Liposomal Bupivacaine Use in Transversus Abdominis Plane Blocks Reduces Pain and Postoperative Intravenous Opioid Requirement After Colorectal Surgery.

BACKGROUND: Enhanced recovery protocols frequently use multimodal postoperative analgesia to improve postoperative outcomes in patients undergoing colorectal surgery. OBJECTIVE: The purpose of this study was to evaluate liposomal bupivacaine use in transversus abdominis plane blocks on postoperative pain scores and opioid use after colorectal surgery. DESIGN: This was a retrospective cohort study comparing outcomes between patients receiving nonliposomal anesthetic (n = 104) and liposomal bupivacaine (n = 303) blocks. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: Patients included those identified within an institutional database as inpatients undergoing colorectal procedures between 2013 and 2015 who underwent transversus abdominis plane block for perioperative analgesia. MAIN OUTCOME MEASURES: The study measured postoperative pain scores and opioid requirements. RESULTS: Patients receiving liposomal bupivacaine had significantly lower pain scores for the first 24 to 36 postoperative hours. Pain scores were similar after 36 hours. The use of intravenous opioids among the liposomal bupivacaine group decreased by more than one third during the hospitalization (99.1 vs 64.5 mg; p = 0.040). The use of ketorolac was also decreased (49.0 vs 18.3 mg; p < 0.001). In subgroup analysis, the decrease in opioid use was observed between laparoscopic and robotic procedures but not with laparotomies. No significant differences were noted in the use of oral opioids, acetaminophen, or ibuprofen. Postoperative length of stay and total cost were decreased in the liposomal bupivacaine group but did not achieve statistical significance. LIMITATIONS: The study was limited by its retrospective, single-center design and heterogeneity of block administration. CONCLUSIONS: Attenuated pain scores observed with liposomal bupivacaine use were associated with significantly lower intravenous opioid and ketorolac use, suggesting that liposomal bupivacaine-containing transversus abdominis plane blocks are well aligned with the opioid-reducing goals of many enhanced recovery protocols.

Institution of a Preoperative Stoma Education Group Class Decreases Rate of Peristomal Complications in New Stoma Patients.

PURPOSE: The purpose of this study was to compare selected postoperative complications (including stomal and peristomal complications), hospital length of stay, and readmission rates in a group of patients who attended a preoperative educational intervention to a retrospective group of patients who did not receive the intervention. DESIGN: Retrospective, comparison cohort study. SUBJECTS AND SETTING: The intervention group comprised 124 patients who attended an educational session for persons with fecal ostomies at a single tertiary care center in the Northeastern United States. They were compared to findings from a group of 94 individuals who underwent ostomy surgery during a 1-year period before initiation of the class. Patients undergoing emergent procedures or who had previous stomas were excluded. We found no significant differences between the 2 cohorts with respect to age, gender, comorbidities, open versus minimally invasive procedures, or colorectal diagnoses. METHODS: A preoperative 2-hour stoma education class was led by certified WOC nurses for all patients undergoing colorectal surgeries in which the creation of a stoma was anticipated. This session included a didactic portion outlining postoperative expectations in the management of new ostomies (including dietary changes, prevention of dehydration, and an overview of ostomy supplies), as well as a hands-on portion to practice stoma care skills. We compared postoperative complications within 30 days (particularly stoma-related complications, including pouch leakage due to loss of seal, and peristomal skin irritation) between the group attending the education session and the control group. We also compared length of stay and 30-day readmission rates. RESULTS: Patients who participated in the educational intervention experienced significantly fewer peristomal complications than did patients in the historic control group (44.7% vs 20.2%, P = .002). Logistic regression analysis revealed that participation in the group was associated with a lower likelihood of peristomal skin complications (odds ratio = 0.35; 95% confidence interval, 0.18-0.67). Their length of stay (median 6 days vs 5 days, P = NS), and the proportion who experienced 30-day readmission (20.2% vs 15.3%, P = NS), did not significantly differ. CONCLUSIONS: A preoperative stoma education group class significantly reduced the likelihood of frequent leakage from the ostomy pouching system and peristomal skin irritation.

Clostridium difficile Infection Is Associated With Lower Inpatient Mortality When Managed by GI Surgeons.

