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A simple low-cost method was used to measure the thermal diffusivity of nine different types of foods: potato, sweet potato, pumpkin, taro, radish, eggplant, lemon, tomato, and onion. We cut the foods into spherical shapes, inserted thermocouple sensors into their centers, and immersed them in boiling water. Fitting the time dependence of the center temperature to a heat-conduction model yielded a value for the thermal diffusivity with good consistency between spheres of different radii. This method can be generalized to determine thermal diffusivity of a wide variety of samples.

Subcrestal placement of implants may have interproximal bone proximity issues that interfere with the submucosal contour of implant-supported zirconia restorations during delivery of the restorations. Modification of the mesial distal submucosal areas may be necessary to fully seat the restoration without impingement of the interproximal bone. Our aim was to determine if modification of submucosal cervical contour of implant supported zirconia-titanium base (Zi-Ti base) restorations resulted in a significant change in fracture strength compared with Zi-Ti base restorations without any modification near the cervical submucosal area. Implant Zi-Ti base restorations designed in the form of a maxillary premolar were made for the Straumann implant lab analog. Zirconia samples were cemented onto the Ti-base and the test group (N = 20) underwent recontouring and polishing at the junction of the Zi-Ti base cervical areas. The control group (N = 20) did not undergo any modifications. All 40 samples underwent fracture testing with an Instron machine. We assessed differences between modified and unmodified implants restorations using a 2-tailed t test for independent samples. Fracture strength values (N) ranged from 4354.68 to 6412.49 in the test group (N = 20) and from 5400.31 to 6953.22 in the control group (N = 20). The average fracture strength in the control group (6154.84 ± 320.50) was higher than in the modified group (5593.13 ± 486.51; P < .001). Modification of submucosal contour significantly decreased fracture strength. However, the average fracture strength exceeded the masticatory forces of humans.

Aims Brain-derived neurotrophic factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, tropomyosin-related kinase receptor (TrkB), are expressed in cardiomyocytes; however, the role of myocardial BDNF signalling in cardiac pathophysiology is poorly understood. Here, we investigated the role of BDNF/TrkB signalling in cardiac stress response to exercise and pathological stress. Methods and results We found that myocardial BDNF expression was increased in mice with swimming exercise but decreased in a mouse heart failure model and human failing hearts. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unravelled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signalling pathway, the pleiotropic transcription factor Yin Yang 1. Conclusion Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.

Determining cell death mechanisms occurring in patient and animal tissues is a longstanding goal that requires suitable biomarkers and accurate quantification. However, effective methods remain elusive. To develop more powerful and unbiased analytic frameworks, we developed a machine learning approach for automated cell death classification. Image sets were collected of HT-1080 fibrosarcoma cells undergoing ferroptosis or apoptosis and stained with an anti-transferrin receptor 1 (TfR1) antibody, together with nuclear and F-actin staining. Features were extracted using high-content-analysis software, and a classifier was constructed by fitting a multinomial logistic lasso regression model to the data. The prediction accuracy of the classifier within three classes (control, ferroptosis, apoptosis) was 93%. Thus, TfR1 staining, combined with nuclear and F-actin staining, can reliably detect both apoptotic and ferroptotis cells when cell features are analyzed in an unbiased manner using machine learning, providing a method for unbiased analysis of modes of cell death.

This is the first study to investigate the use of an esophageal hydrogel spacer in spine stereotactic radiosurgery. The tolerability and the dose reduction to the esophagus are predicted to reduce the incidence of high-grade toxicities, which in turn can permit dose escalation to optimize tumor control.

OBJECTIVEThe current treatment of chordomas is associated with significant morbidity, high rates of local recurrence, and the potential for metastases. Stereotactic radiosurgery (SRS) as a primary treatment could reduce the need for en bloc resection to achieve wide or marginal margins. Spinal SRS outcomes support the exploration of SRS’s role in the durable control of these conventionally radioresistant tumors. The goal of the study was to evaluate outcomes of patients with primary chordomas treated with spinal SRS alone or in combination with surgery.METHODSClinical records were reviewed for outcomes of patients with primary chordomas of the mobile spine and sacrum who underwent single-fraction SRS between 2006 and 2017. Radiographic local recurrence-free survival (LRFS), overall survival (OS), symptom response, and toxicity were assessed in relation to the extent of surgery.RESULTSIn total, 35 patients with de novo chordomas of the mobile spine (n = 17) and sacrum (n = 18) received SRS and had a median post-SRS follow-up duration of 38.8 months (range 2.0–122.9 months). The median planning target volume dose was a 24-Gy single fraction (range 18–24 Gy). Overall, 12 patients (34%) underwent definitive SRS and 23 patients (66%) underwent surgery and either neoadjuvant or postoperative adjuvant SRS. Definitive SRS was selectively used to treat both sacral (n = 7) and mobile spine (n = 5) chordomas. Surgical strategies for the mobile spine were either intralesional, gross-total resection (n = 5) or separation surgery (n = 7) and for the sacrum en bloc sacrectomy (n = 11). The 3- and 5-year LRFS rates were 86.2% and 80.5%, respectively. Among 32 patients (91%) receiving 24-Gy radiation doses, the 3- and 5-year LRFS rates were 96.3% and 89.9%, respectively. The 3- and 5-year OS rates were 90.0% and 84.3%, respectively. The symptom response rate to treatment was 88% for pain and radiculopathy. The extent or type of surgery was not associated with LRFS, OS, or symptom response rates (p > 0.05), but en bloc resection was associated with higher surgical toxicity, as measured using the Common Terminology Criteria for Adverse Events (version 5.0) classification tool, than epidural decompression and curettage/intralesional resection (p = 0.03). The long-term rate of toxicity ≥ grade 2 was 31%, including 20% grade 3 tissue necrosis, recurrent laryngeal nerve palsy, myelopathy, fracture, and secondary malignancy.CONCLUSIONSHigh-dose spinal SRS offers the chance for durable radiological control and effective symptom relief with acceptable toxicity in patients with primary chordomas as either a definitive or adjuvant therapy.

