Species-Specific (Hyalella azteca and Lymnea stagnalis) Dietary Accumulation of Gold Nano-particles Associated with Periphyton.

Ecological effects of gold nano-particles (AuNP) are examined due to growing use in consumer and industrial materials. This study investigated uptake and movement of AuNPs through an aquatic food chain. Simple (single-species) and diverse (multi-species) periphyton communities were exposed to AuNP (0, 100, 500 µg L-1 treatments). AuNP quickly aggregated and precipitated from the water column, suggesting it is an insignificant route of AuNP exposure even at elevated concentrations. Gold was measured in 100 and 500 µg L-1 periphyton treatments. Gold accumulation was similar between periphyton treatments, suggesting physical processes were important for AuNP basal accumulation. Hyalella azteca and Lymnea stagnalis whole body tissue analysis indicated gold accumulation may be attributed to different feeding mechanisms, general versus selective grazing, respectively. Results suggest trophic transfer of AuNP is organism specific and aggregation properties of AuNP are important when considering fate of nano-particles in the environment and movement through aquatic food webs.

Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells.

Replication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity. Therefore, the key link between HR repair and cellular tolerance to replication-associated DSBs provides us with a mechanistic rationale for exploiting synthetic lethality between HR repair inhibition and replication stress. DNA2 nuclease is an evolutionarily conserved essential enzyme in replication and HR repair. Here we demonstrate that DNA2 is overexpressed in pancreatic cancers, one of the deadliest and more aggressive forms of human cancers, where mutations in the KRAS are present in 90-95% of cases. In addition, depletion of DNA2 significantly reduces pancreatic cancer cell survival and xenograft tumor growth, suggesting the therapeutic potential of DNA2 inhibition. Finally, we develop a robust high-throughput biochemistry assay to screen for inhibitors of the DNA2 nuclease activity. The top inhibitors were shown to be efficacious against both yeast Dna2 and human DNA2. Treatment of cancer cells with DNA2 inhibitors recapitulates phenotypes observed upon DNA2 depletion, including decreased DNA double strand break end resection and attenuation of HR repair. Similar to genetic ablation of DNA2, chemical inhibition of DNA2 selectively attenuates the growth of various cancer cells with oncogene-induced replication stress. Taken together, our findings open a new avenue to develop a new class of anticancer drugs by targeting druggable nuclease DNA2. We propose DNA2 inhibition as new strategy in cancer therapy by targeting replication stress, a molecular property of cancer cells that is acquired as a result of oncogene activation instead of targeting currently undruggable oncoprotein itself such as KRAS.

Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.

We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM-BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.

Engineering polarization rotation in a ferroelectric superlattice.

A key property that drives research in ferroelectric perovskite oxides is their strong piezoelectric response in which an electric field is induced by an applied strain, and vice versa for the converse piezoelectric effect. We have achieved an experimental enhancement of the piezoelectric response and dielectric tunability in artificially layered epitaxial PbTiO(3)/CaTiO(3) superlattices through an engineered rotation of the polarization direction. As the relative layer thicknesses within the superlattice were changed from sample to sample we found evidence for polarization rotation in multiple x-ray diffraction measurements. Associated changes in functional properties were seen in electrical measurements and piezoforce microscopy. The results demonstrate a new approach to inducing polarization rotation under ambient conditions in an artificially layered thin film.

Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors.

Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase Fms-like tyrosine kinase-3 (FLT3). Protein tyrosine kinases are integral components of signaling cascades that have a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors. We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease.

Smac mimetics: implications for enhancement of targeted therapies in leukemia.

Drug resistance is a growing concern with clinical use of tyrosine kinase inhibitors. Utilizing in vitro models of intrinsic drug resistance and stromal-mediated chemoresistance, as well as functional mouse models of progressive and residual disease, we attempted to develop a potential therapeutic approach designed to suppress leukemia recurrence following treatment with selective kinase inhibitors. The novel IAP inhibitor, LCL161, [corrected] was observed to potentiate the effects of tyrosine kinase inhibition against leukemic disease both in the absence and presence of a stromal-protected [corrected] environment. LCL161 enhanced the proapoptotic effects of nilotinib and PKC412, against leukemic disease in vitro and potentiated the activity of both kinase inhibitors against leukemic disease in vivo. In addition, LCL161 synergized in vivo with nilotinib to reduce leukemia burden significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib. Finally, LCL161 displayed antiproliferative effects against cells characterized by intrinsic resistance to tyrosine kinase inhibitors as a result of expression of point mutations in the protein targets of drug inhibition. These results support the idea of using IAP inhibitors in conjunction with targeted tyrosine kinase inhibition to override drug resistance and suppress or eradicate residual disease.

