A structural basis for the assembly and functions of a viral polymer that inactivates multiple tumor suppressors.

Evolution of minimal DNA tumor virus' genomes has selected for small viral oncoproteins that hijack critical cellular protein interaction networks. The structural basis for the multiple and dominant functions of adenovirus oncoproteins has remained elusive. E4-ORF3 forms a nuclear polymer and simultaneously inactivates p53, PML, TRIM24, and MRE11/RAD50/NBS1 (MRN) tumor suppressors. We identify oligomerization mutants and solve the crystal structure of E4-ORF3. E4-ORF3 forms a dimer with a central ß core, and its structure is unrelated to known polymers or oncogenes. E4-ORF3 dimer units coassemble through reciprocal and nonreciprocal exchanges of their C-terminal tails. This results in linear and branched oligomer chains that further assemble in variable arrangements to form a polymer network that partitions the nuclear volume. E4-ORF3 assembly creates avidity-driven interactions with PML and an emergent MRN binding interface. This reveals an elegant structural solution whereby a small protein forms a multivalent matrix that traps disparate tumor suppressors.

Donor-recipient race-ethnicity concordance and patient survival after liver transplantation.

INTRODUCTION: We assessed the association between patient survival after liver transplantation (LT) and donor-recipient race-ethnicity (R/E) concordance. METHODS: The Scientific Registry of Transplant Recipients (SRTR) was retrospectively analyzed using data collected between 2002 and 2019. Only adults without history of prior organ transplant and recipients of LT alone were included. The primary outcome was patient survival. Donors and recipients were categorized into five R/E groups: White/Caucasian, African American/Black, Hispanic/Latino, Asian, and Others. Statistical analyses were performed using Kaplan-Meier survival curves and Cox Proportional Hazards models, adjusting for donor and recipient covariates. RESULTS: 85,427 patients were included. Among all the R/E groups, Asian patients had the highest 5-year survival (81.3%; 95% CI = 79.9-82.7), while African American/Black patients had the lowest (71.4%; 95% CI = 70.3-72.6) (P < 0.001). Lower survival rates were observed in recipients who received discordant R/E grafts irrespective of their R/E group. The fully adjusted hazard ratio for death was statistically significant in African American/Black (aHR 1.07-1.18-1.31; P < 0.01) and in White∕Caucasian patients (aHR 1.00-1.04-1.07; P = 0.03) in the presence of donor-recipient R/E discordance. CONCLUSION: Disparities in post-LT outcomes might be influenced by biological factors in addition to well-known social determinants of health.

The closing survival gap after liver transplantation for hepatocellular carcinoma in the United States.

BACKGROUND: Socio-economic inequalities among different racial/ethnic groups have increased in many high-income countries. It is unclear, however, whether increasing socio-economic inequalities are associated with increasing differences in survival in liver transplant (LT) recipients. METHODS: Adults undergoing first time LT for hepatocellular carcinoma (HCC) between 2002 and 2017 recorded in the Scientific Registry of Transplant Recipients (SRTR) were included and grouped into three cohorts. Patient survival and graft survival stratified by race/ethnicity were compared among the cohorts using unadjusted and adjusted analyses. RESULTS: White/Caucasians comprised the largest group (n=9,006, 64.9%), followed by Hispanic/Latinos (n=2,018, 14.5%), Black/African Americans (n=1,379, 9.9%), Asians (n=1,265, 9.1%) and other ethnic/racial groups (n=188, 1.3%). Compared to Cohort I (2002-2007), the 5-year survival of Cohort III (2012-2017) increased by 18% for Black/African Americans, by 13% for Whites/Caucasians, by 10% for Hispanic/Latinos, by 9% for patients of other racial/ethnic groups and by 8% for Asians (All P values<0.05). Despite Black/African Americans experienced the highest survival improvement, their overall outcomes remained significantly lower than other ethnic∕racial groups (adjusted HR for death=1.20; 95%CI 1.05-1.36; P=0.005; adjusted HR for graft loss=1.21; 95%CI 1.08-1.37; P=0.002). CONCLUSION: The survival gap between Black/African Americans and other ethnic/racial groups undergoing LT for HCC has significantly decreased over time. However, Black/African Americans continue to have the lowest survival among all racial/ethnic groups.

A Translational Hepatic Artery Infusion (HAI) Model for Hepatocellular Carcinoma in Woodchucks.