As a radioresistant lesion, chordoma has historically been considered a tumor that is not amenable to radiation therapy. However, beginning in the 1980s, evidence began to develop demonstrating that doses >70Gy could improve local control. Since that time, more advanced technologies have been developed that enable the delivery of therapeutic radiation doses while minimizing toxicities to adjacent tissues, such as the spinal cord and bowel. Evidence from series using these new focused modalities now suggests that radiation therapy in the adjuvant setting may improve local tumor control independent of surgical margin – the classic determinant of local progression-free survival. Evidence is also building that supports the use of focused photon radiation modalities in the neoadjuvant, definitive-intent, and salvage therapy roles. Here we review the new technologies and therapeutic paradigms that have enabled radiotherapy to become a routine part of the therapeutic plan for patients with chordoma of the vertebral column and sacrum.

Summary Background The risk of vertical and perinatal transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, which causes COVID-19), the most appropriate management, and the neonate's risk of developing COVID-19 during the perinatal period are unknown. Therefore, we aimed to elucidate best practices regarding infection control in mother–newborn dyads, and identify potential risk factors associated with transmission. Methods In this observational cohort study, we identified all neonates born between March 22 and May 17, 2020, at three New York Presbyterian Hospitals in New York City (NY, USA) to mothers positive for SARS-CoV-2 at delivery. Mothers could practice skin-to-skin care and breastfeed in the delivery room, but had to wear a surgical mask when near their neonate and practice proper hand hygiene before skin-to-skin contact, breastfeeding, and routine care. Unless medically required, neonates were kept in a closed Giraffe isolette in the same room as their mothers, and were held by mothers for feeding after appropriate hand hygiene, breast cleansing, and placement of a surgical mask. Neonates were tested for SARS-CoV-2 by use of real-time PCR on nasopharyngeal swabs taken at 24 h, 5–7 days, and 14 days of life, and were clinically evaluated by telemedicine at 1 month of age. We recorded demographics, neonatal, and maternal clinical presentation, as well as infection control practices in the hospital and at home. Findings Of 1481 deliveries, 116 (8%) mothers tested positive for SARS-CoV-2; 120 neonates were identified. All neonates were tested at 24 h of life and none were positive for SARS-CoV-2. 82 (68%) neonates completed follow-up at day 5–7 of life. Of the 82 neonates, 68 (83%) roomed in with the mothers. All mothers were allowed to breastfeed; at 5–7 days of life, 64 (78%) were still breastfeeding. 79 (96%) of 82 neonates had a repeat PCR at 5–7 days of life, which was negative in all; 72 (88%) neonates were also tested at 14 days of life and none were positive. None of the neonates had symptoms of COVID-19. Interpretation Our data suggest that perinatal transmission of COVID-19 is unlikely to occur if correct hygiene precautions are undertaken, and that allowing neonates to room in with their mothers and direct breastfeeding are safe procedures when paired with effective parental education of infant protective strategies. Funding None.

