CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma.

Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.

Emerging fungal infections in solid organ transplant recipients: Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice.

These updated AST-IDCOP guidelines review the epidemiology, diagnosis, and management of emerging fungi after organ transplantation. Infections due to numerous generally innocuous fungi are increasingly recognized in solid organ transplant (SOT) recipients, comprising about 7%-10% of fungal infections in this setting. Such infections are collectively referred to as emerging fungal infections and include Mucormycetes, Fusarium, Scedosporium, and dematiaceous fungi among others. The causative organisms are diverse in their pathophysiology, uncommon in the clinical setting, have evolving nomenclature, and are often resistant to multiple commonly used antifungal agents. In recent years significant advances have been made in understanding of the epidemiology of these emerging fungal infections, with improved diagnosis and expanded treatment options. Still, treatment guidelines are generally informed by and limited to experience from cohorts of patients with hematological malignancies and/or solid and stem cell transplants. While multicenter randomized controlled trials are not feasible for these uncommon infections in SOT recipients, collaborative prospective studies can be valuable in providing information on the epidemiology, clinical manifestations, treatment strategies, and outcomes associated with the more commonly encountered infections.

Burden and frequency of viral testing of kidney and non-kidney transplant recipients.

Transplant patients are at risk of infections due to long-term immunosuppression contributing to morbidity and mortality in this population. Post-transplant testing guidelines were established to monitor and guide therapeutic interventions in transplant recipients. We hypothesize that there are gaps in adherence to the recommended frequency of laboratory testing in post-transplant patients. We analyzed national reference laboratory data to compare viral post-transplant infection (PTI) testing frequency with their respective published guidelines to understand patient uptake and compliance. We evaluated the ordering patterns, positivity rates, and frequency of molecular infectious disease tests (MIDTs). We included 345 patients with International Classification of Diseases (ICD)-10 codes for transplant (Z940-Z942, Z944, Z9481, Z9483, Z9484) with at least two tests (within 7 days) in January 2019 and at least one test in December 2020 to find patients in the post-transplant period. We analyzed two cohorts: kidney transplant recipients (KTRs; 40%) and non-KTR (60%) then followed them longitudinally for the study period. In KTR cohort, high-to-low proportion of ordered MIDT was blood BK virus (bBKV) followed by cytomegalovirus (CMV); in non-KTR cohort, CMV was followed by Epstein-Barr virus (EBV). KTR cohort positivity was highest for urine BK virus (uBKV; 58%) followed by EBV (46%), bBKV (40%), and CMV (31%). Non-KTR cohort positivity was highest for uBKV (64%), EBV (51%), CMV (30%), bBKV (8%), and adenovirus (7%). All patients were tested at progressively longer intervals from the date of the first post-transplant ICD-10-coded test. More than 40% of the KTR cohort were tested less frequently for EBV and bBKV, and more than 20% of the non-KTR cohort were tested for EBV less frequently than published guidelines 4 months after transplant. Despite regular testing, the results of MIDT testing for KTR and non-KTR patients in the post-transplant period are not aligned with published guidelines.IMPORTANCEGuidance for post-transplant infectious disease testing is established, however, for certain infections it allows for clinician discretion. This leads to transplant center policies developing their own testing/surveillance strategies based on their specific transplant patient population (kidney, stem cell, etc.). The Organ Procurement and Transplant Network (OPTN) has developed a strategic plan to improve and standardize the transplant process in the US to improve outcomes of living donors and recipients. Publishing national reference lab data on the testing frequency and its alignment with the recommended guidelines for post-transplant infectious diseases can inform patient uptake and compliance for these strategic OPTN efforts.

Use of Low-Cost Task Trainer for Emergency Department Thoracotomy Training in General Surgery Residency Program.

