A Novel Bio-Adhesive Mesh System for Medical Implant Applications: In Vivo Assessment in a Rabbit Model.

Injectable surgical sealants and adhesives, such as biologically derived fibrin gels and synthetic hydrogels, are widely used in medical products. While such products adequately adhere to blood proteins and tissue amines, they have poor adhesion with polymer biomaterials used in medical implants. To address these shortcomings, we developed a novel bio-adhesive mesh system utilizing the combined application of two patented technologies: a bifunctional poloxamine hydrogel adhesive and a surface modification technique that provides a poly-glycidyl methacrylate (PGMA) layer grafted with human serum albumin (HSA) to form a highly adhesive protein surface on polymer biomaterials. Our initial in vitro tests confirmed significantly improved adhesive strength for PGMA/HSA grafted polypropylene mesh fixed with the hydrogel adhesive compared to unmodified mesh. Toward the development of our bio-adhesive mesh system for abdominal hernia repair, we evaluated its surgical utility and in vivo performance in a rabbit model with retromuscular repair mimicking the totally extra-peritoneal surgical technique used in humans. We assessed mesh slippage/contraction using gross assessment and imaging, mesh fixation using tensile mechanical testing, and biocompatibility using histology. Compared to polypropylene mesh fixed with fibrin sealant, our bio-adhesive mesh system exhibited superior fixation without the gross bunching or distortion that was observed in the majority (80%) of the fibrin-fixed polypropylene mesh. This was evidenced by tissue integration within the bio-adhesive mesh pores after 42 days of implantation and adhesive strength sufficient to withstand the physiological forces expected in hernia repair applications. These results support the combined use of PGMA/HSA grafted polypropylene and bifunctional poloxamine hydrogel adhesive for medical implant applications.

Influence of Clinically Relevant Mechanical Forces on Vascular Smooth Muscle Cells Under Chronic High Glucose: An In Vitro Dynamic Disease Model.

BACKGROUND: In this study, we subjected vascular smooth muscle cells (VSMC) to acute and chronic high glucose conditions under physiologically relevant levels of cyclic strain and low wall shear forces to compare phenotypic modulation and thus conceptualize a dynamic-disease test model which captures cellular response more accurately in comparison with static cultures. METHODS: P2-P6 rat aortic smooth muscle cells were seeded on type I collagen-coated silicone membranes and subjected to 0-7% cyclic strain at 1 Hz and 0.3 dynes/cm(2) shear stress from flow for 24 hr under acute (25 mM d-glucose, 84 hr) and chronic high glucose conditions (25 mM d-glucose, 3-4 weeks). Samples were analyzed for cell proliferation, percent apoptosis, cellular hypertrophy, and expression levels of smooth muscle contractile state-associated markers with 0.05 level of significance. RESULTS: Concomitant application of cyclic strain and flow shear resulted in an overall increase in proliferation of VSMCs under both acute and chronic high glucose conditions as compared with normal glucose control (P < 0.0001). Application of both cyclic strain and cyclic strain shear resulted in a significant increase in percent apoptosis with chronic high glucose treatment in comparison with both normal glucose controls (P < 0.0001) and acute high glucose (P < 0.0001). Cellular hypertrophy as estimated by measuring cell area and aspect ratio revealed a significantly altered morphology due to concomitant loading under chronic high glucose conditions with significantly higher cell area (P < 0.0001) and lower aspect ratio (P < 0.0001) indicative of a relatively rounded morphology as compared with normal glucose controls. Western blot analysis demonstrated reduced expression of SM α-actin (P < 0.0001), calponin (P < 0.0001), and SM22α (P = 0.0008) for concomitant loading under chronic high glucose treatment as compared with normal glucose controls. CONCLUSIONS: Concomitant application of cyclic strain and low wall shear stress resulted in greater phenotypic modulation of VSMCs due to chronic high glucose treatment as compared with normal glucose controls, thus implicating cellular-response differences which may impact progression of in-stent restenosis in diabetic patients with poorly controlled hyperglycemia. Similarity of VSMC response from our study to existing preclinical models of diabetes and reports of altered phenotype of VSMCs isolated from diabetic patients substantiate the relevance of our dynamic disease test model.

Geographic disparities in arteriovenous fistula placement in patients approaching hemodialysis in the United States.

Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD). Several factors associated with AVF placement have been identified (e.g., age, sex, race, comorbidities). We hypothesized that geographic location of patient residence might be associated with the probability of AVF placement as the initial access. We used the data from the United States Renal Data System (USRDS) database (2005-2008) linked to Medicare claims (2003-2008). Logistic regression was used to estimate specific characteristics of population associated with the AVF as first access placed or attempted for HD initiation. Our primary variable of interest was the geographic location, and the multivariate model was adjusted for age, sex, race, body mass index, primary cause of end-stage renal disease (ESRD), duration of pre-ESRD nephrology care, comorbidities, employment status, substance abuse, and income. Geographic location was determined using the data collected by the RUCA project and divided population into metropolitan, micropolitan, and rural categories. Patients (n = 111,953) identified from the USRDS database with linked Medicare claims were examined. Rates of fistula placement in the metropolitan, micropolitan, and rural population were 18.5%, 22.4%, and 21.6%, respectively. In comparison, patients who received catheter as the first access were 81.5%, 77.6% and 78.4%, respectively. The odds ratio of AVF placement as a first HD access in the rural and metropolitan population compared with the micropolitan population were 0.96 (0.90-1.03; P = 0.26) and 0.80 (0.76-0.84; P < 0.001), respectively. Our results indicate the presence of geographic disparities in AVF placement with decreased rates of AVF as the first access created in the metropolitan (but not rural) populations compared with the micropolitan communities.

Disparities in arteriovenous fistula placement in older hemodialysis patients.

The benefits of an arteriovenous fistula (AVF) as the preferred vascular access for hemodialysis have been clearly demonstrated. However, only about 20% of patients in the United States initiate hemodialysis with an AVF. In this study, we assessed whether disparities exist in the type of first hemodialysis access placed prior to dialysis start (rather than that used at dialysis initiation), to detect whether certain disadvantaged groups might have lower likelihood of AVF placement. Study cohort of 118,767 incident hemodialysis patients ≥67 years of age (1/2005-12/2008) derived from the United States Renal Data System was linked with Medicare claims data to identify the type of initial access placed predialysis. We used logistic regression model with outcome being the initial predialysis placement of an AVF as opposed to an arteriovenous graft or a central venous catheter. Increasing age, female sex, black race, lower body mass index, urban location, certain comorbidities, and shorter pre-end-stage renal disease nephrology care are all associated with a significantly lower likelihood of AVF placement as initial access predialysis. Our study suggests the presence of significant disparities in the placement of an AVF as initial hemodialysis vascular access. We suggest that additional attention should be paid to these patient groups to improve disparities by patient education, earlier referral, and close follow-up.

Fistula first is not always the best strategy for the elderly.

Whether placing a fistula first is the superior predialysis approach among octogenarians is unknown. We analyzed data from a cohort of 115,425 incident hemodialysis patients ≥67 years old derived from the US Renal Data System with linked Medicare claims, which allowed us to identify the first predialysis vascular access placed rather than the first access used. We used proportional hazard models to evaluate all-cause mortality outcomes based on first vascular access placed, considering the fistula group as the reference. In the study population, 21,436 patients had fistulas as the first predialysis access placed, 3472 had grafts, and 90,517 had catheters. Those patients with a catheter as the first predialysis access placed had significantly inferior survival compared with those patients with a fistula (HR=1.77; 95% CI=1.73 to 1.81; P<0.001). However, we did not detect a significant mortality difference between those patients with a graft as the first access placed and those patients with a fistula (HR=1.05; 95% CI=1.00 to 1.11; P=0.06). Analyzing mortality stratified by age groups, grafts as the first predialysis access placed had inferior mortality outcomes compared with fistulas for the 67 to ≤79-years age group (HR=1.10; 95% CI=1.02 to 1.17; P=0.007), but differences between these groups were not statistically significant for the 80 to ≤89- and the >90-years age groups. In conclusion, fistula first does not seem to be clearly superior to graft placement first in the elderly, because each strategy associates with similar mortality outcomes in octogenarians and nonagenarians.

Access to renal transplantation in the diabetic population-effect of comorbidities and body mass index.