Back in 2008, Panofsky gave an empirical formula, T=11.5W2/3, for turkey baking time, T, in hours vs turkey weight, W, in pounds, the so-called Panofsky formula or Panofsky constant. Compared to the previously existed recipes that are based on the simple linear relationship between turkey weight and baking time, the Panofsky formula provides a more accurate estimate for the baking time. For instance, a general guideline of 13–20 min/lb was widely recommended in all previous turkey baking recipes. In this work, we conduct a comprehensive study of the turkey baking process that leads to a mathematical derivation of the Panofsky formula under some approximations. We also generalize the Panofsky formula to define a general Panofsky formula, T=1PW2/3, where P is defined as the Panofsky constant. Under spherical approximations, we then apply an accurate physical solution of the heat transfer equation and use the rigorous solution with numerical methods to study the generalized Panofsky formula and the Panofsky constant. We found that the generalized Panofsky formula can be perfectly applied to all turkey baking scenarios for baking time calculations. Furthermore, we did a careful analysis of the Panofsky constant, which equals 1.5 in the original Panofsky formula. The dependency of the new Panofsky constant on thermal properties of the turkeys and other initial parameters of baking, e.g., initial and final center temperature of the turkeys, oven temperature, thermal conductivity, specific heat, and turkey’s density, was carefully analyzed and mapped out. The Panofsky constant, P, could vary from 1.1 to 1.9 depending on these thermal parameters.

The notion of influence among people or organizations has been the core conceptual basis for making various decisions. With the increasing availability of datasets in various domains such as social networks and digital healthcare, it becomes more feasible to apply complex analytics on influence networks. In this paper, we present a comprehensive approach to managing influence networks using a set of extended graph models, called graph-based OLAP (GOLAP). The design space for GOLAP is defined by the incorporation of node types (i.e., colors), weights on relationships (i.e., edges), constraints on the number of nodes for a certain node type and constraints on the percentage of nodes for a certain node type. We begin with defining a method to find a strongest influence path (SIP) which is the strongest path from the source node to the target node. We can answer complex queries on influence networks such as “find an SIP with t nodes of color c” or “find an SIP with t% nodes of color c.” Based on the SIP model, we present a set of influence maximization methods which find a set of s seed nodes that can influence the whole graph maximally with various constraints such as having ‘t nodes of color c’. We also address methods for optimizing the time complexity of the analytics algorithms. We apply heuristic-based and graph reduction-based methods to reduce the time complexity. In addition to proving the proposed methods, we present the result of our implementation on the methods.

Of the deaths attributed to cancer, 90% are due to metastasis. Treatments that prevent or cure metastasis remain elusive. Low expression of extracellular superoxide dismutase (EcSOD or SOD3) has been associated with poor outcomes and increased metastatic potential in multiple types of cancer. Here, we characterize the antimetastatic therapeutic mechanisms of a macromolecular extracellular SOD3-mimetic polynitroxyl albumin (PNA, also known as VACNO). PNA is macromolecular human serum albumin conjugated with multiple nitroxide groups and acts as an SOD-mimetic. Here we show that PNA works as a SOD3-mimetic in a highly metastatic 4T1 mouse model of triple negative breast cancer (TNBC). In vitro, PNA dose dependently inhibited 4T1 proliferation, colony formation, and reactive oxygen species (ROS) formation. In vivo, PNA enhanced reperfusion time in the hypoxic cores of 4T1 tumors as measured by ultrasound imaging. Furthermore, PNA enhanced ultrasound signal intensity within the cores of the 4T1 tumors, indicating PNA can increase blood flow and blood volume within the hypoxic cores of tumors. Lung metastasis from 4T1 flank tumor was inhibited by PNA in the presence or absence of doxorubicin, a chemotherapy agent that produces superoxide and promotes metastasis. In a separate study, PNA increased the survival of mice with 4T1 flank tumors when used in conjunction with three standard chemotherapy drugs (paclitaxel, doxorubicin, and cyclophosphamide), as compared to treatment with chemotherapy alone. In this study, PNA-increased survival was also correlated with reduction of lung metastasis. These results support the hypothesis that PNA works through the inhibition of extracellular superoxide/ROS production leading to the conversion of 4T1 cells from a metastatic tumorigenic state to a cytostatic state. These findings support future clinical trials of PNA as an antimetastatic SOD3-mimetic drug to increase overall survival in TNBC patients.

Background and purpose Estimates of appropriate treatment rates are required for monitoring and improving access to cancer care. Optimal utilization rates for palliative radiotherapy (PRT) for patients with non-small cell lung cancer (NSCLC) remain undefined. We aim to estimate the appropriate PRT rate for the general NSCLC population. Materials and methods Ontario’s population-based cancer registry identified patients with NSCLC who died of their disease between 2006 and 2010. Multivariate analysis identified factors affecting PRT use, enabling us to define a benchmark population with unimpeded access to PRT. Proportion of cases treated in the last 2 years of life (PRT2y) was standardized to overall population characteristics. Benchmarks were compared to province-wide PRT2y rates. Results Availability of RT at the diagnosing hospital was the dominant determinant of increased PRT utilization. Patients diagnosed at hospitals with on site RT were therefore designated the benchmark population. The standardized benchmark for PRT2y was 56%, compared to the province-wide rate of 49%. The gap between actual and optimal rates varied across patient ages, treatment indications, and geographic regions. Conclusions Approximately 56% of patients who die of NSCLC in Ontario need PRT, but many are never treated.

