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Parents' attitudes toward contraceptive delivery methods have been shown to impact their adolescents' use of contraceptive methods. However, little is known about the HIV pre-exposure prophylaxis (PrEP) delivery method attitudes of parents of sexual and gender minority (SGM) adolescents assigned male at birth (AMAB). This exploratory, mixed-method formative study examined the PrEP delivery method preferences among a convenience sample of 33 parents of SGM adolescents AMAB who live in Texas. Participants completed an online survey, where they selected their preferred PrEP method for their SGM adolescent AMAB to use: PrEP as a daily oral pill, a bimonthly injectable, or a yearly implant. Parents answered an open-ended question about their reasons for choosing their preferred method. We analyzed data through descriptive statistics and inductive content analysis. Findings from this convenience sample suggest that there is not one PrEP delivery method that parents of SGM adolescents AMAB prefer: one third of parents (33.3%) selected PrEP as a daily oral pill, 45.5% selected PrEP as a bimonthly injectable, and 21.2% selected PrEP as an annual implant. Parents cited multiple reasons for selecting a delivery method over another, with the most prevalent reasons being adherence (57.6%), access or cost (21.2%), and generic convenience or ease (21.2%). Findings from this formative exploratory study sets the stage for future research and intervention development in increasing parental knowledge, preferences, and preference motivations for PrEP delivery methods. [ABSTRACT FROM AUTHOR]

In the United States, adolescents (those 13–18 years old) are a key age group of those at risk for and affected by HIV. Although HIV pre-exposure prophylaxis (PrEP), one promising HIV prevention tool, is approved for eligible adolescents to use, adolescent access to PrEP is limited by primary care providers' (PCPs) willingness to prescribe it. This study examined which Theoretical Domains Framework factors are associated with PCPs' intention to prescribe PrEP to sexually active adolescents. A total of 770 licensed PCPs practicing family medicine, internal medicine, or pediatrics in the United States completed an online cross-sectional questionnaire. Participants were recruited through a Qualtrics panel. We used a hierarchical regression to assess the association of demographic characteristics, sexual health care practices, and the 10 Theoretical Domains Framework factors with intention to prescribe PrEP to sexually active adolescents aged 13–18 years old. Although nearly all PCPs had heard about PrEP (90.9%), 30.6% ever prescribed PrEP to an adolescent. Intention to prescribe PrEP to sexually active adolescents was associated with seven out of the 10 Theoretical Domains Framework factors: knowledge, skills, professional role, belief capacity, belief consequence, environmental resource, social influence, and emotion. Our findings demonstrate that the Theoretical Domains Framework can be employed to understand the intrapersonal, interpersonal, and environmental factors associated with PCPs' intention to prescribe sexually active adolescents PrEP. Implementation strategies are needed to implement interventions that improve provider knowledge, attitudes, and skills related to prescribing PrEP to eligible adolescents. [ABSTRACT FROM AUTHOR]

Because of the high rates of false-negative or nondiagnostic ureteral Piranha microbiopsies associated with low cellularity, we assessed the effect of processing these using cytology. We included 2 groups of 44 consecutive microbiopsies processed from formalin as a standard surgical biopsy and 22 processed by cytology. All samples were from the ureter or renal pelvis or calyx. The cytology samples were collected in alcohol-based media and were prepared with a Cellient cell block only (n = 9) or with a Cellient cell block for the visible particles, together with ThinPrep, to capture the remaining desquamated cells (n = 13). Malignancy was diagnosed in 5 of 44 conventionally processed microbiopsies (11%) compared with 14 of 22 cytologically processed microbiopsies (64%; P < 0.001), including 1 case with invasion. Nineteen site-matched biopsies from 2 patients had undergone both cytologic and surgical processing, with 8 of 8 cytologically processed biopsies diagnosed as malignant. None of the 11 surgically processed biopsies from the same patients matched for site were diagnosed as malignant. Of the 11, 2 (18%) were suspicious for high-grade urothelial carcinoma and 6 (55%) were considered atypical. Increased sensitivity from cytologic processing appears related to increased cell recovery; large numbers of well-preserved urothelial cells were identified in the ThinPrep (range, 1000-25,000 cells/slide), and a nonsignificant trend was found toward increased urothelium (defined as >200 cells/profile) in the Cellient cell blocks (14 of 22 [64%]) compared with the histologic biopsies (17 of 44 [39%]; P = 0.070). Cytologic processing of ureteral microbiopsies showed superior sensitivity for detecting high-grade urothelial carcinoma, apparently owing to the increased cellular recovery. [ABSTRACT FROM AUTHOR]

In-stent restenosis is a pervasive challenge to the durability of stenting for the treatment of lower extremity ischemia. There is considerable controversy about the criteria for diagnosis, indications for treatment, and preferred algorithm for addressing in-stent restenosis. This evidence summary seeks to review existing information on strategies for the treatment of this difficult problem. [ABSTRACT FROM AUTHOR]

Introduction Cytopathologist's review of Papanicolaou tests (PTs) screened by cytotechnologists as negative for intraepithelial lesion or malignancy (NILM) that are positive for high-risk human papillomavirus (hrHPV+) may be a useful quality control measure. Materials and methods From January 1, 2012 to December 31, 2012 all NILM/hrHPV+ PTs underwent cytopathologist's review before report issuance as per routine quality control procedures. HrHPV status was known at the time of screening and at final review. The rate of upgraded diagnoses resulting from the cytopathologist's review were examined. Two-year follow-up was obtained. Results Cytopathologist's review upgraded 250 of 1282 PTs (19.5%) by 1 step to atypical squamous cells of undetermined significance and 13 (1%) were upgraded by 2 steps or more to low-grade squamous intraepithelial lesion or higher. During the same period, significantly fewer NILM PTs (of unknown hrHPV status) were upgraded by 2 steps or more as a result of random 10% rescreening by cytotechnologists (0.2%, P < 0.001). Follow-up was available in 740 of 1282 patients (57.7%). The upgraded group was significantly more likely to be referred for colposcopy (68.3% versus 30.5%, P < 0.001) and cervical intraepithelial neoplasia (CIN) 2 or higher (CIN2+) was diagnosed in more upgraded patients (8.9% versus 3.0%, P < 0.01) than in those not upgraded. There was no significant difference in the percentage of colposcopy patients diagnosed with CIN2+ in the 2 groups, respectively (13.1% versus 9.8%, P = 0.47). Conclusions cytopathologist's review of NILM/hrHPV+ PTs identified more 2-step discrepancies than routine 10% rescreening. Significantly more patients in the upgraded group were found to harbor CIN2+; however, this could be related to the higher rate of referral to colposcopy in this group. [ABSTRACT FROM AUTHOR]

Introduction The goal of Barrett esophagus surveillance is to identify high-grade dysplasia (HGD) for eradication. Surveillance programs currently rely on limited histologic sampling; however, the role of cytology in this setting is not well studied. Materials and methods From December 1, 2011 to March 30, 2014, 45 patients underwent 4 circumferential brushings of the distal tubular esophagus followed by standard 4-quadrant biopsies. One ThinPrep slide and 1 Cellient cellblock (Hologic, Boxborough, Mass) were prepared. Six cytopathologists evaluated each for adequacy, intestinal metaplasia (IM) and dysplasia. Findings were classified using the traditional 5-tier system used for biopsies. A prospectively modified 3-tier cytologic classification was also tested: negative for HGD, indeterminate for HGD, and HGD. Sensitivity, specificity, and kappa values (interobserver agreement) for cytology were calculated. Results Ten of 45 patients had nondiagnostic cytologies; none of whom had dysplasia on biopsy. Cytology had good sensitivity (82%) and specificity (88%) for identifying IM compared with biopsy with moderate interobserver agreement (pairwise average of Fleiss and Krippendorf kappa value = 0.589, 79% agreement). One case had IM on cytology not detected on histology. Six of 45 patients had dysplasia on biopsy including 1 intramucosal adenocarcinoma, 1 indeterminate for dysplasia, 2 high-grade dysplasias, and 2 low-grade dysplasias. A non-negative adequate cytology sample had a sensitivity of 100% and a specificity of 88% and 94% for the 5-tier and the 3-tier classification, respectively. Conclusions Cytology appears to have good sensitivity and specificity for diagnosis of HGD, and cytology may be poised to synergize with advances in other techniques for management of patients with Barrett esophagus. Improvements in brushing devices may help to decrease the nondiagnostic rate. [ABSTRACT FROM AUTHOR]

This article presents an original study commissioned by the UK charity, Together for Short Lives which explored children and young people up to 25 years of age with life-threatening/limiting conditions and their families. Using Appreciative Inquiry and framework analysis, qualitative work sought to explore perceived met and unmet needs of services and care. Fifty-one families were interviewed from one UK area, 18 of which were children/young people up to 25 years old. Findings indicated that children and their families felt medical/nursing needs were well met but provision was needed for broader financial, social and emotional support alongside more responsive specialist therapies. [ABSTRACT FROM AUTHOR]

