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Background: The optimal tumor-free margin width remains controversial and may be inappropriate to investigate without considering differences in the underlying tumor biology., Methods: R1 resection was defined as margin clearance less than 1 mm. R0 resection was further divided into 3 groups: 1-4, 5-9, and ≥10 mm. The impact of margin width on overall survival (OS) relative to KRAS status [wild type (wtKRAS) vs. mutated (mutKRAS)] was assessed., Results: A total of 411 patients met inclusion criteria. Median patient age was 58 years (interquartile range, 49.7-66.7); most patients were male (n = 250; 60.8 %). With a median follow-up of 28.3 months, median and 5-year OS were 69.8 months and 55.1 %. Among patients with wtKRAS tumors, although margin clearance of 1-4 mm or more was associated with improved OS compared to R1 (all P < 0.05), no difference in OS was observed when comparing margin clearance of 1-4 mm to the 5-9 mm and the ≥10 mm groups (all P > 0.05). In contrast, among patients with mutKRAS tumors, all three groups of margin clearance (1-4, 5-9, and ≥10 mm) fared no better in terms of 5-year survival compared to R1 resection (all P > 0.05)., Conclusions: While a 1-4 mm margin clearance in patients with wtKRAS tumors was associated with improved survival, wider resection width did not confer an additional survival benefit. In contrast, margin status-including a 1 cm margin-did not improve survival among patients with mutKRAS tumors.

Objective: To evaluate the impact of transfused packed red blood cell (PRBC) age on perioperative morbidity among patients undergoing major gastrointestinal surgery., Background: Patients undergoing major surgery often receive PRBC transfusions. The effect of PRBC age (ie, storage duration before transfusion) on perioperative surgical outcomes remains poorly defined., Methods: In this study, 1365 patients were identified who underwent a hepato-pancreatic or colorectal resection and received ≥1 unit of PRBCs between 2009 and 2014 at the Johns Hopkins Hospital. Data regarding the storage duration of PRBCs, clinicopathologic characteristics, and perioperative outcomes were obtained and analyzed. Multivariable modified Poisson regression analyses were performed to assess the effect of PRBC age on perioperative morbidity., Results: A total of 5901 PRBC units were transfused for a median of 2 (interquartile range 2-4) units transfused per patient. In all, 936 (68.6%) patients received only units of blood that had been stored for less than 35 days ("fresh" blood), whereas 429 (31.4%) patients received at least 1 unit of PRBC that had been stored for ≥35 days ("older" blood). Overall postoperative morbidity was 32.8%. The incidence of postoperative complications (42.7% vs 28.3%) was higher among patients who received "older" vs "fresh" blood (P < 0.001). After adjusting for confounders on multivariable analysis, transfusion of "older" blood remained independently associated with an increased risk of perioperative morbidity (Relative Risk 1.20, P = 0.03)., Conclusions: The use of "older" blood was an independent predictor of postoperative morbidity among patients undergoing hepato-pancreatic or colorectal procedures. Transfusion of "older" blood products may contribute to a higher risk of postoperative complications.

Background: While survival after malignancies is traditionally reported as actuarial survival, conditional survival (CS) may be more clinically relevant by accounting for "accrued" survival time as time progresses. We sought to compare actuarial and CS among patients with gallbladder carcinoma (GBC) ., Methods: A total of 312 patients who underwent curative intent surgery for GBC between 2000 and 2014 were identified using a multi-institutional database. Overall survival (OS) was estimated using the Kaplan-Meier method. CS was calculated as the probability of surviving an additional 3 years at year "x" after surgery using the formula CS 3  = S (x+3) /S x ., Results: Among all patients, the median actuarial OS was 24.8 months (IQR 13.3-88.9). While actuarial survival decreased over time, 3-year CS (CS 3 ) increased, with CS 3 at 2 years after surgery noted to be 61.8 % compared with the 5-year actuarial OS of 31.6 %. Factors associated with reduced actuarial OS were positive margin status (HR 3.61, 95 % CI 2.47-5.26), increasing tumor size (HR = 1.02, 95 % CI 1.01-1.02), higher tumor grade (HR 2.98, 95 % CI 1.47-6.04), residual disease at repeat resection (HR = 2.78, 95 % CI 1.49-3.49, p < 0.001), and lymph node metastasis (HR = 1.95, 95 % CI 1.39-2.75, all p < 0.001). The calculated CS 3 exceeded the actuarial survival within each high-risk patient subgroup. For example, patients with residual disease at repeat resection had an actuarial survival 23.1 % at 5 years versus a CS 3 of 56.3 % in patients alive at 2 years (Δ = 33.2 %)., Conclusions: CS provides a more accurate, dynamic estimate for survival, especially among high-risk patients. CS estimates can be used to accurately predict survival and guide clinical decision making.

Background: Gallbladder and extrahepatic biliary malignancies are aggressive tumors with high risk of recurrence and death. We hypothesize that elevated preoperative Neutrophil-Lymphocyte Ratios (NLR) are associated with poor prognosis among patients undergoing resection of gallbladder or extrahepatic biliary cancers., Methods: Patients who underwent complete surgical resection between 2000-2014 were identified from 10 academic centers (n=525). Overall (OS) and recurrence-free survival (RFS) were analyzed by stratifying patients with normal (<5) versus elevated (>5) NLR., Results: Overall, 375 patients had NLR <5 while 150 patients had NLR >5. Median OS was 24.5 months among patients with NLR<5 versus 17.0 months among patients with NLR>5 (p<0.001). NLR was also associated with OS in subgroup analysis of patients with gallbladder cancer. In fact, on multivariable analysis, NLR>5, dyspnea and preoperative peak bilirubin were independently associated with OS in patients with gallbladder cancer. Median RFS was 26.8 months in patients with NLR<5 versus 22.7 months among patients with NLR>5 (p=0.030). NLR>5 was independently associated with worse RFS for patients with gallbladder cancer., Conclusions: Elevated NLR was associated with worse outcomes in patients with gallbladder and extrahepatic biliary cancers after curative-intent resection. NLR is easily measured and may provide important prognostic information., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Wetlands mitigate the migration of groundwater contaminants through a series of biogeochemical gradients that enhance multiple contaminant-binding processes. The hypothesis of this study was that wetland plant roots contribute organic carbon and release O2 within the rhizosphere (plant-impact soil zone) that promote the formation of Fe(III)-(oxyhydr)oxides. In turn, these Fe(III)-(oxyhydr)oxides stabilize organic matter that together contribute to contaminant immobilization. Mineralogy and U binding environments of the rhizosphere were evaluated in samples collected from contaminated and non-contaminated areas of a wetland on the Savannah River Site in South Carolina. Based on Mössbauer spectroscopy, rhizosphere soil was greatly enriched with nanogoethite, ferrihydrite-like nanoparticulates, and hematite, with negligible Fe(II) present. X-ray computed tomography and various microscopy techniques showed that root plaques were tens-of-microns thick and consisted of highly oriented Fe-nanoparticles, suggesting that the roots were involved in creating the biogeochemical conditions conducive to the nanoparticle formation. XAS showed that a majority of the U in the bulk wetland soil was in the +6 oxidation state and was not well correlated spatially to Fe concentrations. SEM/EDS confirm that U was enriched on root plaques, where it was always found in association with P. Together these findings support our hypothesis and suggest that plants can alter mineralogical conditions that may be conducive to contaminant immobilization in wetlands., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: The interplay of tumor biology and surgical margin status after resection for colorectal liver metastasis (CRLM) remains controversial. Consequently, we sought to determine the impact of surgical margin status on overall survival (OS) stratified by KRAS mutational status., Materials and Methods: Four hundred eighty-five patients with known KRAS mutational status were identified. Clinicopathologic and long-term survival data were collected and assessed., Results: On pathology, most patients (n = 380; 78.3 %) had an R0 margin, while 105 (21.7 %) had an R1. Roughly two thirds of tumors were KRAS wild type (wtKRAS) (n = 307, 63.3 %), while 36.7 % (n = 178) had KRAS mutations (mutKRAS). Median and 5-year OS of the entire cohort was 65.8 months and 53.8 %, respectively. An R1 resection was associated with worse 5-year OS compared with R0 (42.4 % vs. 57.1 %; hazard ratio (HR) 1.82, 95 % CI 1.28-2.57; P = 0.001). After controlling for KRAS status, the survival benefit associated with an R0 resection persisted only among patients with wtKRAS tumors (HR 2.16, 95 % CI 1.42-3.30; P < 0.001). In contrast, surgical margin had no impact on OS among patients with mutKRAS tumors (5-year OS R0, 40.7 % vs. R1, 46.7 %; HR 1.34, 95 % CI 0.73-2.48; P = 0.348)., Conclusion: The impact of margin status differed by KRAS mutation status. An R0 margin only provided a survival benefit to patients with wtKRAS tumors. Tumor biology and not surgical technique determined prognosis.