BACKGROUND: Woodchucks (Marmota monax) are a well-accepted animal model for the investigation of spontaneous hepatocellular carcinoma (HCC). As HCC tumors obtain nutrient blood supply exclusively from the hepatic artery, hepatic artery infusion (HAI) has been applied to HCC. However, there is a scarcity of experimental animal models to standardize drug regimens and examine novel agents. The purpose of this study was to establish an HAI model in woodchucks. MATERIALS AND METHODS: HAI ports were placed in the gastroduodenal artery (GDA) of 11 woodchucks. The ports were infused with either a vehicle (dextrose 5% in water) or an experimental drug, CBL0137, once a week for 3 wk. Technical success rates, anatomical variation, morbidity and mortality, and tumor responses between groups were analyzed. RESULTS: The GDA access was feasible and reproducible in all woodchucks (11/11). The average operation time was 95 ± 20 min with no increase in the levels of liver enzymes detected from either infusate. The most common morbidity of CBL0137 therapy was anorexia after surgery. One woodchuck died due to hemorrhage at the gallbladder removal site from hepatic coagulopathy. Significantly higher CBL0137 concentrations were measured in the liver compared with blood after each HAI. Tumor growth was suppressed after multiple CBL0137 HAI treatments which corresponded to greater T cell infiltration and increased tumor cell apoptosis. CONCLUSIONS: HAI via GDA was a feasible and reproducible approach with low morbidity and mortality in woodchucks. The described techniques serve as a reliable platform for the identification and characterization of therapeutics for HCC.

Novel mouse models of hepatic artery infusion.

BACKGROUND: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, whereas liver tumors obtain their nutrient blood supply exclusively from the hepatic artery. The focused arterial delivery of anticancer agents to liver tumors has been performed for decades; however, preclinical models to standardize drug regimens and examine novel agents have been lacking. The purpose of this study was to establish preclinical hepatic artery infusion (HAI) models in a mouse and to evaluate the safety and delivery capability of the models. MATERIAL AND METHODS: C57BL/6 and BALB/c mice were used to develop models of HAI via the hepatic artery (HA), superior pancreaticoduodenal artery (SPDA), or lienogastric artery (LGA). Success rates, distribution of perfusion, and associated morbidity and mortality were analyzed between groups. RESULTS: All three models were feasible and reproducible in mice, and there was no statistical difference on body weight change between models. The HA model had a 13.3% mortality from acute liver failure, and the SPDA model demonstrated duodenal and pancreatic toxicity. SPDA and LGA routes had the highest success rates (96.7% and 91.4%, respectively) with low mortality, better drug delivery, and preserved physiologic liver function compared with the HA model. CONCLUSIONS: The optimal route of HAI was mouse breed specific; SPDA access in BALB/c mice, and the LGA access in C57BL/6 mice. The described techniques serve as a reproducible platform for the identification and characterization of therapeutics for diverse metastatic liver tumors.

Survival after live donor versus deceased donor liver transplantation: propensity score-matched study.

BACKGROUND: For individuals with advanced liver disease, equipoise in outcomes between live donor liver transplant (LDLT) and deceased donor liver transplant (DDLT) is uncertain. METHODS: A retrospective cohort study was performed using data extracted from the Scientific Registry of Transplant Recipients. Adults who underwent first-time DDLT or LTDL in the United States between 2002 and 2020 were paired using propensity-score matching with 1:10 ratio without replacement. Patient and graft survival were compared using the model for end-stage liver disease (MELD) score for stratification. RESULTS: After propensity-score matching, 31 522 DDLT and 3854 LDLT recipients were included. For recipients with MELD scores ≤15, LDLT was associated with superior patient survival (HR = 0.92; 95% c.i. 0.76 to 0.96; P = 0.013). No significant differences in patient survival were observed for MELD scores between 16 and 30. Conversely, for patients with MELD scores >30, LDLT was associated with higher mortality (HR 2.57; 95% c.i. 1.35 to 4.62; P = 0.003). Graft survival was comparable between the two groups for MELD ≤15 and for MELD between 21 and 30. However, for MELD between 16 and 20 (HR = 1.15; 95% c.i. 1.00 to 1.33; P = 0.04) and MELD > 30 (HR = 2.85; 95% c.i. 1.65 to 4.91; P = 0.001), graft survival was considerably shorter after LDLT. Regardless of MELD scores, re-transplantation rate within the first year was significantly higher after LDLT. CONCLUSIONS: In this large propensity score-matched study using national data, comparable patient survival was found between LDLT and DDLT in recipients with MELD scores between 16 and 30. Conversely, for patients with MELD > 30, LDLT was associated with worse outcomes. These findings underscore the importance of transplant selection for patients with high MELD scores.

Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19.

BACKGROUND: Oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance. METHODS: Olgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (Mpro), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells. FINDINGS: Olgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115. The dual mechanism of action of olgotrelvir and AC1115 was confirmed by enzyme activity inhibition assays and co-crystal structures of AC1115 with SARS-CoV-2 Mpro and human CTSL. AC1115 displayed antiviral activity by inhibiting replication of all tested SARS-CoV-2 variants in cell culture systems. Olgotrelvir also inhibited viral entry into cells using SARS-CoV-2 Spike-mediated pseudotypes by inhibition of host CTSL. In the K18-hACE2 transgenic mouse model of SARS-CoV-2-mediated disease, olgotrelvir significantly reduced the virus load in the lungs, prevented body weight loss, and reduced cytokine release and lung pathologies. Olgotrelvir demonstrated potent activity against the nirmatrelvir-resistant Mpro E166 mutants. Olgotrelvir showed enhanced oral bioavailability in animal models and in humans with significant plasma exposure without ritonavir. In phase I studies (ClinicalTrials.gov: NCT05364840 and NCT05523739), olgotrelvir demonstrated a favorable safety profile and antiviral activity. CONCLUSIONS: Olgotrelvir is an oral inhibitor targeting Mpro and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19. FUNDING: Funded by Sorrento Therapeutics.

The cytoplasmic domain of rhesus cytomegalovirus Rh178 interrupts translation of major histocompatibility class I leader peptide-containing proteins prior to translocation.

Cytomegalovirus (CMV) efficiently evades many host immune defenses and encodes a number of proteins that prevent antigen presentation by major histocompatibility complex class I (MHC-I) molecules in order to evade recognition and killing of infected cells by cytotoxic CD8(+) T cells. We recently showed that rhesus CMV-specific Rh178 intercepts MHC-I protein translation before interference of MHC-I maturation by homologues of the human CMV US6 family. Here, we demonstrate that Rh178 localizes to the membrane of the endoplasmic reticulum, displaying a short luminal and large cytosolic domain, and that the membrane-proximal cytosolic portion is essential for inhibition of MHC-I expression. We further observed that Rh178 does not require synthesis of full-length MHC-I heavy chains but is capable of inhibiting the translation of short, unstable amino-terminal fragments of MHC-I. Moreover, the transfer of amino-terminal fragments containing the MHC-I signal peptide renders recipient proteins susceptible to targeting by Rh178. The cytosolic orientation of Rh178 and its ability to target protein fragments carrying the MHC-I signal peptide are consistent with Rh178 intercepting partially translated MHC-I heavy chains after signal recognition particle-dependent transfer to the endoplasmic reticulum membrane. However, interference with MHC-I translation by Rh178 seems to occur prior to SEC61-dependent protein translocation, since inhibition of MHC-I translocation by eeyarestatin 1 resulted in a full-length degradation intermediate that can be stabilized by proteasome inhibitors. These data are consistent with Rh178 blocking protein translation of MHC-I heavy chains at a step prior to the start of translocation, thereby downregulating MHC-I at a very early stage of translation.

Chimeric mRNA-based COVID-19 vaccine induces protective immunity against Omicron and Delta variants.

The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the effectiveness of currently approved mRNA vaccines. To achieve wider coverage of VOCs, we first constructed a cohort of mRNAs harboring a furin cleavage mutation in the spike (S) protein of predominant VOCs, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). The mutation abolished the cleavage between the S1 and S2 subunits. Systematic evaluation in vaccinated mice discovered that individual VOC mRNAs elicited strong neutralizing activity in a VOC-specific manner. In particular, the neutralizing antibodies (nAb) produced by immunization with Beta-Furin and Washington (WA)-Furin mRNAs showed potent cross-reactivity with other VOCs. However, neither mRNA elicited strong neutralizing activity against the Omicron variant. Hence, we further developed an Omicron-specific mRNA vaccine that restored protection against the original Omicron variant and some sublineages. Finally, to broaden the protection spectrum of the new Omicron mRNA vaccine, we engineered an mRNA-based chimeric immunogen by introducing the receptor-binding domain of Delta variant into the entire S antigen of Omicron. The resultant chimeric mRNA induced potent and broadly nAbs against Omicron and Delta, which paves the way to developing new vaccine candidates to target emerging variants in the future.