BACKGROUND: Patients admitted with Clostridium difficile infection are managed in a variety of settings. If their care is inadequate, these patients can rapidly deteriorate. OBJECTIVE: The purpose of this study was to evaluate whether mortality for patients admitted with C difficile differed between medical and general/colorectal surgery services. DESIGN: This was a retrospective cohort study with multivariable logistic regression used to evaluate the effect of admitting service on in-hospital mortality rates, with propensity score matching used to validate this relationship. SETTINGS: The study was conducted at a single, tertiary care center. PATIENTS: Inpatients with a positive C difficile stool test within 24 hours of admission to medical or surgical services were identified (2005-2015) using institutional electronic data sources. MAIN OUTCOME MEASURE: We measured inpatient mortality rate. RESULTS: Of 1175 patients, 985 (83%) were admitted to medical services, whereas 190 (17%) were admitted by surgeons. Medical patients were older (63.9 vs 58.9 years; p = 0.001) and had a mean of 0.6 additional comorbidities (p < 0.001); cohorts were similar regarding vasopressors, peak white blood cell counts, and rate of intensive care unit admissions. Mortality was lower among surgery patients (2.6% vs 6.8%; p = 0.028), and logistic regression demonstrated lower odds of mortality for this group OR = 0.18 (95% CI, 0.05-0.58)). After propensity score matching for age, comorbidities, and severity of disease, this difference was confirmed (2.6% vs. 9.5%). A higher incidence of total colectomy for surgery patients (14.2% vs 0.4%) was a causal factor in their longer lengths of stay and higher total hospital costs. The time between orders for stool testing and metronidazole therapy was shorter in the surgery group (1.8 vs 3.8 hours; p = 0.002), although this trend was not observed with vancomycin therapy. LIMITATIONS: This was a retrospective study from a single institution, thereby limiting generalizability, with a lack of information regarding premorbid creatinine levels, ileus, or megacolon. CONCLUSIONS: In-hospital mortality rates for patients admitted with C difficile were lower on surgery services, perhaps in part related to higher colectomy rates.

Nitration of Hsp90 induces cell death.

Oxidative stress is a widely recognized cause of cell death associated with neurodegeneration, inflammation, and aging. Tyrosine nitration in these conditions has been reported extensively, but whether tyrosine nitration is a marker or plays a role in the cell-death processes was unknown. Here, we show that nitration of a single tyrosine residue on a small proportion of 90-kDa heat-shock protein (Hsp90), is sufficient to induce motor neuron death by the P2X7 receptor-dependent activation of the Fas pathway. Nitrotyrosine at position 33 or 56 stimulates a toxic gain of function that turns Hsp90 into a toxic protein. Using an antibody that recognizes the nitrated Hsp90, we found immunoreactivity in motor neurons of patients with amyotrophic lateral sclerosis, in an animal model of amyotrophic lateral sclerosis, and after experimental spinal cord injury. Our findings reveal that cell death can be triggered by nitration of a single protein and highlight nitrated Hsp90 as a potential target for the development of effective therapies for a large number of pathologies.

Structural basis of improved second-generation 3-nitro-tyrosine tRNA synthetases.

Genetic code expansion has provided the ability to site-specifically incorporate a multitude of noncanonical amino acids (ncAAs) into proteins for a wide variety of applications, but low ncAA incorporation efficiency can hamper the utility of this powerful technology. When investigating proteins containing the post-translational modification 3-nitro-tyrosine (nitroTyr), we developed second-generation amino-acyl tRNA synthetases (RS) that incorporate nitroTyr at efficiencies roughly an order of magnitude greater than those previously reported and that advanced our ability to elucidate the role of elevated cellular nitroTyr levels in human disease (e.g., Franco, M. et al. Proc. Natl. Acad. Sci. U.S.A 2013 , 110 , E1102 ). Here, we explore the origins of the improvement achieved in these second-generation RSs. Crystal structures of the most efficient of these synthetases reveal the molecular basis for the enhanced efficiencies observed in the second-generation nitroTyr-RSs. Although Tyr is not detectably incorporated into proteins when expression media is supplemented with 1 mM nitroTyr, a major difference between the first- and second-generation RSs is that the second-generation RSs have an active site more compatible with Tyr binding. This feature of the second-generation nitroTyr-RSs appears to be the result of using less stringent criteria when selecting from a library of mutants. The observation that a different selection strategy performed on the same library of mutants produced nitroTyr-RSs with dramatically improved efficiencies suggests the optimization of established selection protocols could lead to notable improvements in ncAA-RS efficiencies and thus the overall utility of this technology.

Overall survival by pattern of recurrence following curative intent surgery for colorectal liver metastasis.