OBJECTIVE: Emergency department thoracotomy (EDT) is an uncommon but potentially lifesaving procedure that warrants familiarity with anatomy, instruments, and indications necessary for completion. To address this need, we developed a low-cost EDT trainer. The primary objective of this study was to compare the effectiveness of a low-cost EDT trainer to teach emergency department thoracotomy with a discussion-based teaching session. Secondary objective was to study the face validity of the low-cost EDT trainer. DESIGN: A prospective 2-phase randomized control study was conducted. Participants were randomly divided into two groups. In phase one, baseline medical knowledge for both groups was assessed using a multiple-choice question pretest. In Group 1, each participant was taught EDT using a one-on-one discussion with a trauma surgeon, whereas Group 2 used the EDT trainer and debriefing for training. In phase 2 (1 month later), all participants completed a knowledge retention test and performed a videoed EDT using our EDT trainer, the video recordings were later reviewed by content experts blinded to the study participants using a checklist with a maximum score of 22. The participants also completed a reaction survey at the end of phase 2 of the study. SETTING: OhioHealth Riverside Methodist Hospital, an urban tertiary care academic hospital in Columbus, Ohio. PARTICIPANTS: Nine senior surgery residents from training years 3 to 5. RESULTS: The mean score for the performance of the procedure for the simulation-based (Group 2) was significantly higher than that of the discussion-based (Group 1) (Rater 1: 21.2 ± 0.8 vs. 19.0 ± 2.0, p = 0.05, Rater 2: 20.4 ± 1.5 vs. 18.3±1.0, p = 0.04). Group 2 also was quicker than Group 1 in deciding to start the procedure by approximately 56 seconds. When comparing the mean pretest knowledge score to the mean knowledge retention score 30 days after training, the discussion-based group improved from 58.33% to 81.25% (p = 0.01); the simulation-trained group's scores remained at 68.33%. All the participants agreed or strongly agreed that the simulator provided a realistic opportunity to perform EDT and improved their confidence. CONCLUSIONS: The results of this pilot study support our hypothesis that using a low-cost EDT trainer effectively improves general surgery residents' confidence and procedural skills scores in a simulated environment. Further training with low-cost simulators may provide surgical residents with deliberate practice opportunities and improve performance when learning low-frequency procedures.

Minimally invasive surgery adoption into an established surgical practice: impact of a fellowship-trained colleague.

BACKGROUND: Practicing general surgeons adopt minimally invasive techniques using training opportunities such as weekend courses, videos, hands-on conferences, and traveling proctors with varying success. By integrating a fellowship-trained surgeon into an established practice, we show that minimally invasive techniques can be readily adopted. METHODS: A retrospective review of operative reports from July 2004 through June 2008 obtained the number of laparoscopic and open appendectomies, colectomies, ventral/incisional hernias, and inguinal hernias performed by five practicing surgeons. Three time intervals were formed: 18 months before arrival of the MIS-trained surgeon, a 12-month transition period, and the 18 months following. Only cases performed by the five surgeons, and not by the MIS-trained surgeon, were included. A survey elicited the opinions of the five surgeons on various aspects of the transition, including barriers and effectiveness of different methods for learning MIS techniques. RESULTS: A total of 4,016 cases were reviewed. The percentage of total cases performed laparoscopically increased from 12.1 to 48.3 %. Laparoscopic appendectomies significantly increased across time periods from 19 to 80 % (p < 0.0001). Adoption of laparoscopic ventral/incisional hernia repairs increased from 4.8 to 20.1 % (p = 0.0322). Laparoscopic inguinal hernias increased from 0.6 to 31.1 % (p < 0.0001). Finally, laparoscopic colectomies significantly increased from 25 to 52 % (p < 0.0001). Survey responses indicated that "mentoring by a colleague with MIS training" was superior to other methods for learning MIS procedures (p = 0.0327-0.0516). CONCLUSIONS: The integration of a fellowship-trained MIS colleague into a general surgery practice resulted in a 300 % increase in the proportion of appendectomies, ventral hernias, inguinal hernias, and colectomies performed laparoscopically by the other members of the practice. When surveyed, the surgeons felt that mentoring by a colleague with MIS training was the most effective method for adopting MIS procedures into their practice.

Cyclin-dependent kinase-9 in B-cell malignancies: pathogenic role and therapeutic implications.