Background: Although sarcopenia has been identified as a predictor of poor, postoperative, clinical outcomes, the financial impact of sarcopenia remains undetermined. We sought to evaluate the relationship between sarcopenia and hospital finances among a cohort of patients undergoing a hepato-pancreatico-biliary or colorectal resection., Methods: Clinical, financial, and morphometric data were collected for 1,169 patients undergoing operative resection between January 2011 and December 2013 at the Johns Hopkins Hospital. Multivariable regression analysis was performed to assess the relationship between sarcopenia and total hospital costs., Results: Using sex-specific cutoffs for total psoas volume, 293 patients were categorized as sarcopenic. The presence of sarcopenia was associated with a $14,322 increase in the total hospital cost (median covariate-adjusted cost, sarcopenia versus no sarcopenia: $38,804 vs $24,482, P < .001). Patients who presented with sarcopenia demonstrated a higher total hospital cost within the subgroup of patients who developed a postoperative complication (sarcopenia versus no sarcopenia: $65,856 vs $59,609) and among those patients who did not develop a postoperative complication (sarcopenia versus no sarcopenia: $26,282 vs $23,763, both P < .001). Similarly, total hospital costs were higher among patients presenting with sarcopenia regardless of the length of stay for index admission (observed:expected, length of stay < 1: sarcopenia versus no sarcopenia: $25,038 vs $22,827; observed:expected, length of stay > 1: sarcopenia versus no sarcopenia: $43,283 vs $38,679, both P < .001)., Conclusion: As measured by sarcopenia, patient frailty is inversely related to total hospital costs. Sarcopenia represents a novel tool for forecasting patient outcomes and operative costs and can be used to inform quality improvement and cost containment strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Gallbladder cancer is a relatively rare malignancy. The current study aimed to define the incidence and patterns of recurrence following gallbladder cancer resection., Methods: Using a multi-institutional cohort we identified 217 patient undergoing curative intent surgery for gallbladder cancer. Patterns of recurrence were classified as locoregional and distant recurrence., Results: At last follow-up, 76 patients (35.0%) had experienced a recurrence (locoregional only, n = 12, 15.8%; distant only, n = 50, 65.8%; locoregional and distant, n = 14, 18.4%). Median time to recurrence was 9.5 months (IQR 4.7-17.6) and was not associated with recurrence site (all p > 0.05). On multivariable analysis, T3 disease (HR = 8.44, p = 0.014), lymphovascular invasion (HR = 4.24, p < 0.001) and residual disease (HR = 2.04, p = 0.042) were associated with an increased risk of recurrence. Patients who recurred demonstrated a worse 1-, 3- and 5-year OS (1-year OS: 91.3% vs. 68.6%, p = 0.001, 3-year OS: 79.3% vs. 28.7%, p < 0.001, and 5-year OS: 75.9% vs. 16.0%, p < 0.001). After adjusting for other risk factors, recurrence was independently associated with a decreased OS (HR = 3.71, p = 0.006). Of note, receipt of adjuvant therapy was associated with improved OS (HR = 0.56, p = 0.027) among those patients who developed a tumor recurrence., Discussion: Over one-third of patients experienced a recurrence after gallbladder cancer surgery. While chemotherapy did not decrease the rate of recurrence, patients who experienced recurrence after administration of adjuvant treatment faired better than patients who did not receive adjuvant therapy., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Right-sided and left-sided colorectal cancer (CRC) is known to differ in their molecular carcinogenic pathways. We sought to investigate the variable prognostic implication of KRAS mutation after hepatectomy for colorectal liver metastases (CRLM) according to the site of primary CRC., Methods: A total of 426 patients who underwent a curative-intent hepatic resection and whose KRAS status was available were identified. Clinicopathologic characteristics and long-term outcomes were stratified by KRAS status (wild type vs. mutant type) and primary tumor location (right-sided vs. left-sided). Cecum, right and transverse colon were defined as right-sided, whereas left colon and rectum were defined as left-sided., Results: Among patients with a right-sided CRC, 5-year recurrence-free survival (RFS) and overall survival (OS) were not correlated with KRAS status (wild type: 30.8 and 47.2 % vs. mutant type: 38.5 and 49.1 %, respectively) (both P > 0.05). Specifically, mutant-type KRAS was not associated with either RFS or OS on multivariable analysis (hazard ratio [HR] 1.51, 95 % confidence interval [CI] 0.73-3.14, P = 0.23 and HR 1.03, 95 % CI 0.51-2.08, P = 0.95, respectively). In contrast, among patients who underwent resection of CRLM from a left-sided primary CRC, 5-year RFS and OS were worse among patients with mutant-type KRAS (wild type: 23.7 and 57.2 % vs. mutant type: 19.6 and 38.2 %, respectively) (both P < 0.05). On multivariable analysis, mutant-type KRAS remained independently associated with worse RFS and OS among patients with a left-sided primary CRC (HR 1.57, 95 % CI 1.01-2.44, P = 0.04 and HR 1.81, 95 % CI 1.11-2.96, P = 0.02, respectively)., Conclusions: KRAS status has a variable prognostic impact after hepatic resection for CRLM depending on the site of the primary CRC. Future studies examining the impact of KRAS status on prognosis after hepatectomy should take into account the primary CRC tumor site.

