Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth.

Background: Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods: Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results: Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid-structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions: These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

Development of Tissue Engineered Heart Valves for Percutaneous Transcatheter Delivery in a Fetal Ovine Model.

This multidisciplinary work shows the feasibility of replacing the fetal pulmonary valve with a percutaneous, transcatheter, fully biodegradable tissue-engineered heart valve (TEHV), which was studied in vitro through accelerated degradation, mechanical, and hemodynamic testing and in vivo by implantation into a fetal lamb. The TEHV exhibited only trivial stenosis and regurgitation in vitro and no stenosis in vivo by echocardiogram. Following implantation, the fetus matured and was delivered at term. Replacing a stenotic fetal valve with a functional TEHV has the potential to interrupt the development of single-ventricle heart disease by restoring proper flow through the heart.

Spontaneous reversal of stenosis in tissue-engineered vascular grafts.

We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.

Imatinib attenuates neotissue formation during vascular remodeling in an arterial bioresorbable vascular graft.

BACKGROUND: Bioresorbable vascular grafts (BVGs) can transform biologically into active blood vessels and represent an alternative to traditional synthetic conduits, which are prone to complications such as infection and thrombosis. Although platelet-derived growth factors and c-Kit positive cells play an important role in smooth muscle cell (SMC) migration and proliferation in vascular injury, atherosclerosis, or allograft, their roles in the vascular remodeling process of an arterial BVG remains unknown. Thus, we assessed the neottisue formation on arterial BVG remodeling by administrating imatinib, which is both a platelet-derived growth factor receptor kinase inhibitor and c-Kit receptor kinase inhibitor, in a murine model. METHODS: BVGs were composed of an inner poly(L-lactic-co-ε-caprolactone) copolymer sponge layer and an outer electrospun poly(L-lactic acid) nanofiber layer, which were implanted into the infrarenal abdominal aortas of C57BL/6 mice. After graft implantation, saline or 100 mg/kg of imatinib was administrated intraperitoneally daily for 2 weeks (n = 20 per group). Five mice in each group were scheduled to be humanely killed at 3 weeks and 15 at 8 weeks, and BVGs were explanted for histologic assessments. RESULTS: Graft patency during the 8-week observational period was not significantly different between groups (control, 86.7% vs imatinib, 80.0%; P > .999). Neotissue formation consisting of endothelialization, smooth muscle proliferation, and deposition of collagen and elastin was not observed in either group at 3 weeks. Similar endothelialization was achieved in both groups at 8 weeks, but thickness and percent area of neotissue formation were significantly higher in the control group than in the imatinib group, (thickness, 30. 1 ± 7.2 µm vs 19.6 ± 4.5 µm [P = .001]; percent area, 9.8 ± 2.7% vs 6.8 ± 1.8% [P = .005]). Furthermore, SMC layer and deposition of collagen and elastin were better organized at 8 weeks in the control group compared with the imatinib group. The thickness of SMC layer and collagen fiber area were significantly greater at 8 weeks in the control group than in the imatinib group (P < .001 and P = .026, respectively). Because there was no difference in the inner diameter of explanted BVGs (831.7 ± 63.4 µm vs 841.8 ± 41.9 µm; P = .689), neotissue formation was thought to advance toward the outer portion of the BVG with degradation of the polymer scaffold. CONCLUSIONS: Imatinib attenuates neotissue formation during vascular remodeling in arterial bioresorbable vascular grafts (BVGs) by inhibiting SMC layer formation and extracellular matrix deposition. CLINICAL RELEVANCE: This study demonstrated that imatinib attenuated neotissue formation during vascular remodeling in arterial Bioresorbable vascular graft (BVG) by inhibiting smooth muscle cell formation and extracellular matrix deposition. In addition, as imatinib did not modify the inner diameter of BVG, neotissue advanced circumferentially toward the outer portion of the neovessel. Currently, BVGs have not yet been clinically applied to the arterial circulation. The results of this study are helpful for the design of BVG that can achieve an optimal balance between polymer degradation and neotissue formation.

Prehospital Versus Trauma Center Glasgow Coma Scale in Pediatric Traumatic Brain Injury Patients.