Cyclin-dependent kinases (CDK) regulate cell cycle and transcriptional activity. Pan-CDK inhibitors demonstrated early efficacy in lymphoid malignancies, but also have been associated with narrow therapeutic index. Among transcriptional CDKs, CDK7 and CDK9 emerged as promising targets. CDK9 serves as a component of P-TEFb elongation complex and thus is indispensable in mRNA transcription. Selective CDK9 inhibitors demonstrated pre-clinical efficacy in in vitro and in vivo models of B-cell non-Hodgkin lymphoma. CDK9 inhibition results in transcriptional pausing with rapid downmodulation of short-lived oncogenic proteins, e.g. Myc and Mcl-1, followed by cell apoptosis. Early phase clinical trials established safety of CDK9 inhibitors, with manageable neutropenia, infections and gastrointestinal toxicities. In this review, we summarize the rationale of targeting CDK9 in lymphoid malignancies, as well as pre-clinical and early clinical data with pan-CDK and selective CDK9 inhibitors.

Quantifying Gram-Negative Resistance to Empiric Treatment After Repeat ExpoSure To AntimicRobial Therapy (RESTART).

Background: Antibiotic exposure is a primary predictor of subsequent antibiotic resistance; however, development of cross-resistance between antibiotic classes is also observed. The impact of changing to a different antibiotic from that of previous exposure is not established. Methods: This was a retrospective, single-center cohort study of hospitalized adult patients previously exposed to an antipseudomonal ß-lactam (APBL) for at least 48 hours in the 90 days prior to the index infection with a gram-negative bloodstream or respiratory infection. Susceptibility rates to empiric therapy were compared between patients receiving the same (repeat group) versus a different antibiotic from prior exposure (change group). Results: A total of 197 patients were included (n = 94 [repeat group] and n = 103 [change group]). Pathogen susceptibility to empiric therapy was higher in the repeat group compared to the change group (76.6% vs 60.2%; P = .014). After multivariable logistic regression, repeat APBL was associated with an increased likelihood of pathogen susceptibility (adjusted odds ratio, 2.513; P = .012). In contrast, there was no difference in susceptibility rates between the repeat group and the subgroup of change patients who received an empiric APBL (76.6% vs 78.5%; P = .900). Longer APBL exposure duration (P = .012) and chronic kidney disease (P = .002) were associated with higher nonsusceptibility to the exposure APBL. In-hospital mortality was not significantly different between the repeat and change groups (18.1% vs 23.3%; P = .368). Conclusions: The common practice of changing to a different APBL from that of recent exposure may not be warranted.

A cross-sectional study of knowledge, attitude, and practice toward COVID-19 in solid organ transplant recipients at a transplant center in the United States.

Objectives: Knowledge, attitude, and practices (KAP) have been widely used during times of pandemic to quantify and locate gaps of care during pandemics. Using this tool, we can identify and target populations who underwent solid organ transplant (SOT) to bolster preventative practices in these patients during COVID-19. Materials and methods: An institution-based cross-sectional study was conducted between June 1, 2020 and June 30, 2021 on patients who underwent a liver and/or kidney transplant at Methodist Dallas Medical Center in Dallas, Texas, USA. A KAP questionnaire of 26 questions about COVID-19 was designed based on the clinical and community management guidelines published by the WHO. The participant's overall KAP was categorized using Bloom's cut-off point. A KAP domain was considered sufficient if the score was between 60 and 100% and insufficient if the score was <60%. The strength of association was assessed by using odds ratio (OR); only significant independent factors in each tested area were assessed. Results: Respondents with children in the household were less likely to have sufficient practices than those who did not [OR = 0.2491, 95% Confidence Interval (0.0893-0.6120), p = 0.001]. We also found that sufficient levels of knowledge correlated with higher likelihood of sufficient levels of practices [OR = 4.94, 95% CI (1.646-14.2159), p < 0.005]. Interestingly, we found that sufficient levels of attitude did not correlate with sufficient levels of practice (p = 0.201). Conclusion: Our study found that knowledge and having children in the household correlated with higher levels of practice.

