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INTRODUCTION: There is no data regarding the impact of enhanced recovery pathways (ERP) on composite length of stay (CLOS) after procedures with increased risk of morbidity and mortality, such as pancreaticoduodenectomy. METHODS: Patients undergoing open pancreaticoduodenectomy before and after implementation of ERP were prospectively followed for 90 days after surgery and complications were severity graded using the Modified Accordion Grading System. A retrospective analysis of patient outcomes were compared before and after instituting ERP. 1:1 propensity score matching was used to compare ERP patient outcomes to those of matched pre-ERP patients. CLOS is defined as postoperative length of hospital stay (PLOS) plus readmission length of hospital stay within 90 days after surgery. RESULTS: 494 patients underwent open pancreaticoduodenectomy – 359 pre-ERP and 135 ERP. In a 1:1 propensity-score-matched analysis of 110 matched pairs, ERP patients had significantly decreased superficial surgical site infections (5.5% vs 15.5% p=0.015) and significantly increased rates of urinary retention (29.1% vs 7.3% p

OBJECTIVE To identify an oral dose of grapiprant for red-tailed hawks (RTHAs; Buteo jamaicensis) that would achieve a plasma concentration > 164 ng/mL, which is considered therapeutic for dogs with osteoarthritis. ANIMALS 6 healthy adult RTHAs. PROCEDURES A preliminary study, in which grapiprant (4 mg/kg [n = 2], 11 mg/kg [2], or 45 mg/kg [2]) was delivered into the crop of RTHAs from which food had been withheld for 24 hours, was performed to obtained pharmacokinetic data for use with modeling software to simulate results for grapiprant doses of 20, 25, 30, 35, and 40 mg/kg. Simulation results directed our selection of the grapiprant dose administered to the RTHAs in a single-dose study. Plasma grapiprant concentration, body weight, and gastrointestinal signs of RTHAs were monitored. RESULTS On the basis of results from the preliminary study and simulations, a grapiprant dose of 30 mg/kg was used in the single-dose study. The geometric mean maximum observed plasma concentration of grapiprant was 3,184 ng/mL, time to maximum plasma grapiprant concentration was 2.0 hours, and the harmonic mean terminal half-life was 17.1 hours. No substantial adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Although the single dose of grapiprant (30 mg/kg) delivered into the crop achieved plasma concentrations > 164 ng/mL in the RTHAs, it was unknown whether this concentration would be therapeutic for birds. Further research that incorporates multidose assessments, safety monitoring, and pharmacodynamic data collection is warranted on the use of grapiprant in RTHAs from which food was withheld versus not withheld.

Background Little is known about what factors predict better outcomes for patients who undergo minimally invasive pancreaticoduodenectomy (MIPD) versus open pancreaticoduodenectomy (OPD). We hypothesized that patients with dilated pancreatic ducts have improved postoperative outcomes with MIPD compared to OPD. Methods All patients undergoing pancreaticoduodenectomy were prospectively followed over a time period of 47 months, and perioperative and pathologic covariates and outcomes were compared. Ideal outcome after PD was defined as follows: (1) no complications, (2) postoperative length of stay

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

The purpose of this study was to re-evaluate the previously utilized definitions of high volume center for pancreaticoduodenectomy to determine/establish an objective, evidence based threshold of hospital volume associated with improvement in perioperative mortality.Patients who underwent pancreaticoduodenectomy were identified using the National Cancer Database from 2004 to 2015. The relationship between hospital volume and 90-day mortality was assessed using a logistic regression model. Receiver Operator Characteristic analysis was performed and Youden's statistic was utilized to calculate the optimal cut offs.42,402 patients underwent elective Pancreaticoduodenectomy at 1238 unique hospitals. A logistic regression was performed which showed a significant inverse linear association between institutional volume and overall 90 day mortality. The maximum improvement in 90 day mortality is seen if the average annual hospital volume was greater than 9 (OR = 0.647 (0.595-0.702), p 0.0001). When analysis is limited to hospitals that performed9 cases per year, the maximum improvement in 90 day mortality was noticed at 36 cases per year (OR = 0.458 (0.399-0.525), p 0.0001).Based on our results, we recommend defining low, medium, and high volume centers for pancreaticoduodenectomy as hospitals with average annual volume less than 9, 9 to 35, and more than 35 cases per year, respectively.

Obesity is a chronic disease with multisystem morbidity. There are multiple studies reporting the effect of bariatric surgery on cardiovascular and metabolic disease, but few examine its impact on lower urinary tract symptoms. This article aims to perform a systematic review with meta-analysis, to determine the effects of bariatric surgery on lower urinary tract symptoms in male patients. Medline, Embase, conference proceedings, and reference lists were searched for studies reporting the quantitative measurement of lower urinary tract symptoms score pre- and postweight loss surgery. The primary outcome was International Prostate Symptom Score (IPSS) before and after bariatric surgery. Secondary outcomes were changed in body mass index (BMI) and total body weight (TBW). Weighted mean differences (MD) were calculated for continuous outcomes. Seven studies were included in the analysis of 334 patients undergoing bariatric surgery. Mean study follow-up was between 3 and 36 months. IPSS score ranged from 3–12.7 preoperatively and 1.9–6.9 postoperatively. There was a statistically significant improvement in the IPSS score following bariatric surgery (MD 2.82, 95% CI 0.96 to 4.69, p=0.003). Bariatric surgery also resulted in statistically significant reduction of BMI and TBW. Bariatric surgery produces a significant improvement on lower urinary tract symptoms in men with obesity. This may be due to improvement of insulin sensitivity, testosterone levels or lipid profile associated with weight loss.