After the creation of an autogenous lower extremity bypass graft, the vein must undergo a series of dynamic structural changes to stabilize the arterial hemodynamic forces. These changes, which are commonly referred to as remodeling, include an inflammatory response, the development of a neointima, matrix turnover, and cellular proliferation and apoptosis. The sum total of these processes results in dramatic alterations in the physical and biomechanical attributes of the arterialized vein. The most clinically obvious and easily measured of these is lumen remodeling of the graft. However, although somewhat less precise, wall thickness, matrix composition, and endothelial changes can be measured in vivo within the healing vein graft. Recent translational work has demonstrated the clinical relevance of remodeling as it relates to vein graft patency and the systemic factors influencing it. By correlating histologic and molecular changes in the vein, insights into potential therapeutic strategies to prevent bypass failure and areas for future investigation are explored. [ABSTRACT FROM AUTHOR]

Objective We have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD. Methods This was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled in the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation was performed to assess EF. Kidney function was characterized by estimated glomerular filtration rate with the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants. Results Ninety-seven patients with intermittent claudication participated in this study. Mean age was 69 ± 8 years, 97% were male, and 79% were white. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%), and diabetes mellitus (38%). Mean ankle-brachial index was 0.73 ± 0.14 and mean flow-mediated vasodilation was 7.0% ± 3.8%, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 mL/min/1.73 m 2 ; β, 0.12; confidence interval, 0.05-0.20; P = .001). After multivariable regression adjusting for age, race, log tumor necrosis factor α, hypertension, dyslipidemia, and diabetes, estimated glomerular filtration rate remained significantly associated with EF ( P = .033). Conclusions In patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process. [ABSTRACT FROM AUTHOR]

Objective Despite available medical therapies, patients with peripheral arterial disease (PAD) remain at high risk for cardiovascular events. The n-3 polyunsaturated fatty acids (PUFA), derived from marine sources, have been shown to improve cardiovascular mortality. The Omega-3 Index (O3I), a proportion of the n-3 PUFA eicosapentaenoic acid and docosahexaenoic acid in the red blood cell membrane, correlates with cardiovascular risk. Previous investigations have found that n-3 PUFA supplementation, fish consumption, older age, and smoking history affect the O3I in different patient populations, although similar correlations have never been explored in PAD. We hypothesized that in our PAD cohort, blood content of omega-3 fatty acids would directly and positively correlate with a history of fish oil supplementation and older age and inversely correlate with a smoking history and obesity. Methods This cross-sectional study included 111 patients who had an ankle-brachial index of <0.9 associated with claudication symptoms. We used linear regression to determine the association between clinical factors and the O3I. Results The mean age of the cohort was 69 ± 8 years; 37% had diabetes mellitus (hemoglobin A 1c , 7% ± 1%), and 94% reported current smoking or a history of smoking. The mean O3I was 5% ± 2%. In multivariate linear regression analysis, the O3I was associated with older age, increasing body mass index, and a history of smoking and fish oil intake. Conclusions This is the first report of the relation between blood content of omega-3 fatty acids and clinical factors in a PAD population. In patients with PAD, older age, elevated body mass index, and prior fish oil supplementation predicted a higher O3I. A history of smoking correlated with a lower O3I. These results demonstrate that the O3I is a reliable measure of dietary n-3 PUFA intake and that clinical factors related to the O3I in PAD are similar to those observed in other populations. [ABSTRACT FROM AUTHOR]

Background Long-stemmed humeral components are often associated with revision shoulder arthroplasty. However, long-stemmed humeral components will likely prove useful in selected patients with extra large shoulders and in those with bone loss from nonarthroplasty causes and in humeral fractures. This study was developed to examine the frequency of use of longer humeral stems, identify the indications for their use, define the results, and enumerate the complications encountered. Materials and methods Thirty-five primary shoulder arthroplasties were followed-up clinically and radiographically for at least 2 years or until revision surgery. The primary indications for use of an intermediate or long stem were a large humeral canal in 18 shoulders and severe preoperative metaphyseal or diaphyseal bone loss in 17. Average clinical follow-up was 6.5 years. Results Excellent or satisfactory results were achieved in 21 of 35 shoulders. No components met criteria to be considered radiographically at risk for clinical loosening. Intraoperative complications included an unrecognized nondisplaced diaphyseal fracture that later displaced in 1 shoulder. Late complications included deep infection in 1 and fracture nonunion in 1. Conclusions Intermediate or long-stemmed humeral components proved useful in obtaining a secure distal fit in patients with a large humeral canal or in those with significant proximal bone loss. Worse clinical results were achieved in those with bone loss. Radiographic follow-up shows these components are at a low risk for loosening. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to systematically review the current literature on the economic costs of micro preemie as well as evidence on the cost-effectiveness of interventions to improve outcomes for micro preemie babies with a birth weight of ≤500 g.Method: We searched MEDLINE, CINAHL, Scopus, ECONLIT, Business Source Premier and Cochrane Library for studies reporting costs of micro preemie from January 2000. Costs were inflated to 2019 United States dollars (US$). All full-text articles were assessed for eligibility and a quality assessment of included articles was conducted using the Drummond and the Larg and Moss checklists.Results: The search identified three studies that met the inclusion criteria; two cost-of-illness studies and one cost-effectiveness study. Across studies, the mean healthcare spending per micro preemie survivor (in 2019 US$) ranged from US$61,310 (birth admission) to US$263,958 (inpatient and outpatient for the first six months of life). One modelling study reported exclusive human milk diet for micro preemies at birth was more cost-effective compared to the standard approach with cow milk diet from the third-party payer and societal perspectives.Conclusion: Despite significant advances in perinatal care and expanded access to life-saving equipment to improve survival outcomes of micro preemie, there remains a paucity of research on economic costs associated with these babies. No study has utilised quality-adjusted life-years as an outcome measure. Given the chronic conditions and long-term neurologic disability associated with micro preemie survivors, an estimate of the lifetime cost to the individual, healthcare providers and society would provide a benchmark of the potential cost-savings that could accrue from cost-effective interventions to improve the survival rate of micro preemies. [ABSTRACT FROM AUTHOR]

Background: Plasma 25 hydroxycholecalciferol (vitamin D) deficiency has been associated with adverse cardiovascular outcomes in epidemiologic studies. Chronic kidney disease is associated with loss of 1α-hydroxylase and consequently vitamin D deficiency. We hypothesized that vitamin D deficiency was associated with increased mortality and increased vascular access failure in patients undergoing permanent vascular access for end-stage renal disease. Methods: This retrospective cohort study analyzed 128 patients undergoing permanent vascular access surgery between 2003 and 2012 for whom concurrent plasma vitamin D levels were also available. Levels were considered deficient at <20 ng/mL. Multivariable analysis was used to determine the association between vitamin D and mortality and vascular access outcomes. Results: The mean age was 66.7 years, 96.8% were male, 32.0% were African American, and 60.9% had diabetes mellitus. In the entire cohort, 55.5% were vitamin D-deficient, despite similar rates of repletion among the vitamin D-deficient and nondeficient groups. During a median follow-up of 2.73 years, there were 40 deaths (31%). Vitamin D-deficient patients tended to be younger (P = .01) and to have higher total cholesterol (P = .001) and lower albumin (P = .017) and calcium (P = .007) levels. Despite their younger age, mortality was significantly higher (P = .026) and vascular access failure was increased (P = .008) in the vitamin D-deficient group. Multivariate logistic regression analysis found vitamin D deficiency (odds ratio [OR], 3.64; 95% confidence interval [CI], 1.12-11.79; P = .031), hemodialysis through a central catheter (OR, 3.08; 95% CI, 1.04-9.12; P = .042), coronary artery disease (OR, 3.08; 95% CI, 1.06-8.94; P = .039), increased age (OR, 1.09; 95% CI, 1.03-1.15; P = .001), and albumin (OR, 0.27; 95% CI, 0.09-0.83; P = .023) remained independent predictors of mortality. Vitamin D deficiency (hazard ratio [HR], 2.34; 95% CI, 1.17-4.71; P = .02), a synthetic graft (HR, 3.50; 95% CI, 1.38-8.89; P = .009), and hyperlipidemia (HR, 0.42; 95% CI, 0.22-0.81; P = .01) were independent predictors of vascular access failure in a Cox proportional hazard model. Conclusions: Vitamin D deficiency is highly prevalent in patients undergoing vascular access procedures. Patients who are deficient in vitamin D have worse survival and worse vascular access outcomes. Further study is warranted to assess whether aggressive vitamin D repletion will improve outcomes in this population. [Copyright &y& Elsevier]