Sidestream Smoke Extracts from Harm-Reduction and Conventional Camel Cigarettes Inhibit Osteogenic Differentiation via Oxidative Stress and Differential Activation of intrinsic Apoptotic Pathways.

Epidemiological studies suggest cigarette smoking as a probable environmental factor for a variety of congenital anomalies, including low bone mass, increased fracture risk and poor skeletal health. Human and animal in vitro models have confirmed hypomineralization of differentiating cell lines with sidestream smoke being more harmful to developing cells than mainstream smoke. Furthermore, first reports are emerging to suggest a differential impact of conventional versus harm-reduction tobacco products on bone tissue as it develops in the embryo or in vitro. To gather first insight into the molecular mechanism of such differences, we assessed the effect of sidestream smoke solutions from Camel (conventional) and Camel Blue (harm-reduction) cigarettes using a human embryonic stem cell osteogenic differentiation model. Sidestream smoke from the conventional Camel cigarettes concentration-dependently inhibited in vitro calcification triggered by high levels of mitochondrially generated oxidative stress, loss of mitochondrial membrane potential, and reduced ATP production. Camel sidestream smoke also induced DNA damage and caspase 9-dependent apoptosis. Camel Blue-exposed cells, in contrast, invoked only intermediate levels of reactive oxygen species insufficient to activate caspase 3/7. Despite the absence of apoptotic gene activation, damage to the mitochondrial phenotype was still noted concomitant with activation of an anti-inflammatory gene signature and inhibited mineralization. Collectively, the presented findings in differentiating pluripotent stem cells imply that embryos may exhibit low bone mineral density if exposed to environmental smoke during development.

Associating local strains to global pressure-volume mouse lung mechanics using digital image correlation.

Pulmonary diseases alter lung mechanical properties, can cause loss of function, and necessitate use of mechanical ventilation, which can be detrimental. Investigations of lung tissue (local) scale mechanical properties are sparse compared to that of the whole organ (global) level, despite connections between regional strain injury and ventilation. We examine ex vivo mouse lung mechanics by investigating strain values, local compliance, tissue surface heterogeneity, and strain evolutionary behavior for various inflation rates and volumes. A custom electromechanical, pressure-volume ventilator is coupled with digital image correlation to measure regional lung strains and associate local to global mechanics by analyzing novel pressure-strain evolutionary measures. Mean strains at 5 breaths per minute (BPM) for applied volumes of 0.3, 0.5, and 0.7 ml are 5.0, 7.8, and 11.3%, respectively, and 4.7, 8.8, and 12.2% for 20 BPM. Similarly, maximum strains among all rate and volume combinations range 10.7%-22.4%. Strain values (mean, range, mode, and maximum) at peak inflation often exhibit significant volume dependencies. Additionally, select evolutionary behavior (e.g., local lung compliance quantification) and tissue heterogeneity show significant volume dependence. Rate dependencies are generally found to be insignificant; however, strain values and surface lobe heterogeneity tend to increase with increasing rates. By quantifying strain evolutionary behavior in relation to pressure-volume measures, we associate time-continuous local to global mouse lung mechanics for the first time and further examine the role of volume and rate dependency. The interplay of multiscale deformations evaluated in this work can offer insights for clinical applications, such as ventilator-induced lung injury.

Aspirin-Triggered Resolvin D1 Reduces Chronic Dust-Induced Lung Pathology without Altering Susceptibility to Dust-Enhanced Carcinogenesis.