Psychophysical and ergogenic effects of synchronous music during treadmill walking.

The present study examined the impact of motivational music and oudeterous (neutral in terms of motivational qualities) music on endurance and a range of psychophysical indices during a treadmill walking task. Experimental participants (N=30; mean age=20.5 years, SD=1.0 years) selected a program of either pop or rock tracks from artists identified in an earlier survey. They walked to exhaustion, starting at 75% maximal heart rate reserve, under conditions of motivational synchronous music, oudeterous synchronous music, and a no-music control. Dependent measures included time to exhaustion, ratings of perceived exertion (RPE), and in-task affect (both recorded at 2-min intervals), and exercise-induced feeling states. A one-way repeated measures ANOVA was used to analyze time to exhaustion data. Two-way repeated measures (Music Condition ? Trial Point) ANOVAs were used to analyze in-task measures, whereas a one-way repeated measures MANOVA was used to analyze the exercise-induced feeling states data. Results indicated that endurance was increased in both music conditions and that motivational music had a greater ergogenic effect than did oudeterous music (p<.01). In addition, in-task affect was enhanced by motivational synchronous music when compared with control throughout the trial (p<.01). The experimental conditions did not impact significantly (p>.05) upon RPE or exercise-induced feeling states, although a moderate effect size was recorded for the latter (etap2=.09). The present results indicate that motivational synchronous music can elicit an ergogenic effect and enhance in-task affect during an exhaustive endurance task.

Utilization of F1 information in estimating QTL effects in F2 crosses between outbred lines.

Quantitative trait loci (QTL) analysis in designed experiments is investigated using a mixed model framework through the modification of segment mapping techniques. Allele effects are modelled in the F1 generation allowing the estimation of additive substitution effects while accounting for QTL segregation within lines and differences in mean QTL effects between lines. The resulting approach is called F1 segment mapping. Simulation is used to illustrate the method and its properties. F1 segment mapping has advantages over F2 segment mapping in the derivation of exact additive genetic covariances and in the computation time for variance component estimation.

Nuclear import strategies of high-risk HPV18 L2 minor capsid protein.

We have investigated the nuclear import strategies of high-risk HPV18 L2 minor capsid protein. HPV18 L2 interacts with Kap alpha2 adapter, and Kap beta2 and Kap beta3 nuclear import receptors. Moreover, binding of RanGTP to either Kap beta2 or Kap beta3 inhibits their interaction with L2, suggesting that these Kap beta/L2 complexes are import competent. Mapping studies show that HPV18 L2 contains two NLSs: in the N-terminus (nNLS) and in the C-terminus (cNLS), both of which can independently mediate nuclear import. Both nNLS and cNLS form a complex with Kap alpha2beta1 heterodimer and mediate nuclear import via a classical pathway. The nNLS is also essential for the interaction of HPV18 L2 with Kap beta2 and Kap beta3. Interestingly, both nNLS and cNLS interact with the viral DNA and this DNA binding occurs without nucleotide sequence specificity. Together, the data suggest that HPV18 L2 can interact via its NLSs with several Kaps and the viral DNA and may enter the nucleus via multiple import pathways mediated by Kap alpha2beta1 heterodimers, Kap beta2 and Kap beta3.

Estimating the impact of renal replacement therapy choice on outcome in severe acute renal failure.

BACKGROUND: Mortality in severe acute renal failure (ARF) requiring renal replacement therapy (RRT) approximates 50% and varies with clinical severity. Continuous RRT (CRRT) has theoretical advantages over intermittent hemodialysis (IHD) for critical patients, but a survival advantage with CRRT is yet to be clearly demonstrated. To date, no prospective controlled trial has sufficiently answered this question, and the present prospective outcome study attempts to compare survival with CRRT versus that with IHD. METHODS: Multivariable Cox-proportional hazards regression was used to analyze the impact of RRT modality choice (CRRT vs. IHD) on in-hospital and 100-day mortality among ARF patients receiving RRT during 2000 and 2001 at University of Michigan, using an "intent-to-treat" analysis adjusted for multiple comorbidity and severity factors. RESULTS: Overall in-hospital mortality before adjustment was 52%. Triage to CRRT (vs IHD) was associated with higher severity and unadjusted relative rate (RR) of in-hospital death (RR = 1.62, p = 0.001, n = 383). Adjustment for comorbidity and severity of illness reduced the RR of death for patients triaged to CRRT and suggested a possible survival advantage (RR = 0.81, p = 0.32). Analysis restricted to patients in intensive care for more than five days who received at least 48 hours of total RRT, showed the RR of in-hospital mortality with CRRT to be nearly 45% lower than IHD (RR = 0.56, n = 222), a difference in RR that indicates a strong trend for in-hospital mortality with borderline statistical significance (p = 0.069). Analysis of 100-day mortality also suggested a potential survival advantage for CRRT in all cohorts, particularly among patients in intensive care for more than five days who received at least 48 h of RRT (RR = 0.60, p = 0.062, n = 222). CONCLUSION: Applying the present methodology to outcomes at a single tertiary medical center, CRRT may appear to afford a survival advantage for patients with severe ARF treated in the ICU. Unless and until a prospective controlled trial is realized, the present data suggest potential survival advantages of CRRT and support broader application of CRRT among such critically ill patients.