Objective: Patients with peripheral artery disease (PAD) have varying degrees of walking disability that do not completely correlate with ankle-brachial index (ABI) or angiographic anatomy. We hypothesized that endothelial function (EF) is an independent predictor of symptom severity in PAD patients. Methods: This was a cross-sectional study of 100 PAD patients presenting to a vascular surgery clinic. All patients received ABI testing and brachial artery flow-mediated, endothelium-dependent vasodilation (FMD) to assess arterial EF. Symptom severity and walking disability reported by Rutherford category was based on the patient's self-report during the clinic visit and recorded by the investigator-vascular surgeons. Demographic, biochemical, and physiologic parameters were entered into regression equations to determine association with symptom severity. Results: Patients were a mean age of 66 ± 8 years, and 43% had diabetes. Mean FMD was 7.4%, indicating impaired EF. EF progressively declined as Rutherford category increased (P = .01). Brachial artery FMD, ABI, systolic blood pressure, C-reactive protein, low-density lipoprotein, high-density lipoprotein, β-blocker use, and a history of diabetes or coronary artery disease were all associated with Rutherford category (all P < .05). Multivariable regression showed EF (P < .02) and ABI (P < .0001) were independently associated with walking disability. When the cohort was restricted to claudicant patients (n = 73), EF remained associated with walking disability after adjustment for other covariates (P = .0001). Conclusions: Symptom severity in PAD is multifactorial, reflecting impaired hemodynamics and vascular dysfunction. This is the first report demonstrating that walking disability in PAD is associated with arterial EF. The mechanistic link underlying these observations remains to be defined. [Copyright &y& Elsevier]

Objective: Restenosis following endovascular treatment of the femoropopliteal segment is associated with the inflammatory response produced in the artery wall at the time of the procedure. Although local drug delivery to the superficial femoral and popliteal arteries promises improved patency, data are currently limited. We hypothesized that improved percutaneous delivery of an anti-inflammatory compound into the adventitia of the femoropopliteal at the time of endovascular treatment would be safe, feasible, and decrease the inflammatory response. Methods: This was a prospective, investigator-initiated, phase I, first-in-man study testing the safety and feasibility of percutaneous adventitial delivery of dexamethasone. Following successful intervention, an adventitial microinfusion catheter was advanced over a 0.014-inch wire to the treated segment. Its microneedle (0.9 mm long × 140-μm diameter) was deployed into the adventitia to deliver dexamethasone (4 mg/mL) mixed with contrast agent (80:20 ratio), providing fluoroscopic visualization. The primary safety outcome measure was freedom from vessel dissection, thrombosis, or extravasation while the primary efficacy outcome was duplex-determined binary restenosis defined as a peak systolic velocity ratio >2.5. Results: Twenty patients with Rutherford clinical category 2-5 enrolled in this study. The mean age was 66, and 55% had diabetes mellitus. Treated lesion length was 8.9 ± 5.3 cm, and 50% were chronic total occlusions. Eighty percent of treated lesions were in the distal superficial femoral or popliteal arteries. All lesions were treated by balloon angioplasty with provisional stenting (n = 6) for suboptimal result. Three patients were treated with atherectomy as well. A mean of 1.6 ± 1.1 mg (0.5 ± 0.3 mL) of dexamethasone sodium phosphate was injected per centimeter of lesion length. In total, a mean of 12.1 ± 6.1 mg of dexamethasone was injected per patient. The mean number of injections required per lesion was 3.0 ± 1.3 cm, minimum one and maximum six injections. There was 100% technical success of drug delivery and no procedural or drug-related adverse events. The mean Rutherford score decreased from 3.1 ± .7 (median, 3.0) preoperatively to .5 ± .7 at 6 months (median, 0.0; P < .00001). Over this same time interval, the index leg ankle-brachial index increased from .68 ± .15 to .89 ± .19 (P = .0003). The preoperative C-reactive protein in this study was 6.9 ± 8.5 indicating severe baseline inflammation, which increased to 14.0 ± 23.1 mg/L (103% increase) at 24 hours following the procedure. However, this increase did not reach statistical significance of P = .14. Two patients met the primary efficacy end point of loss of primary patency by reoccluding their treated segment of the index lesion during the follow-up period. Conclusions: Adventitial drug delivery via a microinfusion catheter is a safe and feasible alternative to intimal-based methods for adjunctive treatment in the femoropopliteal segment. The 6-month preliminary results suggest perivascular dexamethasone treatment may improve outcomes following angioplasty to the femoral and popliteal arteries, and support further clinical investigation of this approach. [Copyright &y& Elsevier]

Introduction: Low-grade intraductal papillary mucinous neoplasms (IPMN) are challenging to diagnose because of an absence of reliable morphologic or immunohistochemical features to distinguish them from contaminating gastric foveolar epithelium. After noting intranuclear cytoplasmic inclusions (ICIs) in some cases of IPMN, we investigated whether ICIs could be used as a specific feature to distinguish IPMN from gastric foveolar epithelium. Materials and methods: A consecutive cohort of 61 transduodenal endoscopic fine-needle aspirations of histologically or clinically verified pancreatic IPMNs without high-grade dysplasia from 2005 to 2012 were identified. A control cohort of 24 endoscopic fine-needle aspirations containing gastric epithelium was selected from transgastric specimens of nonpancreatic targets from the same period. Every fragment of mucinous epithelium in the 2 cohorts was examined in alcohol-fixed and cell block sections at high magnification to identify ICIs. Results: ICIs were observed in 31% (19 of 61) of cases in mucinous epithelial fragments obtained by fine-needle aspirations from low-grade IPMNs. When present, they were seen in about 1% of all cells. No ICIs were identified in the control cohort of 24 patients with normal gastric epithelium (P = 0.001 Fisher exact test). BRAF mutation (V600E) testing was performed on 5 IPMN cases, and was negative in all cases including 2 with and 3 without ICIs. KRAS mutation testing was performed on 9 cases of IPMN cases. Two cases with ICIs tested positive for KRAS mutations. Four cases without ICIs also tested positive, and 3 cases without ICIs tested negative. Conclusions: ICIs are a specific morphologic feature found in about one third of low-grade IPMNs, but absent in gastric foveolar epithelium. There is no obvious molecular correlate with the presence of ICIs. [Copyright &y& Elsevier]

Objective: The n-3 polyunsaturated fatty acids are dietary components derived from fish oil with beneficial cardiovascular effects that may relate in part to anti-inflammatory properties. Peripheral artery disease (PAD) is characterized by a marked proinflammatory state. We hypothesized that the n-3 polyunsaturated fatty acids content of red blood cells (omega-3 index) would be correlated with biomarkers of inflammation and vascular function in a PAD cohort. Methods: This was a cross-sectional study of subjects who presented to an outpatient vascular surgery clinic for evaluation of PAD. We used linear regression to evaluate the independent association between the omega-3 index, inflammatory biomarkers (C-reactive protein [CRP], intercellular adhesion molecule-1, interleukin-6, and tumor-necrosis-factor-α) and endothelial function (brachial artery flow mediated dilation). Results: 64 subjects (61 claudicants and three with critical limb ischemia) were recruited for the study. The mean CRP level was 5.0 ± 5.0 mg/L, and the mean omega-3 index was 5.0% ± 1.8%. In an unadjusted model, the omega-3 index was negatively associated with CRP (38% increase in CRP for one standard deviation decrease in the omega-3 index; P = .007), which remained significant after adjustment for age, body mass index, smoking, ankle-brachial index, and high-density lipoprotein (33%; P = .04). There was also evidence for independent associations between the omega-3 index and IL-6 (P = .001). There were no significant associations between the omega-3 index and vascular function tests. Conclusions: In a cohort of patients with PAD, the omega-3 index was inversely associated with biomarkers of inflammation even after adjustment for covariates including the ankle-brachial index. Because patients with PAD have a high inflammatory burden, further studies should be conducted to determine if manipulation of omega-3 index via dietary changes or fish oil supplementation could improve inflammation and symptoms in these patients. [Copyright &y& Elsevier]