SUMMARY Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ~4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts., Graphical Abstract, In Brief Feng et al. find that 3F3-FMA detects ferroptotic cells by screening ~4,750 antibodies generated from mice immunized with membranes from DLBCL cells undergoing ferroptosis. The antigen of 3F3-FMA is the TfR1 protein. 3F3-FMA and other anti-TfR1 antibodies can be used to detect ferroptosis in cell culture and in cancer models.

Patients on long-term bisphosphonate therapy may have an increased incidence of low-energy subtrochanteric and diaphyseal (SD) femoral fractures. However, the incidence and risk factors associated with these fractures have not been well defined.The objective of the study was to determine the incidence of and risk factors for low-energy SD fractures in the Study of Osteoporotic Fractures (SOF).Low-energy SD fractures were identified from a review of radiographic reports obtained between 1986 and 2010 in women in the SOF. Among the SD fractures, pathological, periprosthetic, and traumatic fractures were excluded. We assessed risk factors for SD fractures as well as risk factors for femoral neck (FN) and intertrochanteric (IT) hip fractures using both age-adjusted and multivariate time-dependent proportional hazards models. During this follow-up, only a small minority had ever used bisphosphonates.Forty-five women sustained low-energy subtrochanteric/diaphyseal femoral fractures over a total follow-up of 140 000 person-years. The incidence of SD fracture was 3.2 per 10 000 person-years compared with a total hip fracture incidence of 110 per 10 000 person-years. A total of about 12% of women reported bisphosphonate use at 1 or more visits. In multivariate analyses, age, total hip bone mineral density (BMD), bisphosphonate use, and history of diabetes emerged as independent risk factors for SD fractures. Risk factors for FN and IT fractures included age, BMD, and history of falls or prior fractures. Bisphosphonate use was protective against FN fractures, whereas there was an increased risk of SD fractures (hazard ratio 2.58, P = .049) with bisphosphonate use after adjustment for other risk factors for fracture.In SOF, low-energy SD fractures were rare occurrences, far outnumbered by FN and IT fractures. Typical risk factors were associated with FN and IT fractures, whereas only age, total hip BMD, and history of diabetes were independent risk factors for SD fractures. In addition, bisphosphonate use was a marginally significantly predictor although the SOF study has limited ability to assess this association.

Eosinophilic angiocentric fibrosis (EAF) is an exceedingly rare and potentially disfiguring and obstructing benign lesion involving the upper airways. We report two cases of EAF originating from the nasal cavity in a 31-year-old female and a 58-year-old male exhibiting nasal obstructive symptoms, with imaging features and histopathology characteristic of EAF. Surgical excision was performed on one patient with a disfiguring nasal mass at a tertiary referral rhinology practice within a university centre. Summarized are the relevant clinical issues to increase awareness of this disease. The slow progression and rarity of the disease has previously resulted in diagnostic difficulty. We review the limited current literature surrounding the clinical features and treatment options for this progressive and potentially morbid condition. These cases reinforce that, while rare, inflammatory and fibrosing lesions in general should still be considered as part of the differential diagnosis in patients presenting with obstructive lesions in the sinonasal tract.

Aim: Current synthetic tubular conduits are inferior to nerve autograft for the repair of segmental peripheral nerve injuries. We examined motor outcomes with the use of longitudinally aligned poly (L-lactide-co-caprolactone) nanofiber conduits for repair of nerve gap injury in a rat model. Methods: Ten-millimeter segments of sciatic nerve were resected in 44 Lewis rats. The gaps were either left unrepaired (n = 6), repaired with nerve autograft (n = 19), or repaired with conduit (n = 19). After 12 weeks, nerve conduction latency, compound muscle action potential amplitude, muscle force and muscle mass were measured. The numbers of axons and axon diameters both within the grafts and distally were determined. Results: After 12 weeks, gastrocnemius isometric tetanic force and muscle mass for the conduit group reached 85 and 82% of autograft values, respectively. Nerve conduction and compound muscle action potential were not significantly different between these two groups, although the latter approached significance. There was no recovery in the unrepaired group. Conclusion: Muscle recovery for the animals treated with this aligned nanofiber conduit approached that of autograft, suggesting the importance of internal conduit structure for nerve repair.