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies.

Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants. STI-2020 and STI-5041 were protective when administered intravenously or intranasally in the golden (Syrian) hamster model of COVID-19 challenged with the WA-1 strain or Beta variant. The ability to administer nAbs intravenously and intranasally may have important therapeutic implications and Phase 1 healthy subjects clinical trials are ongoing.

Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants.

BACKGROUND: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant and its BA.X lineages, has rendered ineffective a number of previously FDA emergency use authorized SARS-CoV-2 neutralizing antibody therapies. Furthermore, those approved antibodies with neutralizing activity against Omicron BA.1 are reportedly ineffective against the subset of Omicron subvariants that contain a R346K substitution, BA.1.1, and the more recently emergent BA.2, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. METHODS: Following a campaign of antibody discovery based on the vaccination of Harbor H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. FINDINGS: STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against each of the tested Omicron subvariants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. CONCLUSIONS: With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for intravenous or intranasal use in human clinical trials. FUNDING: Funded by CRIPT (no. 75N93021R00014), DARPA (HR0011-19-2-0020), and NCI Seronet (U54CA260560).

Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus.

The US2-11 region of human and rhesus cytomegalovirus encodes a conserved family of glycoproteins that inhibit MHC-I assembly with viral peptides, thus preventing cytotoxic T cell recognition. Since HCMV lacking US2-11 is no longer able to block assembly and transport of MHC-I, we examined whether this is also observed for RhCMV lacking the corresponding region. Unexpectedly, recombinant RhCMV lacking US2-11 was still able to inhibit MHC-I expression in infected fibroblasts, suggesting the presence of an additional MHC-I evasion mechanism. Progressive deletion analysis of RhCMV-specific genomic regions revealed that MHC-I expression is fully restored upon additional deletion of rh178. The protein encoded by this RhCMV-specific open reading frame is anchored in the endoplasmic reticulum membrane. In the presence of rh178, RhCMV prevented MHC-I heavy chain (HC) expression, but did not inhibit mRNA transcription or association of HC mRNA with translating ribosomes. Proteasome inhibitors stabilized a HC degradation intermediate in the absence of rh178, but not in its presence, suggesting that rh178 prevents completion of HC translation. This interference was signal sequence-dependent since replacing the signal peptide with that of CD4 or murine HC rendered human HCs resistant to rh178. We have identified an inhibitor of antigen presentation encoded by rhesus cytomegalovirus unique in both its lack of homology to any other known protein and in its mechanism of action. By preventing signal sequence-dependent HC translocation, rh178 acts prior to US2, US3 and US11 which attack MHC-I proteins after protein synthesis is completed. Rh178 is the first viral protein known to interfere at this step of the MHC-I pathway, thus taking advantage of the conserved nature of HC leader peptides, and represents a new mechanism of translational interference.

Dehydrated Human Amnion Chorion Membrane as Treatment for Pediatric Burns.

Objective: Pediatric burns are a major source of injury and in the absence of adequate care can lead to lifelong functional loss and disfigurement. While split thickness skin autografts are the current standard of care for deep partial and full-thickness burns, this approach is associated with considerable morbidity. For this reason, alternative skin substitutes such as allografts have gained interest. Approach: In the present study, we present a case series of 30 children with various types of burns treated with dehydrated human amnion chorion membrane (dHACM). Results: We show that treatment with dHACM is associated with an excellent rate of healing comparable to split thickness skin grafts with less rate of hypertrophic scar and contracture. Innovation: Treatment with dHACM is particularly attractive as it consists of many tissue regenerative factors, such as growth factors and immune modulators, thus it will reduce the risk of scaring. Conclusion: While dHACM is associated with an increased upfront cost, treating patients with small to moderate-sized burns with dHACM in their regional centers works to decrease downstream costs such as management of prolonged pain from donor-site morbidity, revisional surgeries from scar and contractures of split thickness grafts, and avoiding the cost of transfer to higher level centers of care. Our findings challenge the current standard of care, suggesting that dHACM provides an alternative to the current use of split thickness skin grafting and is a safe, feasible, and potentially superior substitute for the management of small to moderate total body surface area partial and full-thickness pediatric burns.

