The Role of the Uncinate Margin in Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma: A Survival Analysis

Introduction: Positive margins during pancreaticoduodenectomy for pancreatic cancer portend worse survival, but additional resection of the uncinate margin is typically unfeasible without major vascular reconstruction. The survival benefit of resecting additional neck or bile duct margins in the face of a positive uncinate is also unknown. We examined the impact of re-resection of these margins on survival. Methods: Patients with pancreatic adenocarcinoma who underwent pancreaticoduodenectomy from 2006-2015. Pancreatic neck, bile duct, uncinate, and duodenal frozen section margins were assessed before and after resection of positive margins. Kaplan-Meier survival curves were compared with log-rank tests. Multivariable Cox regression was used to assess the effect of margin status on overall survival. Results: Among 508 patients identified, 388 (76.4%) underwent a pylorus-preserving procedure, 435 (85.6%) had T3 tumors, and 379 (74.6%) had nodal involvement. There were 21 instances where an uncinate margin was concurrently positive with a neck or bile duct margin; this additional neck or bile duct margin was resected in 13 cases (61.9%). Resection of additional margins when the uncinate was concurrently positive was not associated with improved survival (p=0.36). Median survival with and without positive uncinate margins was 13.8 vs. 19.7 months (p=0.04). A positive uncinate margin was associated with decreased survival independent of other margins and cancer stage (HR 1.28 [95% CI 1.00-1.65]). Conclusion: In patients with pancreatic adenocarcinoma, positive uncinate margins are associated with decreased overall survival; resection of additional margins at the neck and bile duct in those with a positive uncinate margin is not warranted

3D Printing of Bone Spurs Before Surgical Removal

Project Background: In the US alone, total knee arthroplasty is the most common performed orthopedic surgery, with over 700,000 cases per year.1 Overall, 21-25% underwent revision due to instability.2 The stability of a TKA depends largely on soft tissue balance for proper alignment in flexion and extension. Soft tissue balancing in TKA depends on posterior femoral condylar osteophytes, which prevent full extension of the knee and increase tension posteriorly. Pre-operative soft tissue visualization is difficult and this leaves an increased chance for implant failure and revision surgery. Having a 3D model of the bone spur before and during the surgery may decrease risk of complication and enhance soft tissue modification for proper knee balancing post TKA. Proposed Methods: We will 3D print a knee via MRI or CT that has been de-identified and provided by our mentor. The orthopedic surgeon will use this print out before or during surgery to address any concerns they have during the surgery in terms of proper balancing of the soft tissue of the knee. After approximately 10 uses within the OR, we will interview the surgeons and patients for their feedback. Patients undergoing total knee arthroplasty using the 3D printed knee will be matched with historic records of those who had undergone TKA. Rates of revision, patient satisfaction, and OR time will be compared across groups using chi-square and t-tests where appropriate. Results: We anticipate reduced OR time, increased patient satisfaction and decreased rates of revision. Conclusions: Our study demonstrates an initial use for 3D models as an aid or guide for total knee arthroplasty. Using a 3D model for TKA helps the surgeon visualize osteophytes and reduces the need for revision surgery. A larger study will need to be conducted in order to test the feasibility and practicality of 3D printing for surgery

3D Printing of Knee Models to Decrease OR Time and Reduce Revisional Surgery in Total Knee Arthroplasty (TKA)

Project Background: Osteophytes are a common problem, affecting 2% of the United States population. For many elderly people, these osteophytes will cause them to seek medical attention. Due to the 2-D nature of MRIs and CT scans, it can be difficult to gain a complete understanding of the complicated soft tissue structures surrounding the joint when performing a Total Knee Arthroplasty(TKA). Without proper removal of osteophytes and correct soft tissue balancing, there is an increased rate of revisional surgery. By utilizing a 3-D model preoperatively and within the OR, surgeons can visualize various aspects of the knee to determine what may be contributing to a soft tissue imbalance. Proposed Methods: We plan to conduct a prospective cohort study at the Rothman Institute. We will use CT images to create 3-D printed models of knees complicated with osteophytes. The surgeon will have the model to reference both preoperatively and during the surgery. We will measure the effectiveness of model by collecting data on the total procedural time, the rate of revisional surgery within the next year, and through feedback from the surgeons. Results: Although we do not currently have any results, we anticipate approval for our project shortly. We hope to have data collected within the next few months supporting our hypothesis that 3-D models will decrease both OR time and revisional surgeries. Conclusions: While the literature shows that these 3-D models may help with OR time, we have been unable to verify this yet. Additionally, revisional surgery can happen months later, so this data may be more difficult to collect in our time frame. After the pilot study has been completed, if we have promising results we hope to expand the project to include other types of surgeries affected by soft tissue balancing