Objective: Successful adaptation of a vein graft to an arterial environment is incompletely understood. We sought to investigate whether early vein graft remodeling is predictive of subsequent patency. Methods: A prospective longitudinal study was conducted of 67 patients undergoing lower extremity bypass with autogenous vein between February 2004 and April 2008. Preoperative blood samples were drawn for biomarkers. During the bypass operation, a 5-cm index segment of the graft was registered for serial lumen diameter measurements at 0, 1, 3, 6, 9, and 12 months using duplex ultrasound imaging. The imaging substudy analysis included patients with at least two ultrasound assessments. Results: Patients (55% male) were a median age of 70 years (interquartile range [IQR], 59-76 years), 40% had diabetes mellitus, 49% had critical limb ischemia, 75% were taking a statin, and 91% were taking an antiplatelet medication. Median follow-up was 32 months (IQR, 15-47 months). The median baseline high-sensitivity C-reactive protein level (hsCRP) was 3.2 mg/L (IQR, 1.4-9.7 mg/L). The average intraoperative, postimplantation vein lumen diameter was 3.9 ± 1.0 mm, increasing to 4.7 ± 1.1 mm at 1 month, an average 24% ± 27% change per patient. By 3 months, the average lumen diameter was 5.1 ± 1.6 mm, with little subsequent change observed to 12 months. Nonwhite race, baseline hsCRP ≥5 mg/L, statin use, and initial lumen diameter were significantly associated with early (0- to 1-month) vein remodeling in a multivariable regression model. The primary patency rate for the cohort was 60% ± 6.3% at 2 years. Initial lumen diameter of the index segment was not associated with primary patency, whereas larger lumen diameter achieved at 1 month (≥5.1 mm) was positively associated with primary patency (log-rank, P = .03). Early (30-day) remodeling behavior was used to divide patients into “poor remodelers” (<−5% lumen diameter change, n = 6), “modest remodelers” (−5% to 25% change, n = 29), and “robust remodelers” (>+25% change, n = 30). Early remodeling category was significantly associated with primary patency rate at 2 years (log-rank, P = .02). A multivariable Cox proportional hazards model showed that modest remodelers (hazard ratio, 3.9; 95% confidence interval, 1.02-15; P = .04) and poor remodelers (hazard ratio, 13; 95% confidence interval; P = .008) had significantly higher hazard ratios for graft failure than robust early remodelers. Conclusions: Early remodeling of the arterialized vein appears to predict midterm bypass graft patency. In addition to baseline diameter, race, inflammation, hsCRP, and statin use are associated with early adaptive remodeling, but the mechanisms for these observations are not understood. [Copyright &y& Elsevier]

During the past 2 decades, atherosclerosis and its clinical sequelae have increasingly been recognized as an inflammatory disease. Examination of multiple circulating inflammatory biomarkers has shown that they independently predict cardiovascular risk in patients with and without overt cardiovascular disease. Among these, high-sensitivity C-reactive protein has proved to be most robust in adding to global risk prediction models. Statins, a class of drugs that reduce levels of high-sensitivity C-reactive protein and other inflammatory biomarkers, have been the most thoroughly studied anti-inflammatory agents to reduce cardiovascular risk. However, all such trials are necessarily confounded by the ability of statins to markedly reduce cholesterol, a well-known causal risk factor for adverse vascular outcomes. Nevertheless, the provocative results of several key statin trials have provided the scientific basis to test the hypothesis that reducing inflammation will improve cardiovascular outcomes with novel and specific anti-inflammatory agents. These newer drugs promise to reduce inflammatory marker levels without affecting lipids, glucose, or blood pressure. The results of these trials will provide key data to help us understand the relationship between inflammation and vascular risk. [Copyright &y& Elsevier]

Background: Patients with advanced peripheral artery disease (PAD) have a high prevalence of cardiovascular (CV) risk factors and shortened life expectancy. However, CV risk factors poorly predict midterm (<5 years) mortality in this population. This study tested the hypothesis that baseline biochemical parameters would add clinically meaningful predictive information in patients undergoing lower extremity bypass operations. Methods: This was a prospective cohort study of patients with clinically advanced PAD undergoing lower extremity bypass surgery. The Cox proportional hazard model was used to assess the main outcome of all-cause mortality. A clinical model was constructed with known CV risk factors, and the incremental value of the addition of clinical chemistry, lipid assessment, and a panel of 11 inflammatory parameters was investigated using the C statistic, the integrated discrimination improvement index, and Akaike information criterion. Results: The study monitored 225 patients for a median of 893 days (interquartile range, 539-1315 days). In this study, 50 patients (22.22%) died during the follow-up period. By life-table analysis (expressed as percent surviving ± standard error), survival at 1, 2, 3, 4, and 5 years, respectively, was 90.5% ± 1.9%, 83.4% ± 2.5%, 77.5% ± 3.1%, 71.0% ± 3.8%, and 65.3% ± 6.5%. Compared with survivors, decedents were older, diabetic, had extant coronary artery disease, and were more likely to present with critical limb ischemia as their indication for bypass surgery (P < .05). After adjustment for the above, clinical chemistry and inflammatory parameters significant (hazard ratio [95% confidence interval]) for all-cause mortality were albumin (0.43 [0.26-0.71]; P = .001), estimated glomerular filtration rate (0.98 [0.97-0.99]; P = .023), high-sensitivity C-reactive protein (hsCRP; 3.21 [1.21-8.55]; P = .019), and soluble vascular cell adhesion molecule (1.74 [1.04-2.91]; P = .034). Of the inflammatory molecules investigated, hsCRP proved most robust and representative of the integrated inflammatory response. Albumin, eGFR, and hsCRP improved the C statistic and integrated discrimination improvement index beyond that of the clinical model and produced a final C statistic of 0.82. Conclusions: A risk prediction model including traditional risk factors and parameters of inflammation, renal function, and nutrition had excellent discriminatory ability in predicting all-cause mortality in patients with clinically advanced PAD undergoing bypass surgery. [Copyright &y& Elsevier]

Objective: This study was conducted to determine if there are sex-based differences in the inflammatory phenotype of patients undergoing lower extremity bypass (LEB) and if they correlate with clinical outcomes. Methods: This was a retrospective analysis of a prospective cohort of 225 patients (161 men and 64 women) who underwent autogenous vein LEB between February 2004 and May 2008. Fasting baseline blood samples were obtained before LEB, and the inflammatory biomarkers high-sensitivity C-reactive protein (CRP) and fibrinogen were assessed. All patients underwent ultrasound graft surveillance. CRP levels were dichotomized at 5 mg/L and fibrinogen levels at 600 mg/dL. Results: There were no significant differences in age, race, history of hypertension or diabetes mellitus, body mass index, or coronary artery disease between men and women. Men were more likely to be current smokers (P = .02), have a history of hypercholesterolemia (P = .02), and be taking statins (P = .02). Women were more likely to present with critical limb ischemia (P = .03) and had higher median baseline CRP levels (5.15 mg/L; interquartile range [IQR], 1.51-18.62 mg/L) than men (2.70; IQR, 1.24-6.98 mg/L; P = .02). Median follow-up was 893 days (IQR, 539-1315 days). A multivariable Cox proportional hazards model for primary vein graft patency showed a significant interaction between sex and CRP (P = .03) and fibrinogen (P = .02). After adjustment for key covariates, primary vein graft patency was significantly less in women with CRP >5 mg/L compared with women with CRP <5 mg/L (P = .02). No such difference was seen in men (P = .95). Primary graft patency was also decreased in women with fibrinogen >600 mg/dL vs women with fibrinogen <600 mg/dL (P = .002); again, this pattern was not evident in men (P = .19). Conclusions: Women undergoing LEB for advanced peripheral artery disease have a different inflammatory phenotype than men. Elevated baseline levels of CRP and fibrinogen are associated with inferior vein graft patency in women but not in men. These findings indicate an important interaction between sex and inflammation in the healing response of vein grafts for LEB. Women with elevated preoperative CRP and fibrinogen levels may benefit from more intensive postoperative graft surveillance protocols. [Copyright &y& Elsevier]

Abstract: Polyphenolic profiles in the berry samples of 344 European grape (Vitis vinifera) cultivars were evaluated for two consecutive years. These cultivars represent a diverse collection of V. vinifera germplasm maintained at the USDA-Agricultural Research Service Vitis Clonal Repository in Davis of California, USA. A total of 36 polyphenolic compounds, including 16 anthocyanins, 6 flavonols, 6 flavanols, 6 hydroxycinnamic acids and 2 hydroxybenzoic acids, were identified via HPLC–MS and quantified by HPLC–DAD. The mean contents for anthocyanins, flavanols, flavonols, hydroxycinnamic acids and hydroxybenzoic acids were 0.946 (coloured cultivars), 0.147, 0.043, 0.195 and 0.016mgg−1 FW, respectively. On average, wine grapes had higher concentrations than had table grapes for all of these compounds except hydroxycinnamic acids. Berry colours affected the total contents of anthocyanins, but not others. Positive correlations (0.151–0.535) were found among these groups of compounds. As expected, these groups of compounds were all negatively correlated with berry weight. [Copyright &y& Elsevier]