Introduction: Although widely used, the 7th edition American Joint Committee on Cancer (AJCC) staging system for perihilar cholangiocarcinoma (PHC) may be limited. Disease-specific nomograms have been proposed as a better means to predict long-term survival for individual patients. We sought to externally validate a recently proposed nomogram by Memorial Sloan Kettering Cancer Center (MSKCC) for PHC, as well as identify factors to improve the prediction of prognosis for patients with PHC., Methods: Four hundred seven patients who underwent surgery for PHC between 1988 and 2014 were identified using an international, multi-center database. Standard clinicopathologic and outcome data were collected. The predictive power of the AJCC staging system and nomogram were assessed., Results: Median survival was 24.4 months; 3- and 5-year survival was 37.2 and 20.8 %, respectively. The AJCC 7th edition staging system (C-index 0.570) and the recently proposed PHC nomogram (C-index 0.587) both performed poorly. A revised nomogram based on age, lymphovascular invasion, perineural invasion, and lymph node metastases performed better (C-index 0.682). The calibration plot of the revised PHC nomogram demonstrated good calibration., Conclusion: The 7th edition AJCC staging system and the MSKCC nomogram had a poor ability to predict long-term survival for individual patients with PHC. A revised nomogram provided more accurate prediction of survival, but will need to be externally validated.

Background: Seventh AJCC distal cholangiocarcinoma T-stage classification inadequately separates patients by survival. This retrospective study aimed to define a novel T-stage system to better stratify patients after resection., Methods: Curative-intent pancreaticoduodenectomies for distal cholangiocarcinoma (1/2000-5/2015) at 10 US institutions were included. Relationships between tumor characteristics and overall survival (OS) were assessed and incorporated into a novel T-stage classification., Results: 176 patients (median follow-up: 24mo) were included. Current AJCC T-stage was not associated with OS (T1: 23mo, T2: 20mo, T3: 25mo, T4: 12mo; p = 0.355). Tumor size ≥3 cm and presence of lymphovascular invasion (LVI) were associated with decreased OS on univariate and multivariable analyses. Patients were stratified into 3 groups [T1: size <3 cm and (-)LVI (n = 69; 39.2%); T2: size ≥3 cm and (-)LVI or size <3 cm and (+)LVI (n = 82; 46.6%); and T3: size ≥3 cm and (+)LVI (n = 25; 14.2%)]. Each progressive proposed T-stage was associated with decreased median OS (T1: 35mo; T2: 20mo; T3: 8mo; p = 0.002)., Conclusion: Current AJCC distal cholangiocarcinoma T-stage does not adequately stratify patients by survival. This proposed T-stage classification, based on tumor size and LVI, better differentiates patient outcomes after resection and could be considered for incorporation into the next AJCC distal cholangiocarcinoma staging system., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: While the prognostic role of KRAS status after resection of CRLM has been previously explored, the importance of KRAS status relative to the receipt of preoperative chemotherapy remains largely unknown., Methods: A total of 430 patients who underwent curative-intent surgery for CRLM between 2000 and 2015 and who had available KRAS genotype data were identified. Data regarding KRAS mutation status, receipt of preoperative chemotherapy, and overall survival (OS) were assessed using univariable and multivariable analyses., Results: Median patient age was 58 years (IQR, 50.4-66.4 years). A total of 258 patients (60.0%) received preoperative chemotherapy, while 172 (40.0%) had upfront surgery. Median and 5-year OS in the entire cohort was 65.1 months and 53.2%, respectively. KRAS mutation was associated with a worse 5-year OS compared with wild-type tumors (HR 1.41; P = 0.042). After stratifying by the receipt of preoperative chemotherapy, the prognostic value of KRAS mutation only persisted among patients who had received preoperative chemotherapy (HR 1.67; P = 0.012). In contrast, KRAS mutation status had no impact on OS among patients who had not received preoperative chemotherapy (P = 0.597)., Conclusions: KRAS mutation status was an independent predictor of OS among patients undergoing liver resection of CRLM. However, after stratifying by receipt of preoperative chemotherapy, KRAS was informative relative to prognosis only among patients who received preoperative chemotherapy. J. Surg. Oncol. 2016;114:361-367. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Introduction: Extrahepatic biliary malignancies are often diagnosed at an advanced stage. We compared patients with unresectable perihilar cholangiocarcinoma (PHCC) and gallbladder cancer (GBC) who underwent a palliative procedure versus an aborted laparotomy., Methods: Seven hundred seventy-seven patients who underwent surgery for PHCC or GBC between 2000 and 2014 were identified. Uni- and multivariable analyses were performed to identify factors associated with outcome., Results: Utilization of preoperative imaging increased over time (CT use, 80.1 % pre-2009 vs. 90 % post-2009) (p < 0.001). The proportion of the patients undergoing curative-intent resection also increased (2000-2004, 67.0 % vs. 2005-2009, 74.5 % vs. 2010-2014, 78.8 %; p = 0.001). The planned surgery was aborted in 106 (13.7 %) patients and 94 (12.1 %) had a palliative procedure. A higher incidence of postoperative complications (19.2 vs. 3.8 %, p = 0.001) including deep surgical site infections (8.3 vs. 1.1 %), bleeding (4.8 vs. 0 %), bile leak (6.0 vs. 0 %) and longer length of stay (7 vs. 4.5 days) were observed among the patients who underwent a palliative surgical procedure versus an aborted non-therapeutic, non-palliative laparotomy (all p < 0.05). OS was comparable among the patients who underwent a palliative procedure (8.7 months) versus an aborted laparotomy (7.8 months) (p = 0.23)., Conclusion: Increased use of advanced imaging modalities was accompanied by increased curative-intent surgery. Compared with patients in whom surgery was aborted, patients who underwent surgical palliation demonstrated an increased incidence of postoperative morbidity with comparable survival.

Background: Although radical re-resection for gallbladder cancer (GBC) has been advocated, the optimal extent of re-resection remains unknown. The current study aimed to assess the impact of common bile duct (CBD) resection on survival among patients undergoing surgery for GBC., Methods: Patients undergoing curative-intent surgery for GBC were identified using a multi-institutional cohort of patients. Multivariable Cox-proportional hazards regression was performed to identify risk factors for a poor overall survival (OS)., Results: Among the 449 patients identified, 26.9% underwent a concomitant CBD resection. The median number of lymph nodes harvested did not differ based on CBD resection (CBD, 4 [IQR: 2-9] vs. no CBD, 3 [IQR: 1-7], P = 0.108). While patients who underwent a CBD resection had a worse OS, after adjusting for potential confounders, CBD resection did not impact OS (HR = 1.40, 95%CI 0.87-2.27, P = 0.170). Rather, the presence of advanced disease (T3: HR = 3.11, 95%CI 1.22-7.96, P = 0.018; T4: HR = 7.24, 95%CI 1.70-30.85, P = 0.007) and the presence of disease at the surgical margin (HR = 2.58, 95%CI 1.26-5.31, P = 0.010) were predictive of a worse OS., Conclusions: CBD resection did not yield a higher lymph node count and was not associated with an improved survival. Routine CBD excision in the re-resection of GBC is unwarranted and should only be performed selectively. J. Surg. Oncol. 2016;114:176-180. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Introduction: The impact of phosphorus as well as glycemic alterations on liver regeneration has not been directly examined. We sought to determine the impact of phosphorus and glucose on liver regeneration after major hepatectomy., Methods: Early and late liver regeneration index was defined as the relative increase of liver volume (RLV) within 2[(RLV2m-RLVp)/RLVp] and 7 months[(RLV7m-RLVp)/RLVp] following surgery. The association of perioperative metabolic factors, liver regeneration, and outcomes was assessed., Results: On postoperative day 2, 50 (52.6 %) patients had a low phosphorus level (≤2.4 mg/dl), while 45 (47.4 %) had a normal/high phosphorus level (>2.4 mg/dl). Despite comparable clinicopathologic characteristics (all P > 0.05) and RLV/TLV at surgery (P = 0.84), regeneration index within 2 months was lower in the normal/high phosphorus group (P = 0.01) with these patients having increased risk for postoperative liver failure (P = 0.01). The inhibition of liver regeneration persisted at 7 months (P = 0.007) and was associated with a worse survival (P = 0.02). Preoperative hypoglycemia was associated only with a lower early regeneration index (P = 0.02)., Conclusions: Normal/high phosphorus was associated with inhibition of early and late liver regeneration, as well as with an increased risk of liver failure and worse long-term outcomes. Immediate preoperative hypoglycemia was associated with a lower early volumetric gain. Metabolic factors may represent early indicators of liver failure that could identify patients at increased risk for worse outcomes.