This prospective study evaluated oral transmucosal pentobarbital sodium at three doses in 110 wild-caught wild birds requiring euthanasia. Birds received transmucosal pentobarbital at five (430 mg/kg), six (516 mg/kg), and seven times (602 mg/kg) the intravenous dose for mammals. Time to first effects and loss of consciousness, presence of pupillary light and corneal reflexes, apnea, and asystole were recorded each minute. When asystole was not achieved at 5 minutes, IV pentobarbital was administered. Combining data for all doses, loss of consciousness occurred at a median (range) of 2 minutes (0-4.75 min), apnea at 3 minutes (0-6 min), and asystole at 4 minutes (0.5-5 min). Loss of consciousness and apnea occurred significantly faster in the 602 mg/kg dose group than in the 430 mg/kg group (p = 0.009, difference of 0.6 ± 0.2 min; p = 0.024, difference of 0.7 ± 0.3 min), respectively. Apnea and asystole were achieved in 80/110 birds within 5 minutes. Oral transmucosal pentobarbital results in rapid loss of consciousness and respiratory arrest and provides a reliable alternative euthanasia method compared to intravenous administration.

Metabolic surgery provision is severely limited despite extensive supportive trial evidence. This study estimated the eligible population and the unmet need for metabolic surgery within English regions. Health Survey for England, National Diabetes Audit and population estimates were used to estimate the metabolic surgery eligible population by English region. Hospital Episode Statistics data was examined for metabolic surgery procedure volume by region (2013-2019). Regression analysis examined factors associated with metabolic surgery eligibility. 7.3% of the English population is potentially eligible for metabolic surgery; equivalent to 3.21 million people. Only 0.20% of the eligible English population receive metabolic surgery per year (regional variation 0.08-0.41%). The metabolic surgery eligible population was more likely to be female, older, have fewer educational qualifications and live in more deprived areas.

Subtotal cholecystectomy (SC) is a technique to manage the difficult gallbladder and avoid hazardous dissection and biliary injury. Until recently it was used infrequently. However, because of reduced exposure to open total cholecystectomy in resident training, we recently adopted subtotal cholecystectomy as the bail-out procedure of choice for resident teaching. This study reports our experience and outcomes with subtotal cholecystectomy in the years immediately preceding adoption and since adoption. A retrospective analysis was conducted of patients undergoing SC from July 2010 to June 2019. Outcomes, including bile leak, reoperation and need for additional procedures, were analyzed. Complications were graded by the Modified Accordion Grading Scale (MAGS). 1571 cholecystectomies were performed of which 71 were SC. Subtotal cholecystectomy patients had several indicators of difficulty including prior attempted cholecystectomy and previous cholecystostomy tube insertion. The most common indication for SC was marked inflammation in the hepatocystic triangle (51%). As our experience increased, fewer patients required open conversion to accomplish SC and SC was completed laparoscopically, usually subtotal fenestrating cholecystectomy (SFC). Most patients (85%) had a drain placed and 28% were discharged with a drain. The highest MAGS complication observed was grade 3 (11 patients, 15%). Six patients had a bile leak from the cystic duct resolved by ERCP. At mean follow-up of about 1 year no patient returned with recurrent symptoms. Subtotal fenestrating cholecystectomy is a useful technique to avoid biliary injury in the difficult gallbladder and can be performed with very satisfactory rates of bile fistula, ERCP, and reoperation.

Recent studies have shown that suicidality among transgender youth are 3.6 times more likely to report suicidal ideation and 3.2 times more likely to attempt suicide compared with cisgender youth. To alleviate the suicide rates among transgender youth, research suggests the need for family-based interventions. This case study explores the integration of structural family therapy and the Satir growth model to increase connection and support within the family, while also creating clear boundaries that are protective and growth-enhancing. This study provides a session by session overview of how the therapist integrated the models while working with the entire family unit.

In this study, we examined the relationships between prior trauma, alexithymia, and sexual aggression perpetration among 610 U.S. college students and 107 college students from the Philippines utilizing a cross-sectional retrospective design. We tested a moderated mediation model with alexithymia as the mediator between prior trauma and sexual aggression perpetration, and alcohol use as a moderator of the alexithymia–sexual aggression link. Moreover, given that cultural norms may influence these relationships, we also examined the structural invariance of the proposed moderated mediation model. Path analyses and multiple group analysis were used to examine the moderated mediation model, and examine model differences between samples. We did not find evidence for alexithymia as a mediator, but there was a significant interaction between alcohol use severity and alexithymia on sexual aggression perpetration across both samples. Alexithymia is a key variable in understanding the alcohol use–sexual aggression perpetration relationship. Clinical implications and recommendations for future research are also discussed.