BACKGROUND: Traumatic brain injury (TBI) is a major source of morbidity and mortality in children. The Glasgow Coma Scale (GCS) can be challenging to calculate in pediatric patients. Our objective was to determine its reproducibility between prehospital providers and pediatric trauma hospital personnel. MATERIALS AND METHODS: The institutional trauma database for a level 1 pediatric trauma center was queried for patients aged ≤18 y who presented with a TBI. Demographics, mechanism, prehospital GCS, and trauma center GCS were collected. Agreement was evaluated with weighted kappa (κ) coefficients (0 = agreement no better than that expected by chance alone, 1 = perfect agreement). RESULTS: The inclusion criteria were met by 1711 patients, 263 of whom were aged <3 y. Prehospital GCS and trauma center GCS differed in 766 patients (44.8%). Agreement between prehospital GCS and trauma center GCS was moderate for all patients (κ = 0.61, 95% confidence interval [CI] 0.57-0.64). Agreement was slightly better than chance alone in patients with trauma center GCS between 9 and 12 y (κ = 0.09, 95% CI 0.03-0.15) and was lower for children aged 0-2 y (κ = 0.51, 95% CI 0.42-0.61) than for those aged between 3 and 18 y (κ = 0.63, 95% CI 0.59-0.66). Younger children were more likely to have score differences of at least 3 points (21.3% versus 13.6% of 3- to 18-y-olds, P < 0.001). CONCLUSIONS: Prehospital and trauma center GCS scores frequently disagree in children, particularly in TBI patients aged <3 y and those with moderate TBI. Centers should consider the inconsistency of the pediatric GCS when triaging TBI patients.

The relationships of surgeon volume and specialty with outcomes following pediatric thyroidectomy.

BACKGROUND: Previous studies of pediatric thyroidectomies suggest a volume-outcome relationship, but none have focused exclusively on pediatric surgical specialists. Our objective was to examine the effects of pediatric surgeon volume and specialty on post-thyroidectomy outcomes. METHODS: The Pediatric Health Information System was queried for patients ≤21 years who underwent partial or total thyroidectomy between 2005 and 2016. Multivariable logistic regression with propensity score weighting was used to assess the relationships between surgeon volume or specialty and 90-day thyroidectomy-specific complications. High-volume surgeons/hospitals were defined as those in the top tertile of annual thyroidectomies. RESULTS: The inclusion criteria were met by 3149 patients. Patients treated by higher-volume surgeons had significantly fewer complications than those treated by lower-volume surgeons (15.0% vs. 19.2%, p = 0.01). Patients with thyroid cancer also had less morbidity when treated by higher-volume surgeons compared to lower-volume surgeons (25.0% vs. 35.1%, p = 0.03), as did children with Graves' disease (19.8% vs. 29.3%, p = 0.007). Patients managed by pediatric surgeons had fewer complications than those managed by pediatric otolaryngologists across all patients (14.0% vs. 22.5%, p < 0.001) and among cancer (25.3% vs. 42.1%, p < 0.001) and Graves' patients (20.1% vs. 37.3%, p < 0.001) specifically. CONCLUSIONS: Morbidity following pediatric thyroidectomy is associated with surgeon volume. TYPE OF STUDY: Prognostic Study. LEVEL OF EVIDENCE: Level II.

Complications after proctocolectomy and ileal pouch-anal anastomosis in pediatric patients: A systematic review.

BACKGROUND/PURPOSE: Colectomy with ileal pouch-anal anastomosis (IPAA) is the standard of care for patients with familial adenomatous polyposis (FAP) and refractory ulcerative colitis (UC). The rates of postoperative complications are not well established in children. The objective of this systematic review is to establish benchmark data for morbidity after pediatric IPAA. METHODS: PubMed, Embase, and The Cochrane Library were searched for studies of colectomy with IPAA in patients ≤21 years old. UC studies were limited to the anti-tumor necrosis factor-α agents era (1998-present). All postoperative complications were extracted. RESULTS: Thirteen studies met the inclusion criteria (763 patients). Compared to patients with FAP, UC patients had a higher prevalence of pouch loss (10.6% vs. 1.5%). Other major complications such as anastomotic leak, abscess, and fistula were uncommon (mean prevalence 4.9%, 4.2%, and 5.0%, respectively, for patients with UC; 8.7%, 4.2%, and 4.3% for FAP). The most frequent complication was pouchitis (36.4% of UC patients). CONCLUSIONS: Devastating complications from colectomy and IPAA are rare, but patients with UC have poorer outcomes than those with FAP. Much of the morbidity may therefore stem from patient or disease factors. Multicenter, prospective studies are needed to identify modifiable risks in patients with UC undergoing IPAA. LEVEL OF EVIDENCE: Prognostic, level II.