Background: Large variations exist regarding the type and volume of fluid to be administered to patients. This study aimed to quantitate variations in the administration of crystalloid fluids at the level of the patient, provider, and procedure at a large, tertiary care center., Method: Patients who underwent major cardiac, thoracic, or abdominal procedures between 2011 and 2014 were identified. Variations in crystalloid administration were compared by procedure and provider using a coefficient of variation (CV). Multivariable hierarchical linear modeling was performed to identify factors predictive of fluid administration and quantitate variation at the level of the patient and provider., Results: Among 6248 patients who met inclusion criteria, the average crystalloid volume was 25.8 mL kg(-1) m(2) h(-1), corresponding to a CV of 55%. Patients who underwent pancreatectomy received the highest corrected crystalloid volume (32.7 mL kg(-1) m(2) h(-1)), whereas those who underwent coronary artery bypass grafting received the lowest corrected crystalloid volume (14.7 mL kg(-1) m(2) h(-1)). Variations in fluid practices were noted between providers (corrected CV; 14.7%-97.1%) and within the practices of the same provider (corrected CV range; 24.1%-87.9%). On multivariable analysis, age and changes in hemoglobin concentration were associated with a higher crystalloid volume (both P < 0.05). Although over 90% of the variation was attributed to patient-level factors, approximately 10% was due to factors at level of the provider (surgeon: 5.8% versus anesthesiologist: 3.4%)., Conclusions: Wide variations were noted in crystalloid administration between procedures, providers, and within providers. Evidence-based practices and goal-directed therapies should be incorporated to avoid unwanted variations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: While traditional survival analyses focus on factors determined at the time of surgery, conditional survival (CS) estimates prognosis relative to time following treatment. We sought to compare actuarial and CS among patients undergoing curative intent surgery for hilar cholangiocarcinoma., Methods: 242 patients undergoing surgery between 2000 and 2014 were identified using a multi-institutional database. CS was calculated as the probability of surviving an additional 3 years, given that the patient had already survived "x" years from surgery., Results: Median patient age was 67 years (IQR: 57-73) and most patients were male (n = 140, 57.9%). Lymph node metastases were noted in 79 (32.6%) patients while an R0 margin was obtained in 66.1% (n = 160). Median OS was 22.3 months. Actuarial survival decreased over time from 46.3% at 2 years following surgery to 18.2% at 5 years; in contrast, the 3-year CS (CS3) increased with time (CS3 at 2 years was 39.3% versus 54.4% at 5 years). CS3 exceeded actuarial survival for high-risk patients with patients with perineural invasion demonstrating an actuarial survival of 15.4% at 5 years versus CS3 of 37.6% at 2 years following surgery (Δ = 22.2%)., Conclusions: CS provides a more accurate, dynamic estimate for survival, especially among high-risk patients., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Although perioperative platelet count has been associated with postoperative morbidity and mortality, its impact on liver regeneration has not been examined directly. This study sought to determine the impact of platelet count on liver regeneration after major liver resection using cross-sectional imaging volumetric assessment., Methods: Patients who underwent major liver resection between 2004 and 2015 and had available data on immediate postoperative platelet count, as well as preoperative and postoperative CT images, were identified retrospectively. Resected liver volume was subtracted from total liver volume (TLV) to define postoperative remnant liver volume (RLVp ). The liver regeneration index was defined as the relative increase in liver volume within 2 months ((RLV2m  - RLVp )/RLVp , where RLV2m is the remnant liver volume around 2 months after surgery). The association between platelet count, liver regeneration and outcomes was assessed., Results: A total of 99 patients met the inclusion criteria. Overall, 25 patients (25 per cent) had a low platelet count (less than 150 × 10(9) /l), whereas 74 had a normal-high platelet count (at least 150 × 10(9) /l). Despite having comparable clinicopathological characteristics and RLVp /TLV at surgery (P = 0·903), the relative increase in liver volume within 2 months was considerably lower in the low-platelet group (3·9 versus 16·5 per cent; P = 0·043). Patients with a low platelet count had an increased risk of postoperative complications (72 versus 38 per cent; P = 0·003), longer hospital stay (8 versus 6 days; P = 0·004) and worse median overall survival (24·5 versus 67·3 months; P = 0·005) than those with a normal or high platelet count., Conclusion: After major liver resection, a low postoperative platelet count was associated with inhibited liver regeneration, as well as worse short- and long-term outcomes. Immediate postoperative platelet count may be an early indicator to identify patients at increased risk of worse outcomes., (© 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: The influence of intraoperative blood loss (IBL) on long-term outcomes of patients undergoing liver resection for colorectal cancer liver metastases (CRLM) remains not well defined., Materials and Methods: A total of 433 patients who underwent curative-intent hepatic resection for CRLM between 2000 and 2013 at Johns Hopkins were identified. Demographics, IBL data, and long-term outcomes were collected and analyzed. Clinicopathologic predictors of IBL and the association of IBL and outcomes were assessed., Results: The median patient age was 54 y (interquartile range, 44-64), most patients were male (58.9%; n = 255). At surgery, the median IBL was 400 mL (range, 10-5100 mL). Two-hundred eighty-seven patients (66.3%) had an IBL of >250 mL. Factors associated with increased IBL (>250 mL) on multivariate analysis were male sex (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.68-4.09; P < 0.001), tumor size >3 cm (OR, 1.88; 95% CI, 1.18-2.99; P = 0.008), and major hepatic resection (OR, 3.08; 95% CI, 1.92-4.92; P < 0.001). At a median follow-up time of 30.6 mo, the median survival times were 70.5, 56.4, and 36.9 mo for IBL <250, 250-1000, and >1000 mL, respectively (P = 0.004). IBL >250 mL remained an independent prognostic factor of overall survival in multivariate analysis (hazard ratio, 1.41; 95% CI, 1.01-1.97; P = 0.04) after adjusting for other factors including the receipt of blood transfusion., Conclusions: The magnitude of IBL during CRLM resection was related to biologic characteristics of the tumor and the extent of surgery. Increased IBL during CRLM resection was an independent prognostic factor for worse patient survival. Furthermore, a dose-response relationship between increasing IBL and worsening survival was evident., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although it is a useful metric for preoperative risk stratification, frailty can be difficult to identify in patients before surgery. We sought to develop a preoperative frailty-risk model combining sarcopenia with clinical parameters to predict 1-year mortality using a cohort of patients undergoing gastrointestinal cancer surgery., Study Design: We identified 1,326 patients undergoing hepatobiliary, pancreatic, or colorectal surgery between 2011 and 2014. Sarcopenia defined by psoas density was measured using preoperative cross-sectional imaging. Multivariable Cox regression analysis was performed to identify preoperative risk factors associated with 1-year mortality and used to develop a preoperative risk-stratification score., Results: Among all patients identified, 640 (48.3%) patients underwent pancreatic surgery, 347 (26.2%) underwent a hepatobiliary procedure, and 339 (25.5%) a colorectal procedure. Using sex-specific cut-offs, 398 (30.0%) patients were categorized as sarcopenic. Sarcopenic patients were more likely to develop postoperative complications vs non-sarcopenic patients (odds ratio [OR] 1.80, 95% CI 1.42 to 2.29; p < 0.001). Overall 1-year mortality was 9.4%. On multivariable analysis, independent risk factors for 1-year mortality included increasing age (65 to 75 years: [hazard ratio (HR) 1.81, 95% CI 1.05 to 3.14] greater than 75 years [HR 2.79, 95% CI 1.55 to 5.02]), preoperative anemia hemoglobin < 12.5 g/dL (HR 1.68, 95% CI 1.17 to 2.40), and preoperative sarcopenia (HR 1.98, 95% CI 1.36 to 2.88; all p < 0.05). Using these variables, a 28-point weighed composite score was able to stratify patients by their risk for mortality 1 year after surgery (C-statistic = 0.70). The proposed score outperformed other indices of frailty including the modified Frailty Index (C-statistic = 0.55) and the Eastern Cooperative Oncology Group (ECOG) performance score (C-statistic = 0.57) (both p < 0.05)., Conclusion: Sarcopenia was combined with clinical factors to generate a composite risk-score that can be used to identify frail patients at greatest risk for 1-year mortality after gastrointestinal cancer surgery., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Although previous reports have focused on factors at the hospital level to explain variations in postoperative outcomes, less is known regarding the effect of provider-specific factors on postoperative outcomes such as failure-to-rescue (FTR) and postoperative mortality. The current study aimed to quantify the relative contributions of surgeon and hospital volume on the volume-outcomes relationship among a cohort of patients undergoing liver resection., Methods: Patients undergoing liver surgery for cancer were identified using the Nationwide Inpatient Sample from 2001 and 2009. Multivariable logistic regression analysis was performed to identify factors associated with mortality and FTR. Point estimates were used to calculate the relative effects of hospital and surgeon volume on mortality and FTR., Results: A total of 5,075 patients underwent liver surgery and met inclusion criteria. Median patient age was 62 years (interquartile range, 52-70) and 55.2% of patients were male. Mortality was lowest among patients treated at high-volume hospitals and among patients treated by high-volume surgeons (both P < .001). Similar patterns in FTR were noted relative to hospital and surgeon volume (hospital volume: low vs intermediate vs high; 10.3 vs 9.0 vs 5.2%; surgeon volume: low vs intermediate vs high, 11.1 vs 9.1 vs 4.1%; both P < .05). On multivariable analysis, compared with high-volume surgeons, lower volume surgeons demonstrated greater odds for mortality (intermediate: odds ratio [OR], 2.27 [95% CI, 1.27-4.06; P = .006]; low, OR, 2.83 [95% CI, 1.52-5.27; P = .001]), and FTR (intermediate: OR, 2.86 [95% CI, 1.53-5.34, P = .001]; low, OR, 3.40 [95% CI, 1.75-6.63; P < .001]). While hospital volume accounted for 0.5% of the surgeon volume effect on increased FTR for low-volume surgeons, surgeon volume accounted for nearly all of the hospital volume effect on increased FTR in low-volume hospitals., Conclusion: The risk of complications, mortality, and FTR were less among both high-volume hospitals and high-volume surgeons, but the beneficial effect of volume on outcomes was attributable largely to surgeon volume., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Rationale and Objectives: This investigation aimed to evaluate the impact on treatment regimen and clinical outcome of dual-energy computed tomography (DECT) in patients with suspected gouty arthritis., Materials and Methods: We retrospectively analyzed electronic medical records (EMR) of 39 patients (36 male, 3 female; age range, 36-85 years) who underwent DECT of peripheral joints because of suspected gouty arthritis. We assessed the prior medical history, lab results, treatment regimen, and medications before and after DECT, and changes in subjective severity of symptoms as stated by patients in the EMR. The presence of monosodium urate (MSU) crystals in the index joint was verified with DECT., Results: Several patients had a prior diagnosis of gout (n = 9), hyperuricemia (n = 6), rheumatoid arthritis (n = 3), or psoriatic arthritis (n = 3). Elevated uric acid blood levels were detected in 32 patients (82%) before DECT. On DECT, MSU crystals were detected in 23 patients (59%). Of the 36 cases, the current treatment regimen was modified after DECT to gout-specific therapy in 22 cases and other rheumatic diseases were targeted in 14 cases. Several medications were prescribed more frequently based after DECT compared to before DECT imaging, including steroids (n = 20 vs. n = 12, respectively), colchicine (n = 13 vs. n = 4, respectively), and urate-lowering medication (n = 18 vs. n = 11, respectively). A subjective reduction of clinical symptoms during cumulative follow-up was reported by 34 patients (87.2%)., Conclusions: Both positive and negative findings of MSU crystals on DECT have a significant impact on the treatment regimen and clinical outcome of patients with suspected gouty arthritis and facilitate differentiation from other rheumatic diseases., (Copyright © 2015 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Post-hepatectomy liver failure (PHLF) is a major source of morbidity and mortality in patients undergoing liver resection. The aim of this review is to summarize the recent literature available on PHLF including its definition, predictive factors, preoperative risk assessment, severity grading, preventative measures, and management strategies., Methods: A systematic literature search was carried out with the search engines PubMed, Medline, and Cochrane Database using the keywords related to "liver failure", "posthepatectomy", and "hepatic resection"., Results: Liver resection is a curative treatment of liver tumors. However, it leads to concurrent death and regeneration of the remaining hepatocytes. Factors related to the patient, liver parenchyma and the extent of surgery can inhibit regeneration leading to PHLF., Conclusion: Given its resistance to treatment and the high postoperative mortality associated with PHLF, great effort has been put in to both accurately identify patients at high risk and to develop strategies that can help prevent its occurrence.

