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BACKGROUND This study aims to compare the LACE + readmission index to a novel hepatopancreatobiliary readmission risk score (HRRS) in predicting post-operative hepatopancreatobiliary (HPB) cancer patient readmissions. METHODS A retrospective review of 104 postoperative HPB cancer patients from January 2017 to July of 2019 was performed. Univariable and multivariable analyses were utilized. RESULTS The LACE + index did not predict 30-day (OR 1.01, 95% CI, 0.97-1.05, p = 0.81, c-statistic = 0.52) or 90-day (OR 1.02, 95% CI, 0.98-1.05, p = 0.43) readmission. Patients readmitted within 30 days had significantly increased HRRS scores compared to those who were not (0 vs 34, p

Background The robotic approach to pancreaticoduodenectomy is thought by many to be associated with increased financial burden for hospitals. We undertook this study to analyze and compare the cost of “open” pancreaticoduodenectomy with that associated with the application of the robotic surgical system to pancreaticoduodenectomy in our hepatobiliary program. Study Design With IRB approval, all patients undergoing pancreaticoduodenectomy at our institution, from August 2012 to November 2019, were prospectively followed. Cost, including total, variable, fixed-direct, fixed-indirect, and profitability for robotic and “open” pancreaticoduodenectomy were analyzed and compared. Data are presented as median (mean ± SD). Results There were 386 patients who underwent pancreaticoduodenectomy; 205 patients underwent robotic pancreaticoduodenectomy and 181 underwent “open” pancreaticoduodenectomy. Costs are presented as mean ± SD. Overall, the cost of care for robotic pancreaticoduodenectomy was $31,389 ($36,611 ± $20,545.40) vs $23,132 ($31,323 ± $28,885.50) for “open” pancreaticoduodenectomy (p = 0.04); total variable cost was $20,355 ($22,747 ± $11,127.60) vs $11,680 ($16,032 ± $14,817.20) (p = 0.01), total fixed direct cost was $1,999 ($2,330 ± $1,363.10) vs $2,073 ($2,983 ± $3,209.00) (p = 0.01), and total indirect cost was $7,217 ($9,354 ± $6,802.40) vs $6,802 ($9,505 ± $9,307.20) (p = 0.86), for robotic vs “open” pancreaticoduodenectomy, respectively. Since 2016, profitability was achieved in 29% of patients undergoing robotic pancreaticoduodenectomy. Conclusions Robotic pancreaticoduodenectomy had lower estimated blood loss and shorter length of stay. Cost of care for robotic pancreaticoduodenectomy was greater across all categories, except for total indirect cost, than “open” pancreaticoduodenectomy. For our institution, profitability was accomplished in less than one-third of patients undergoing robotic pancreaticoduodenectomy. The role of the robotic platform for pancreaticoduodenectomy needs to be discussed among all stakeholders.

Objectives: Peritonsillar abscess (PTA) is the most common deep neck space infection and a frequent cause for otolaryngology consultation. Patients often undergo computed tomography (CT) scan for confirmation in addition to physical examination. Our aims were to determine whether patients unnecessarily undergo CT scans in the emergency department (ED) when presenting with sore throat and identify physical examination characteristics that predict PTA. Methods: The electronic medical records of all patients (>18 years) presenting to an ED between June 2014 and June 2015 with a primary diagnosis of acute pharyngitis, acute tonsillitis, or PTA were reviewed for presenting symptoms and diagnostic imaging use. Results: Four hundred eight patients met inclusion criteria; 21 were diagnosed with PTA, including 13 based on history and physical alone. A total of 21 CT scans were ordered, 11 (52.3%) of which did not demonstrate abscess. Soft palatal fullness, uvular deviation, drooling, and muffled voice were all significantly associated with increased CT usage (all P values Conclusions: Patients with severe symptoms of PTA, including uvular deviation, drooling, and soft palatal fullness, were most likely to undergo CT imaging. Given the high likelihood of PTA, patients presenting with these symptoms could forego CT imaging, reducing exposure to ionizing radiation.