Comparison of diagnostic imaging modalities for the evaluation of pancreatic duct injury in children: a multi-institutional analysis from the Pancreatic Trauma Study Group.

PURPOSE: Determining the integrity of the pancreatic duct is important in high-grade pancreatic trauma to guide decision making for operative vs non-operative management. Computed tomography (CT) is generally an inadequate study for this purpose, and magnetic resonance cholangiopancreatography (MRCP) is sometimes obtained to gain additional information regarding the duct. The purpose of this multi-institutional study was to directly compare the results from CT and MRCP for evaluating pancreatic duct disruption in children with these rare injuries. METHODS: Retrospective study of data obtained from eleven pediatric trauma centers from 2010 to 2015. Children up to age 18 with suspected blunt pancreatic duct injury who had both CT and MRCP within 1 week of injury were included. Imaging findings of both studies were directly compared and analyzed using descriptive statistics, Chi square, Wilcoxon rank-sum, and McNemar's tests. RESULTS: Data were collected for 21 patients (mean age 7.8 years). The duct was visualized more often on MRCP than CT (48 vs 5%, p < 0.05). Duct disruption was confirmed more often on MRCP than CT (24 vs 0%), suspected based on secondary findings equally (38 vs 38%), and more often indeterminate on CT (62 vs 38%). Overall, MRCP was not superior to CT for determining duct integrity (62 vs 38%, p = 0.28). CONCLUSIONS: In children with blunt pancreatic injury, MRCP is more useful than CT for identifying the pancreatic duct but may not be superior for confirmation of duct integrity. Endoscopic retrograde cholangiogram (ERCP) may be necessary to confirm duct disruption when considering pancreatic resection. LEVEL OF EVIDENCE: III.

Abnormal lymphocyte response after pediatric thermal injury is associated with adverse outcomes.

BACKGROUND: Burns are a leading cause of morbidity in children, with infections representing the most common group of complications. Severe thermal injuries are associated with a profound inflammatory response, but the utility of laboratory values to predict infections in pediatric burn patients is poorly understood. MATERIALS AND METHODS: Our institutional burn database was queried for patients aged 18 y and younger with at least 10% total body surface area burns. Demographics, mechanism, laboratory results, and outcomes were extracted from the medical record. Patients were classified as having an abnormal or normal total white blood cell count, neutrophil percentage, and lymphocyte percentage using the first complete blood count drawn 72 or more hours postinjury. Outcomes were compared between groups. RESULTS: White blood cell data were available for 90 patients, 84 of whom had neutrophil and lymphocyte percentages. Abnormal lymphocyte percentage 72 h or more after burn injury was associated with a significant increase in infections (67.9% versus 32.3%, P = 0.003), length of stay (33.1 versus 18.8 d, P = 0.02), intensive care unit length of stay (13.1 versus 3.7 days, P = 0.01), and ventilator days (5.8 versus 2.3, P = 0.02). It was also an independent predictor of infection (odds ratio 7.2, 95% confidence interval 2.1-24.5). CONCLUSIONS: Abnormal lymphocyte percentage at or after 72 h after burn injury is associated with adverse outcomes, including increased infectious risk.

Oversized Biodegradable Arterial Grafts Promote Enhanced Neointimal Tissue Formation.