Dynamic control of tumor vasculature improves antitumor responses in a regional model of melanoma.

Despite advances in therapy for melanoma, heterogeneous responses with limited durability represent a major gap in treatment outcomes. The purpose of this study was to determine whether alteration in tumor blood flow could augment drug delivery and improve antitumor responses in a regional model of melanoma. This approach to altering tumor blood flow was termed "dynamic control." Dynamic control of tumor vessels in C57BL/6 mice bearing B16 melanoma was performed using volume expansion (saline bolus) followed by phenylephrine. Intravital microscopy (IVM) was used to observe changes directly in real time. Our approach restored blood flow in non-functional tumor vessels. It also resulted in increased chemotherapy (melphalan) activity, as measured by formation of DNA adducts. The combination of dynamic control and melphalan resulted in superior outcomes compared to melphalan alone (median time to event 40.0 vs 25.0 days, respectively, p = 0.041). Moreover, 25% (3/12) of the mice treated with the combination approach showed complete tumor response. Importantly, dynamic control plus melphalan did not result in increased adverse events. In summary, we showed that dynamic control was feasible, directly observable, and augmented antitumor responses in a regional model of melanoma. Early clinical trials to determine the translational feasibility of dynamic control are ongoing.

The adherence of adult trauma centers to American Pediatric Surgical Association guidelines on management of blunt splenic injuries.

BACKGROUND: Nonoperative management (NOM) is commonly utilized in hemodynamically stable children with blunt splenic injuries (BSI). Guidelines published by the American Pediatric Surgical Association over the past 15 years support this approach. We sought to determine the rates and outcomes of NOM in pediatric BSI and compare trends between pediatric (PTC), mixed (MTC) and adult trauma centers (ATC). METHODS: This was a retrospective database analysis of the NTDB data from 2011 to 2015 including pediatric patients with BSI, as described by ICD-9-CM Codes 865.00-865.09. Patients with head injuries with AIS > 2, multiple intraabdominal injuries, and transfers-out were excluded. According to ACS and/or state designation, trauma facilities were defined as PTC (level I/II pediatric only), MTC (level I/II adult and pediatric) and ATC (level I/II adult only). OM group was defined as presence of procedure codes reflecting exploratory laparotomy/laparoscopy and/or any splenic procedures. NOM group consisted of patients who were observed, transfused or had transarterial embolization (TAE). Variables analyzed were age, ISS, spleen AIS, amount and type of blood products transfused, and intensive care unit (ICU) and hospital (H) length of stay (LOS). RESULTS: 5323 children met the inclusion criteria. 11.4% received care at PTC (NOM, 97%), 40.7% at MTC (NOM, 89.9%) and 47.8% at ATC (NOM, 83.8%) (P < 0.001). In NOM group, PTC patients had the highest spleen AIS (3.46 ±â€¯0.95, P < 0.001). TAE was predominantly used at MTC and ATC (P = 0.001). MTC and ATC were more likely to transfuse than PTC (P = 0.002). MTC and ATC OM rates were lower in children aged ≤12 than in children aged >12 (P < 0.001). Splenectomy rate was 1.5% at PTC, 8.4% at MTC, and 14.4% at ATC (P < 0.001). In OM group, PTC patients had a higher ISS (P = 0.018) and spleen AIS (P = 0.048) than both MTC and ATC. The proportion of patients treated by NOM at ATC increased during the 5-year period studied (P = 0.015). Treatment at MTC or ATC increased the risk for OM by 3.89 and 5.36 times respectively (P < 0.001). CONCLUSIONS: PTCs still outperform ATCs in NOM success rates despite higher ISS and splenic injury grades. From 2011 to 2015, ATC OM rates dropped from 17% to 12.4% suggesting increased adoption of the APSA guidelines. Further educational initiatives may help augment this trend. LEVEL OF EVIDENCE: II TYPE OF STUDY: Retrospective.

Improving the performance of the Revised Trauma Score using Shock Index, Peripheral Oxygen Saturation, and Temperature-a National Trauma Database study 2011 to 2015.