We present a new methodology for measuring few-femtosecond electronic and nuclear dynamics in both atoms and polyatomic molecules using multidimensional high harmonic generation (HHG) spectroscopy measurements, in which the spectra are recorded as a function of the laser intensity to form a two-dimensional data set. The method is applied to xenon atoms and to benzene molecules, the latter exhibiting significant fast nuclear dynamics following ionization. We uncover the signature of the sub-cycle evolution of the returning electron flux in strong-field ionized xenon atoms, implicit in the strong field approximation but not previously observed directly. We furthermore extract the nuclear autocorrelation function in strong field ionized benzene cations, which is determined to have a decay of $$\tau _0 = 4 \pm 1$$ τ 0 = 4 ± 1 fs, in good agreement with the $$ \tau _0 = 3.5$$ τ 0 = 3.5 fs obtained from direct dynamics variational multi-configuration Gaussian calculations. Our method requires minimal assumptions about the system, and is applicable even to un-aligned polyatomic molecules.

Sedation and/or anesthesia is routinely and successfully used in raptors for a wide variety of procedures from the routine such as physical examination, radiographs, or venipuncture, to the more complex, such as orthopedic surgeries. Understanding the anatomy and physiology of raptor patients who present for care, and being fully prepared before the start of any procedure, can increase the success of anesthetic procedures. Recent advances in raptor sedation and anesthesia continue to improve the health and welfare of these avian patients.

Single cell RNA sequencing (scRNA-seq) is a powerful technology to investigate the transcriptional programs in stromal, immune and tumor cells or neuron cells within the tumor or Alzheimer’s Disease (AD) brain microenvironment (ME) or niche. Cell-cell communications within ME play important roles in disease progression and immunotherapy response, and are novel and critical therapeutic targets. Though many tools of scRNA-seq analysis have been developed to investigate the heterogeneity and sub-populations of cells, few were designed for uncovering cell-cell communications of ME and predict the potentially effective drugs to inhibit the communications. Moreover, the data analysis processes of discovering signaling communication networks and effective drugs using scRNA-seq data are complex and involving a set of critical analysis processes and external supportive data resources, which are difficult for researchers who have no strong computational background and training in scRNA-seq data analysis. To address these challenges, in this study, we developed a novel computational tool, SC2MeNetDrug (https://fuhaililab.github.io/sc2MeNetDrug/). It was specifically designed using scRNA-seq data to identify cell types within MEs, uncover the dysfunctional signaling pathways within individual cell types, inter-cell signaling communications, and predict effective drugs that can potentially disrupt cell-cell signaling communications. SC2MeNetDrug provided a user-friendly graphical user interface to encapsulate the data analysis modules, which can facilitate the scRNA-seq data based-discovery of novel inter-cell signaling communications and novel therapeutic regimens.

Allogeneic cancer vaccines are designed to induce antitumor immune responses with the goal of impacting tumor growth. Typical allogeneic cancer vaccines are produced by expansion of established cancer cell lines, transfection with vectors encoding immunostimulatory cytokines, and lethal irradiation. More than 100 clinical trials have investigated the clinical benefit of allogeneic cancer vaccines in various cancer types. Results show limited therapeutic benefit in clinical trials and currently there are no FDA-approved allogeneic cancer vaccines. We used recently developed bioinformatics tools including the pVACseq suite of software tools to analyze DNA/RNA-sequencing data from the The Cancer Genome Atlas to examine the repertoire of antigens presented by a typical allogeneic cancer vaccine, and to simulate allogeneic cancer vaccine clinical trials. Specifically, for each simulated clinical trial, we modeled the repertoire of antigens presented by allogeneic cancer vaccines consisting of three hypothetical cancer cell lines to 30 patients with the same cancer type. Simulations were repeated ten times for each cancer type. Each tumor sample in the vaccine and the vaccine recipient was subjected to human leukocyte antigen (HLA) typing, differential expression analyses for tumor-associated antigens (TAA), germline variant calling, and neoantigen prediction. These analyses provided a robust, quantitative comparison between potentially beneficial TAAs and neoantigens versus distracting antigens present in the allogeneic cancer vaccines. We observe that distracting antigens greatly outnumber shared TAAs and neoantigens, providing one potential explanation for the lack of observed responses to allogeneic cancer vaccines. This analysis provides additional rationale for the redirection of efforts toward a personalized cancer vaccine approach. Significance: A comprehensive examination of allogeneic cancer vaccine antigen repertoire using large-scale genomics datasets highlights the large number of distracting antigens and argues for more personalized approaches to immunotherapy that leverage recent strategies in tumor antigen identification.

