The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Advanced biliary tract cancer: clinical outcomes with ABC-02 regimen and analysis of prognostic factors in a tertiary care center in the United States

BackgroundGemcitabine plus cisplatin (GC) is currently the standard regimen for advanced biliary tract cancers (BTC) based on the outcomes in ABC-02 trial. Multiple factors can affect outcomes in these patients. This retrospective review evaluates the University of Cincinnati experience with GC in advanced intrahepatic (IHC)/extrahepatic cholangiocarcinoma (EHC) and gall bladder carcinoma (GBC).MethodsIn this study approved by University of Cincinnati IRB, retrospective analysis of advanced BTC patients seen between 01/2008 and 01/2015 was done. Kaplan Meyer method was used to calculate progression free survival (PFS), and overall survival (OS). Cox model was used to test the association between baseline variables and OS/PFS, adjusting for gender and age at diagnosis. Patients were identified using ICD code for BT tumors, 26 patients met inclusion criteria: histologically proven advanced BTC that received GC as their initial chemotherapy. GC was given as per ABC-02 protocol with appropriate modifications until disease progression or unacceptable toxicities.ResultsMedian age at diagnosis was 62 years (range, 31-81 years). Eighteen (69%) were IHC, 5 EHC, 3 GBC, 61% male, 73% whites. Performance status (PS): 0-1: 69%, PS 2: 31%. Baseline CA19-9 data was available for 21 patients, (range 1 to 69,543), and abnormal CA19-9 was seen in 14 patients (54%). PFS was 4.5 months (95% CI: 3.1-8.9 months) and OS was 10.5 months (95% CI: 7.9-18.8 months). OS at 6 and 12 months was 69% (18/26) and 42% (11/26). Thirty-eight percent (10/26) received 2nd line chemotherapy, of these 9/10 received 5FU based chemotherapy. Eleven percent (3/26) received 3rd line chemotherapy. Increase in baseline carcinoembryonic antigen (CEA), alanine aminotransferase, alkaline phosphatase (ALP) and total bilirubin was associated with increased risk of death while increase in baseline CEA and ALP was associated with increased risk of progression (P valve <0.05). In the group of patients who had all three major risk factors (PS ≥2, CEA >3, and stage IVb), the median survival was 2.9 months (95% CI: 2.6-9.3 months), which was significantly worse compared to rest of the population [median 18 months (95% CI: 5.4-19.5 months), P<0.01].ConclusionsOur data supports the use of GC as a first line regimen for advance BTC in a non-clinical trial setting. Results are comparable to those reported in ABC-02 trial, despite inclusion of PS 2 patients whom constituted 31% of our population. In the patient population studied, baseline CEA and liver function test appeared able to predict response to GC in advanced BTC. Patients with all three high risk factors (PS ≥2, CEA >3, and stage IVb) did poorly and may need careful selection prior to initiating chemotherapy

Biophysical Elucidation of Amyloid Fibrillation Inhibition and Prevention of Secondary Nucleation by Cholic Acid: An Unexplored Function of Cholic Acid

Protein misfolding and its deviant self-assembly to converge into amyloid fibrils is associated with the perturbation of cellular functions and thus with debilitating neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, etc. A great deal of research has already been carried out to discover a potential amyloid inhibitor that can slow down, prevent, or remodel toxic amyloids. In the present study with the help of a combination of biophysical, imaging, and computational techniques, we investigated the mechanism of interaction of cholic acid (CA), a primary bile acid, with human insulin and Aβ-42 and found CA to be effective in inhibiting amyloid formation. From ThT data, we inferred that CA encumbers amyloid fibrillation up to 90% chiefly by targeting elongation of fibrils with an insignificant effect on lag time, while in the case of Aβ-42, CA stabilizes the peptide in its native state preventing its fibrillation. Strikingly upon adding initially at the secondary nucleation stage, CA also detained the progression/growth of insulin fibrils. CA is unable to prevent the conformational changes completely during fibrillation but tends to resist and maintain an α helical structure up to a significant extent at a primary nucleation stage while reducing the β sheet rich content at the secondary nucleation stage. Moreover, CA treated samples exhibited reduced cytotoxicity and different morphology. Furthermore, the results obtained after molecular docking indicated that CA is interacting with insulin via hydrogen bonds. For future research, this study can be considered as preliminary research for the development of CA, a metabolite of our body, as a potential therapeutic agent against Alzheimer’s disease without even stimulating the immunological responses

Stabilizing proteins to prevent conformational changes required for amyloid fibril formation

Amyloid fibrillation is associated with several human maladies, such as Alzheimer’s, Parkinson’s, Huntington’s diseases, prions, amyotrophic lateral sclerosis, and type 2 diabetes diseases. Gaining insights into the mechanism of amyloid fibril formation and exploring novel approaches to fibrillation inhibition are crucial for preventing amyloid diseases. Here, we hypothesized that ligands capable of stabilizing the native state of query proteins might prevent protein unfolding, which, in turn, may reduce the propensity of proteins to form amyloid fibrils. We demonstrated the efficient inhibition of amyloid formation of the human serum albumin (HSA) (up to 85%) and human insulin (up to 80%) by a nonsteroidal anti-inflammatory drug, ibuprofen (IBFN). IBFN significantly increases the conformational stability of both HSA and insulin, as confirmed by differential scanning calorimetry (DSC). Moreover, increasing concentration of IBFN boosts its amyloid inhibitory propensity in a linear fashion by influencing the nucleation phase as assayed by thioflavin T fluorescence, transmission electron microscopy, and dynamic light scattering. Furthermore, circular dichroism analysis supported the DSC results, showing that IBFN binds to the native state of proteins and almost completely prevents their tendency to lose secondary and tertiary structures. Cell toxicity assay confirms that species formed in the presence of IBFN are less toxic to neuronal cells (SH-SY5Y). These results demonstrate the feasibility of using a small molecule to stabilize the native state of proteins, thereby preventing the amyloidogenic conformational changes, which appear to be the common link in several human amyloid diseases

Stabilizing Proteins to Prevent Conformational Changes Required for Amyloid Fibril Formation

Amyloid fibrillation is associated with several human maladies, such as Alzheimer’s, Parkinson’s, Huntington’s diseases, prions, amyotrophic lateral sclerosis, and type 2 diabetes diseases. Gaining insights into the mechanism of amyloid fibril formation and exploring novel approaches to fibrillation inhibition are crucial for preventing amyloid diseases. Here, we hypothesized that ligands capable of stabilizing the native state of query proteins might prevent protein unfolding, which, in turn, may reduce the propensity of proteins to form amyloid fibrils. We demonstrated the efficient inhibition of amyloid formation of the human serum albumin (HSA) (up to 85%) and human insulin (up to 80%) by a nonsteroidal anti-inflammatory drug, ibuprofen (IBFN). IBFN significantly increases the conformational stability of both HSA and insulin, as confirmed by differential scanning calorimetry (DSC). Moreover, increasing concentration of IBFN boosts its amyloid inhibitory propensity in a linear fashion by influencing the nucleation phase as assayed by thioflavin T fluorescence, transmission electron microscopy, and dynamic light scattering. Furthermore, circular dichroism analysis supported the DSC results, showing that IBFN binds to the native state of proteins and almost completely prevents their tendency to lose secondary and tertiary structures. Cell toxicity assay confirms that species formed in the presence of IBFN are less toxic to neuronal cells (SH-SY5Y). These results demonstrate the feasibility of using a small molecule to stabilize the native state of proteins, thereby preventing the amyloidogenic conformational changes, which appear to be the common link in several human amyloid diseases