Background: The objective of the current study was to characterize the prevalence of the expectation that surgical resection of lung or colorectal cancer might be curative. The authors sought to assess patient-level, tumor-level, and communication-level factors associated with the perception of cure., Methods: Between 2003 and 2005, a total of 3954 patients who underwent cancer-directed surgery for lung (30.3%) or colorectal (69.7%) cancer were identified from a population-based and health system-based survey of participants from multiple US regions., Results: Approximately 80.0% of patients with lung cancer and 89.7% of those with colorectal cancer responded that surgery would cure their cancer. Even 57.4% and 79.8% of patients with stage IV lung and colorectal cancer, respectively, believed surgery was likely to be curative. On multivariable analyses, the odds ratio (OR) of the perception of curative intent was found to be higher among patients with colorectal versus lung cancer (OR, 2.27). Patients who were female, with an advanced tumor stage, unmarried, and having a higher number of comorbidities were less likely to believe that surgery would cure their cancer; educational level, physical function, and insurance status were not found to be associated with perception of cure. Patients who reported optimal physician communication scores (reference score, 0-80; score of 80-100 [OR, 1.40] and score of 100 [OR, 1.89]) and a shared role in decision-making with their physician (OR, 1.16) or family (OR, 1.17) had a higher odds of perceiving surgery would be curative, whereas patients who reported physician-controlled (OR, 0.56) or family-controlled (OR, 0.72) decision-making were less likely to believe surgery would provide a cure., Conclusions: Greater focus on patient-physician engagement, communication, and barriers to discussing goals of care with patients who are diagnosed with cancer is needed., (© 2015 American Cancer Society.)

