Protein-Engineered Fibers For Drug Encapsulation Traceable via 19F Magnetic Resonance.

Theranostic materials research is experiencing rapid growth driven by the interest in integrating both therapeutic and diagnostic modalities. These materials offer the unique capability to not only provide treatment but also track the progression of a disease. However, to create an ideal theranostic biomaterial without compromising drug encapsulation, diagnostic imaging must be optimized for improved sensitivity and spatial localization. Herein, we create a protein-engineered fluorinated coiled-coil fiber, Q2TFL, capable of improved sensitivity to 19F magnetic resonance spectroscopy (MRS) detection. Leveraging residue-specific noncanonical amino acid incorporation of trifluoroleucine (TFL) into the coiled-coil, Q2, which self-assembles into nanofibers, we generate Q2TFL. We demonstrate that fluorination results in a greater increase in thermostability and 19F magnetic resonance detection compared to the nonfluorinated parent, Q2. Q2TFL also exhibits linear ratiometric 19F MRS thermoresponsiveness, allowing it to act as a temperature probe. Furthermore, we explore the ability of Q2TFL to encapsulate the anti-inflammatory small molecule, curcumin (CCM), and its impact on the coiled-coil structure. Q2TFL also provides hyposignal contrast in 1H MRI, echogenic signal with high-frequency ultrasound and sensitive detection by 19F MRS in vivo illustrating fluorination of coiled-coils for supramolecular assembly and their use with 1H MRI, 19F MRS and high frequency ultrasound as multimodal theranostic agents.

Are there geographical disparities in access to liver transplantation in Atlantic Canada?

OBJECTIVE: To characterize the patient population served by Atlantic Canada's Multi-Organ Transplant Program liver transplant service over the first five years of activity in its current iteration. METHODS: Data from a prospective institutional database, supplemented by retrospective medical record review, were used to identify and characterize the cohort of patients assessed for consideration of first liver transplant between December 1, 2004 and December 1, 2009. RESULTS: In the five-year period after reactivation, the program assessed 337 patients for first liver transplant. The median age at referral for this group of 199 men (59.0%) and 138 women (41.0%) was 56.1 years (range 16.3 to 72.3 years). The leading three liver diseases indicating liver replacement were alcohol-related end-stage liver disease (20.5%), hepatocellular cancer (16.6%) and hepatitis C-related end-stage liver disease (14.0%). When evaluated according to provincial population-standardized incidence, significant differences in the incidence of liver transplant assessment among the four Atlantic Canadian provinces were found (per 100,000 inhabitants: Nova Scotia 19.8, New Brunswick 13.0, Newfoundland and Labrador 9.1 and Prince Edward Island 11.0; Fisher's exact P<0.001). Of the 337 individuals who began the assessment process, 153 (45.4%) were assigned to the wait list. The probability of an individual being assigned to the wait list was not found to differ according to province of residence (Nova Scotia 45.3%, New Brunswick 40.0%, Newfoundland and Labrador 58.7% and Prince Edward Island 40.0%; Fisher's exact P=0.206). CONCLUSIONS: The analysis suggests that there are geographical disparities in access to liver transplantation in Atlantic Canada. These disparities appear to be related to factors that precede the transplant assessment process.

Rural residency and the risk of mortality while waiting for liver transplantation.

Our liver transplant program services a region that has a prominent rural demographic. The influence of rural residency on liver transplant wait-list mortality has not been previously studied. We hypothesized that residence in a rural setting, by imposing challenges to medical care access, might be associated with inferior survival while waiting for liver transplantation. To test this hypothesis, multivariable time-to-event analysis was performed using Cox proportional hazards and competing risks regression on data from a consecutive five-yr cohort of 159 primary liver transplant candidates, to derive covariate adjusted effect measures for the association between residence in a rural area and wait-list mortality. For the primary analysis, a standardized, census-based, definition was used to assign rural residency status. The Kaplan-Meier estimated 90-d and one-yr wait-list mortality for the cohort was 7.6% (95% CI: 4.2-13.8) and 15.6% (95% CI: 9.4-25.2). The covariate adjusted hazard ratio for the relationship between Rural and Small Town residency status and wait-list mortality was 0.497 (95% CI: 0.171-1.438, p = 0.197) for the Cox regression model and 0.628 (95% CI: 0.224-1.757, p = 0.376) for the competing risk regression model. As defined in this study, candidate residence in a rural setting was not found to be associated with inferior survival while awaiting liver transplantation.

The Model for End-stage Liver Disease accurately predicts 90-day liver transplant wait-list mortality in Atlantic Canada.

OBJECTIVE: To determine the generalizability of the predictions for 90-day mortality generated by Model for End-stage Liver Disease (MELD) and the serum sodium augmented MELD (MELDNa) to Atlantic Canadian adults with end-stage liver disease awaiting liver transplantation (LT). METHODS: The predictive accuracy of the MELD and the MELDNa was evaluated by measurement of the discrimination and calibration of the respective models' estimates for the occurrence of 90-day mortality in a consecutive cohort of LT candidates accrued over a five-year period. Accuracy of discrimination was measured by the area under the ROC curves. Calibration accuracy was evaluated by comparing the observed and model-estimated incidences of 90-day wait-list failure for the total cohort and within quantiles of risk. RESULTS: The area under the ROC curve for the MELD was 0.887 (95% CI 0.705 to 0.978) - consistent with very good accuracy of discrimination. The area under the ROC curve for the MELDNa was 0.848 (95% CI 0.681 to 0.965). The observed incidence of 90-day wait-list mortality in the validation cohort was 7.9%, which was not significantly different from the MELD estimate of 6.6% (95% CI 4.9% to 8.4%; P=0.177) or the MELDNa estimate of 5.8% (95% CI 3.5% to 8.0%; P=0.065). Global goodness-of-fit testing found no evidence of significant lack of fit for either model (Hosmer-Lemeshow c2 [df=3] for MELD 2.941, P=0.401; for MELDNa 2.895, P=0.414). CONCLUSION: Both the MELD and the MELDNa accurately predicted the occurrence of 90-day wait-list mortality in the study cohort and, therefore, are generalizable to Atlantic Canadians with end-stage liver disease awaiting LT.