Objective: A significant portion of patients undergoing lower extremity bypass surgery (LEB) for peripheral arterial disease (PAD) will have cardiovascular or graft-related events. It has been previously demonstrated that systemic inflammation is associated with PAD and its clinical outcomes. We hypothesized that serum biomarkers of insulin resistance and inflammation would identify a subgroup at elevated risk for graft failure, limb loss, and mortality. Methods: This was a prospective longitudinal study of patients (n = 225) undergoing LEB using autogenous vein. Baseline blood samples were obtained prior to surgery in the fasting state. High-sensitivity C-reactive protein (hsCRP) and the adipokines resistin and high-molecular weight adiponectin (HMWA) were measured by enzyme-linked immunosorbent assay (ELISA). Median follow-up was 893 days. The major endpoints of primary patency (PP) and amputation-free survival (AFS) were examined using multivariable methods. Endpoints were screened against biomarkers and patient characteristics for univariate associations. Promising explanatory variables (P < .1) were included in multivariable Cox proportional hazard models. Results: The mean age of subjects was 67.6 years; 71.6% were male and 87.1% were Caucasian. One hundred thirty-three (59.1%) subjects underwent bypass for critical limb ischemia (CLI) and 73 (32.4%) had tissue loss. Patients with CLI and diabetes demonstrated elevated resistin and hsCRP levels. HMWA levels correlated with CLI and with a measure of insulin resistance (HOMA-IR) but not with clinical diabetes. Baseline biomarkers were higher in those presenting with tissue loss and in patients with postoperative events (mortality, limb loss). After multivariable analysis (including CLI, diabetes, age, estimated glomerular filtration rate [eGFR], adiponectin, resistin, and CRP), resistin (hazard ratio [HR] 1.75, 95% confidence interval [CI], 1.07-2.85; P = .025) and CRP (HR 2.39, 95% CI, 1.30-4.39; P = .005) were independently predictive of reduced AFS. However, only resistin maintained its significance when restricted to the diabetic cohort (HR 2.10, 95% CI, 1.10-3.99; P = .025). Higher levels of HMWA were found to be associated with primary graft patency (HR 0.73 for graft failure; 95% CI, 0.55 to 0.97; P = .031) in a multivariable model adjusting for diabetes, CRP, African-American race, CLI, high-risk conduits, and redo bypass procedures. Conclusion: These findings suggest that serum biomarkers of insulin resistance and inflammation may be predictive of clinical outcomes following LEB. Improving the systemic milieu of insulin resistance and inflammation in these high-risk patients may lead to reduced morbidity and mortality. [Copyright &y& Elsevier]

For patients with the most severe manifestations of lower extremity arterial occlusive disease, bypass surgery using autogenous vein has been the most durable reconstruction. However, the incidence of bypass graft stenosis and graft failure remains substantial and wholesale improvements in patency are lacking. One potential explanation is that stenosis arises not only from over exuberant intimal hyperplasia, but also due to insufficient adaptation or remodeling of the vein to the arterial environment. Although in vivo human studies are difficult to conduct, recent advances in imaging technology have made possible a more comprehensive structural examination of vein bypass maturation. This review summarizes recent translational efforts to understand the structural and functional properties of human vein grafts and places it within the context of the rich existing literature of vein graft failure. [Copyright &y& Elsevier]

Lower-extremity vein graft failure causes significant morbidity, increases health care costs, and negatively impacts patient quality of life. Identification of risk factors is essential for patient selection, risk factor modification, and identifying individuals who would benefit from more stringent surveillance protocols. Risk factors can be considered as either patient-related or technical. Here we discuss the patient-related risk factors for vein graft failure. Nontechnical factors related to the indication for operation include operation after a previously failed graft, or redo bypass, critical limb ischemia, and infection. Risk factors for vein graft failure are distinct from the risk factors for cardiovascular events. Young age and African American and Hispanic race are risk factors for lower-extremity vein graft failure. Hypercoaguable and inflammatory states also increase risk for vein graft failure. Therapy with statins is indicated in patients with peripheral atherosclerosis and may have beneficial effects on vein graft function, although further studies are needed in this area. [Copyright &y& Elsevier]

Objective: As in arteries, venous endothelium modulates vessel homeostasis and tone. The effect of an arterialized environment on venous endothelial function remains poorly understood. In particular, regulation of saphenous vein graft (SVG) blood flow and lumen caliber remains undefined. We hypothesized that mature SVGs would exhibit endothelium-dependent, flow-mediated vasodilation (FMD). We further hypothesized that endothelium-derived nitric oxide (NO) was an important mediator. Methods: Patients with femoral to popliteal artery SVGs that had maintained primary patency and were at least 1 year from surgery were enrolled. High-resolution, B-mode ultrasound scans were used to measure vein graft diameter before and 1 minute after reactive hyperemia (RH) to determine FMD. RH was created through application of 220 mm Hg to the calf for 5 minutes with a sphygmomanometric cuff. After a 10-minute recovery period, nitroglycerin-mediated, endothelium-independent vasodilation was measured 3 minutes after administration of nitroglycerin 0.4 mg sublingually. Brachial artery FMD was determined by validated techniques. L-NGmonomethyl arginine (L-NMMA; 1 mg/kg infusion over 10 minutes) was used in a subset of patients (n = 6) to competitively inhibit endothelial NO synthase. Results: Nineteen subjects were enrolled. The median age of the SVGs was 34.6 (21.0-49.7) months. SVG flow-mediated, endothelium-dependent vasodilation was measured at 5.28% ± 3.1% mean change in lumen diameter (range, 1.99%-9.36%; P < .0001 for diameter change). Nitroglycerin-mediated vasodilation was 3.7% ± 1.0%, (range, 16%-10.04%; P < .005). Intravenous administration of L-NMMA abolished SVG FMD (5.7 ± 1.4% before L-NMMA vs 0.01 ± 0.01% during L-NMMA infusion; P = .0088) and attenuated brachial artery FMD (7.54% ± 1.0% vs 5.7 ± 1.4; P = .05). Conclusion: SVGs manifest flow-mediated, endothelium-dependent, and nitroglycerin-mediated endothelium-independent vasodilation. Vein graft endothelium-dependent FMD is likely mediated by NO. Further investigation will be required to determine the role of endothelial function in vein graft patency. [Copyright &y& Elsevier]

Objectives: To assess and compare the attitudes of primary care physicians and midlevel providers toward community pharmacists by surveying the frequency and perceived helpfulness of practitioner-pharmacist interactions, as well as attitudes toward traditional and expanded functions. Methods: A sample of primary care physicians, physician assistants, and nurse practitioners (n = 3,851) in eight western states was mailed a survey. The survey used 5-point Likert-type scales to assess the frequency and helpfulness of interactions with community pharmacists, as well as level of agreement with specific statements relating to pharmacists' current and possible expanded roles. Responses ranged from +2 (very frequently/very helpful/strongly agree) to-2 (very infrequently/ not helpful at all/strongly disagree). Results: 799 analyzable questionnaires were received. On average, midlevel providers interacted with pharmacists more frequently (median -0.23 and -0.51 for mid-levels and physicians, respectively, P < 0.01). The helpfulness of interactions was rated positively by both groups, but the median rating by midlevel providers was higher compared with physicians (0.86 vs. 0.59, P < 0.01). Community pharmacists were rated most favorably on their traditional functions, including patient counseling and reporting drug allergies/interactions. Results were weakly favorable toward expanded functions, such as discussing therapeutic alternatives with patients and dispensing sample medications from pharmacies. Both groups agreed that community pharmacists are valuable sources of information, with midlevel providers indicating a significantly higher level of agreement (1.07 vs. 0.80, P< 0.01 ). Conclusion: Most primary care physicians and midlevel providers support the current role of community pharmacists. Midlevel providers appeared to interact more frequently with pharmacists and indicated higher average helpfulness ratings for pharmacists. For pharmaceutical care to be realized in the community setting, a concerted effort by the pharmacy profession will be necessary to further demonstrate its benefits and feasibility. Midlevel providers may be helpful in facilitating this process. [ABSTRACT FROM AUTHOR]