Background: A large subset of patients with neuroendocrine liver metastasis (NELM) is symptomatic at the time of presentation. In addition to improving survival, treatment of NELM seeks to provide palliation of symptoms. However, data on health-related quality of life (QoL) are uncommon. We sought to define patient-reported QoL after treatment of NELM., Methods: Patients who underwent treatment of NELM at Johns Hopkins Hospital between 1998 and 2013 and who were alive as of March 2014 were identified (n = 125). These patients were invited to complete a QoL survey designed using validated assessment tools, to assess their physical, mental, and general health before treatment, after the most recent treatment and at the time of the study. Clinicopathologic data were collected and correlated with QoL data., Results: The response rate was 68.0% (n = 85). Median patient age was 55 y and most were male (59.2%). Most patients had a pancreatic (24.7%) or a small bowel (37.7%) primary tumor; the overwhelming majority had multiple NELM (83.5%). Patient-reported symptoms before any treatment included diarrhea (41.1%), flushing (34.1%), fatigue (36.5%), and osteoarticular pain (18.8%). Initial treatment of NELM consisted of surgery in 55 patients (64.7%) and nonsurgical treatment in 30 patients (35.3%). Many patients reported an overall improvement in physical health and mental health. Specifically, the proportion of patients reporting diarrhea (before any treatment, 41.1% versus currently, 25.9%; P = 0.019) and flushing (before any treatment, 34.1% versus currently, 10.5%; P < 0.001) tended to decrease over time and a lower proportion of patients reported to be currently sad about being ill (before any treatment, 31.8% versus currently, 23.2%; P = 0.009). Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. Interestingly, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical; however, a lower proportion of patients were dissatisfied with surgery versus nonsurgical therapy (5.4% versus 9.4%; P = 0.001)., Conclusions: Less than one-fourth of patients experienced a significant improvement in QoL after treatment of NELM. The patients who benefit the most of treatment were those who were more symptomatic before any treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mitochondrial apoptosis-inducing factor (AIF) influences the oxidative phosphorylation (OXPHOS) system and can be recruited as a mediator of cell death. Pathogenic mutations in the AIFM1 gene cause severe human diseases. Clinical manifestations include inherited peripheral neuropathies, prenatal cerebral abnormalities and progressive mitochondrial encephalomyopathies. In humans, rodents and invertebrates, AIF deficiency results in loss of respiratory complexes and, therefore, impaired OXPHOS. The molecular mechanisms underlying AIF-induced mitochondrial dysfunction remain elusive. Here we show that AIF physically interacts with the oxidoreductase CHCHD4/MIA40. In patient-derived fibroblasts as well as in tissues and glia cells from Harlequin (Hq) mutant mice, AIF deficiency correlates with decreased MIA40 protein levels, without affecting mRNA transcription. Importantly, MIA40 overexpression counteracts loss of respiratory subunits in Hq cells. Together, our findings suggest that MIA40 reduction contributes to the effects of AIF deficiency on OXPHOS, as it may impact on the correct assembly and maintenance of the respiratory subunits. This may be relevant for the development of new therapeutic approaches for AIF-related mitochondrial disorders.

Background: Illicit drug abuse is an independent risk factor for chronic kidney disease, but the pathogenic consequences of long-term exposure to illicit drugs and contaminants under unsterile conditions remains unclear., Study Design: Case series., Setting & Participants: All deceased persons (n 5 129) who underwent forensic autopsy because of suspected connection with illicit drug abuse between January 1, 2009, and April 30, 2011, in Frankfurt/Main, Germany., Predictor: Clinical characteristics and patterns of drug abuse., Outcomes: Histopathologic alterations of the kidney., Measurements: Hematoxylin and eosin, periodic acid-Schiff, Sirius, and Congo Red stainings and immunoglobulin A immunohistochemistry of all cases; additional histochemical stainings or immunohistochemistry and electron microscopy in selected cases., Results: Individuals were mostly white (99.2%), were male (82.2%), and had intravenous drug use (IVDU) (81.4%). Median age at death was 39 years and duration of drug abuse was 17 years. The majority (79.1%) took various drugs in parallel as assessed by toxicologic analysis. Despite a young age, the deceased had a high burden of comorbid conditions, especially cardiovascular disease, liver cirrhosis, and infections. Evaluation of the kidneys demonstrated a broad spectrum of pathologic alterations predominated by arteriosclerotic and ischemic damage, mild interstitial inflammation, calcification of renal parenchyma, and interstitial fibrosis and tubular atrophy, with hypertensive-ischemic nephropathy as the most common cause of nephropathy. Interstitial inflammation (OR, 16.59; 95% CI, 3.91-70.39) and renal calcification (OR, 2.43; 95% CI, 1.03- 5.75) were associated with severe IVDU, whereas hypertensive and ischemic damage were associated with cocaine abuse (OR, 6.00; 95% CI, 1.27-28.44). Neither specific glomerular damage indicative for heroin and hepatitis C virus-related disease nor signs of analgesic nephropathy were found., Limitations: White population, lack of a comparable control group, incomplete clinical data, and absence of routine immunohistochemistry and electron microscopy., Conclusions: Illicit drug abuse is associated with a broad but unspecific spectrum of pathologic alterations of the kidneys. Cocaine abuse has a deleterious role in this setting by promoting hypertensive and ischemic damage.

Purpose: In membrane-based therapeutic plasma exchange (TPE), regional citrate anticoagulation (RCA) is associated with difficulties because of citrate accumulation and consequent, potentially significant, metabolic complications, especially when using fresh frozen plasma (FFP) as replacement fluid. We modified the technical setup of a commercially available continuous veno-venous hemodialysis RCA module (multiFiltrate Ci-Ca®) to establish an RCA-protocol for TPE., Methods: Description of the modified technical setup and retrospective analysis of the feasibility of the RCA-protocol for TPE in all patients treated between 2009 and 2010., Results: 411 consecutive TPE with RCA were performed in 42 patients, all using FFP as replacement fluid. Median procedure characteristics were: blood flow 160 ml/min, filtrate flow 36 ml/min, duration 93 min, processed total plasma volume 3600 mL. Trisodium citrate was infused at a rate of 0.43 mmol/min to achieve post-filter ionized calcium levels of <0.4 mmol/l. Calcium substitution rate was 0.19 mmol/min to maintain physiologic iCa levels. RCA was well tolerated with no significant differences in pH, iCa, bicarbonate or potassium after repeated sessions. Clotting events complicated 7.3% of the procedures. Adverse events occurred in 3.4% of TPE procedures; none was severe or fatal. No significant differences were observed comparing the rate of adverse events to those observed in TPE using standard anticoagulation at our center (4.8%)., Conclusions: We describe for the first time a modified protocol for RCA in TPE using an integrated citrate module. Based on our experience, this RCA protocol is a feasible alternative for anticoagulation in TPE with FFP, especially in patients with a high risk of bleeding.