BACKGROUND: In this study, we hypothesized that higher level of comorbidity and greater body mass index (BMI) may mediate the association between diabetes and access to transplantation. METHODS: We used data from the United States Renal Data System (01/01/2000-24/09/2007; n = 619,151). We analyzed two outcomes using Cox model: (i) time to being placed on the waiting list or transplantation without being listed and (ii) time to transplantation after being listed. Two primary Cox models were developed based on different levels of adjustment. RESULTS: In Cox models adjusted for a priori defined potential confounders, history of diabetes was associated with reduced transplant access (compared with non-diabetic population) - both for wait-listing/transplant without being listed (hazard ratio, HR = 0.80, p < 0.001) and for transplant after being listed (HR = 0.72, p < 0.001). In Cox models adjusted for BMI and comorbidity index along with the potential confounders, history of diabetes was associated with shorter time to wait-listing or transplantation without being listed (HR = 1.07, p < 0.001), and there was no significant difference in time to transplantation after being listed (HR = 1.01, p = 0.42). CONCLUSION: We demonstrated that higher level of comorbidity and greater BMI mediate the association between diabetes and reduced access to transplantation.

Social adaptability index predicts overall mortality in patients with diabetes.

BACKGROUND: A quantifiable assessment of socioeconomic status and its bearing on clinical outcome in patients with diabetes is lacking. The social adaptability index (SAI) has previously been validated in the general population and in patients with chronic kidney disease, including those on dialysis and with kidney transplant. We hypothesize that SAI could be used in diabetes practice to identify a disadvantaged population at risk for inferior outcomes. METHODS: The NHANES-3 database of patients who have diabetes was analyzed. The association of the SAI (calculated as the linear combination of indicators of education status, employment, income, marital status, and substance abuse) with patient survival was evaluated using Cox model. RESULTS: The study population consisted of 1634 subjects with diabetes mellitus with mean age of 61.9±15.3 years; 40.9% males; 38.5% white, 27.7% African American, and 31.3% Mexican American. The highest SAI was in whites (6.9±2.5), followed by Mexican Americans (6.5±2.3), and then African Americans (6.1±2.6) (ANOVA, P<.001). SAI was higher in subjects living in metropolitan areas (6.8±2.6) compared to the rural population (6.3±2.4) (T test, P<.001). Also, SAI was greater in males (7.1±2.4) than in females (6.1±2.4) (T test, P<.001). SAI had significant association with survival (hazard ratio 0.9, P<.001) in the entire study population and in most of the subgroups (divided by race, sex, and urban/rural location). Furthermore, SAI divided into tertiles (≤5, 6 to 8, >8) demonstrated a significant and "dose-dependent" association with survival. CONCLUSION: Social adaptability index is associated with mortality in the diabetic population and is useful in identifying individuals who are at risk for inferior outcomes.

Hyperlipidemia and long-term outcomes in nondiabetic chronic kidney disease.

BACKGROUND AND OBJECTIVES: Dyslipidemia confers a paradoxical survival advantage in patients with kidney failure. Data are limited in the earlier stages of chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This was a cohort study in 840 subjects with stage 3 to 4 CKD enrolled in the Modification of Diet in Renal Disease study. Cox models were used to examine the relationship of total cholesterol (TC), non-HDL-cholesterol (NHDL-C), triglycerides (TG), and HDL-cholesterol (HDL-C) with all-cause and cardiovascular disease (CVD) mortality and progression to kidney failure. RESULTS: During a mean follow-up of 10 years, there were 208 deaths, 128 deaths from CVD, and 554 subjects reached kidney failure. There was no association between tertiles of any of the lipid variables and mortality; the lowest HDL-C tertile (1.44, 1.18 to 1.78) had increased risk of kidney failure but covariate adjustment abolished this association. In analyses with lipids as continuous variables, there was a significant association with all-cause mortality for TC (hazard ratio [HR] per 10-mg/dl increase, 95% confidence intervals [CI] = 1.03, 1.0 to 1.06) that disappeared with covariate adjustment; there was no association of TG, HDL-C, and NHDL-C as continuous variables with all-cause or CVD mortality. There was a significant inverse association between HDL-C and kidney failure (HR = 0.93, CI = 0.87 to 0.99) in an unadjusted Cox model that was attenuated after adjustment for covariates (HR = 0.98 CI = 0.91 to 1.06). CONCLUSIONS: In this cohort, with predominantly nondiabetic CKD patients, hyperlipidemia is not an independent predictor of long-term outcomes.

Monocular blindness during therapy for cerebral neurocysticercosis.

Neurocysticercosis is endemic in India, cerebral and ocular manifestations being common. A 32 yr old man on treatment with Albendazole for cerebral neurocysticercosis for 10 days presented with 3 days of painful uniocular blindness. He had only light perception in the left eye, left pupil was non-reactive to light and left disc was edematous. B-scan of eye revealed retinal detachment due to sub retinal cyst and CT brain showed multiple parenchymal cysticerci. The natural history of ocular neurocysticercosis or enhanced sub-retinal inflammation due to Albendazole therapy could have resulted in the retinal detachment in this case.