Atherosclerosis is a chronic inflammatory disease that has been reported to affect the cardiovascular system of many avian species. However, atherosclerosis in raptor species has not been fully evaluated. The aim of this study was to histologically characterize central and peripheral atherosclerotic lesions in raptors that were submitted to a pathology service in Northern California from 1986 to 2013. We also evaluated risk factors, including age, gender, origin, and avian family. Atherosclerotic lesions were categorized as minimal, mild, moderate, or severe, based on the severity of the lesions and their distribution within the arterial wall. Among the central arteries, lesions were determined to be of greater severity in the aorta than in the pulmonary artery. More than 50% of the peripheral arteries were affected, including 53.1% (17/32) myocardial, 52% (13/25) coronary, 62.9% (22/35) arteries in the kidney, 52.2% (12/23) gonadal and 51.7% (15/29) splenic arteries; however, hepatic and pulmonary arteries were uncommonly affected. Atherosclerosis was diagnosed in 17 raptor species representing 4 families: Accipitridae, Cathartidae, Falconidae, and Strigidae. The overall prevalence (95% CI) of atherosclerosis in raptors was 2.3% (36/1574; range, 1.63%-3.19%) with the Falconidae having the highest prevalence at 7.4% (9/122; range 3.64%-13.93%) and with 0% detected in the Tytonidae and Pandionidae families. A multiple logistic regression model that jointly accounted for differences in risk by family, age, and gender found that the risk in Accipitridae was significantly less than that of Falconidae, that adult raptors were at greater risk of atherosclerotic lesions than juveniles were, and that females were more frequently affected than males were.

Chlamydial infections, caused by a group of obligate, intracellular, gram-negative bacteria, have health implications for animals and humans. Due to their highly infectious nature and zoonotic potential, staff at wildlife rehabilitation centers should be educated on the clinical manifestations, prevalence, and risk factors associated with Chlamydia spp. infections in raptors. The objectives of this study were to document the prevalence of chlamydial DNA shedding and anti-chlamydial antibodies in raptors admitted to five wildlife rehabilitation centers in California over a one-year period. Chlamydial prevalence was estimated in raptors for each center and potential risk factors associated with infection were evaluated, including location, species, season, and age class. Plasma samples and conjunctiva/choana/cloaca swabs were collected for serology and qPCR from a subset of 263 birds of prey, representing 18 species. Serologic assays identified both anti-C. buteonis IgM and anti-chlamydial IgY antibodies. Chlamydial DNA and anti-chlamydial antibodies were detected in 4.18% (11/263) and 3.14% (6/191) of patients, respectively. Chamydial DNA was identified in raptors from the families Accipitridae and Strigidae while anti-C.buteonis IgM was identified in birds identified in Accipitridae, Falconidae, Strigidae, and Cathartidae. Two of the chlamydial DNA positive birds (one Swainson’s hawk (Buteo swainsoni) and one red-tailed hawk (Buteo jamaicensis)) were necropsied, and tissues were collected for culture. Sequencing of the cultured elementary bodies revealed a chlamydial DNA sequence with 99.97% average nucleotide identity to the recently described Chlamydia buteonis. Spatial clusters of seropositive raptors and raptors positive for chlamydial DNA were detected in northern California. Infections were most prevalent during the winter season. Furthermore, while the proportion of raptors testing positive for chlamydial DNA was similar across age classes, seroprevalence was highest in adults. This study questions the current knowledge on C. buteonis host range and highlights the importance of further studies to evaluate the diversity and epidemiology of Chlamydia spp. infecting raptor populations.

Background Obesity is a chronic disease with multisystem morbidity. There are multiple studies reporting the effect of bariatric surgery on cardiovascular and metabolic disease but only few examine its impact on lower urinary tract symptoms. This article aims to perform a systematic review with meta-analysis in order to determine the effects of bariatric surgery on lower urinary tract symptoms in male patients. Methods Medline, Embase, conference proceeding and reference lists were searched for studies reporting the quantative measurement of lower urinary tract symptoms score pre- and post-weight loss surgery. The primary outcome was International Prostate Symptom Score (IPSS) before and after bariatric surgery. Secondary outcomes were change in Body Mass Index (BMI) and Total Body Weight (TBW). Weighted mean differences (MD) were calculated for continuous outcomes. Results Seven studies were included in the analysis of 334 patients undergoing bariatric surgery. Mean study follow-up was between 3 and 36 months. There was a statistically significant improvement in the IPSS score following bariatric surgery (MD 2.82, 95% CI 0.96 to 4.69, p = 0.003). Bariatric surgery also resulted in statistically significant reduction of BMI and TBW. Conclusion Bariatric surgery produces a significant improvement on lower urinary tract symptoms in men with obesity. This may be due to improvement of insulin sensitivity, testosterone levels or lipid profile associated with weight loss. Further studies are necessary to investigate in detail the pathophysiological mechanisms through which lower urinary tract symptoms develop in obese patients, and their improvement following weight loss surgery.

Accurate grading of neuroendocrine neoplasms (NENs) is crucial for proper assessment of prognosis. Estimation of the proliferative indices, if not performed properly, is largely erroneous due to significant intratumoral heterogeneity. We sought to establish the degree of error in the grading of a cohort of curatively resected pancreatic NENs (PanNENs) and the theoretical impact of that in a larger cohort of Surveillance, Epidemiology, and End Results (SEER) patients. A retrospective query of an institutional surgical database was performed from 2000 to 2018 to identify optimally resected PanNENs, which were reviewed by two gastrointestinal pathologists and regraded according to the WHO 2017 classification. Overall survival and recurrence-free survival were estimated using the Kaplan–Meier method for original and new grading systems, respectively and Cox proportional hazards models were used to evaluate the effect of the interested variables, including new grading systems. A total of 176 cases were identified. After regrading, 17/64 (26.6%) G1 neoplasms were classified as G2 and 12/95 (12.6%) G2 neoplasms were classified as G1, while 1/11 (9.1%) G3 neoplasms were classified as G2. Our expert gastrointestinal pathologists agreed on 97% of reclassified cases by blind review. Application of the G1/G2 misclassification errors on various groups, including PanNENs, in a SEER database of 1385 patients rendered the reported survival differences nonsignificant (1000 repetitions; p = 0.063, 95% confidence interval 0.056–0.070). Mischaracterization of grade is common in optimally resected PanNENs but is eliminated with proper training and adherence to guidelines. The discrepancy rates can cast doubt on the generally accepted survival differences between G1 and G2 patients, as surmised by large database analyses.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8+ T cells was driven by B cell– but not regulatory T cell–specific production of IL35. We also demonstrated that B cell–specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti–PD-1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3−CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell–mediated IL35/gp130/STAT3 signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.

