the BKER performance shows an increased improvement over 2-bit conventional GMSK when compared to the corresponding BER performance, owing to increased error propagation. Since fading gives rise to bursty bit errors, the actual BKER is lower than the predicted assuming independent bit errors. In all fading cases, 1-bit conventional GMSK has a better BKER performance over 2-bit conventional GMSK when Eb/NQ >25 dB. In the case of decision feedback, similar performance trends are observed.

In rabbit lenses subjected to oxidative stress, induced by 1 mM diquat in vitro, there were 7- to 10-fold increases (p less than 0.001) in malondialdehyde, conjugated dienes, and carbonyl dienes, indicating extensive peroxidation of cellular membrane lipids, and approximately a 60% decrease in reduced glutathione. In the presence of 0.1-5 mM Desferal-Mn(III) these changes were diminished by 50-70%. In an experimental group of 12 rabbits having diquat-induced cataract, Desferal-Mn(III) (5% w/v) applied topically as a 50-microliters eye drop four times per day and a single intraperitoneal dose of 64 mg/kg body wt daily for 5 weeks (including pretreatment for 1 week) retarded the progression of lens opacities, whereas, in a control group of 6 rabbits treated with the vehicle (0.15 M NaCl) cataract progressed to an advanced grade. Treatment with Desferal-Mn(III) also significantly diminished production of O2.- and OH. in the lens, aqueous humor, and vitreous humor, and of H2O2 in the aqueous humor and vitreous humor. It also suppressed lipid peroxidation and oxidation of protein-SH of the lens and restored lenticular glutathione and ascorbate to normal levels.