This study aimed to evaluate the impact of expert breast pathology consultation on operative management and predictive factors of discordant diagnosis.A retrospective review of patients referred with breast biopsies and subsequent expert pathology consultation from 2014 to 2019. Discordance in diagnosis and documented changes in therapy were recorded. Univariate and multivariable analyses were performed.Ninety-one (91/263, 35%) patients had discordant findings after expert pathology consultation. No benign or in situ diagnoses were upgraded to invasive cancer. Tumor subtype changed in 10% while change in invasive cancer grade was most common (45%). Clinical management was altered in 3/263 (1%) with one change in surgical plan. Benign lesions without atypia (7.5% vs. 1.1%, p = 0.03) and excisional biopsies (8.7% vs. 2.2%, p = 0.04) were more often associated with non-discordant pathology. No independent predictors of discordance were observed.Discordant diagnoses after expert pathology consultation are common despite few changes in operative management. Excisional biopsy and benign lesions without atypia may be associated with less pathologic discordance after expert review.

In this thesis we will study recent examples of exotic, topological, and many body localized quantum phase transitions. In Chapter 2 we study the quantum phase transition between the Z_2 spin liquid and valence bond solid (VBS) orders on a triangular lattice. We find a possible nematic Z_2 spin liquid intermediate phase and predict a continuous 3d XY* transition to the neighboring columnar and resonating-plaquette VBS phases. In Chapter 3 we demonstrate that an extended Kane-Mele Hubbard model on a bilayer honeycomb lattice has two novel quantum phase transitions. The first is a quantum phase transition between the weakly interacting gapless Dirac fermion phase and a strongly interacting fully gapped and symmetric trivial phase, which cannot be described by the standard Gross-Neveu model. The second is a quantum critical point between a quantum spin Hall insulator with spin S^z conservation and the previously mentioned strongly interacting fully gapped phase. We argue that the first quantum phase transition is related to the Z_16 classification of the topological superconductor ^3He-B phase with interactions, while the second quantum phase transition is a topological phase transition described by a bosonic O(4) nonlinear sigma model field theory with a Theta-term. In Chapter 4 we propose that if the highest and lowest energy eigenstates of a Hamiltonian belong to different SPT phases, then this Hamiltonian can't be fully many body localized. In Chapter 5 we study the disordered XYZ spin chain and its marginally many body localized critical lines, which we find to be characterized by an effective central charge c'=ln2 and continuously varying critical exponents.

High-pressure-torsion (HPT) processing introduces a large density of dislocations that form sub-grain boundaries within the refined nano-scale structure, leading to changes in precipitate morphology compared to hot-rolled maraging steels. The impact of such nanostructuring on the deformation and fracture micro-mechanisms is being reported for the first time using in situ characterization techniques along with transmission electron microscopy and atom probe tomography analysis, in this study. Digital image correlation has been used to quantify the full field strain maps in regions of severe strain localization as well as to determine the fracture toughness through critical crack tip opening displacements. It is seen that the phenomenon of planar slip leads to strain softening under uniaxial deformation and to crack branching under a triaxial stress state in hot rolled maraging steels. On the other hand, nano-structuring after HPT processing creates a large number of high angle grain boundaries as dislocation barriers, leading to strain hardening under uniaxial tension and nearly straight crack path with catastrophic fracture under triaxial stress state. Upon overaging, the hot-rolled sample shows signature of transformation induced plasticity under uniaxial tension, which is absent in the HPT processed overaged samples, owing to the finer reverted austenite grains containing higher Ni concentration in the latter. In the overaged fracture test samples of both the hot-rolled and HPT conditions, crack tips show a signature of strain induced transformation of the reverted austenite to martensite, due to the accompanying severe strain gradients. This leads to a higher fracture toughness even while achieving high strengths in the overaged conditions of the nanocrystalline HPT overaged samples. The results presented here will aid in design of suitable heat treatment or microstructure engineering of interface dominated nano-scale maraging steels with improved damage tolerance.