The tumor microenvironment in pancreatic ductal adenocarcinoma plays a vital role in treatment response, and therefore, patient survival. We and others have observed an intimate association of neoplastic ductal cells with non-neoplastic islet cells, recapitulating the ducto-insular complex. We define this phenomenon as tumor-insular complex. Herein, we describe the clinicopathologic characteristics of tumor-insular complex in neoadjuvant treated pancreatic ductal adenocarcinoma cases for the first time. We retrospectively reviewed the pathology of 105 cases of neoadjuvant treated pancreatic ductal adenocarcinoma resected at our institution. Tumor-insular complex was noted in 35 cases (33.3%), the mean tumor bed size was 2.7 ±1.0 cm, mean percentage of residual tumor 40 ±28% and mean residual tumor index (an index previously established as a prognostic parameter by our group) was 1.1 ±1.0. Tumor-insular complex was significantly associated with perineural invasion (p=0.001), higher tumor bed size (p=0.007), percentage of residual tumor (p=0.009), residual tumor index (p=0.001), ypT-stage (p=0.045), and a poor treatment response, grouped by a previously established criteria (p=0.010). Using our prior binary reported prognostic cutoff for residual tumor index of ≤0.35 and >0.35, tumor-insular complex was associated with a residual tumor index >0.35 (p=0.002). Moreover, patients who did not receive neoadjuvant radiation were associated with a higher frequency of tumor-insular complex (p=0.003). In this cohort, residual tumor index but not tumor-insular complex, was also shown to be a significant independent prognosticator for recurrence free and overall survival on multivariate analysis. In conclusion, tumor-insular complex is significantly associated with a more aggressive neoplasm which shows a poor treatment response. Further studies will be needed to better understand the tumor biology of tumor-insular complexes.

The goal of this pilot study was to track patient outcomes after an expedited discharge after enhanced recovery after surgery (ERAS) pathway for pancreaticoduodenectomy (PD). A quantitative content analysis approach was used. All PD patients in a single academic medical center between February 2017 and June 2018 were called twice by specialized physician extenders after discharge. A semi-structured interview approach was used to identify patient's symptoms or concerns, proactively educate them, and provide outpatient management when indicated. A detailed narrative of the conversation was documented. Ninety patients (mean age 66.3; 58.1% males) were included in the study. Of all, 88.9 per cent of the patients received follow-up phone calls in accordance with our PD ERAS protocol. Among the 80 patients called, 71 (88.8%) reported at least one symptom, issue, or self-care need. The most common issues involved bowel movements and nutrition. A total of 147 interventions were performed to address patient needs including medication management, local care coordination, and outpatient referral to a healthcare provider. The intervention led to the identification of 15 patients for earlier evaluation. This identification was associated with the total number of reported symptoms ( X2 = 15.6, P = 0.004). Most patients require additional care after discharge after traditional ERAS pathways. ERAS transitional care protocols uncovered an unmet need for additional patient support after PD.

PURPOSE: Postoperative length of stay (PLOS) and readmission rate are pancreatoduodenectomy (PD) outcome measures, which are reported individually but may be interrelated. The purpose of this study was to evaluate how well a composite length of stay measure (CLOS) that included PLOS and readmission length of stay describes outcomes. To do so, we evaluated how well CLOS correlated to postoperative complications absolutely and compared to PLOS. METHODS: A total of 668 PDs performed between 2011 and 2018 were evaluated. CLOS was calculated from PLOS and readmission length of stay. Complication severity was judged by the Modified Accordion Grading System (MAGS). Multinomial logistical regression models (MLRM) were used to investigate the relationship between either PLOS or CLOS and complications. Multilevel and pairwise area under curves (AUC) using SAS macro %MultAUC were provided for both models. RESULTS: A total of 432 of 668 patients (65%) developed complications. One hundred seventy-seven patients (27%) were readmitted. Mean PLOS was 10.2 days (7.1 SD) and mean CLOS was 12.3 days (10.1 SD). PLOS and CLOS both were correlated linearly to MAGS grade. Spearman correlation coefficient for CLOS vs. MAGS of 0.68 was higher than that of 0.49 for PLOS vs. MAGS. Multilevel AUC from MLRM using PLOS was 0.66, but multilevel AUC from MLRM using CLOS was 0.71. DISCUSSION: CLOS provides an accurate estimate of hospital day utilization per patient for PD, reflecting not only the basal hospital recovery time for PD but the added time needed because of readmissions due to complications. It is tightly correlated to number and severity of postoperative complications.