Context: Femoral shaft cortical thickening has been mentioned in reports of atypical subtrochanteric and diaphyseal (S/D) femur fractures, but it is unclear whether thickening precedes fracture or results from a preceding stress fracture and what role bisphosphonates might play in cortical thickening. Objective: Our objective was to examine the relationship of cortical thickness to S/D fracture risk as well as establish normal reference values for femoral cortical thickness in a large population-based cohort of older women. Design: Using pelvic radiographs obtained in 1986–1988, we measured femoral shaft cortical thickness 3 cm below the lesser trochanter in women in the Study of Osteoporotic Fractures. We measured this in a random sample and in those with S/D fractures and femoral neck and intertrochanteric fractures. Low-energy S/D fractures were identified from review of radiographic reports obtained between 1986 and 2010. Radiographs to evaluate atypia were not available. Analysis used case-cohort, proportional hazards models. Outcomes: Cortical thickness as a risk factor for low-energy S/D femur fractures as well as femoral neck and intertrochanteric fractures in the Study of Osteoporotic Fractures, adjusting for age and bone mineral density in proportional hazards models. Results: After age adjustment, women with thinner medial cortices were at a higher risk of S/D femur fracture, with a relative hazard of 3.94 (95% confidence interval = 1.23–12.6) in the lowest vs. highest quartile. Similar hazard ratios were seen for femoral neck and intertrochanteric fractures. Medial or total cortical thickness was more strongly related to fracture risk than lateral cortical thickness. Conclusions: In primarily bisphosphonate-naive women, we found no evidence that thick femoral cortices placed women at higher risk for low-energy S/D femur fractures; in fact, the opposite was true. Women with thin cortices were also at a higher risk for femoral neck and intertrochanteric fractures. Whether cortical thickness among bisphosphonate users plays a role in atypical S/D fractures remains to be determined.

Limited literature is available regarding treatment strategies for three concurrent potentially curable malignancies, and only one case of primary breast cancer with bilateral primary lung cancers has been reported. There is no literature available on approaches to radiation treatment planning and delivery in this challenging scenario. We report a case of a 66-year-old female who underwent partial mastectomy and sentinel node biopsy for left-sided breast cancer, pT1cN1(mic). Metastatic work-up revealed bilateral primary lung cancers, biopsy-proven, each Stage cT1N0. Distinguishing synchronous primary tumours from metastatic disease can be challenging. The histological examination suggested three distinct primaries and each was potentially curable. Devising a treatment strategy required balancing the incremental benefits with the toxicity of combining each of the treatments. Stereotactic ablative radiotherapy was the treatment of choice for the patient's lung primaries, as she was deemed a high-risk surgical candidate. Tangential whole breast radiotherapy with regional nodal irradiation was deemed appropriate for her breast cancer. Treatment for all three sites was planned concurrently, taking into account any potential overlap of dose in the composite plan. Each lung lesion was treated with 48 Gy in 4 fractions with stereotactic ablative radiotherapy using volumetric modulated arc therapy technique. The breast and supraclavicular regions were treated with 50 Gy in 25 daily fractions using a field-in-field technique. Optimal clinical outcomes for patients with multiple primary cancers require optimal definitive management. In this unique case of triple primaries, curative-intent radiotherapy to both lungs, the left breast and regional nodes was planned to be given concurrently and treatment was successfully delivered without significant toxicity.

e16551 Background: Evidence-based guidelines confirm a survival advantage of adjuvant radiotherapy (ART) for prostatectomy (RP) patients with high-risk pathology. The efficacy of deferred salvage RT is under evaluation as an alternative strategy, and guidelines recommend radiation oncology (RO) referral for discussion of options. We report RO referral patterns, ART use, and factors associated with these patterns in a contemporary population-based RP cohort. Methods: Electronic treatment records were linked to Ontario's cancer registry. Multivariable regression was used to evaluate clinical and health systems factors associated with RO referral and ART use ≤ 6 months post-RP. Results: From January to November 2012, 2,663 prostate cancer patients received RP in Ontario. Among 1,261 with adverse pathology, 492 (39%) were referred to RO ≤ 6 months post-RP, of which 51% received ART. Multivariable analysis demonstrated that RO referral was more frequent for cases of T3b/T4 disease [OR 17.87; p < 0.0001], T3a disease [OR 5.24; p < 0.0001], Gleason score 8-10 disease [OR 11.32; p < 0.0001], Gleason score 7 disease [OR 4.18; p < 0.0001], at least one non-apex margin positive [OR 4.20; p < 0.0001], an apex only positive margin [OR 2.60; p < 0.0001], RO referral prior to RP [OR 1.95; p < 0.0001], low RP volume hospitals [OR 2.50; p < 0.0001], and increased distance of patient residence from cancer center [OR 1.73; p = 0.01]. There was wide geographic variation in RO referral rates (range 6%-66%; p < 0.0001). Among patients seen by RO, only T3b/T4 disease [OR 5.37; p < 0.0001], T3a disease [OR 2.72; p < 0.0001], at least one non-apex positive margin [OR 2.81; p < 0.0001], and an apex only positive margin [OR 1.32; p < 0.0001] remained predictive of ART on multivariable analysis. Conclusions: Nonmedical factors are important determinants of whether patients are referred for discussion of ART post-RP. Post-RO consultation, treatment decisions are correlated with pathologic findings. Large inter-center variations persist in referral and treatment post-RP, suggesting that further understanding of the reasons for variation could improve access to potentially curative RT in this setting.