Background and objectives The purpose of this study is to report our early experience and outcomes, the first in North America, of Extrahepatic Cholangiocarcinoma (EHC) resection with Roux-en Y Hepaticojejunostomy reconstruction via the robotic approach. Methods With Institutional Review Board approval, 15 patients who underwent robotic resection of EHC were studied. Results Patients were 74 (73 ± 8.9) years of age. There were 9 men and 6 women. Average body mass index was 24 (27 ± 6.3) kg·m-2 . Mean & Median ASA class was 3. Median Tumor size was 2 (2 ± 1.3) cm. There were no intraoperative complications. Operative duration was 453 (443 ± 85.0) minutes and the estimated blood loss was 150 (182 ± 138.4) ml. No patient required admission to the intensive care unit. Hospital length of stay was 4 (6 ± 3.2) days. There was one patient with Clavien-Dindo Class 3 or greater complication. No mortality was seen in this series. Discussion Robotic resection of EHC is safe, feasible, and reproducible with excellent clinical outcomes. Consequently, the robotic technique should be considered in some patients requiring EHC resection.

p53 is a tumor cell suppressor protein that is activated upon cellular stress to induce DNA repair, senescence, or apoptosis. Its importance can be seen in that 50% of human cancers have a mutation in the TP53 gene, and in the greatly increased probability for cancer in Li-Fraumeni syndrome patients, in which germline mutations in the TP53 gene increase the probability of homozygous mutations. The vast majority of p53 mutations found in cancer are located in a few key residues of the DNA-binding domain (DBD) of the protein, referred to as "hotspot mutations." The goal of this thesis is to elucidate the structural and biophysical properties of four p53 hotspot mutants in order to better understand their inactivation mechanism. I have shown these common mutants have a severely reduced ability to bind DNA, while retaining the majority of the three dimensional structure. Additionally, I show that these mutants as well as the wild-type p53 DBD form amyloid fibers at high concentrations

In a manufacturer-independent laboratory validation study, the Xpert MTB/XDR® assay demonstrated equivalent limit of detection to Xpert MTB/RIF®, detected 100% of tested resistance mutations and showed some utility for resistance detection in strain mixtures. The Xpert MTB/XDR assay is a reliable, sensitive assay for tuberculosis and expanded resistance detection.

Background With a less than 5% overall survival rate, esophageal adenocarcinoma (EAC) is one of the leading causes of death in the United States. Epithelial cell adhesion molecule (EpCAM) is a cancer stem cell (CSC) marker that is expressed in various epithelial carcinomas, including EAC. Accumulating evidence indicates that CSC subpopulations can initiate cancer development and, in addition, drive metastasis, recurrence and drug resistance. It has also been reported that EpCAM up-regulation in EAC may lead to an aggressive behavior and, thus, an adverse clinical outcome. Here, we aimed to determine whether treatment with standard chemotherapeutic agents may induce EpCAM expression and, concomitantly, increases in malignant potential and drug resistance in EAC. Methods EpCAM expression was assessed in 20 primary human EAC/adjacent normal tissues, as well as in a human EAC-derived cell line (OE-19), in a pre-malignant Barrett’s Esophagus cell line (Bar-T) and in a benign esophageal cell line (HET 1-A), using immunohistochemistry, Western blotting and qRT-PCR, respectively. Drug-induced resistance was investigated in OE-19-derived spheres treated with (a combination of) adriamycin, cisplatin and 5-fluorouracil (ACF) using survival, adhesion and flow cytometric assays, respectively, and compared to drug resistance induced by standard chemotherapeutic agents (CTA). Finally, ACF treatment-surviving cells were evaluated for their tumor forming capacities both in vitro and in vivo using spheroid formation and xenograft assays, respectively. Results High EpCAM expression was observed in esophageal cancer tissues and esophageal cancer-derived cell lines, but not in adjacent benign esophageal epithelia and benign esophageal cell lines (HET 1-A and Bar-T). The OE-19 cell spheres were drug resistant and EpCAM expression was significantly induced in the OE-19 cell spheres compared to the non-sphere OE-19 cells. When OE-19 cell spheres were challenged with ACF, the EpCAM mRNA and protein levels were further up-regulated up to 48 h, whereas a decreased EpCAM expression was observed at 72 h. EpCAM down-regulation by RNA interference increased the ACF efficacy to kill OE-19 cells. Increased EpCAM expression coincided with the CSC marker CD90 and was associated with an aggressive growth pattern of OE-19 cell spheres in vivo. Conclusions From our data we conclude that an ACF-induced increase in EpCAM expression reflects the selection of a CSC subpopulation that underlies tumor development and drug resistance in EAC.