Lung cancer is the leading cause of cancer-related deaths worldwide, with increased risk being associated with unresolved or chronic inflammation. Agricultural and livestock workers endure significant exposure to agricultural dusts on a routine basis; however, the chronic inflammatory and carcinogenic effects of these dust exposure is unclear. We have developed a chronic dust exposure model of lung carcinogenesis in which mice were intranasally challenged three times a week for 24 weeks, using an aqueous dust extract (HDE) made from dust collected in swine confinement facilities. We also treated mice with the omega-3-fatty acid lipid mediator, aspirin-triggered resolvin D1 (AT-RvD1) to provide a novel therapeutic strategy for mitigating the inflammatory and carcinogenic effects of HDE. Exposure to HDE resulted in significant immune cell influx into the lungs, enhanced lung tumorigenesis, severe tissue pathogenesis, and a pro-inflammatory and carcinogenic gene signature, relative to saline-exposed mice. AT-RvD1 treatment mitigated the dust-induced inflammatory response but did not protect against HDE + NNK-enhanced tumorigenesis. Our data suggest that chronic HDE exposure induces a significant inflammatory and pro-carcinogenic response, whereas treatment with AT-RvD1 dampens the inflammatory responses, providing a strong argument for the therapeutic use of AT-RvD1 to mitigate chronic inflammation.

A High Docosahexaenoic Acid Diet Alters the Lung Inflammatory Response to Acute Dust Exposure.

Agricultural workers are at risk for the development of acute and chronic lung diseases due to their exposure to organic agricultural dusts. A diet intervention using the omega-3 fatty acid docosahexaenoic acid (DHA) has been shown to be an effective therapeutic approach for alleviating a dust-induced inflammatory response. We thus hypothesized a high-DHA diet would alter the dust-induced inflammatory response through the increased production of specialized pro-resolving mediators (SPMs). Mice were pre-treated with a DHA-rich diet 4 weeks before being intranasally challenged with a single dose of an extract made from dust collected from a concentrated swine feeding operation (HDE). This omega-3-fatty-acid-rich diet led to reduced arachidonic acid levels in the blood, enhanced macrophage recruitment, and increased the production of the DHA-derived SPM Resolvin D1 (RvD1) in the lung following HDE exposure. An assessment of transcript-level changes in the immune response demonstrated significant differences in immune pathway activation and alterations of numerous macrophage-associated genes among HDE-challenged mice fed a high DHA diet. Our data indicate that consuming a DHA-rich diet leads to the enhanced production of SPMs during an acute inflammatory challenge to dust, supporting a role for dietary DHA supplementation as a potential therapeutic strategy for reducing dust-induced lung inflammation.

Simulation-Based Communication Training for General Surgery and Obstetrics and Gynecology Residents.

BACKGROUND: There is a critical relationship between team communication and patient safety in the operating room (OR), but limited opportunities are available to help OR trainees develop the communication skills needed to be good team players. The purpose of this study was to evaluate the effectiveness of a simulation-based communication-training program developed for general surgery and obstetrics and gynecology residents. METHODS: Following a group lecture on diagnostic laparoscopy, 34 residents independently completed a laparoscopy case on a patient simulator followed by a structured debrief that targeted team-based communication skills. Integrated into the case were 2 events (bradycardia and OR fire) that provided additional opportunities for the resident to communicate with his/her team. The mean Likert scale score for 11 post-training survey questions were calculated to determine residents' reaction to the training. Additionally, mean scores of observer ratings of communication performance after the simulation were calculated and analyzed using separate Wilcoxon Sign-Rank tests and kappa statistics. RESULTS: Of the 41 GS and ObGyn residents, 34 (83%) participated in the training. 18 (53%) residents completed the simulation once and 16 (47%) completed it twice. Overall, residents had a positive reaction to the training program (average survey score = 4.56 of 5) and participation in the program improved their ability to use effective communication techniques during the bradycardia and OR fire events (p < 0.05, κ = 0.61). CONCLUSIONS: Residents had a positive reaction to the training program and participation in the program improved their ability to use effective communication techniques throughout the procedure.

Splenic artery embolization and endovascular stapler integrity in a porcine model.