In an intra-articular calcaneal fracture, the sustentaculum tali is generally thought to remain tightly bound to the talus by the interosseous talocalcaneal ligaments, spring ligament, and deltoid ligament, providing a "constant" fragment that remains anatomically aligned. The extensile lateral approach is commonly used for reduction based on this assumption, but because it provides only limited access to the medial aspect of the calcaneus, indirect fracture reduction is required to restore an anatomic relationship of these fragments to the sustentacular fragment. The purpose of this study was to determine the prevalence and displacement of sustentacular fractures in patients with an intra-articular calcaneal fracture, and thus determine whether the sustentacular fragment can be accurately considered as constant and can be consistently relied on to maintain anatomic alignment.All patients with an intra-articular calcaneal fracture who presented to two level-I trauma centers from 2006 to 2012 were included in the study if computed tomography scanning was performed. The presence or absence of a sustentacular fracture was documented, along with the displacement and the comminution of any such fracture and the subluxation or dislocation of the sustentaculum tali.Sustentacular fractures were present in ninety-four (44.3%) of the 212 patients who met the inclusion criteria. Seventy-two (76.6%) of the sustentacular fractures were nondisplaced, eleven (11.7%) were displaced, and ten (10.6%) were comminuted. The articulation between the sustentaculum tali and the talus was anatomically aligned in 166 (78.3%) of the calcaneal fractures, subluxated in forty-three (20.3%), and dislocated in two (0.9%).This study provides a detailed description of the frequency of sustentacular fractures, the displacement of such fractures, and articular subluxation or dislocation associated with intra-articular calcaneal fractures. Fixation by means of a lateral approach may be compromised when the sustentaculum tali is fractured or subluxated. A medial approach or combined medial and lateral approaches may be considered in such circumstances. Special attention should be paid to the integrity and alignment of the sustentacular fragment prior to surgical fixation.Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Repair of peripheral nerve defects with current synthetic, tubular nerve conduits generally shows inferior recovery when compared with using nerve autografts, the current gold standard. We tested the ability of composite collagen and hyaluronan hydrogels, with and without the nerve growth factor (NGF), to stimulate neurite extension on a promising aligned, nanofiber poly-L-lactide-co-caprolactone (PLCL) scaffold. In vitro, the hydrogels significantly increased neurite extension from dorsal root ganglia explants. Consistent with these results, the addition of hydrogels as luminal fillers within aligned, nanofiber tubular PLCL conduits led to improved sensory function compared to autograft repair in a critical-size defect in the sciatic nerve in a rat model. Sensory recovery was assessed 3 and 12 weeks after repair using a withdrawal assay from thermal stimulation. The addition of hydrogel did not enhance recovery of motor function in the rat model. The NGF led to dose-dependent improvements in neurite out-growth in vitro, but did not have a significant effect in vivo. In summary, composite collagen/hyaluronan hydrogels enhanced sensory neurite outgrowth in vitro and sensory recovery in vivo. The use of such hydrogels as luminal fillers for tubular nerve conduits may therefore be useful in assisting restoration of protective sensation following peripheral nerve injury.

286 Background: Adjuvant radiotherapy (ART) post-radical prostatectomy (RP) has been shown to benefit patients with pathologic T3 or margin-positive prostate cancer. It remains unclear whether early salvage radiotherapy (SRT) confers equivalent outcomes to ART. Practice Guidelines recommend referral to radiation oncology (RO) within 6 months of RP to discuss ART and SRT. The study objectives were to (1) assess post-RP referral patterns to RO; (2) describe ART and SRT utilization; and (3) compare time trends before and after seminal trials and guidelines were published. These provide indications of access to quality care. Methods: This was a retrospective cohort study. Electronic clinic visit and RT treatment records were linked to the population-based Ontario Cancer Registry. The study population included all prostate cancer cases treated with RP in Ontario January 1, 2003 - November 30, 2012. ART was defined as curative RT within 6 months of RP, and SRT was 6 - 24 months post-RP. Changes in RO referral and RT rates over time were statistically analyzed using the Cochran-Mantel-Haenszel Chi-Square test. Results: Over the study period, 30,447 prostate cancer patients received RP and 15.2% saw an RO within 6 months of RP. This proportion doubled between 2003 and 2012 (from 10.7% in 2003-2004 to 21.7% in 2011-2012, p < 0.001 for trend). The annual percentage change was largest 2009-2011 (3.4%). In comparison, the proportion seen within 24 months of RP remained stable at 32.3% ± 1.4%. Amongst the 4,641 patients seen by an RO within 6 months of RP for consideration of ART or SRT, the proportion receiving ART remained relatively constant at 51.0% ± 3.0%. Commensurate with RO referral trends, there was a doubling in ART rates amongst all RP cases, ranging from 5.4% in 2003-2004 to 11.0% in 2011-2012 (p < 0.001), compared to relatively stable SRT rates of 8.5% ± 0.2% (7.9% in 2003-2004, 8.9% in 2010-2011). Consequently, the total proportion receiving RT within 24 months of RP increased from 14.1% in 2003-2004 to 19.8% in 2010-2011 (p < 0.0001). Conclusions: There was an increase in access to early RO referral post-RP and in ART utilization in Ontario from 2003 to 2012, following publication of key clinical trials and guidelines.