Multilocus sequence typing (MLST) and antibiotic resistance patterns of Campylobacter jejuni and Campylobacter coli from retail chicken meat showed high overlap with isolates collected at slaughterhouses, indicating little selection along the production chain. They also showed significant common sequence types with human clinical isolates, revealing chicken meat as a likely source for human infection.

Background: Accurate real-time 3D models of the operating field have the potential to enable augmented reality for endoscopic surgery. A new system is proposed to create real-time 3D models of the operating field that uses a custom miniaturized stereoscopic video camera attached to a laparoscope and an image-based reconstruction algorithm implemented on a graphics processing unit (GPU)., Methods: The proposed system was evaluated in a porcine model that approximates the viewing conditions of in vivo surgery. To assess the quality of the models, a synthetic view of the operating field was produced by overlaying a color image on the reconstructed 3D model, and an image rendered from the 3D model was compared with a 2D image captured from the same view., Results: Experiments conducted with an object of known geometry demonstrate that the system produces 3D models accurate to within 1.5 mm., Conclusions: The ability to produce accurate real-time 3D models of the operating field is a significant advancement toward augmented reality in minimally invasive surgery. An imaging system with this capability will potentially transform surgery by helping novice and expert surgeons alike to delineate variance in internal anatomy accurately.

Background: With increasing childhood obesity, adolescent bariatric surgery has been increasingly performed. We used a national database to analyze current trends in laparoscopic bariatric surgery in the adolescent population and related short-term outcomes., Methods: Discharge data from the University Health System Consortium (UHC) database was accessed using International Classification of Disease codes during a 36 month period. UHC is an alliance of more than 110 academic medical centers and nearly 250 affiliate hospitals. All adolescent patients between 13 and 18 years of age, with the assorted diagnoses of obesity, who underwent laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy (SG), and laparoscopic Roux-en-Y gastric bypass (LRYGB) were evaluated. The main outcome measures analyzed were morbidity, mortality, length of hospital stay (LOS), overall cost, intensive care unit (ICU) admission rate, and readmission rate. These outcomes were compared to those of adult bariatric surgery., Results: Adolescent laparoscopic bariatric surgery was performed on 329 patients. At the same time, 49,519 adult bariatric surgeries were performed. One hundred thirty-six adolescent patients underwent LAGB, 47 had SG, and 146 patients underwent LRYGB. LAGB has shown a decreasing trend (n = 68, 34, and 34), while SG has shown an increasing trend (n = 8, 15, and 24) over the study years. LRYGB remained stable (n = 44, 60, and 42) throughout the study period. The individual and summative morbidity and mortality rates for these procedures were zero. Compared to adult bariatric surgery, 30 day in-hospital morbidity (0 vs. 2.2 %, p < 0.02), the LOS (1.99 ± 1.37 vs. 2.38 ± 3.19, p < 0.03), and 30 day readmission rate (0.30 vs. 2.02 %, p < 0.05) are significantly better for adolescent bariatric surgery, while the ICU admission rate (9.78 vs. 6.30 %, p < 0.02) is higher and overall cost ($9,375 ± 6,452 vs. $9,600 ± 8,016, p = 0.61) is comparable., Conclusion: Trends in adolescent laparoscopic bariatric surgery reveal the increased use of sleeve gastrectomy and adjustable gastric banding falling out of favor.

During the past decade, cell death researchers have witnessed a gradual but deep conceptual revolution: it has been unequivocally shown that necrosis, which for long had been considered as a purely accidental cell death mode, can also be induced by finely regulated signal transduction pathways. In particular, when caspases are inhibited by pharmacological or genetic means, the ligation of death receptors such as the tumor necrosis factor receptor 1 (TNFR1) can lead to the assembly of a supramolecular complex containing the receptor-interacting protein kinases 1 and 3 (RIP1 and RIP3) that delivers a pronecrotic signal. Such complex has recently been dubbed necrosome and mediates the execution of a specific instance of regulated necrosis, necroptosis. Soon, it turned out that programmed necrosis occurs in nonmammalian model organisms and that it is implicated in human diseases including ischemia and viral infection. In this review, we first describe the historical evolution of the concept of programmed necrosis and the molecular mechanisms that underlie necroptosis initiation and execution. We then provide evidence suggesting that necroptosis represents an ancient and evolutionarily conserved cell death modality that may be targeted for drug development., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Knowledge on the relative importance of alternative sources of human campylobacteriosis is important in order to implement effective disease prevention measures. The objective of this study was to assess the relative importance of three key exposure pathways (travelling abroad, poultry meat, pet contact) for different patient age groups in Switzerland. With a stochastic exposure model data on Campylobacter incidence for the years 2002-2007 were linked with data for the three exposure pathways and the results of a case-control study. Mean values for the population attributable fractions (PAF) over all age groups and years were 27% (95% CI 17-39) for poultry consumption, 27% (95% CI 22-32) for travelling abroad, 8% (95% CI 6-9) for pet contact and 39% (95% CI 25-50) for other risk factors. This model provided robust results when using data available for Switzerland, but the uncertainties remained high. The output of the model could be improved if more accurate input data are available to estimate the infection rate per exposure. In particular, the relatively high proportion of cases attributed to 'other risk factors' requires further attention.

Obesity is characterised by lipid accumulation in non-adipose tissues, leading to organ degeneration and a wide range of diseases, including diabetes, heart attack and liver cirrhosis. Free fatty acids (FFA) are believed to be the principal toxic triggers mediating the adverse cellular effects of lipids. Here, we show that various cooking oils used in human nutrition cause cell death in yeast in the presence of a triacylglycerol lipase, mimicking the physiological microenvironment of the small intestine. Combining genetic and cell death assays, we demonstrate that elevated FFA concentrations lead to necrotic cell death, as evidenced by loss of membrane integrity and release of nuclear HMGB1. FFA-mediated necrosis depends on functional mitochondria and leads to the accumulation of reactive oxygen species. We conclude that lipotoxicity is executed via a mitochondrial necrotic pathway, challenging the dogma that the adverse effects of lipid stress are exclusively apoptotic.

Surgical robots in popular clinical use are generally large machines, which limits their practical use to some extent. This study aims to investigate the potential of a small, table-mounted robot for tool guidance in minimally invasive surgery (MIS). In particular, its multipurpose use for guidance of various tools was investigated. A compact robot capable of manipulating MIS tools was designed and built. The robot can move in four degrees of freedom (DOF): three rotational and one translational. These DOF correspond to motion constrained by a trocar. The robot kinematics are based on a bevel-geared "spherical mechanism," which allows trocar-constrained motion using a small mechanical device. The robot was tested in a porcine model by manipulating scopes and robotic grasping tools using a joystick as directed by a surgeon. Holding a laparoscope, the robot provided superior stability as a camera assistant. It manipulated the scope for visualization of the liver, spleen, bowel, etc. during manual tissue manipulation. Its compactness allowed increased space around the operating table, and the robot was in fact manipulated by joystick from across the room. Maneuvering grasping tools, the robot similarly provided a stable and dexterous platform for tissue manipulation. The test results suggest that the use of robotics for surgery may be enhanced via compact devices to include more hybrid robotic-manual procedures. The robot motion is smoother and more repeatable than that of a human operator. Use of a foot joystick could also place camera control directly with the surgeon. Flexible endoscopes can also be used with the robot for highly dexterous visualization. Notably, changing tools with this system is a very straightforward process and can be achieved without re-registration of the robot's position/orientation. Therefore, combined with other simple robotic tools for grasping, cautery, etc., compact robotic systems based on this technology could replace the large systems in current use, potentially increasing the impact of robots on medical care. This represents an important step towards multifunctional compact surgical robots.