BACKGROUND: Following curative intent surgery (CIS) for colorectal liver metastasis (CRLM), patterns of recurrence and subsequent survival outcomes are not widely reported. METHODS: An institutional database (January 2002-December 2012) was reviewed to evaluate patterns of recurrence following CIS for CRLM. RESULTS: 163 patients with CRLM underwent successful CIS. Median follow-up and disease-free interval were 33 and 16 months, respectively. 5-year overall survival (OS) was 55%. After initial CIS, 102 (63%) patients recurred: liver-44% (5-year OS 55%), lung-15% (5-year OS 45%), and other/multifocal-41% (5-year OS 24%). OS for isolated liver and lung recurrences were not significantly different. Liver only recurrence was associated with 1-5 mm liver resection margins (P = 0.048). Lung only recurrence was associated with extrahepatic metastasis (at the time of initial CRLM) (P = 0.025). Other/multifocal recurrence was associated with bilobar CRLM (P = 0.026), and extrahepatic metastasis (P = 0.028). CONCLUSIONS: Patterns of recurrence following CIS for CRLM have important implications for OS. 5-year OS was similar between isolated lung and liver recurrences. During CIS, decreased liver resection margin may be associated with increased risk of liver only recurrence. Patients with aggressive primary or metastatic liver disease are at higher risk for pulmonary or other/multifocal recurrence.

Variation in the management of adolescent patients with blunt abdominal solid organ injury between adult versus pediatric trauma centers: an analysis of a statewide trauma database.

BACKGROUND: Optimal management of adolescent trauma patients with blunt abdominal solid organ injury (SOI) remains controversial. The purpose of this study was to identify management differences in adolescents with SOI treated at adult trauma centers (ATC) versus pediatric trauma centers (PTC). We hypothesized that adolescents with SOI would undergo different treatment at ATC and PTC. MATERIALS AND METHODS: Retrospective review of the Pennsylvania Trauma Systems Foundation database from 2005-2010 was performed. Adolescent patients (13-18 y old) with SOI (spleen, liver, and kidney injury) were included. Patient baseline characteristics and care processes for each injury were compared between ATC and PTC. RESULTS: A total of 1532 patients with at least one SOI were identified: 946 patients had a splenic injury, 505 had a liver injury, and 424 had a kidney injury. Spleen and liver procedures were performed more often at ATC than at PTC irrespective of injury grade (respectively, 16.1% versus 3.2%, 5.9% versus 0%; P < 0.01). Transarterial embolization for splenic injury was more frequently performed at ATC (2.8% versus 0.6%; P = 0.02). After adjusting for potential confounding factors, care at PTC was significantly associated with lower odds of splenic procedure for patients with splenic injury (OR: 0.16, 95% CI: 0.08-0.36, P < 0.001). In a subgroup analysis of nontransfer patients, care at PTC remained significantly associated with lower odds of splenic procedure (OR: 0.24, 95% CI: 0.10-0.59, P = 0.002) despite higher median injury severity score than ATC. CONCLUSIONS: Significant differences in the management of adolescents with SOI were identified in Pennsylvania. Operative intervention for SOI was more often performed at ATC than at PTC. Further study will be needed to address the impact of these disparities on patient outcomes.

Genetically encoded initiator for polymer growth from proteins.

Despite the importance of protein-polymer bioconjugates, there is no general method for producing homogeneous recombinant protein that contains polymer initiators at defined sites. To address this deficiency, we designed the amino acid 4-(2'-bromoisobutyramido)phenylalanine (1) as an initiator in atom-transfer radical polymerization (ATRP) that would provide a stable linkage between the protein and growing polymer. We synthesized 1 and evolved a Methanococcus jannaschii tyrosyl-tRNA synthetase/tRNA(CUA) pair to genetically encode this initiator in response to an amber codon. To demonstrate the utility of this initiator, we produced green fluorescent protein (GFP) with 1 site-specifically incorporated on its surface (GFP-1). Purified GFP-1 was then used as an initiator under standard ATRP conditions with a monomer, oligo(ethylene oxide) monomethyl ether methacrylate, efficiently producing a polymer-GFP bioconjugate where the polymer is connected at our selected site on GFP.

Rates and trends for inpatient surgeries in pediatric Crohn's disease in the United States from 2003 to 2012.

BACKGROUND: Pediatric Crohn's disease (CD) is increasing in incidence globally. Trends in specific types of inpatient pediatric CD-related surgical procedures have not been widely reported. METHODS: Patients ≤20 years of age with CD were identified in the Kids' Inpatient Database for 2003, 2006, 2009, and 2012. Bowel resection, stoma creation, and perianal or percutaneous drainage procedures were identified using ICD-9 procedure codes, and trends were identified. Logistic regression was used to identify factors associated with surgical intervention and trends. RESULTS: Rates of overall bowel resection (including ileocolic resection, other small bowel resection, or other colon resection) did not change significantly over time. However, the odds of having a laparoscopic colon resection increased by 41% annually (p<0.001). Rates of subsequent ileostomy formation increased (odds ratio 1.09, p<0.001). Older age, male sex, fewer comorbidities, and treatment in large urban teaching hospitals were also associated with higher odds of undergoing bowel resection. CONCLUSIONS: This study noted a stable rate of all types of bowel resections and increase in post resection ileostomy formation in US pediatric inpatients with CD from 2003-2012. Other rates of many CD-related procedures have remained stable. Further studies correlating the effects of biologic agents on surgical rates are warranted. TYPE OF STUDY: Treatment Study LEVEL OF EVIDENCE: Level III.