Most tissue-engineered arterial grafts are complicated by aneurysmal dilation secondary to insufficient neotissue formation after scaffold degradation. The optimal graft would form an organized multilayered structure with a robust extracellular matrix that could withstand arterial pressure. The purpose of the current study was to determine how oversizing a biodegradable arterial scaffold affects long-term neotissue formation. Size-matched (1.0 mm, n = 11) and oversized (1.6 mm, n = 9) electrospun polycaprolactone/chitosan scaffolds were implanted as abdominal aortic interposition grafts in Lewis rats. The mean lumen diameter of the 1.6 mm grafts was initially greater compared with the native vessel, but matched the native aorta by 6 months. In contrast, the 1.0 mm grafts experienced stenosis at 6 and 9 months. Total neotissue area and calponin-positive neotissue area were significantly greater in the 1.6 mm grafts by 6 months and similar to the native aorta. Late-term biomechanical testing was dominated by remaining polymer, but graft oversizing did not adversely affect the biomechanics of the adjacent vessel. Oversizing tissue-engineered arterial grafts may represent a strategy to increase the formation of organized neotissue without thrombosis or adverse remodeling of the adjacent native vessel by harnessing a previously undescribed process of adaptive vascular remodeling.

Tissue-Engineered Heart Valves: A Call for Mechanistic Studies.

Heart valve disease carries a substantial risk of morbidity and mortality. Outcomes are significantly improved by valve replacement, but currently available mechanical and biological replacement valves are associated with complications of their own. Mechanical valves have a high rate of thromboembolism and require lifelong anticoagulation. Biological prosthetic valves have a much shorter lifespan, and they are prone to tearing and degradation. Both types of valves lack the capacity for growth, making them particularly problematic in pediatric patients. Tissue engineering has the potential to overcome these challenges by creating a neovalve composed of native tissue that is capable of growth and remodeling. The first tissue-engineered heart valve (TEHV) was created more than 20 years ago in an ovine model, and the technology has been advanced to clinical trials in the intervening decades. Some TEHVs have had clinical success, whereas others have failed, with structural degeneration resulting in patient deaths. The etiologies of these complications are poorly understood because much of the research in this field has been performed in large animals and humans, and, therefore, there are few studies of the mechanisms of neotissue formation. This review examines the need for a TEHV to treat pediatric patients with valve disease, the history of TEHVs, and a future that would benefit from extension of the reverse translational trend in this field to include small animal studies.

Proposed clinical pathway for nonoperative management of high-grade pediatric pancreatic injuries based on a multicenter analysis: A pediatric trauma society collaborative.

BACKGROUND: Guidelines for nonoperative management (NOM) of high-grade pancreatic injuries in children have not been established, and wide practice variability exists. The purpose of this study was to evaluate common clinical strategies across multiple pediatric trauma centers to develop a consensus-based standard clinical pathway. METHODS: A multicenter, retrospective review was conducted of children with high-grade (American Association of Surgeons for Trauma grade III-V) pancreatic injuries treated with NOM between 2010 and 2015. Data were collected on demographics, clinical management, and outcomes. RESULTS: Eighty-six patients were treated at 20 pediatric trauma centers. Median age was 9 years (range, 1-18 years). The majority (73%) of injuries were American Association of Surgeons for Trauma grade III, 24% were grade IV, and 3% were grade V. Median time from injury to presentation was 12 hours and median ISS was 16 (range, 4-66). All patients had computed tomography scan and serum pancreatic enzyme levels at presentation, but serial enzyme level monitoring was variable. Pancreatic enzyme levels did not correlate with injury grade or pseudocyst development. Parenteral nutrition was used in 68% and jejunal feeds in 31%. 3Endoscopic retrograde cholangiopancreatogram was obtained in 25%. An organized peripancreatic fluid collection present for at least 7 days after injury was identified in 59% (42 of 71). Initial management of these included: observation 64%, percutaneous drain 24%, and endoscopic drainage 10% and needle aspiration 2%. Clear liquids were started at a median of 6 days (IQR, 3-13 days) and regular diet at a median of 8 days (IQR 4-20 days). Median hospitalization length was 13 days (IQR, 7-24 days). Injury grade did not account for prolonged time to initiating oral diet or hospital length; indicating that the variability in these outcomes was largely due to different surgeon preferences. CONCLUSION: High-grade pancreatic injuries in children are rare and significant variability exists in NOM strategies, which may affect outcomes and effective resource utilization. A standard clinical pathway is proposed. LEVEL OF EVIDENCE: Therapeutic/care management, level V (case series).

Tissue-engineered vascular grafts for congenital cardiac disease: Clinical experience and current status.