To identify pressures created by surgical culture and social setting and explore mechanisms for how they might impact operative decision-making.Surgeons apply judgments within a powerful social context and are constantly socialized and influenced by communicative exchanges. In this study, the authors characterized the nature of the surgical social context, focusing on the interactions between external social influences and the cognitive ability of the surgeon to respond to uncertain, unexpected, or critical moments in operations.The authors reviewed the sociological and psychosocial literatures to examine concepts in identity construction, socialization process, and image management literatures and synthesized a conceptual framework allowing for the examination of how social factors and image management might impact surgical performance.The surgeon's professional identity is constructed and negotiated on the basis of the context of surgical culture. Trainees are socialized to display confidence and certainty as part of the "hidden curriculum" and several sociocultural mechanisms regulating "appropriate" surgical behavior exist in this system. In the image management literature, individuals put on a "front" or social performance that is socially acceptable. Several mechanisms for how image management might impact surgical judgment and decision-making were identified through an exploration of the cognitive psychology literature.Sociopsychological literatures can be linked with decision-making and cognitive capacity theory. When cognitive resources reach their limit during critical and uncertain moments of an operation, the consumption of resources by the pressures of reputation and ego might interfere with the thought processes needed to execute the task at hand. Recognizing the effects of external social pressures may help the surgeon better self-regulate, respond mindfully to these pressures, and prevent surgical error.

The sea occupies three quarters of the area on the earth and provides various kinds of resources to mankind in the form of minerals, food, medicines and even energy. “Seabed exploitation” specifically deals with recovery of the resources that are found on the seabed, in the form of solids, liquids and gasses (methane hydrates, oil and natural gas). The resources are abundant; nevertheless the recovery process from the seabed, poses various challenges to mankind. This study starts with a review on three types of resources: polymetallic manganese nodules, polymetallic manganese crusts and massive sulphides deposits. Each of them are rich in minerals, such as manganese, cobalt, nickel, copper and some rare earth elements. They are found at many locations in the deep seas and are potentially a big source of minerals. No commercial seabed mining activity has been accomplished to date due to the great complexities in recovery. This book describes the various challenges associated with a potential underwater mineral recovery operation, reviews and analyses the existing recovery techniques, and provides an innovative engineering system. It further identifies the associated risks and a suitable business model.Chapter 1 presents a brief background about the past and present industrial trends of seabed mining. A description of the sea, seabed and the three types of seabed mineral resources are also included. A section on motivations for deep sea mining follows which also compares the latter with terrestrial mining.Chapter 2 deals with the decision making process, including a market analysis, for selecting manganese nodules as the resource of interest. This is followed by a case study specific to the location of interest: West COMRA in the Clarion-Clipperton Zone. Specific site location is determined in order to estimate commercial risk, environmental impact assessment and logistic challenge.Chapter 3 lists the existing techniques for nodule recovery operation. The study identifies the main components of a nodules recovery system, and organizes them into: collector, propulsion and vertical transport systems.Chapter 4 discusses various challenges posed by manganese nodules recovery, in terms of the engineering and environment. The geo-political and legal-social issues have also been considered. This chapter plays an important role in defining the proposed engineering system, as addressing the identified challenges will better shape the proposed solution.Chapter 5 proposes an engineering system, by considering the key components in greater details. An innovative component, the black box is introduced, which is intended to be an environmentally-friendly solution for manganese nodules recovery. Other auxiliary components, such as the mother ship and metallurgical processing, are briefly included. A brief power supply analysis is also provided.Chapter 6 assesses the associated risks, which are divided into sections namely commercial viability, logistic challenges, environmental impact assessment and safety assessment. The feasibility of the proposed solution is also dealt with.Chapter 7 provides a business model for the proposed engineering system. Potential customers are identified, value proposition is determined, costumer relation is also suggested. Public awareness is then discussed and finally a SWOT analysis is presented. This business model serves as an important bridge to reach both industry and research institutes.Finally, Chapter 8 provides some conclusions and recommendation for future work.

TAp73 is a p53 tumor suppressor gene homologue that is known to be mainly involved in apoptosis. We report here that TAp73 is necessary for the cellular response to oxidative stress and that TAp73 functions as a downstream target of p53 in this process. We show that p53 physically interacts with the TAp73 promoter under stress conditions that lead to cell death. Particularly, p53 binds to a palindromic site in the TAp73 promoter, activates the promoter of TAp73, and selectively induces TAp73 transcription. TAp73 expression is highly increased under oxidative stress in a p53-dependent manner. Furthermore, knock-down of TAp73 expression inhibits the cellular apoptotic response to oxidative damage. In contrast, the ectopic expression of TAp73 in p53(-/-) mouse embryonic fibroblasts induces oxidative cell death. Our findings demonstrate that p53 is a direct transcriptional regulator of TAp73. Our data reveal a new pathway for cellular protection against oxidative damage and provide evidence that TAp73 is a stress-response gene and a downstream effector in the p53 pathway.