Maraging steels are precipitation strengthened martensitic steels with an unusual combination of strength and ductility. High Pressure Torsion (HPT) has been used in this study to produce maraging steel 250 grade (AMS 6512) with finer laths and higher dislocation density, both of which act as nucleation sites for precipitation, and reverted austenite formation. This study focusses on the effect of such a processing on the evolution of the microstructure, including kinetics of precipitation, recrystallisation and austenite reversion as well as the stability of the precipitates thus formed. It was found that the aging kinetics accelerated substantially in the HPT processed samples, by achieving peak aging conditions at considerably shorter temperature/time durations and also a peak hardness higher than the as-received sample by 41%. Detailed microstructural characterisation revealed a change in the precipitate morphology from spherical to plate like form in the overaged conditions. The impact of this on mechanical response of these steels was quantified using tensile tests. A 70% increase in ultimate tensile strength was achieved in HPT processed samples after peak aging. Changes in strength and ductility were correlated to the changes in the microstructure and their impending contributions to different strengthening mechanisms at play to enable better design of maraging steels.

Background Oxidative stress secondary to bile-acid exposure has been associated with metaplastic degeneration of normal esophageal mucosa into Barrett's esophagus (BE) cells and eventually esophageal adenocarcinoma. We previously reported that the macromolecular response of BE cells to this stress was largely regulated by the expression of manganese-dependent mitochondrial superoxide dismutase (MnSOD). As the mitochondrion plays a vital role in MnSOD activation, this study sought to determine the location and activity of MnSOD within BE cells after exposure to oxidative stress. Methods A human BE cell line, BAR-T cell, was exposed 0.4 mM concentrations of taurocholic acid (Tau) or a 0.4 mM 1:1 mixture of bile salts for 4 h. Cell viability was performed with 3-(4, 5-dimthyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays. Proteins were extracted and separated into mitochondrial, nuclear, and cytoplasmic fractions followed by analysis by a western blot and enzymatic activities. Results BAR-T cell showed resistance to the bile-salt insults. Expression of MnSOD was significantly increased in the cells exposed to a mixture of bile acids and Tau versus control. Mitochondria MnSOD is abundant and highly active. Nuclear fraction displayed presence of both MnSOD and Cu/zinc superoxide dismutase secondary to bile-acid exposure; however, the MnSOD was inactive in nuclear fraction. Conclusions This is the first study to specifically evaluate cellular fraction MnSOD expression, increased in BE cells in response to the oxidative stress of bile exposure. Mitochondrial MnSOD contributes to resistance of BAR-T cells to the bile-salt insults. Further investigation is required to determine the potential correlation between bile exposure and BE to adenocarcinoma progression via MnSOD-mediated cell signaling.