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host immune response to infection. The purpose of this investigation was to determine the differential effect of sepsis on innate versus adaptive immunity, in humans, by examining RNA expression in specific immune cell subsets, including monocytes/macrophages and CD4 and CD8 T cells. A second aim was to determine immunosuppressive mechanisms operative in sepsis that might be amenable to immunotherapy. Finally, we examined RNA expression in peripheral cells from critically ill nonseptic patients and from cancer patients to compare the unique immune response in these disorders with that occurring in sepsis. Monocytes, CD4 T cells, and CD8 T cells from septic patients, critically ill nonseptic patients, patients with metastatic colon cancer, and healthy controls were analyzed by RNA sequencing. Sepsis induced a marked phenotypic shift toward downregulation of multiple immune response pathways in monocytes suggesting that impaired innate immunity may be fundamental to the immunosuppression that characterizes the disorder. In the sepsis cohort, there was a much more pronounced effect on gene transcription in CD4 T cells than in CD8 T cells. Potential mediators of sepsis-induced immunosuppression included Arg-1, SOCS-1, and SOCS-3, which were highly upregulated in multiple cell types. Multiple negative costimulatory molecules, including TIGIT, Lag-3, PD-1, and CTLA-4, were also highly upregulated in sepsis. Although cancer had much more profound effects on gene transcription in CD8 T cells, common immunosuppressive mechanisms were present in all disorders, suggesting that immunoadjuvant therapies that are effective in one disease may also be efficacious in the others.

Ewing sarcoma is a bone tumor most commonly diagnosed in adolescents and young adults. Survival for patients with recurrent or metastatic Ewing sarcoma is dismal and there is a dire need to better understand the mechanisms of cell metastasis specific to this disease. Our recent work demonstrated that microenvironmental stress leads to increased Ewing sarcoma cell invasion through Src activation. Additionally, we have shown that the matricellular protein tenascin C (TNC) promotes metastasis in Ewing sarcoma. A major role of both TNC and Src is mediation of cell–cell and cell-matrix interactions resulting in changes in cell motility, invasion, and adhesion. However, it remains largely unknown, if and how, TNC and Src are linked in these processes. We hypothesized that TNC is a positive regulator of invadopodia formation in Ewing sarcoma through its ability to activate Src. We demonstrate here that both tumor cell endogenous and exogenous TNC can enhance Src activation and invadopodia formation in Ewing sarcoma. We found that microenvironmental stress upregulates TNC expression and this is dampened with application of the Src inhibitor dasatinib, suggesting that TNC expression and Src activation cooperate to promote the invasive phenotype. This work reports the impact of stress-induced TNC expression on enhancing cell invadopodia formation, provides evidence for a feed forward loop between TNC and Src to promote cell metastatic behavior, and highlights a pathway by which microenvironment-driven TNC expression could be therapeutically targeted in Ewing sarcoma.

Background Mammary fibroadenomas are one of the most common tumors of female companion rats (Rattus norvegicus forma domestica). The objectives of this study were to determine if subcutaneous administration of a deslorelin implant following excision of fibroadenomas can prevent or delay development of additional mammary tumors and increase survival in companion rats. Methods Female intact client-owned rats with benign mammary tumors were divided into three groups: no implant (n = 10), placebo implant (n = 10), or 4.7 mg deslorelin implant (n = 10) placed within 2 months of tumor excision. Rats were monitored for subsequent mammary tumors for 10 months following treatment. Expression of estrogen α, progesterone, prolactin, and androgen receptors stained by immunohistochemistry in primary masses of rats included in the deslorelin-treated group was evaluated using the Allred scoring system. Results In the control non-implanted group, four of the 10 rats developed another mammary tumor, including one anaplastic carcinoma. In the control placebo group, five of the 10 rats developed another mammary tumor, including one ductal carcinoma. In the deslorelin-treated group, three of 10 rats developed another mammary tumor, including one adenocarcinoma. Median time between surgery and new mass detection did not differ significantly among groups (55 days in the deslorelin group vs. 77 days in the control placebo group, P = 0.25). Median survival times after surgery did not differ significantly among groups. No correlation was noted between receptor expression and response to treatment with deslorelin. Conclusions and clinical relevance Deslorelin implants placed within 2 months of benign mammary tumor surgical excision were not associated with a decreased risk of developing subsequent mammary tumors, nor with an increased survival in female rats. Further studies are needed to define useful adjunct therapy to surgery.

OBJECTIVE: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy. BACKGROUND: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown. METHODS: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19–9 decrease ≥50% vs

Research suggests college-aged young adults are hesitant to seek treatment for alcohol use disorder and highlights barriers contributing to a gap in treatment utilization. One barrier to treatment utilization is the lack of information about available treatment resources. Motivated by the literature on web-based screening and brief interventions (eSBIs), the current study examined whether providing a brief online feedback of one's alcohol use risk severity will make college students more likely to access information about available treatment options for alcohol-related issues. College students (N = 724) who responded to the Alcohol Use Disorder Identification Test ( Babor, Higgins-Biddle, Saunders, & Monteiro, 2001 ) were randomly assigned to receive a brief online feedback on their alcohol use risk or to a no-feedback condition. Overall, only 20% of all participants opted to view available treatment services for alcohol issues. Participants in the feedback group (15%) were significantly less likely to view information for available services compared to the no-feedback group (24%). A significant feedback condition x stigma interaction effect was found, such that those with average and high stigma towards substance use scores were less likely to view treatment information when provided feedback. Without a thorough discussion of individual risks and without the safeguards against psychological reactance present in eSBIs, providing college students with brief online feedback about their alcohol use risk severity made them less likely to access information concerning available on-campus mental health resources for alcohol issues. On the other hand, improving help-seeking attitudes could help increase treatment utilization.