Introduction: Recent evidence suggests disparities exist among racial groups with peripheral arterial disease (PAD). Hispanics (HI) are the fastest growing demographic in the United States, but little outcome data is available for this population. Therefore, we undertook this study to compare the results of autogenous infrainguinal bypass grafting in HI to Caucasians (CA) and African Americans (AA). Methods: This was a comparative cohort study of prospectively collected registry data of infrainguinal bypass performed at a tertiary center. Patient demographics and comorbidities, operative indications, bypass graft characteristics, and postoperative courses were analyzed. Cumulative patency rates, limb salvage, mortality, and factors associated with these outcomes were determined using Kaplan-Meier analysis and Cox proportional hazards models. Results: From January 1, 1985, through December 31, 2007, 1646 consecutive patients (1408 CA, 57 HI, and 181 AA) underwent 1646 autogenous infrainguinal reconstructions. HI and AA were younger and more often diabetic than CA but HI had less chronic renal insufficiency (CRI) and dialysis-dependence than AA. AA, but not HI, more commonly underwent bypass for critical limb ischemia (CLI) in comparison to CA (AA 90% vs CA 80%, P < .0001; HI 86%). HI and AA bypass grafts had inflow and outflow distal to that in CA. Perioperative mortality (2.3%) and morbidity were similar between groups. Five-year primary patency (± standard error [SE]) was significantly lower in HI compared to CA and similar to that in AA (HI 54% ± 7% vs CA 69% ± 1%, P = .02; AA 58% ± 4%). Cox proportional hazard modeling showed high-risk conduit, age <65, CLI, female gender, and AA race were risk factors for failure of primary patency. Secondary patency of HI grafts, unlike AA, was not different than that in CA. Five-year limb salvage (± SE) was significantly lower in HI compared to CA and similar to that in AA (HI 80% ± 6% vs CA 91% ± 1%, P = .004; AA 83% ± 3%). Hispanic ethnicity, CLI, high-risk conduit, age <65, CRI, female gender, and diabetes were significant predictors of limb loss. Conclusion: Autogenous infrainguinal bypass surgery in HI is associated with primary patency and limb salvage inferior to that of CA and similar to that of AA, despite HI rates of CLI equivalent to CA and HI comorbidities less severe than AA. HI ethnicity was an independent predictor of limb loss. Our data provides evidence of outcome disparities in HI treated aggressively for their PAD. Further investigation with regard to biologic and social factors is required to delineate the reasons for these inferior outcomes in HI patients. [Copyright &y& Elsevier]

Objectives: With the increasing use of endovascular aneurysm repair, a greater proportion of open aneurysm repairs in the future are expected to be more complex and require suprarenal cross-clamping. We sought to evaluate the effects of suprarenal (SR) vs infrarenal (IR) aortic cross-clamp position in abdominal aortic aneurysm (AAA) repair in an updated single center series. Methods: All elective open AAA repairs performed at our institution between 1990 and 2006 were entered into a prospective database and reviewed retrospectively. Our main stratification variable was SR vs IR. The SR group was further subdivided into those requiring an adjunctive renal revascularization procedure (SR+RRP; n = 54) and those who did not (SR−RRP; n = 117). Univariate and multivariate models were used to analyze the effect of baseline variables and operative variables on our primary endpoint 30-day mortality as well as secondary endpoints such as major adverse events, postoperative decline in renal function (defined as doubling of baseline creatinine to level >2 mg/dL, or new-onset dialysis) and long-term survival. A propensity score model was developed to control for confounding variables associated with the use of an SR cross-clamp. Results: A total of 1020 patients underwent elective AAA repair, of which 849 (83.2%) were IR and 171 (16.8%) were SR. Diabetes (14.6% vs 9.1%, P = .027), hypertension (70.2% vs 61.4%, P = .03), and chronic renal failure (14.0% vs 4.7%, P = .001) were more prevalent in the SR group, and mean aneurysm size was larger (6.0 cm vs 5.6 cm, P = .001). Estimated blood loss was higher (1919 mL vs 1257 mL, P = .001) in the SR group, as was mean length of stay (12.6 days vs 10.7 days, P = .047). Perioperative (30-day) mortality rate was 1.8% for the SR group and 1.2% for the IR group (P = .44). Postoperative decline in renal function was 17.0% in SR vs 9.5% in IR (P = .003), however, new-onset dialysis was rare (0.6% SR, 0.8% IR, P = NS). The combination of SR+RRP was associated with an increased risk for postoperative decline in renal function (14.8% SR+RRP, 4.3% SR−RRP, P = .016). Preoperative renal failure was strongly associated with postoperative renal decline (odds ratio [OR] 8.15, 2.92-22.8, P < .0001). Propensity score analysis demonstrated that the use of an SR cross-clamp was associated with an increased risk for postoperative renal decline (OR 2.66, 1.28-5.50, P = .009). Major adverse events were more prevalent in the SR group compared to the IR group (17.0% vs 9.5%, P = .003). Five-year survival was 69.1% + 1.9% for the IR group and 67.7% + 4.3% for the SR group (P = 0.38) by life table analysis. Conclusion: Suprarenal cross-clamping is associated with low mortality and significant but acceptable morbidity, including postoperative decline in renal function. The results from this series may serve as relevant background data when evaluating emerging branched and fenestrated endograft technologies. [Copyright &y& Elsevier]

Restenosis following lower-extremity revascularization remains a significant and costly public health burden. Technical advances in endovascular therapy afford us the choice of treating longer and more distal lesions, which were heretofore reserved for vein bypass surgery. While contemporary vascular surgeons are well-versed in both open and percutaneous techniques, predictive models of who is at risk for failure from a specific mode of therapy are lacking. Traditional Framingham cardiovascular risk factors have not been successful in discriminating risk for failure of peripheral bypass or angioplasty. At the heart of this is our inability to make sophisticated measurements necessary to resolve phenotypic profiles into those likely to experience restenosis versus those likely to enjoy long-term patency. In this article we outline the available literature in an epidemiological framework of the association of traditional cardiovascular risk factors, emerging risk factors, as well as novel biomarkers with failure of both endovascular and open lower-extremity reconstructive procedures. [Copyright &y& Elsevier]

Background: The remodeling of vein bypass grafts after arterialization is incompletely understood. We have previously shown that significant outward lumen remodeling occurs during the first month of implantation, but the magnitude of this response is highly variable. We sought to examine the hypothesis that systemic inflammation influences this early remodeling response. Methods: A prospective observational study was done of 75 patients undergoing lower extremity bypass using autogenous vein. Graft remodeling was assessed using a combination of ultrasound imaging and two-dimensional high-resolution magnetic resonance imaging. Results: The vein graft lumen diameter change from 0 to 1 month (22.7% median increase) was positively correlated with initial shear stress (P = .016), but this shear-dependent response was disrupted in subjects with an elevated baseline high-sensitivity C-reactive protein (hsCRP) level of >5 mg/L. Despite similar vein diameter and shear stress at implantation, grafts in the elevated hsCRP group demonstrated less positive remodeling from 0 to 1 month (13.5% vs 40.9%, P = .0072). By regression analysis, the natural logarithm of hsCRP was inversely correlated with 0- to 1-month lumen diameter change (P = .018). Statin therapy (β = 23.1, P = .037), hsCRP (β = −29.7, P = .006), and initial shear stress (β = .85, P = .003) were independently correlated with early vein graft remodeling. In contrast, wall thickness at 1 month was not different between hsCRP risk groups. Grafts in the high hsCRP group tended to be stiffer at 1 month, as reflected by a higher calculated elastic modulus (E = 50.4 vs 25.1 Mdynes/cm2, P = .07). Conclusions: Early positive remodeling of vein grafts is a shear-dependent response that is modulated by systemic inflammation. These data suggest that baseline inflammation influences vein graft healing, and therefore, inflammation may be a relevant therapeutic target to improve early vein graft adaptation. [Copyright &y& Elsevier]

Objective: Evidence suggesting a beneficial effect of cardioprotective medications in patients with lower extremity atherosclerosis derives largely from secondary prevention studies of heterogeneous populations. Patients with critical limb ischemia (CLI) have a large atherosclerotic burden with related high mortality. The effect of such therapies in this population is largely inferred and unproven. Methods: The Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III) cohort comprised 1404 patients with CLI who underwent lower extremity bypass grafting in a multicenter, randomized prospective trial testing the efficacy of edifoligide for the prevention of graft failure. Propensity scores were used to evaluate the influence of statins, β-blockers, and antiplatelet agents on outcomes while adjusting for demographics, comorbidities, medications, and surgical variables that may influence drug use. Primary outcomes were major adverse cardiovascular events ≤30 days, vein graft patency, and 1-year survival assessed by Kaplan-Meier method. Potential determinants of 1-year survival were modeled using a multivariate Cox regression. Results: In this cohort, 636 patients (45%) were taking statins, 835 (59%) were taking β-blockers, and 1121 (80%) were taking antiplatelet drugs. Perioperative major adverse cardiovascular events (7.8%) and early mortality (2.7%) were not measurably affected by the use of any drug class. Statin use was associated with a significant survival advantage at 1 year of 86% vs 81% (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98; P = .03) by analysis of both unweighted and propensity score-weighted data. Use of β-blockers and antiplatelet drugs had no appreciable impact on survival. None of the drug classes were associated with graft patency measures at 1 year. Significant predictors of 1-year mortality by Cox regression modeling were statin use (HR, 0.67; 95% CI, 0.51-0.90; P = .001), age >75 (HR, 2.1; 95% CI, 1.60-2.82; P = .001), coronary artery disease (HR, 1.5; 95% CI, 1.15-2.01; P = .001), chronic kidney disease stages 4 (HR, 2.0; 95% CI, 1.17-3.55; P = .001) and 5 (HR, 3.4; 95% CI, 2.39-4.73; P < .001), and tissue loss (HR, 1.9; 95% CI, 1.23-2.80; P = .003). Conclusions: Statin use is associated with improved survival in CLI patients 1 year after surgical revascularization. Further studies are indicated to determine optimal dosing in this population and to definitively address the question of relationship to graft patency. These data add to the growing literature supporting statin use in patients with advanced peripheral arterial disease. [Copyright &y& Elsevier]