Risk factors for albicans and non-albicans candidemia in the intensive care unit.

OBJECTIVE: To determine risk factors for bloodstream infections (BSI) with Candida non-albicans (C-NA) species and Candida albicans (CA) among critically ill patients. DESIGN: Case-control study. SETTING: Adult medical and surgical intensive care units (ICUs) at two university hospitals. PATIENTS: Consecutive patients with C-NA and CA BSIs from 1995-2005 formed the two case groups. Controls were patients without candidemia who were randomly selected in a ratio of 5:1 and matched by study hospital, ICU type (medical vs. surgical) and by ICU admission date within a 3-month period. INTERVENTIONS: Data collected included demographics, comorbidities, exposure to antibiotics and antifungals, and ICU factors such as total parenteral nutrition (TPN), blood product transfusions, invasive procedures, central venous catheters, hemodialysis, and mechanical ventilation. We built multivariable logistic regression models, which identified risk factors for C-NA or CA BSIs compared with controls. Variables were adjusted for time-at-risk. MEASUREMENTS AND MAIN RESULTS: There were 67 patients with C-NA BSIs, 79 patients with CA BSIs, and 780 controls. In multivariable models, factors associated with an increased risk of C-NA compared with controls included major pre-ICU operations [odds ratio; (95% confidence interval)] [2.12; (1.14-3.97)], gastrointestinal procedures [2.24; (1.49-3.38)], enteric bacteremia [3.43; (1.39-8.48)], number of hemodialysis days [6.20; (2.67-14.4)], TPN duration [2.87; (1.40-5.90)], and mean number of red blood cell transfusions [2.72; (1.33-5.58)]. Factors associated with an increased risk of CA BSIs compared to controls were very similar and included major ICU operations [1.26; (1.14-3.97)], enteric bacteremia [3.45; (1.38-8.63)], number of hemodialysis days [3.84; (1.75-8.40)], TPN duration [11.0; (5.52-21.7)] and mean number of red blood cell transfusions [1.97; (0.98-3.99)]. CONCLUSIONS: We found multiple common risk factors for both non-C. albicans and C. albicans BSIs, however we could not differentiate between these two groups based on clinical characteristics alone.

Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit.

BACKGROUND: Candida albicans has been the most common cause of fungal bloodstream infections (BSIs) in intensive care units (ICUs); however, infections due to non-albicans Candida species have been increasing in prevalence. We examined factors associated with BSIs due to non-albicans Candida species, compared with C. albicans BSIs, in an ICU patient population. METHODS: For our case-comparator study, we identified consecutive adult ICU patients with BSIs due to non-albicans Candida species or C. albicans at 2 tertiary care hospitals during the period 1995-2005. Data collected included demographic characteristics, comorbidities, exposure to antibiotics and antifungals, and ICU-related factors, such as total parenteral nutrition, blood product transfusions, invasive procedures, central venous catheter use, hemodialysis, and mechanical ventilation. We built a multivariable logistic regression model that identified variables that differentiate BSIs due to non-albicans Candida species from BSIs due to C. albicans. RESULTS: There were 67 patients with BSIs due to non-albicans Candida species and 79 patients with C. albicans BSIs. Variables were adjusted for time at risk. In multivariable models, factors associated with an increased risk of BSIs due to non-albicans Candida species, compared with C. albicans BSIs, included fluconazole exposure (odds ratio, 11.6; 95% confidence interval, 2.28-58.8), central venous catheter exposure (odds ratio, 1.95; 95% confidence interval, 1.10-3.47), and mean number of antibiotics per day (odds ratio, 2.31; 95% confidence interval, 0.71-7.54). Total parenteral nutrition exposure was associated with a decreased risk (odds ratio, 0.16; 95% confidence interval, 0.05-0.47) of BSIs due to non-albicans Candida species, compared with C. albicans BSIs. Duration of stay in the ICU was not significantly different between the 2 groups. Specific antibiotics, such as vancomycin and piperacillin-tazobactam, were not independently associated with BSI due to non-albicans Candida species. CONCLUSIONS: Receipt of fluconazole and central venous catheter exposure were associated with an increased risk of BSI due to non-albicans Candida species, and total parenteral nutrition was associated with a decreased risk of BSI due to non-albicans Candida species, compared with BSI due to C. albicans. Patients without characteristics of infection due to non-albicans Candida species might benefit from empirical antifungal therapy with fluconazole.