Predictive modelling of post-onset xenoma growth during microsporidial gill disease (Loma salmonae) of salmonids.

Loma salmonae, an obligate intracellular microsporidian parasite, is the causal agent of microsporidial gill disease of salmon (MGDS), characterized by the production, growth and eventual rupture of spore-filled xenomas. MGDS in farmed chinook salmon remains occult until xenoma rupture, at which time the infected fish respond with intense branchitis and high rates of mortality. The present study showed that in experimentally infected fish the rate of change of xenoma diameter could be modelled through regression analysis, particularly through the period of 4-9 weeks post-infection, yielding the predictive equation: xenoma diameter=-42.9 microns +15.3 microns x (number of weeks post-infection). This provides a tool for diagnosticians to predict the time to xenoma rupture and hence to the initiation of the clinical phase of MGDS.

A case of pulmonary lymphangioleiomyomatosis.

A case of pulmonary lymphangioleiomyomatosis (PLAM) occurring in a 48-year-old Jamaican female is presented. The clinical, radiological, and pathological findings are typical of this rare condition, and serve to emphasize the need for a high index of suspicion in order to make the diagnosis and commence therapy early in the course of the disease. The outlook for patients with PLAM continues to be poor.

A case of pulmonary lymphangioleiomyomatosis

A case of pulmonary lymphangioleiomyomatosis (PLAM) occurring in a 48-year-old Jamaican female is presented. The clinical, radiological, and pathological findings are typical of this rare condition, and serve to emphasize the need for a high index of suspicion in order to make the diagnosis and commence therapy early in the course of the disease. The outlook for patients with PLAM continues to be poor

Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery.

BACKGROUND: Pneumonia is a common postoperative complication associated with substantial morbidity and mortality. OBJECTIVE: To develop and validate a preoperative risk index for predicting postoperative pneumonia. DESIGN: Prospective cohort study with outcome assessment based on chart review. SETTING: 100 Veterans Affairs Medical Centers performing major surgery. PATIENTS: The risk index was developed by using data on 160 805 patients undergoing major noncardiac surgery between 1 September 1997 and 31 August 1999 and was validated by using data on 155 266 patients undergoing surgery between 1 September 1995 and 31 August 1997. Patients with preoperative pneumonia, ventilator dependence, and pneumonia that developed after postoperative respiratory failure were excluded. MEASUREMENTS: Postoperative pneumonia was defined by using the Centers for Disease Control and Prevention definition of nosocomial pneumonia. RESULTS: A total of 2466 patients (1.5%) developed pneumonia, and the 30-day postoperative mortality rate was 21%. A postoperative pneumonia risk index was developed that included type of surgery (abdominal aortic aneurysm repair, thoracic, upper abdominal, neck, vascular, and neurosurgery), age, functional status, weight loss, chronic obstructive pulmonary disease, general anesthesia, impaired sensorium, cerebral vascular accident, blood urea nitrogen level, transfusion, emergency surgery, long-term steroid use, smoking, and alcohol use. Patients were divided into five risk classes by using risk index scores. Pneumonia rates were 0.2% among those with 0 to 15 risk points, 1.2% for those with 16 to 25 risk points, 4.0% for those with 26 to 40 risk points, 9.4% for those with 41 to 55 risk points, and 15.3% for those with more than 55 risk points. The C-statistic was 0.805 for the development cohort and 0.817 for the validation cohort. CONCLUSIONS: The postoperative pneumonia risk index identifies patients at risk for postoperative pneumonia and may be useful in guiding perioperative respiratory care.

Preoperative risk factors for 30-day mortality after elective surgery for vascular disease in Department of Veterans Affairs hospitals: is race important?