Azoarcus sp. strain BH72 is a Gram-negative proteobacterium of the beta subclass; it is a diazotrophic endophyte of graminaceous plants and can provide significant amounts of fixed nitrogen to its host plant Kallar grass. We aimed to obtain a physical map of the Azoarcus sp. strain BH72 chromosome to be directly used in functional analysis and as a part of an Azoarcus sp. BH72 genome project. A bacterial artificial chromosome (BAC) library was constructed and analysed. A representative physical map with a high density of marker genes was developed in which 64 aligned BAC clones covered almost the entire genome.

Heart development is complex and requires the sequential and timely interplay of regulatory master proteins, notably several transcription factors. Germline mutations in the human transcription factor genes have been associated with congenital heart disease (CHD), but familial cases studied so far have different mutations. There is no strict genotype-phenotype correlation and mutations in transcription factor genes are rare in unrelated patients. Most cases of CHD come from unaffected family members. The study of archived, but morphologically well-characterized malformed hearts for DNA alterations provides important clues regarding cardiogenic transcription factor genes that would lead to loss-of-function of the protein. Identification of tissue-restricted multiple mutations and multiple haplotypes suggests that somatic mutation and mosaicism are linked to cardiac anomalies. Altogether, somatic mutations and genomic instability in the diseased cardiac tissues of patients with CHD provide a novel mechanism of disease.

NKX2-5 is a pivotal transcription factor in heart development. Previous studies on lymphocytic DNA provided evidence of familial NKX2-5 gene mutations in cardiac malformations. Common mutations are rare in unrelated families. We analysed, by direct sequencing, the gene encoding NKX2-5 in the diseased heart tissues of 68 patients with complex congenital heart disease, focussing particularly on atrial, ventricular, and atrioventricular septal defects. We identified 35 non-synonymous NKX2-5 mutations in the diseased heart tissues of patients. These mutations were mainly absent in normal, for example, unaffected, heart tissue of the same patient, indicating the somatic nature and mosaicism of mutations. We also observed multiple mutations and multiple haplotypes, as well as mutations in Down's syndrome patients with cardiac malformations. Taken collectively, the above results suggest the somatic nature of NKX2-5 mutations associated with complex cardiac malformations. Somatic mutations in transcription factor genes of cardiac progenitor cells provide a novel mechanism of disease.

The analysis of proteomes of biological organisms represents a major challenge of the post-genome era. Classical proteomics combines two-dimensional electrophoresis (2-DE) and mass spectrometry (MS) for the identification of proteins. Novel technologies such as isotope coded affinity tag (ICAT)-liquid chromatography/mass spectrometry (LC/MS) open new insights into protein alterations. The vast amount and diverse types of proteomic data require adequate web-accessible computational and database technologies for storage, integration, dissemination, analysis and visualization. A proteome database system (http://www.mpiib-berlin.mpg.de/2D-PAGE) for microbial research has been constructed which integrates 2-DE/MS, ICAT-LC/MS and functional classification data of proteins with genomic, metabolic and other biological knowledge sources. The two-dimensional polyacrylamide gel electrophoresis database delivers experimental data on microbial proteins including mass spectra for the validation of protein identification. The ICAT-LC/MS database comprises experimental data for protein alterations of mycobacterial strains BCG vs. H37Rv. By formulating complex queries within a functional protein classification database "FUNC&#95;CLASS" for Mycobacterium tuberculosis and Helicobacter pylori the researcher can gather precise information on genes, proteins, protein classes and metabolic pathways. The use of the R language in the database architecture allows high-level data analysis and visualization to be performed "on-the-fly". The database system is centrally administrated, and investigators without specific bioinformatic competence in database construction can submit their data. The database system also serves as a template for a prototype of a European Proteome Database of Pathogenic Bacteria. Currently, the database system includes proteome information for six strains of microorganisms.

In a prospective cohort study 8466 women attending routine cervical cancer screening were recruited. Colposcopy was performed on women with any degree of atypia on cytology and/or a positive high-risk human papillomavirus (HPV)-DNA test (HC2; Hybrid Capture 2((c))), and for a randomly selected sample of 3.4% women with negative findings on both. Quality control included reviews of cytology, histology, colposcopy images and retesting of samples with polymerase chain reaction. Test diagnostic performances were based on 7908 women who had complete baseline and follow-up results. Routine histology identified 86 women with high-grade cervical intraepithelial neoplasia (CIN2+), which was confirmed by review histology in only 46 cases. Sensitivity of routine cytology for the detection of CIN2+ was 43.5%, with a specificity, positive predictive value (PPV), negative predictive value (NPV) of 98.0, 11.4 and 99.7%, respectively. Sensitivity of the HC2 test for the detection of CIN2+ was 97.8%, with a specificity, PPV and NPV, of 95.3, 10.9 and 100%, respectively. No high-grade neoplasia was detected in the randomly selected control group. A negative HPV-test result, even in combination with a positive Papanicolaou (Pap) result, virtually excluded any risk of underlying high-grade disease, but this was not the case for a negative Pap result. These data show that HPV testing is of value for the detection or exclusion of prevalent CIN in a routine cervical cancer-screening setting and could be used for further risk classification of women for follow-up management.

Beyond the theoretical basis for integration, three core considerations stand out as the primary reasons for pursuing integration from a physician's perspective. In the authors' experience, the ability to make a case for physician integration stands or falls based on the ability of the integrated delivery system to address these considerations: Gain greater access to capital; develop human resources with talents in managed care and the full spectrum of care services; and sustain an information infrastructure. This article explores the lessons learned in pursuing physician integration.

An arabinogalactan-coated ultrasmall superparamagnetic iron oxide (AG-USPIO) preparation specific for asialoglycoprotein (ASG) receptors on hepatocytes was used as a magnetic resonance (MR) imaging contrast agent in the evaluation of a spectrum of benign liver diseases in animal models. The activity of hepatocyte ASG receptors, which directly reflects liver function, was directly assessed by measuring liver relaxation times in vitro and MR signal intensity in vivo. The following measurements allowed three-dimensional assessment of liver function: (a) liver relaxation time, (b) native MR signal intensities of liver, (c) response of liver to the AG-USPIO probe (percentage decrease of liver signal intensity after intravenous administration of 10 mumol/kg of AG-USPIO: normal liver 55%, fatty liver 57%, acute hepatitis 36%, chronic hepatitis 29%, and cirrhosis 46%), and (d) redistribution of hepatocyte-specific AG-USPIO to the spleen (present in hepatitis and cirrhosis but not in normal liver and fatty liver). The results of this study indicate that cellular hepatic abnormalities can be detected and quantitated with MR receptor imaging.