BACKGROUND: The Revised Trauma Score is the standard physiologic injury severity indicator used in trauma research and quality control. Shock index, peripheral oxygen saturation, and temperature have emerged as strong predictors for mortality and morbidity. We hypothesized that replacing systolic blood pressure and respiratory rate with age-adjusted shock index and peripheral oxygen saturation and adding temperature would generate a more accurate model, valid across all ages. METHODS: This is a retrospective database analysis using children and adults from the National Trauma Data Bank for years 2011 to 2015. Glasgow Coma Scale, systolic blood pressure, heart rate, respiratory rate, peripheral oxygen saturation, temperature, and shock index (calculated as heart rate/systolic blood pressure) were used as predictor variables, alone or in combination, in logistic models with survival as primary outcome. Bayesian information criterion and area under the receiver operator characteristic curve were used to compare models' performances. To adjust for age, models tested on the entire population (children and adults) used Z-scores derived on age-based homogenous intervals rather than the raw value. RESULTS: The analysis included 283,724 pediatric and 1,555,478 adult patients. Overall mortality was 0.7% and 2.7%, respectively. The Glasgow Coma Scale + shock index + peripheral oxygen saturation + temperature model outperformed the revised trauma score in both adults (Bayesian information criterion 296,345.94 vs 298,494.72; area under the receiver operator characteristic curve 0.831 vs 0.809, P < .001) and children (Bayesian information criterion 12,251.48 vs 12,283.48; area under the receiver operator characteristic curve 0.974 vs 0.968, P = .05) cohorts. On the merged (children and adults) cohort the Glasgow Coma Scale + Z-scores derived on age-based homogenous intervals + peripheral oxygen saturation + temperature model outperformed the Revised Trauma Score (Bayesian information criterion 313,814.78 vs 317,781.31; area under the receiver operator characteristic curve 0.852 vs 0.809, P < .001). CONCLUSIONS: Replacing systolic blood pressure and respiratory rate with shock index and peripheral oxygen saturation in the Revised Trauma Score model and adding temperature generated a more accurate model in both children and adults. Adjusting shock index for age rendered the model accurate across all ages. Calibration on population-derived nomograms of vital signs would further increase the model's accuracy and precision.

Thrombosis of the Lap-Band system.

BACKGROUND: The laparoscopic adjustable gastric band (LAGB) has proven itself a procedure with excellent long-term weight loss results and extremely low morbidity and mortality. The LAGB has become an indispensable addition to the armamentarium of most bariatric surgeons. Commonly reported complications associated with the lap band system include gastric prolapse, band erosion, hardware infection, and port/tubing leakage. METHODS: We report a case of a patient suspected of having a Lap-Band leak. He presented with a clinical course of multiple adjustments without restriction and inability to aspirate the expected volume from the band. Following adjustment under fluoroscopy he became severely dysphagic. He underwent urgent operative exploration and was found to have an intact but overinflated band. Under close inspection, a clot in the proximal band was noted, acting as a ball valve allowing the addition of fluid but not aspiration. CONCLUSIONS: This case highlights an unusual explanation for what is thought of as typical signs of band leakage. In addition it raises serious questions about the importance of preventing blood and particulate matter from entering the Lap-Band system both at the initial operation and at subsequent adjustments.

Intra-arterial Versus Intravenous Adoptive Cell Therapy in a Mouse Tumor Model.

Adoptive cell transfer therapy for cancer has existed for decades and is experiencing a resurgence in popularity that has been facilitated by improved methods of production, techniques for genetic modification, and host preconditioning. The trafficking of adoptively transferred lymphocytes and infiltration into the tumor microenvironment is sine qua non for successful tumor eradication; however, the paradox of extremely poor trafficking of lymphocytes into the tumor microenvironment raises the issue of how best to deliver these cells to optimize entry into tumor tissue. We examined the route of administration as a potential modifier of both trafficking and antitumor efficacy. Femoral artery cannulation and tail vein injection for the intra-arterial (IA) and IV delivery, respectively, were utilized in the B16-OVA/OT-I mouse model system. Both IV and IA infusions showed decreased tumor growth and prolonged survival. However, although significantly increased T-cell tumor infiltration was observed in IA mice, tumor growth and survival were not improved as compared with IV mice. These studies suggest that IA administration produces increased early lymphocyte trafficking, but a discernable survival benefit was not seen in the murine model examined.