Abstract: Background: Carisoprodol is a muscle relaxant indicated as adjunctive therapy in acute, painful musculoskeletal conditions. Case reports of drug-seeking behavior and utilization of carisoprodol in combination with opioids have suggested abuse potential. Objectives: We undertook a retrospective review of claims data to identify and characterize potential indicators of abuse in long-term users of carisoprodol and to determine any continued use of the drug by former long-term users following prior authorization implementation. Methods: The Idaho Medicaid pharmacy and medical claims database was queried from January 1 to December 31, 2005, to identify long-term users of muscle relaxants. Use of concomitant opioids and coded diagnoses relating to past drug abuse were analyzed and compared between patients who used carisoprodol and patients who used other muscle relaxants. Data from 11 of 30 surveys mailed to pharmacies filling prescriptions for long-term users of carisoprodol were also collected to determine the frequency of self-pay-continued use after Medicaid coverage of the drug was discontinued. Results: Long-term users of carisoprodol (n = 340) and other skeletal muscle relaxants (SMRs) (n = 453) were identified from among 130,000 individuals in the Idaho Medicaid pharmacy and medical claims database in calendar year 2005. Patients in both groups were similar in terms of mean age (~47 years) and sex (71.5% female). Patients using carisoprodol used concomitant opioids more frequently (81.5% vs 59.8%; P < 0.01), more commonly had past diagnoses indicating other drug abuse (34.1% vs 21.4%; P < 0.01), and in 80% of reported cases, continued to pay out of pocket for carisoprodol when third-party coverage was discontinued. Taken together, these findings are consistent with published case reports suggesting the abuse potential of carisoprodol. Conclusions: The results from this review suggest that, compared with long-term users of other SMRs, carisoprodol patients utilized concomitant opioids more frequently and concomitant NSAIDs less frequently, more commonly had past diagnoses indicating other drug dependence or abuse, and continued to pay out of pocket for carisoprodol when third-party coverage was discontinued. While none of these issues alone may be direct indicators of abuse, collectively they suggest that patients who used carisoprodol long term displayed abuse potential characteristics more frequently than long-term users of other agents. (Clin Ther. 2007;29:2222-2225) Copyright © 2007 Excerpta Medica, Inc. [Copyright &y& Elsevier]

Objective: End-stage renal disease (ESRD) imparts a significant survival disadvantage to individuals undergoing lower extremity revascularization; however, the influence of lesser degrees of renal impairment remains unclear. This study examined the prognostic significance of the chronic kidney disease (CKD) classification on survival, limb salvage, and graft patency in patients undergoing lower extremity arterial reconstruction. Methods: A prospective registry was evaluated for consecutive patients between January 31, 1995, and December 21, 2004, undergoing first-time, lower extremity vein bypass surgery. Glomerular filtration rate (GFR) was estimated with the Modification of Diet in Renal Disease equation using each patient’s preoperative creatinine concentration. CKD categories were taken from current National Kidney Foundation Kidney Disease Outcomes Quality Initiative staging criteria. Results: The cohort included 456 subjects, with a mean (± SD) age of 68.1 ± 10.8 years. There were 274 men (60%) and 378 Caucasians (82.5%). Comorbidities included diabetes mellitus in 270 (59.0%), hypertension in 333 (72.7%), coronary artery disease in 242 (52.8%), and dyslipidemia in 203 (44.5%). The surgical indication was critical limb ischemia in 384 (83.8%). Among the variables examined, diabetes and critical ischemia as the indication for bypass were significantly skewed toward higher CKD classifications (P < .001). The 5-year survival rates by CKD class were, CKD 1 and 2, 57%; CKD 3, 46%; CKD 4, 23%; and CKD 5, 9.5%. On univariate analysis, age, coronary artery disease, diabetes mellitus, hypertension, critical ischemia, and CKD were significant predictors of mortality. After adjustment, however, only age (hazard ratio [HR], 1.05, 95% confidence interval [CI], 1.03 to 1.06) and CKD stages 4 (HR, 4.23; 95% CI, 2.04 to 8.75) and 5 (HR, 3.27; 95% CI, 1.96 to 5.45) retained significance. Subjects within the CKD 5 classification were more likely to have a major amputation (P = .018) compared with all other CKD classes. Notably, no relationship was detected between CKD category and graft patency. Conclusion: CKD staging adequately differentiates survival curves and risk for major amputation among patients with renal impairment who are undergoing lower extremity bypass surgery. This may help in clinical decision analysis as well as in the refinement of stratification in future clinical trial design where survival is an end point. [Copyright &y& Elsevier]

Background: Iliac angioplasty in preparation for an infrainguinal bypass graft has been shown to be an effective strategy. We undertook this study to determine if superficial femoral artery (SFA) angioplasty offers durable inflow for distal origin grafts originating from the SFA or popliteal artery. Methods: All distal origin grafts performed at a single institution between 1988 and 2006, ≤30 days of an ipsilateral SFA percutaneous intervention, were reviewed retrospectively. Patients were identified from a computerized vascular registry, and data were obtained by review of patient charts, angiograms, and duplex studies. Results: We identified 23 autogenous distal origin grafts procedures performed distal to an SFA intervention, of which 22 were performed for critical limb ischemia (96%). The SFA lesions intervened on (20 angioplasty alone, 3 angioplasty with stenting) included 11 TransAtlantic Inter-Society Consensus (TASC) A (48%), seven TASC B (30%), five TASC C (22%), and no TASC D (0%). Of the bypasses, five originated from the distal SFA, five originated from the above knee popliteal artery, and 13 originated from the below knee popliteal artery. A significant majority of the patients (87%) were diabetic. No deaths, amputations, or early graft failures occurred during the perioperative period. The mean duration of follow-up was 40.8 months. By life-table analysis, the primary patency rate was 58% at 5 years. The primary assisted patency rate was 69% at 5 years. Of the seven interventions required to maintain patency, only one targeted the SFA. None of the graft failures could be specifically attributed to disease progression of the SFA. The 5-year limb salvage rate was 70% and the survival rate was 65%. Conclusions: Percutaneous SFA intervention in preparation for a distal origin graft is a useful and effective strategy in select patients. The durability appears comparable with distal origin grafts performed in the absence of an SFA intervention. This strategy provides a good option in the setting of both atherosclerotic SFA disease and limited autogenous conduit. [Copyright &y& Elsevier]

Objectives: Inflammatory markers such as high-sensitivity C-reactive protein (hsCRP) are associated with an increased risk of cardiovascular events and with the severity of peripheral arterial disease. The effects of inflammation on the development of vein graft disease remain speculative. We hypothesized that high levels of inflammatory markers would identify patients at increased risk for adverse events (graft failure, major cardiovascular events) after lower extremity bypass surgery. Methods: Patients (n = 91) scheduled to undergo lower extremity bypass using autogenous vein were enrolled into a prospective study at two institutions. Exclusion criteria included the presence of major infection. A baseline plasma sample was obtained on the morning of lower extremity bypass. Biomarkers for inflammation included hsCRP, fibrinogen, and serum amyloid A (SAA). Values between patients with and without critical limb ischemia were compared. Proportions of events among dichotomized populations (upper limit of normal of each laboratory assay) were compared by log-rank test. Results: Of the patients undergoing lower extremity bypass, 69% were men, 53% were diabetic, 81% were smokers, and their mean ankle-brachial index was 0.51 ± 0.19. The indication for lower extremity bypass was critical limb ischemia in 55%. There were no perioperative deaths and two early graft occlusions. During a mean follow-up of 342 days (range, 36-694 days) there were four deaths, 27 graft-related events, and 10 other cardiovascular events. No relationships were found between events and demographics, comorbidities, baseline ankle-brachial index, or statin use. High-sensitivity CRP (P = .005), fibrinogen (P < .001), and SAA (P = .0001) levels were associated with critical limb ischemia at presentation. Among patients with an elevated hsCRP (>5 mg/L) immediately before surgery, major postoperative vascular events occurred in 60% (21/35), compared with a 32% (18/56) rate in those with a baseline CRP <5 mg/L (P = .004, log-rank test). On multivariable analysis, only elevated hsCRP correlated with adverse graft-related or cardiovascular events (P = .018). Conclusions: The inflammatory biomarkers of hsCRP, fibrinogen, and SAA correlate with peripheral arterial disease severity at presentation in patients undergoing lower extremity bypass. Patients with elevated hsCRP are at increased risk for postoperative vascular events, most of which are related to the vein graft. These findings suggest a potential relationship between inflammation and outcomes after lower extremity vein bypass surgery. [Copyright &y& Elsevier]