3D Printing of Bone Spurs Before Surgical Removal During Total Knee Arthroplasty

Background: In the United States, total knee arthroplasty (TKA) is the most common performed orthopedic surgery, with over 700,000 cases per year. Overall, 21-25% underwent revision due to instability. Incorrect soft tissue balancing during the procedure can lead to improper alignment, flexion, and extension. Visualization of osteophytes in a 3D manner prior to removal is difficult and poses significant risks for improper balancing on TKA. The purpose of the study is to determine whether the utilization of 3D osteophyte models is beneficial to Orthopaedic surgeons in the course of care, specifically with regard to improving outcomes, decreasing complication rates, and decreasing OR time. Methods: A pilot study will be performed pending the approval of the IRB and research proposal by the Rothman Institute. Deidentified 3D models for upcoming procedures will be printed utilizing patient CT scans prior to date of operation. The models will be provided to Orthopaedic Surgeons at the Rothman Institute prior to the procedure. Data from at least 10 cases will be collected post-operatively, in which operating surgeons will be interviewed assess beliefs on utility of models, OR times, and rates of revision. Results: Direct interviews with Orthopaedic surgeons and residents of the Rothman Institute demonstrate early interest and support of the utilization of 3D models in the OR. Lack of IRB prevents the utilization of models in the OR, but we anticipate decrease OR time and increased satisfaction by involved surgeons. Conclusions: Initial feedback from Orthopaedic surgeons suggest a space for the utility of 3D models in the OR. A significant limitation may be accessing CT images of patients and they are often not performed prior to operations. Next steps include IRB approval and finalizing a logistical blueprint for utilization for the models in the OR, specifically whether the models will be use preoperatively or perioperatively

Network analysis of a corpus of undeciphered Indus civilization inscriptions indicates syntactic organization

Archaeological excavations in the sites of the Indus Valley civilization (2500-1900 BCE) in Pakistan and northwestern India have unearthed a large number of artifacts with inscriptions made up of hundreds of distinct signs. To date there is no generally accepted decipherment of these sign sequences and there have been suggestions that the signs could be non-linguistic. Here we apply complex network analysis techniques to a database of available Indus inscriptions, with the aim of detecting patterns indicative of syntactic organization. Our results show the presence of patterns, e.g., recursive structures in the segmentation trees of the sequences, that suggest the existence of a grammar underlying these inscriptions.Comment: 17 pages (includes 4 page appendix containing Indus sign list), 14 figure

Bioenergetic profile of human coronary artery smooth muscle cells and effect of metabolic intervention

Bioenergetics of artery smooth muscle cells is critical in cardiovascular health and disease. An acute rise in metabolic demand causes vasodilation in systemic circulation while a chronic shift in bioenergetic profile may lead to vascular diseases. A decrease in intracellular ATP level may trigger physiological responses while dedifferentiation of contractile smooth muscle cells to a proliferative and migratory phenotype is often observed during pathological processes. Although it is now possible to dissect multiple building blocks of bioenergetic components quantitatively, detailed cellular bioenergetics of artery smooth muscle cells is still largely unknown. Thus, we profiled cellular bioenergetics of human coronary artery smooth muscle cells and effects of metabolic intervention. Mitochondria and glycolysis stress tests utilizing Seahorse technology revealed that mitochondrial oxidative phosphorylation accounted for 54.5% of ATP production at rest with the remaining 45.5% due to glycolysis. Stress tests also showed that oxidative phosphorylation and glycolysis can increase to a maximum of 3.5 fold and 1.25 fold, respectively, indicating that the former has a high reserve capacity. Analysis of bioenergetic profile indicated that aging cells have lower resting oxidative phosphorylation and reduced reserve capacity. Intracellular ATP level of a single cell was estimated to be over 1.1 mM. Application of metabolic modulators caused significant changes in mitochondria membrane potential, intracellular ATP level and ATP:ADP ratio. The detailed breakdown of cellular bioenergetics showed that proliferating human coronary artery smooth muscle cells rely more or less equally on oxidative phosphorylation and glycolysis at rest. These cells have high respiratory reserve capacity and low glycolysis reserve capacity. Metabolic intervention influences both intracellular ATP concentration and ATP:ADP ratio, where subtler changes may be detected by the latter

B-Chromosome Ribosomal DNA Is Functional in the Grasshopper Eyprepocnemis plorans