Splenic artery embolization is often used before laparoscopic splenectomy in cases of splenomegaly to reduce blood loss and facilitate the procedure. The aim of this study was to examine the general reliability of endovascular staplers when fired at the site of embolization coil deployment using a porcine model. Ex vivo and in vivo experiments were conducted on porcine abdominal aortas, which are similar in diameter to those of the splenic artery in the human. When the endovascular staplers were fired across the porcine vessels at the area of embolization coil deployment ex vivo, the staple lines all failed. In contrast, in vivo, the staple lines remained intact with no bleeding despite resistance imposed by the intravascular coils. Despite consistent failure in the ex vivo studies, in vivo all staple lines held and permitted safe transection of the vessel. We presume that the hemostatic properties of the coils caused sufficient thrombosis in this model, which mimics the clinical situation, to permit division of the previously embolized splenic vessel.

Laparoscopic accessory splenectomy for recurrent idiopathic thrombocytopenic purpura.

BACKGROUND: Splenectomy has 50% to 70% long-term efficacy for immune thrombocytopenic purpura (ITP). In some patients, relapse is due to the presence of residual accessory splenic tissue. METHODS: A 44-year-old male had ITP since 1983 with splenectomy in 1985. He had a transient response, but then developed severe thrombocytopenia refractory to multiple modalities for 20 years. An accessory spleen was first visualized in 2000. RESULTS: A laparoscopic accessory splenectomy was performed without difficulty. The patient had an initial response with a significant increase in platelet count. Although over time the thrombocytopenia recurred, there has been a long-term benefit in that the patient is on much lower doses of prednisone to maintain an adequate platelet count. CONCLUSION: The finding of accessory splenic tissue after prior splenectomy may be an increasingly common problem in patients with recurrent ITP. Although reported response rates for resection of residual splenic tissue vary, the availability of a safe, less morbid, minimally invasive approach makes the decision to operate easier.

Impact of morbid obesity on outcome of laparoscopic splenectomy.

BACKGROUND: Because of the obesity epidemic, surgeons are operating on morbidly obese patients in increasing numbers. The aim of this study was to evaluate the impact of morbid obesity on the outcome of laparoscopic splenectomy. METHODS: The study group consisted of 120 consecutive patients who underwent laparoscopic splenectomy for benign and malignant disease from March 1996 to May 2005. These patients were retrospectively divided into three groups. Group 1 had a body mass index (BMI) < 30. Group 2 patients had a BMI > or = 30 and < 40 and were considered obese. Group 3 had a BMI > or = 40 and were considered morbidly obese. Data including surgical approach (laparoscopic vs. hand-assisted), operative time, conversion rate, estimated blood loss, splenic weight, length of stay, time to tolerate a diet, pathologic diagnosis, complications, and mortality were recorded. RESULTS: Complete data were available for evaluation of 112 patients of whom 73 (65%) had a BMI < 30, 32 (29%) had a BMI > or = 30 and < 40, and 7 (6%) had a BMI > or = 40. The most frequent indication for splenectomy in all three groups was idiopathic thrombocytopenic purpura (ITP). The operative times were significantly higher in patients with a BMI > 40. Conversion rates were also higher in this group, although this did not reach statistical significance. Patients with a BMI > 30 experienced similar complication rates when compared with patients with a BMI < 30. Only when patients had a BMI > 40 did they experience more complications. CONCLUSIONS: Laparoscopic splenectomy was performed safely in obese patients (BMI > 30) with similar results to those of nonobese patients. Only in morbidly obese patients (BMI > 40) do outcomes and complications appear to be affected. Obesity should not be a contraindication to laparoscopic splenectomy.

Patient characteristics, outcomes and costs following interhospital transfer to a tertiary facility for appendectomy versus patients who present directly.

BACKGROUND: Recent healthcare policy changes have emphasized pay-for-performance. Previous studies have not examined outcome differences between primary presenting appendicitis patients and transferred patients. METHODS: A retrospective cohort design examined appendicitis patients between March 2011 and 2013. Patients < age 18, were scheduled for an elective appendectomy, who were pregnant or had an interval appendectomy were excluded. RESULTS: The transfer cohort (n = 59) had more comorbidities, more severe American Society of Anesthesiologists status, a higher rate of pre-operative abscess/rupture as well as higher rates of perforation, gangrene, intra-operative drain placement and open conversion versus primary presenting patients (n = 622). After statistical regression adjustment, a higher open conversion rate in the transfer cohort, OR = 3.48 (95%CI: 1.04-11.61) and higher total costs $672.47 (95%CI: $68.75-$1276.19) remained. CONCLUSIONS: Adjustments in clinical outcome/reimbursement metrics may be needed to address the complexity of transfers and the subsequent higher in-hospital costs on tertiary facilities. LEVEL OF EVIDENCE: IV.