PURPOSE: Racial variation in health care outcomes is an important topic. Risk-adjustment models have not been developed for elective abdominal aortic aneurysm repair (AAA), lower extremity bypass revascularization (LEB), or lower extremity amputation (AMP). Earlier studies examining racial variation in mortality and morbidity from AAA, LEB, or AMP were limited to administrative data. This study determined risk factors for mortality after surgery for vascular disease and determined whether race is an important risk factor. METHODS: Data in this prospective observational study were obtained from the Department of Veterans Affairs (VA) National Surgical Quality Improvement Program. Detailed demographic and clinical data were collected prospectively from patients' medical records by trained nurse reviewers. Eligible patients were those 18 years and older who underwent elective AAA, LEB, or AMP at one of 44 VA medical centers performing both vascular and cardiac surgery (phase I; October 1991 to December 1993) and at one of these 44 or 79 additional VA medical centers performing vascular but not cardiac surgery (phase II; January 1994 to August 1995). The independent association of several preoperative factors with the 30-day postoperative mortality rate was examined with stepwise logistic regression analysis for AAA, LEB, and AMP. Models were developed in the combined 44 VA medical centers and validated in the 79 VA medical centers. The independent association of race with the 30-day postoperative mortality rate was examined after controlling for important preoperative risk factors for each operation. RESULTS: More than 10,000 surgical operations were examined, and 5, 3, and 10 independent preoperative predictors of 30-day mortality rate were identified for AAA, LEB, and AMP, respectively. The observed mortality rate for patients undergoing AAA was higher (7.2% vs 3.2%; P =.02) in African American patients than in white patients in the 44 VA medical centers, although the differences were not significant in LEB and AMP or at the additional 79 hospitals. After important preoperative risk factors were controlled, there was no difference in 30-day mortality rates between African American patients and white patients. CONCLUSION: We identified several important preoperative risk factors for 30-day mortality rate in three vascular operations. From the results of this study, race was determined not to be an independent predictor of mortality.

Guidelines for the management of patients with chronic stable angina: treatment.

The dual aims of treating patients with chronic stable angina are 1) to reduce morbidity and mortality and 2) to eliminate angina with minimal adverse effects and allow the patient to return to normal activities. In the absence of contraindications, beta-blockers are recommended as initial therapy. All beta-blockers seem to be equally effective. If the patient has serious contraindications to beta-blockers, unacceptable side effects, or persistent angina, calcium antagonists should be administered. Long-acting dihydropyridine and nondihydropyridine agents are generally as effective as beta-blockers in relieving angina. Long-acting nitrates are considered third-line therapy because a nitrate-free interval is required to avoid developing tolerance. All long-acting nitrates seem to be equally effective. Patients with angina should take 75 to 325 mg of aspirin daily unless they have contraindications. Such risk factors as smoking, elevated low-density lipoprotein cholesterol level, diabetes, and hypertension should be treated appropriately. Coronary revascularization has not been shown to improve survival for most patients with chronic angina but may be required to control symptoms. However, coronary artery bypass grafting (CABG) is often indicated for symptomatic patients with left-main disease, three-vessel disease, or two-vessel disease including proximal stenosis of the left anterior descending coronary artery; it improves their survival. Percutaneous transluminal coronary angioplasty is an alternative to CABG for patients with normal left ventricular function and favorable angiographic features. Coronary artery bypass grafting is initially more effective in relieving angina than medical therapy, but the two procedures yield similar results after 5 to 10 years. Eighty percent of patients who undergo CABG remain angina-free 5 years after surgery. In low-risk patients, percutaneous transluminal coronary angioplasty seems to control angina better than medical therapy, but recurrent angina and repeated procedures are more likely than with CABG. Patient education is an important component of management. Long-term follow-up should be individualized to ascertain clinical stability at regular intervals and to reassess prognosis when warranted.

Nigrostriatal collaterals to thalamus degenerate in parkinsonian animal models.

Movement, cognition, emotion, and positive reinforcement are influenced by mesostriatal, mesocortical, and mesolimbic dopamine systems. We describe a fourth major pathway originating from mesencephalic dopamine neurons: a mesothalamic system. The dopamine transporter, specific to dopamine containing axons, was histochemically visualized in thalamic motor and limbic-related nuclei and regions that modulate behavioral state as opposed to sensory nuclei in rats, nonhuman primates, and humans. Anatomical tracing established this innervation's origin via axon collaterals from the mesostriatal pathway. These findings implicate the thalamus as a novel site for disease specific alterations in dopamine neurotransmission, such as exist with nigral degeneration attending Parkinson's disease. This was confirmed in hemiparkinsonian animals where reduction of thalamic dopamine innervation occurred coincident with signs of active axonal degeneration. Individual mesencephalic dopamine neurons therefore have the potential to modulate normal and pathologic behavior not only through traditional nigrostriatal pathways but also by way of axon collaterals that innervate the thalamus.