B-chromosomes are frequently argued to be genetically inert elements, but activity for some particular genes has been reported, especially for ribosomal RNA (rRNA) genes whose expression can easily be detected at the cytological level by the visualization of their phenotypic expression, i.e., the nucleolus. The B24 chromosome in the grasshopper Eyprepocnemis plorans frequently shows a nucleolus attached to it during meiotic prophase I. Here we show the presence of rRNA transcripts that unequivocally came from the B24 chromosome. To detect these transcripts, we designed primers specifically anchoring at the ITS-2 region, so that the reverse primer was complementary to the B chromosome DNA sequence including a differential adenine insertion being absent in the ITS2 of A chromosomes. PCR analysis carried out on genomic DNA showed amplification in B-carrying males but not in B-lacking ones. PCR analyses performed on complementary DNA showed amplification in about half of B-carrying males. Joint cytological and molecular analysis performed on 34 B-carrying males showed a close correspondence between the presence of B-specific transcripts and of nucleoli attached to the B chromosome. In addition, the molecular analysis revealed activity of the B chromosome rDNA in 10 out of the 13 B-carrying females analysed. Our results suggest that the nucleoli attached to B chromosomes are actively formed by expression of the rDNA carried by them, and not by recruitment of nucleolar materials formed in A chromosome nucleolar organizing regions. Therefore, B-chromosome rDNA in E. plorans is functional since it is actively transcribed to form the nucleolus attached to the B chromosome. This demonstrates that some heterochromatic B chromosomes can harbour functional genes.This study was supported by a grant from the Spanish Ministerio de Ciencia e Innovación (CGL2009-11917), and was partially performed by FEDER funds. M. Ruiz-Estévez was supported by a fellowship (FPU) from the Spanish Ministerio de Ciencia e Innovación

Attrition and bias in the MRC cognitive function and ageing study: an epidemiological investigation

BACKGROUND: Any hypothesis in longitudinal studies may be affected by attrition and poor response rates. The MRC Cognitive Function and Ageing study (MRC CFAS) is a population based longitudinal study in five centres with identical methodology in England and Wales each recruiting approximately 2,500 individuals. This paper aims to identify potential biases in the two-year follow-up interviews. METHODS: Initial non-response: Those not in the baseline interviews were compared in terms of mortality to those who were in the baseline interviews at the time of the second wave interviews (1993–1996). Longitudinal attrition: Logistic regression analysis was used to examine baseline differences between individuals who took part in the two-year longitudinal wave compared with those who did not. RESULTS: Initial non-response: Individuals who moved away after sampling but before baseline interview were 1.8 times more likely to die by two years (95% Confidence interval(CI) 1.3–2.4) compared to respondents, after adjusting for age. The refusers had a slightly higher, but similar mortality pattern to responders (Odds ratio 1.2, 95%CI 1.1–1.4). Longitudinal attrition: Predictors for drop out due to death were being older, male, having impaired activities of daily living, poor self-perceived health, poor cognitive ability and smoking. Similarly individuals who refused were more likely to have poor cognitive ability, but had less years of full-time education and were more often living in their own home though less likely to be living alone. There was a higher refusal rate in the rural centres. Individuals who moved away or were uncontactable were more likely to be single, smokers, demented or depressed and were less likely to have moved if in warden-controlled accommodation at baseline. CONCLUSIONS: Longitudinal estimation of factors mentioned above could be biased, particularly cognitive ability and estimates of movements from own home to residential homes. However, these differences could also affect other investigations, particularly the estimates of incidence and longitudinal effects of health and psychiatric diseases, where the factors shown here to be associated with attrition are risk factors for the diseases. All longitudinal studies should investigate attrition and this may help with aspects of design and with the analysis of specific hypotheses

Evolutionary diversity and developmental regulation of X-chromosome inactivation

X-chromosome inactivation (XCI) results in the transcriptional silencing of one X-chromosome in females to attain gene dosage parity between XX female and XY male mammals. Mammals appear to have developed rather diverse strategies to initiate XCI in early development. In placental mammals XCI depends on the regulatory noncoding RNA X-inactive specific transcript (Xist), which is absent in marsupials and monotremes. Surprisingly, even placental mammals show differences in the initiation of XCI in terms of Xist regulation and the timing to acquire dosage compensation. Despite this, all placental mammals achieve chromosome-wide gene silencing at some point in development, and this is maintained by epigenetic marks such as chromatin modifications and DNA methylation. In this review, we will summarise recent findings concerning the events that occur downstream of Xist RNA coating of the inactive X-chromosome (Xi) to ensure its heterochromatinization and the maintenance of the inactive state in the mouse and highlight similarities and differences between mammals

Elevated 17β-Estradiol Protects Females from Influenza A Virus Pathogenesis by Suppressing Inflammatory Responses

Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load