Traumatic bile leaks from blunt liver injury in children: a multidisciplinary and minimally invasive approach to management.

BACKGROUND: Selective non-operative management (NOM) of hemodynamically stable pediatric patients with blunt hepatic trauma is the standard of care. Traumatic bile leaks (TBL) are a potential complication following liver injury. The use of endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis and treatment of TBL is described in adults, but limited in the pediatric literature. We report our experience with a multidisciplinary and minimally invasive approach to the management of TBL. METHODS: This was an IRB-approved 13-year retrospective review (January 1999-December 2012) of an institutional pediatric trauma registry; 294 patients (≤ 17 years old) sustained blunt hepatic injury. Those with TBL were identified. Patient demographics, mechanism of injury, management strategy and outcomes were reviewed. RESULTS: Eleven patients were identified with TBL. Hepatobiliary iminodiacetic scan (HIDA) was diagnostic. Combinations of peri-hepatic drain placement, ERCP with biliary stenting and/or sphincterotomy were performed with successful resolution of TBL in all cases. No child required surgical repair or reconstruction of the leak. Cholangitis developed in one child. There were no long-term complications. CONCLUSIONS: A multidisciplinary and minimally invasive approach employing peri-hepatic external drainage catheters and ERCP with sphincterotomy and stenting of the ampulla is a safe and effective management strategy for TBL in children.

Determinants of repeat curative intent surgery in colorectal liver metastasis.

INTRODUCTION: Following curative intent surgery (CIS) for colorectal liver metastasis (CRLM), repeat CIS for recurrence improves survival. The factors associated with repeat CIS are not widely reported. METHODS: An institutional database (January 2002-December 2012) was reviewed to evaluate factors influencing repeat CIS. RESULTS: One hundred sixty-three patients with colorectal liver metastasis (CRLM) underwent successful CIS. Median follow-up and disease-free interval (DFI) was 33 and 16 months, respectively. After initial CIS, 102 patients (63%) recurred. Fifty-three patients (52%) underwent a repeat CIS. After repeat CIS, 33 patients (62%) developed a second recurrence, and in 13 patients (39%), a third CIS was possible. DFI decreased following initial CIS (first CIS vs. second CIS vs. third CIS [20 vs. 15 vs. 8.5 months], p < 0.001). Overall 5-year survival in all patients was 55%; patients who recurred had a 5-year survival of 67% if they underwent repeat CIS vs. 7.8% if they were managed palliatively. Second CIS was less likely with a postoperative complication, other/multifocal recurrence, or DFI <12 months. CONCLUSION: Despite high recurrence and decreasing DFI, repeat CIS provides a survival benefit. Postoperative complications, DFI, number, and pattern of recurrence influence the decision to pursue repeat CIS.

An unexpected presentation: minimal change disease in an adult with treatment-naïve hepatitis C.

Minimal change disease is the most common glomerular disease affecting children; its prevalence among adults, however, is eclipsed by other glomerular pathologies. Each of these diseases has a number of classic associations, such as membranoproliferative glomerulonephritis with hepatitis C. We report the case of a middle-aged African-American male who presented with the nephrotic syndrome and acute renal failure and was concomitantly diagnosed with a new hepatitis C infection. He also had a history of urethral strictures with potential reflux nephropathy, which--in combination with his African-American race--also made focal segmental glomerulosclerosis a diagnostic possibility. Full laboratory evaluation did not distinguish the cause of his massive proteinuria; subsequent renal biopsy ultimately revealed minimal change disease. A full course of high-dose steroids eventually reduced his proteinuria, after which his renal failure resolved as well without need for hemodialysis.

Enhancing the utility of unnatural amino acid synthetases by manipulating broad substrate specificity.

Many unnatural amino acid synthetases have been evolved to enable the site-specific in vivo incorporation of many useful functionalities into proteins. While these unnatural amino acid-tRNA synthetase-tRNA(CUA) pairs do not incorporate endogenous amino acids, their substrate specificity has not been assessed for other unnatural amino acids. Here we demonstrate that the unnatural synthetases can be permissive to many unnatural amino acid substrates. The utility of unnatural synthetases can be further expanded by manipulating the synthetase active sites by mutagenesis. Here we have also shown that an l-2-naphthylalanine synthetase can be converted into a permissive l-4-benzoylphenylalanine synthetase with a single mutation without compromising fidelity. Permissive unnatural amino acid synthetases should significantly expand the tool set available for manipulation of proteins.