Congenital heart disease is a leading cause of death in the newborn period, and man-made grafts currently used for reconstruction are associated with multiple complications. Tissue engineering can provide an alternative source of vascular tissue in congenital cardiac surgery. Clinical trials have been successful overall, but the most frequent complication is graft stenosis. Recent studies in animal models have indicated the important role of the recipient׳s immune response in neotissue formation, and that modulating the immune response can reduce the incidence of stenosis.

Neuroleptic malignant syndrome in the trauma intensive care unit: Diagnosis and management of a rare disease in a challenging population.

Neuroleptic malignant syndrome (NMS) is a life-threatening neurological disorder associated with the use of antipsychotic medications. Many of its classic signs, such as fever and altered mental status, are nonspecific in trauma intensive care unit (ICU) patients, and its rarity makes it a difficult diagnosis in this population. However, delays in treatment can be costly both in terms of hospital resources and patient outcomes. We herein report a case of a 54-year-old trauma patient with NMS precipitated by a combination of cocaine withdrawal and neuroleptic medications. Few cases of NMS in the intubated polytrauma patient have been described in the literature previously. Given the poor outcomes associated with this disorder, ICU patients would benefit from risk stratification and avoidance of neuroleptic medications in those at highest risk for NMS, particularly patients who are withdrawing from dopaminergic agents.

A 20-year experience with thoracic endovascular aortic repair.

BACKGROUND: Endovascular approaches (thoracic endovascular aortic repair) have revolutionized treatment of thoracic aortic disease. OBJECTIVE: We report our 20-year experience with this therapy. METHODS: Four hundred twenty patients (mean age = 69.0 years; 54% male) underwent thoracic endovascular aortic repair (1993-2013), predominantly for fusiform aneurysm (n = 144), saccular aneurysm (n = 94), acute (n = 64) or chronic (n = 36) dissection, or traumatic injury (n = 39). Rupture was present in 80 patients (19.1%). Most patients (78.3%) were at high risk for open repair. Mean aortic diameter was 5.5 cm. Extent of repair included arch in 218 patients, total descending aorta in 193 patients, and thoracoabdominal aorta in 35 patients. RESULTS: Thirty-day mortality occurred in 20 patients (4.8%). Neurologic events included stroke (5.0%) and spinal cord ischemia (permanent 1.7%, temporary 7.9%). Although dialysis was only required in 1.4% of the patients, 19% had renal failure by RIFLE (Risk, Injury, Failure) criteria. Endoleak occurred in 32.9% of the patients. Ten-year freedom from dissection, rupture, or need for reintervention in treated or adjacent aortic segments (ie, treatment failure) was 63.2%. Independent predictors included presentation with rupture, preexisting renal failure, or intervention on the arch aorta (all Ps < 0.03). Aortic pathology also independently predicted treatment failure (P = 0.026). The 15-year survival rate was 32.3%. Advancing age, presence of coronary artery disease, rupture, or postoperative renal failure (all Ps < 0.05), but not treatment failure (P = 0.926), independently predicted late mortality. CONCLUSIONS: Thoracic endovascular aortic repair can be performed with acceptable results in a high-risk population. The risk of treatment failure persists, underscoring the importance of continued long-term endograft surveillance, but this does not seem to impact late mortality.

The impact of acute renal failure on early and late outcomes after thoracic aortic endovascular repair.

BACKGROUND: The incidence of acute kidney injury (AKI) after thoracic aortic endovascular repair (TEVAR) is variably reported at 1% to 34%. This study utilized the RIFLE (risk, injury, failure) criteria to evaluate the incidence, risk factors, and late implications of AKI after TEVAR. METHODS: In all, 350 patients without prior dialysis requirement underwent TEVAR (1993 to 2013). The mean age was 68.7 years (54% male). The mean preoperative glomerular filtration rate was 76.5 ± 37.6 mL/min, with 39 patients (11.7%) in chronic kidney stage 3 or 4. The TEVAR was performed for rupture in 20.6%. The mean contrast volume administered was 95.7 ± 52.9 mL. RESULTS: Early mortality was seen in 17 patients (4.9%). Acute kidney injury defined as RIFLE classes risk, injury, or failure was seen in 59 patients (17%; risk = 36, injury = 14, failure = 9). Independent predictors of AKI included history of saccular aneurysm, presentation with rupture, or need for arch repair or red blood cell transfusion (all p < 0.05). Only 2 patients (0.6%) needed dialysis, with none requiring permanent dialysis. Importantly, 10-year freedom from dialysis was 97.7%. Development of AKI predicted early mortality (p < 0.001, odds ratio 9.8). Ten-year survival was 38.1%. Both injury and failure AKI classes independently predicted late mortality (p < 0.05). CONCLUSIONS: The prevalence of AKI after TEVAR as assessed by RIFLE criteria is higher than seen in previous reports. Despite its infrequent progression to permanent dialysis dependence, AKI remains an important risk factor for both early and late mortality. Future studies should evaluate strategies to reduce the incidence of AKI after TEVAR to improve both early and late outcomes.