Purpose: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1− tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines. Experimental Design: ASS1− tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1+) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX. Results: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM:DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma. Conclusions: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.

Children who experience enuresis and encopresis can face many difficulties, including social isolation, shame, embarrassment, anxiety, and depression. Due to the prevalence of enuresis and encopresis, it is essential for mental health professionals to understand the common symptoms and available treatment options for enuresis and encopresis, particularly to assist parents struggling to help their children overcome these challenges. Despite this need, there is very little clinical literature that incorporates a systemic approach for families who have a child diagnosed with enuresis and encopresis. Furthermore, common treatment approaches may unwittingly reinforce children’s perception that these problems are rooted in their identity. In an effort to address these concerns, the present case study aims to illustrate how a narrative therapy approach was utilized to effectively treat a child with enuresis and encopresis. Narrative therapy can uniquely assist children and their parents by helping them externalize the problem, overcome the problem-saturated view of their lives, and create new experiences where the problem is nonexistent.

A 4-year-old intact female Holland lop rabbit (Oryctolagus cuniculus) was referred for evaluation of a luxated right coxofemoral joint. Cranioventral luxation of the right femoral head was confirmed with pelvic radiographs at the referring veterinarian 3 days prior. On presentation, a nonweight bearing right pelvic limb lameness was appreciated. A closed hip reduction under anesthesia was attempted but not successful. The rabbit underwent an open coxofemoral reduction and the reduction was protected using a toggle rod stabilization method. A toggle pin was placed on the medial aspect of the acetabulum and fastened with suture to a second toggle pin on the lateral aspect of the femur, via a bone tunnel through the fovea capitus. Postoperative radiographs confirmed reduction of the coxofemoral joint and appropriate implant placement. Immediately following surgery, the rabbit began weight bearing on the right pelvic limb. Repeat evaluations showed a complete resolution to the rabbit's lameness, with no recurrence of the coxofemoral luxation. At rest, the right pelvic limb was intermittently mildly abducted; however, gait was not affected. This is the first case report to document a toggle pin fixation for successful repair of a coxofemoral luxation in a rabbit.

Purpose This study aimed to improve the understanding of deviations between planned and accumulated doses and to establish metrics to predict clinically significant dosimetric deviations midway through treatment to evaluate the potential need to re-plan during fractionated radiation therapy (RT). Methods and materials A total of 100 patients with head and neck cancer were retrospectively evaluated. Contours were mapped from the planning computed tomography (CT) scan to each fraction cone beam CT via deformable image registration. The dose was calculated on each cone beam CT and evaluated based on the mapped contours. The mean dose at each fraction was averaged to approximate the accumulated dose for structures with mean dose constraints, and the daily maximum dose was summed to approximate the accumulated dose for structures with maximum dose constraints. A threshold deviation value was calculated to predict for patients needing midtreatment re-planning. This predictive model was applied to 52 patients treated at a separate institution. Results Dose was accumulated on 10 organs over 100 patients. To generate a threshold deviation that predicted the need to re-plan with 100% sensitivity, the submandibular glands required re-planning if the delivered dose was at least 3.5 Gy higher than planned by fraction 15. This model predicts the need to re-plan the submandibular glands with 98.7% specificity. In the independent evaluation cohort, this model predicts the need to re-plan the submandibular glands with 100% sensitivity and 98.0% specificity. The oral cavity, intermediate clinical target volume, left parotid, and inferior constrictor patient groups each had 1 patient who exceeded the threshold deviation by the end of RT. By fraction 15 of 30 to 35 total fractions, the left parotid gland, inferior constrictor, and intermediate clinical target volume had a dose deviation of 3.1 Gy, 5.9 Gy, and 4.8 Gy, respectively. When a deformable image registration failure was observed, the dose deviation exceeded the threshold for at least 1 organ, demonstrating that an automated deformable image registration–based dose assessment process could be developed with user evaluation for cases that result in dose deviations. Conclusions A midtreatment threshold deviation was determined to predict the need to replan for the submandibular glands by fraction 15 of 30 to 35 total fractions of RT.

While similarities exist between male and female survivors of sexual assault, unique barriers often prohibit males from speaking out about their experiences. The me too hashtag was created ...