Objectives: Numerous real-time PCR assays have been described for detection of the influenza A H275Y alteration. However, the performance of these methods can be undermined by sequence variation in the regions flanking the codon of interest. This is a problem encountered more broadly in microbial diagnostics. Methods: In this study, we developed a modification of hybridization probe-based melting curve analysis, whereby primers are used to mask proximal mutations in the sequence targets of hybridization probes, so as to limit the potential for sequence variation to interfere with typing. The approach was applied to the H275Y alteration of the influenza A (H1N1) 2009 strain, as well as a Neisseria gonorrhoeae mutation associated with antimicrobial resistance. Assay performances were assessed using influenza A and N. gonorrhoeae strains characterized by DNA sequencing. Results: The modified hybridization probe-based approach proved successful in limiting the effects of proximal mutations, with the results of melting curve analyses being 100% consistent with the results of DNA sequencing for all influenza A and N. gonorrhoeae strains tested. Notably, these included influenza A and N. gonorrhoeae strains exhibiting additional mutations in hybridization probe targets. Of particular interest was that the H275Y assay correctly typed influenza A strains harbouring a T822C nucleotide substitution, previously shown to interfere with H275Y typing methods. Conclusions: Overall our modified hybridization probe-based approach provides a simple means of circumventing problems caused by sequence variation, and offers improved detection of the influenza A H275Y alteration and potentially other resistance mechanisms.

We examined 10,025 respiratory samples collected for 4 years (2001–2004) and found a 7.1% average annual incidence of human metapneumovirus. The epidemic peak of infection was late winter to spring, and genotyping showed a change in predominant viral genotype in 3 of the 4 years.

The molecular epidemiologic profile of human metapneumovirus (hMPV) infection has likely been skewed toward certain genetic subtypes because of assay-design issues, and no comprehensive studies have been conducted to date. Here, reverse-transcription polymerase chain reaction was used to screen 10,319 specimens from patients presenting to hospitals with suspected respiratory tract infections during 2001-2004. After analysis of 727 Australian hMPV strains, 640 were assigned to 1 of 4 previously described subtypes. hMPV was the most common pathogen detected, and subtype B1 was the most common lineage. Concurrent, annual circulation of all 4 hMPV subtypes in our study population was common, with a single, usually different hMPV subtype predominating in each year.

The recent description of the respiratory pathogen human metapneumovirus (hMPV) has highlighted a deficiency in current diagnostic techniques for viral agents associated with acute lower respiratory tract infections. We describe two novel approaches to the detection of viral RNA by use of reverse transcriptase PCR (RT-PCR). The PCR products were identified after capture onto a solid-phase medium by hybridization with a sequence-specific, biotinylated oligonucleotide probe. The assay was applied to the screening of 329 nasopharyngeal aspirates sampled from patients suffering from respiratory tract disease. These samples were negative for other common microbial causes of respiratory tract disease. We were able to detect hMPV sequences in 32 (9.7%) samples collected from Australian patients during 2001. To further reduce result turnaround times we designed a fluorogenic TaqMan oligoprobe and combined it with the existing primers for use on the LightCycler platform. The real-time RT-PCR proved to be highly reproducible and detected hMPV in an additional 6 out of 62 samples (9.6%) tested during the comparison of the two diagnostic approaches. We found the real-time RT-PCR to be the test of choice for future investigation of samples for hMPV due to its speed, reproducibility, specificity, and sensitivity.

Several different viruses have been proposed to play a role in breast carcinogenesis. The aim of this study was to investigate the prevalence of a subset of viruses in breast cancer tissue. We investigated the prevalence of 12 DNA viruses: EBV and CMV from the Herpesviridae family and SV40, BKV, JCV, MCV, WUV, KIV, LPV, HPyV6, HPyV7, and TSV from the Polyomaviridae family in 54 fresh frozen breast tumour specimens. Relevant clinical data and basic lifestyle data were available for all patients. The tissue samples were DNA extracted and real-time PCR assays were used for viral detection. The highest prevalence, 10% (5/54), was found for EBV. MCV, HPyV6, and HPyV7 were detected in single patient samples (2% each), while WUV, KIV, JCV, BKV, LPV, SV40, TSV and CMV were not detected in the 54 breast cancer specimens analysed here. Further investigations are needed to elucidate the potential role of viruses, and particularly EBV, in breast carcinogenesis.

The gonococcal porA pseudogene is a popular target for in-house Neisseria gonorrhoeae PCR methods. With this study we present two novel findings: the first case of an N. gonorrhoeae porA pseudogene PCR false-negative result caused by sequence variation, and in the same organism, the first description of a clinical N. gonorrhoeae strain harbouring an N. meningitidis porA sequence.