A statewide, community-based assessment of alvimopan's effect on surgical outcomes.

OBJECTIVE: Alvimopan was approved by the Food and Drug Administration in May 2008 and has been shown to accelerate gastrointestinal recovery after colectomy. Our independent study evaluated alvimopan as it is used in actual hospital practice in the state of Michigan. We hypothesized that alvimopan significantly decreases incidence of prolonged ileus and reduces length of stay (LOS) in patients who have undergone colectomy. METHODS: We identified 4749 patients from the Michigan Surgical Quality Collaborative (N = 28 hospitals) database between August 2007 and December 2010 who underwent elective colectomy operations. A total of 528 patients received alvimopan both pre- and postoperatively. We first selected a control group of patients from hospitals that had never administered alvimopan (n = 1833) and used propensity matching to manage differences in patient demographics and clinical characteristics. To control for hospital and surgeon characteristics, we then performed a sensitivity analysis, using a separate group of historical control patients treated before May 2008 in hospitals that would later administer alvimopan (n = 270). The Fisher exact test was used to compare complication rates, and the Student t test was used to compare LOS. RESULTS: Patients who received alvimopan had significantly lower incidence of prolonged ileus (2.3% vs 7.9%; P < 0.001) and a significantly shorter LOS (4.84 ± 4.54 vs 6.40 ± 4.45 days; P < 0.001) than control patients in hospitals that had never administered alvimopan. No differences were noted in these outcomes using sensitivity analysis. CONCLUSION: This study suggests that the actual utilization of alvimopan leads to a reduction in prolonged ileus and LOS in patients who underwent colectomy. By accelerating postoperative recovery, alvimopan has the potential to benefit patients and health care systems by improving outcomes, ensuring patient comfort, and reducing cost.

Identification of the minimal functional unit of the homo-oligomeric human reduced folate carrier.

The reduced folate carrier (RFC) is the major transport system for folates in mammals. We previously demonstrated the existence of human RFC (hRFC) homo-oligomers and established the importance of these higher order structures to intracellular trafficking and carrier function. In this report, we examined the operational significance of hRFC oligomerization and the minimal functional unit for transport. In negative dominance experiments, multimeric transporters composed of different ratios of active (either wild type (WT) or cysteine-less (CLFL)) and inactive (either inherently inactive (Y281L and R373A) due to mutation, or resulting from inactivation of the Y126C mutant by (2-sulfonatoethyl) methanethiosulfonate (MTSES)) hRFC monomers were expressed in hRFC-null HeLa (R5) cells, and residual WT or CLFL activity was measured. In either case, residual transport activity with increasing levels of inactive mutant correlated linearly with the fraction of WT or CLFL hRFC in plasma membranes. When active covalent hRFC dimers, generated by fusing CLFL and Y126C monomers, were expressed in R5 cells and treated with MTSES, transport activity of the CLFL-CLFL dimer was unaffected, whereas Y126C-Y126C was potently (64%) inhibited; heterodimeric CLFL-Y126C and Y126C-CLFL were only partly (27 and 23%, respectively) inhibited by MTSES. In contrast to Y126C-Y126C, trans-stimulation of methotrexate uptake by intracellular folates for Y126C-CLFL and CLFL-Y126C was nominally affected by MTSES. Collectively, these results strongly support the notion that each hRFC monomer comprises a single translocation pathway for anionic folate substrates and functions independently of other monomers (i.e. despite an oligomeric structure, hRFC functions as a monomer).