CASE DESCRIPTION A 4-year-old spayed female mixed-breed rabbit was evaluated because of a 3-year history of sneezing and nasal discharge that were refractory to medical management. CLINICAL FINDINGS Signs of chronic left-sided rhinitis and sinusitis were observed on physical examination and confirmed by CT evaluation. Lysis of the rostral aspect of the left maxillary bone and destruction of nasal turbinates were evident on CT images. TREATMENT AND OUTCOME Pararhinotomy of the left maxillary sinus through the facies cribrosa was performed. Purulent material was removed from the maxillary sinus recesses, a middle meatal antrostomy was completed to allow permanent drainage into the left middle nasal meatus, and the tissues were closed routinely. Microbial culture of a sample from the maxillary sinus recesses revealed Bordetella bronchiseptica, undetermined fastidious nonenteric bacteria, and Streptococcus viridans. Medical management was continued, and nasal discharge resolved but sneezing persisted. Increased sneezing and bilateral nasal discharge developed 1.5 years later; CT examination revealed right-sided rhinitis, and culture of a nasal swab sample revealed Bordetella spp, Staphylococcus spp, and Micrococcus spp. Right-sided pararhinotomy and middle meatal antrostomy were performed, and medical management continued. A subsequent recurrence was managed without additional surgery; 4 years after the initial surgery, the rabbit was still receiving medical treatment, with mild intermittent nasal discharge and sneezing reported. CLINICAL RELEVANCE This report describes a surgical approach for treatment of chronic rhinitis in companion rabbits with maxillary sinus involvement that included creation of a permanent drainage pathway from the maxillary sinus to the middle nasal meatus.

Purpose: FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system. Experimental Design: Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (n = 20) and FOLFIRINOX-treated patients (n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF). Results: Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27−Tbet+ effector/effector memory subsets of CD4 and CD8 T cells. Conclusions: Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.

Childhood abuse and sexual violence against women are prevalent in the United States. However, researchers have not fully explored the intersection among important predisposing factors that predict recent sexual violence experienced by women who are also survivors of childhood abuse. The purpose of this study was to examine the relationships among early childhood trauma, alexithymia, impulsivity, alcohol use severity, and sexual victimization in later life among female college students from the United States ( n = 1,178). Participants were part of a larger cross-cultural study, conducted between 2012 to 2014, which examined sexual aggression and victimization in the context of alcohol use. The current study aimed to examine if: (a) early trauma, impulsivity, alexithymia, and alcohol use severity impact sexual victimization in later life, and (b) if impulsivity, alexithymia, and alcohol use severity mediate the relationship between early trauma and victimization in later life. It was hypothesized that impulsivity, alexithymia, and alcohol use severity would significantly mediate the relationship between early trauma and sexual victimization in later life. Using a multiple mediation path analysis, results indicated that early childhood trauma was significantly linked with impulsivity, alcohol use severity, and sexual victimization in later life. A partial mediation through impulsivity and alcohol use severity was observed. Alexithymia did not produce mediation effects. These findings align with previous research examining how early childhood trauma influences the occurrence of sexual victimization in later life and provides further recommendations for helping professionals as they attempt to stifle the sexual victimization rates among female college students.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

Purpose/objective(s) Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with a poor prognosis. There is a critical need for robust biomarkers to better risk-stratify patients and personalize treatment. Here, we utilize single-cell RNA sequencing (scRNA-seq) and CIBERSORTx deconvolution to genomically classify PDAC based on distinct tumor cell states in order to more accurately prognosticate patients. Materials/methods scRNA-seq was conducted on 24 PDAC patient samples prior to any systemic therapy at Washington University (19 core needle pancreatic biopsies from the time of diagnosis and 5 surgical PDAC resections) and from the public domain (n = 34). The resulting scRNA-seq data from 58 patients was integrated and clustered in order to identify distinct tumor cell states. Following gene expression profiling analysis to characterize each distinct tumor cell state, CIBERSORTx was used to deconvolve 125 bulk RNA-seq early-stage PDAC tumor samples from The Cancer Genome Atlas (TCGA), and each tumor was classified based on the dominant malignant cell state present. Following this, survival analysis was performed to compare between different groupings of TCGA patients based on their dominant malignant cell states. Results scRNA-seq data from 58 public and in-house samples were clustered and cell types were annotated based on known expression markers. We then clustered the malignant cell cluster (Epcam+) into 5 distinct tumor cell states. Fractions of these 5 malignant cell states were then quantified in TCGA via deconvolution using CIBERSORTx. TCGA samples were categorized into 5 groups based on the dominating malignant (mal) cell state fraction value - ranging from mal 0 to mal 4. In this fashion, we identified 39 patients as mal 0, 9 as mal 1, 6 as mal 2, 2 as mal 3, and 69 as mal 4. Gene expression profiling analysis revealed that the mal 0 cell state is representative of the "squamous-like" or "basal" subtype reported in prior literature, while mal 1-4 more likely represent the previously described "classical" subtype. We then aimed to perform survival analysis. To achieve meaningful statistical power, we grouped mal 1-3 into one category (called mixed) containing 17 patients. Kaplan-Meier analysis revealed the following median survival times (in months): mal 0 (9 months), mal 4 (16 months), and mixed (15 months). Log-rank statistical testing revealed that patients classified as mal 0 experienced significantly worse overall survival than those classified as other mal subtypes (P Conclusion We analyzed scRNA-seq data from 58 independent PDAC patients, which we used to identify 5 distinct tumor cell states. These tumor cell states appear to correspond with the previously reported "squamous-like" or "basal" vs. "classical" subtypes, correlate significantly with overall survival, and could potentially inform more personalized treatment strategies including radiotherapy in the future.