A pilot study examining experiential learning vs didactic education of abdominal compartment syndrome.

BACKGROUND: Current surgical education relies on simulated educational experiences or didactic sessions to teach low-frequency clinical events such as abdominal compartment syndrome (ACS). The purpose of this pilot study was to evaluate if simulation would improve performance and knowledge retention of ACS better than a didactic lecture. METHODS: Nineteen general surgery residents were block randomized by postgraduate year level to a didactic or a simulation session. After 3 months, all residents completed a knowledge assessment before participating in an additional simulation. Two independent reviewers assessed resident performance via audio-video recordings. RESULTS: No baseline differences in ACS experience were noted between groups. The observational evaluation demonstrated a significant difference in performance between the didactic and simulation groups: 9.9 vs 12.5, P = .037 (effect size = 1.15). Knowledge retention was equivalent between groups. CONCLUSIONS: This pilot study suggests that simulation-based education may be more effective for teaching the basic concepts of ACS.

Neutral evolution of drug resistant colorectal cancer cell populations is independent of their KRAS status.

Emergence of tumor resistance to an anti-cancer therapy directed against a putative target raises several questions including: (1) do mutations in the target/pathway confer resistance? (2) Are these mutations pre-existing? (3) What is the relative fitness of cells with/without the mutation? We addressed these questions in patients with metastatic colorectal cancer (mCRC). We conducted an exhaustive review of published data to establish a median doubling time for CRCs and stained a cohort of CRCs to document mitotic indices. We analyzed published data and our own data to calculate rates of growth (g) and regression (d, decay) of tumors in patients with CRC correlating these results with the detection of circulating MT-KRAS DNA. Additionally we estimated mathematically the caloric burden of such tumors using data on mitotic and apoptotic indices. We conclude outgrowth of cells harboring intrinsic or acquired MT-KRAS cannot explain resistance to anti-EGFR (epidermal growth factor receptor) antibodies. Rates of tumor growth with panitumumab are unaffected by presence/absence of MT-KRAS. While MT-KRAS cells may be resistant to anti-EGFR antibodies, WT-KRAS cells also rapidly bypass this blockade suggesting inherent resistance mechanisms are responsible and a neutral evolution model is most appropriate. Using the above clinical data on tumor doubling times and mitotic and apoptotic indices we estimated the caloric intake required to support tumor growth and suggest it may explain in part cancer-associated cachexia.

A prospective study of bile leaks after laparoscopic cholecystectomy for acute cholecystitis.

Surgeons are increasingly performing laparoscopic cholecystectomy in the setting of acute cholecystitis. The acutely inflamed gallbladder poses a more technically demanding dissection with potential for an increase in bile leak rates. Clinical and subclinical bile leak rates after laparoscopic and open cholecystectomy in the elective setting are known. This study prospectively evaluates the rate of clinical and subclinical bile leaks after laparoscopic cholecystectomy in the setting of acute cholecystitis. One hundred patients underwent laparoscopic cholecystectomy for acute cholecystitis, as determined intraoperatively and by history, ultrasound, fever, or leukocytosis. On postoperative Day 1, the patients underwent cholescintigraphy (PIPIDA scan) analyzed by a board-certified radiologist for evidence of bile leaks. Postoperative cholescintigraphy revealed eight scans positive for bile leaks. Regardless of scan result, no patient experienced a clinically symptomatic bile leak. Laparoscopic cholecystectomy is a safe and effective treatment for acute cholecystitis with acceptable clinical and subclinical bile leak rates.