Background: The geometric and biomechanical changes that contribute to vein graft remodeling are not well established. We sought to measure patterns of adaptation in lower extremity vein grafts and assess their correlation with clinical outcomes. Methods: We conducted a prospective, longitudinal study of patients undergoing infrainguinal reconstruction with autogenous conduit. In addition to standard duplex surveillance, lumen diameter (of a defined index segment of the conduit) and pulse wave velocity (PWV) were assessed by ultrasound imaging at surgery and at 1, 3, and 6 months postoperatively. Graft dimensions and wall stiffness were correlated with clinical outcomes. Results: There were 92 patients and 96 limbs in this study. On average, vein graft lumen diameter increased during the first month of implantation from 0.37 ± .01 cm to 0.45 ± 0.02 cm (mean ± SEM; P = .002), representing a relative change of +21.6% (median ± 14%; range, −31 to +67%) during this period. Of the entire cohort, 72% of grafts demonstrated appreciable dilation of the index segment during the first month. Index segment lumen diameter did not change appreciably beyond 1 month, with the notable exception of arm vein conduits, which showed continued tendency to dilate. PWV increased during the first 6 months (17.2 ± 1.2 m/s to 23.2 ± 2.4 m/s; P = .008), reflecting a nearly 40% increase in conduit stiffness (2.0 ± .6 Mdynes/cm to 3.3 ± .8 Mdynes/cm, P = .01). The greatest relative increase (25%) in PWV occurred from months 1 to 3. Loss of primary patency occurred in 24 cases (19 revisions, 5 occlusions), with a mean reintervention time of 7.6 months. Grafts that demonstrated early positive remodeling (lumen dilatation) had a trend of increased primary patency (P = .08, log rank). Among the grafts that failed, a trend was noted toward greater wall stiffness at 1 month, 2.7 vs 1.5 Mdynes (P = .08). Conclusion: Vein graft remodeling appears to involve at least two distinct temporal phases. Outward remodeling of the lumen occurs early, and wall stiffness changes occur in a more delayed fashion. Early outward remodeling may be important for successful vein graft adaptation. [Copyright &y& Elsevier]

Summary: The well-described histologic and electron microscopic findings in Fabry disease cardiomyopathy are hypertrophic vacuolated cells with electron dense concentric lamellar bodies. We present altered findings in an endomyocardial biopsy from a patient with treated Fabry disease. A 51-year-old male with Fabry disease, treated with recombinant α-galactosidase enzyme replacement therapy for over 18 months, underwent an endomyocardial biopsy for heart failure. The histologic changes showed widespread hypertrophy and vacuolization with rare eosinophilic bodies. Electron microscopy failed to reveal the characteristic globotriaosylceramide concentric lamellar bodies (myelin figures) in the sarcoplasm. Instead, extensive aggregates and single tubular crystalline structures, giant secondary lysosomes as well as abnormal branched chain glycogen were present. This is the first histologic description of long-standing treated Fabry disease in cardiac myocytes. [Copyright &y& Elsevier]

Renal venous thrombosis most commonly occurs in the setting of nephrotic syndrome, hypercoagulability, or dehydration. This can usually be treated with systemic anticoagulation, and the diversion is via natural draining tributaries, eg, adrenal, lumbar, or gonadal veins. Occasionally, renal venous thrombosis results from extension of a thrombotic process, such as a large renal cell carcinoma with tumor thrombus extension into the infrahepatic inferior vena cava resulting in thrombosis of the inferior vena cava and contralateral renal vein. Herein, we report a case of left renal vein thrombosis relieved by diversion through the inferior mesenteric vein. [Copyright &y& Elsevier]

Abstract: Serious neurodegenerative disorders are increasingly prevalent in our society and excessive oxidative stress may be a key mediator of neuronal cell death in many of these conditions. A variety of metals, such as manganese and zinc, are essential trace elements but can reach localized toxic concentrations through various disease processes or environmental exposures and have been implicated as having a role in neurodegeneration. Both manganese and zinc exist as bivalent cations and are essential cofactors/activators for numerous enzymes. Evidence suggests one action of these metals, when concentrated beyond physiological levels, may be to inhibit cellular energy production, ultimately leading to increased radical formation. Our studies were undertaken to directly investigate the toxic effects of manganese and zinc in an immortalized neuronal-like cell line (SK-N-SH) by testing interactions with the antioxidant, 17β-estradiol, and the neurotoxin, ethanol. Employing undifferentiated SK-N-SH cells, we found that these metals caused biphasic effects, enhancing cell proliferation at low doses and inducing cell death at higher doses. Zinc was both more efficacious and more potent than manganese in enhancing growth and in causing cell death. 17β-Estradiol and ethanol enhanced the proliferative actions of zinc and manganese across a wide concentration range. Furthermore, co-treatment with either 17β-estradiol or ethanol afforded protection against manganese-, but not zinc-induced toxicity. Finally, combined administration of 17β-estradiol and ethanol to SK-N-SH cells resulted in both a loss of growth enhancement and protective properties that were observed when these substances were administered individually. We also noted that the toxic effects occurred more rapidly from zinc than manganese exposure. Taken together, these data suggest that oxidative stress likely has a role in cell death resulting from toxic exposure to either zinc or manganese, but there is a difference in the precise mechanism of their effects. [Copyright &y& Elsevier]

Mesenteric vein thrombosis is a rare disorder that is often the first manifestation of a systemic condition such as a hypercoagulable state or cancer. In particular, myeloproliferative disorders can present as mesenteric vein thrombosis even in the setting of relatively normal peripheral blood counts. A recent novel mutation in the Janus activated kinase 2 gene involving a gain-of-function substitute of valine to phenylalanine at position 617 (JAK2 V617F) has been discovered to be prevalent in patients with mesenteric vein thrombosis and myeloproliferative disorders. This article reports a patient who presented with mesenteric vein thrombosis and relatively normal peripheral blood counts. He was diagnosed with essential thrombocythemia after he tested positive for the JAK2 V617F mutation. [Copyright &y& Elsevier]

In the more than 15 years since its introduction, quantitative microbial risk assessment (QMRA) has become a widely used technique for assessing population health risk posed by waterborne pathogens. However, the variation in approaches taken for QMRA in relation to drinking water supply is not well understood. This systematic review identifies, categorises, and critically synthesises peer-reviewed and academic case studies of QMRA implementation for existing distributed public drinking water supplies. Thirty-nine English-language, peer-reviewed and academic studies published from 2003 to 2019 were identified. Key findings were synthesised in narrative form. The overall designs of the included studies varied widely, as did the assumptions used in risk calculation, especially in relation to pathogen dose. There was also substantial variation in the degree to which the use of location-specific data weighed with the use of assumptions when performing risk calculation. In general, the included studies' complexity did not appear to be associated with greater result certainty. Factors relating to pathogen dose were commonly influential on risk estimates whereas dose-response parameters tended to be of low relative influence. In two of the included studies, use of the 'susceptible fraction' factor was inconsistent with recognised guidance and potentially led to the underestimation of risk. While approaches and assumptions used in QMRA need not be standardised, improvement in the reporting of QMRA results and uncertainties would be beneficial. It is recommended that future authors consider the water supply QMRA reporting checklist developed for the current review. Consideration of the broad types of uncertainty relevant to QMRA is also recommended. Policy-makers should consider emergent discussion on acute microbial health-based targets when setting normative guidelines. The continued representation of QMRA case studies within peer-reviewed and academic literature would also enhance future implementation. Further research is needed on the optimisation of QMRA resourcing given the application context. Image 1 • First systematic review of QMRA implementation for public drinking water supplies. • Current approaches varied most for deriving dose and varied least for dose-response. • Factors for dose were commonly the most influential determinant of risk. • QMRA study complexity did not indicate greater certainty of risk estimates. • Greater consistency in reporting QMRA assumptions would be beneficial overall. [ABSTRACT FROM AUTHOR]

Rarely, biliary-enteric fistula can result in duodenal obstruction or Bouveret’s syndrome. Boerhaave’s syndrome is a distal esophageal rupture in the setting of severe emesis. This case is the first reported successful management of these clinical scenarios occurring simultaneously and highlights important features in presentation, diagnosis, and surgical treatment. [Copyright &y& Elsevier]

The presence of an abdominal aortic aneurysm (AAA) can be a contraindication to placement of a HeartMate left ventricular assist device (LVAD) for end-stage heart failure. We describe a 65-year-old patient who underwent endovascular repair of an AAA before placement of a LVAD as destination therapy for end-stage heart failure. This case is the first report of endovascular AAA repair before VAD placement. It not only demonstrates the utility of endovascular AAA repair in patients with undue co-morbidities, but also that the presence of an AAA should not be a contraindication to LVAD placement, if corrected. [Copyright &y& Elsevier]