Comparison of surgical outcomes between teaching and nonteaching hospitals in the Department of Veterans Affairs.

OBJECTIVE: To determine whether the investment in postgraduate education and training places patients at risk for worse outcomes and higher costs than if medical and surgical care was delivered in nonteaching settings. SUMMARY BACKGROUND DATA: The Veterans Health Administration (VA) plays a major role in the training of medical students, residents, and fellows. METHODS: The database of the VA National Surgical Quality Improvement Program was analyzed for all major noncardiac operations performed during fiscal years 1997, 1998, and 1999. Teaching status of a hospital was determined on the basis of a background and structure questionnaire that was independently verified by a research fellow. Stepwise logistic regression was used to construct separate models predictive of 30-day mortality and morbidity for each of seven surgical specialties and eight operations. Based on these models, a severity index for each patient was calculated. Hierarchical logistic regression models were then created to examine the relationship between teaching versus nonteaching hospitals and 30-day postoperative mortality and morbidity, after adjusting for patient severity. RESULTS: Teaching hospitals performed 81% of the total surgical workload and 90% of the major surgery workload. In most specialties in teaching hospitals, the residents were the primary surgeons in more than 90% of the operations. Compared with nonteaching hospitals, the patient populations in teaching hospitals had a higher prevalence of risk factors, underwent more complex operations, and had longer operation times. Risk-adjusted mortality rates were not different between the teaching and nonteaching hospitals in the specialties and operations studied. The unadjusted complication rate was higher in teaching hospitals in six of seven specialties and four of eight operations. Risk adjustment did not eliminate completely these differences, probably reflecting the relatively poor predictive validity of some of the risk adjustment models for morbidity. Length of stay after major operations was not consistently different between teaching and nonteaching hospitals. CONCLUSION: Compared with nonteaching hospitals, teaching hospitals in the VA perform the majority of complex and high-risk major procedures, with comparable risk-adjusted 30-day mortality rates. Risk-adjusted 30-day morbidity rates in teaching hospitals are higher in some specialties and operations than in nonteaching hospitals. Although this may reflect the weak predictive validity of some of the risk adjustment models for morbidity, it may also represent suboptimal processes and structures of care that are unique to teaching hospitals. Despite good quality of care in teaching hospitals, as evidenced by the 30-day mortality data, efforts should be made to examine further the structures and processes of surgical care prevailing in these hospitals.

Postoperative and amputation-free survival outcomes after femorodistal bypass grafting surgery: findings from the Department of Veterans Affairs National Surgical Quality Improvement Program.

PURPOSE: A noncardiac surgery risk model was used as a means of analyzing variations in postoperative mortality and amputation-free survival for older veterans undergoing femorodistal bypass grafting surgery. METHODS: A prospective cohort study was undertaken in 105 Veterans Affairs (VA) hospitals at the time of index operation from 1991 to 1995. Each patient was linked to subsequent hospitalizations, major amputation surgery, and survival through 1999. Logistic regression and proportional hazards models were used as a means of developing risk indices on the basis of risk factors from the VA National Surgical Quality Improvement Program. A total of 4288 male veterans 40 years or older underwent artificial, vein, or in situ bypass grafting surgery at the femoral to tibial level. The main outcome measures were 30-day postoperative mortality and amputation-free survival. RESULTS: Approximately half of all patients had undergone an earlier revascularization or amputation at any level for vascular disease. The 30-day postoperative mortality rate was 2.1% and varied greatly between mortality risk index quartiles (0.6%-5.2%). In a median 44.3 months of follow-up, surviving patients had 17,694 subsequent VA hospitalizations, 1147 patients (26.7%) underwent subsequent major amputation, and 1913 patients (44.6%) died. The overall survival probability was 88% at 1 year and 63% at 5 years; 1- and 5-year (any sided) limb salvage rates were 87% and 74%, respectively, for patients who underwent a femoropopliteal bypass grafting procedure, compared with 77% and 63%, respectively, for patients who underwent a tibial bypass grafting procedure. When amputation and death were combined as end points, amputation-free survival probability rates at 1, 3, and 7.5 years were 74%, 56%, and 29%, respectively. Patients with the best 20% survival risk scores had observed mean survival probability rates 30% higher than patients in the poorest 20% of survival risk. CONCLUSION: Risk indices derived from the preoperative workup may be of use to clinicians in assessing and communicating risk and prognosis. Risk-adjustment of outcomes is critical for evaluating future disease management initiatives for patients with advanced peripheral arterial disease.