The design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. These molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [Leu(14)]exenatide-ABD is an 88 residue peptide amide incorporating an Albumin Binding Domain (ABD) scaffold. [Leu(14)]exenatide-ABP is a 53 residue peptide incorporating a short Albumin Binding Peptide (ABP). [Leu(14)]exenatide-ABD and [Leu(14)]exenatide-ABP exhibited nanomolar functional GLP-1 receptor potency and were metabolically stable in vitro in human plasma and in a pancreatic digestive enzyme mixture. Both molecules displayed picomolar and nanomolar binding association with albumin across multiple species and circulating half lives of 16 and 11 hours, respectively, post a single IV dose in rats. Unlike exenatide, both molecules elicited robust glucose lowering when injected 1 day prior to an oral glucose tolerance test, indicative of their extended duration of action. [Leu(14)]exenatide-ABD was compared to exenatide in a Lep (ob/ob) mouse model of diabetes. Twice-weekly subcutaneously dosed [Leu(14)]exenatide-ABD displayed superior glucose lowering and weight loss in diabetic mice when compared to continuously infused exenatide at the same total weekly dose. A single oral administration of each molecule via an enteric coated capsule to cynomolgus monkeys showed superior pharmacokinetics for [Leu(14)]exenatide-ABD as compared to [Leu(14)]exenatide-ABP with detectable exposure longer than 14 days. These studies support the potential use of these novel long acting exenatide analogs with different routes of administration for the treatment of type 2 diabetes.

Introduction Hemolysis after IVIG infusion has been observed in clinical trials and case reports. Certain factors seem to place a patient receiving IVIG at higher risk for hemolytic anemia: 1) having blood type A, B, or AB and 2) receiving high doses of IVIG (≥ 2g/kg). IVIG contains isohemagglutinins that coat red blood cells and may cause red cell clearance by the RES (Table 1). Anti-A, Anti-B, and Anti-D titers have been detected in IVIG products at varying concentrations by different IVIG manufacturers. It has been suggested that Anti-A titers > 1:16 are more likely to cause clinically significant hemolysis and thus anemia in recipients. 15 summarized studies reported 63 patients who experienced hemolysis after IVIG infusion and showed the higher risk of non-group O recipients to hemolyze with IVIG: In the current study, we sought to explore the degree of anemia as related to ABO blood types in mothers treated with IVIG for fetal alloimmune thrombocytopenia (AIT). Methods A retrospective chart review was conducted on 84 women who had received IVIG for AIT treatment during their pregnancy to increase the fetal platelet count. Women were randomized to receive IVIG 2g/kg/wk (arm A, n=43) or IVIG 1g/kg/wk + prednisone (arm B, n=41) starting at 20-30 weeks of gestation until delivery. One CBC per month was collected from each mother from the start of treatment until delivery. Hemoglobins and mean corpuscular volumes (MCVs) were tracked and development of anemia was compared among women with blood types (BT) A, B, AB and O in each treatment arm. Patients who non-randomly received IVIG 2g/kg/wk + prednisone together as rescuetreatment were excluded from this study. Results 36 of the 84 women had hemoglobins less than 10 on at least one CBC during IVIG treatment. All 36 had MCV values in the normocytic range (80-100). The degree of anemia was significantly greater in Arm A (IVIG 2g/kg) than Arm B (IVIG 1g/kg + pred) (Fisher's exact test, p=0.016; table 3). Among women in arm A (IVIG 2g/kg), BT non-O had a significantly higher incidence of marked anemia (Hg There was no significant difference among women by blood type O (n=4) versus non-O (A=4,B=2,AB=0,unknown=2) in the incidence of anemia in arm B (IVIG 1g/kg + pred); both BT groups showed a low incidence of hemolysis (table 5). Conclusions Patients who were on 2g/kg/wk IVIG became substantially more anemic than those on the 1g/kg/wk IVIG + prednisone dose, which supports reported findings that higher dose (HD) IVIG is associated with a greater risk of anemia. Note: receiving IVIG 2g/kg/wk for multiple weeks is very high dose IVIG. In particular, those patients receiving HD IVIG who were BT A had a greater risk of developing a greater extent of anemia than those of blood type O. This finding is consistent with the hypothesis that blood-group specific antibodies in IVIG result in immune hemolysis primarily in BT A recipients because of the higher anti-A titers. Furthermore, while 1 g/kg/wk of IVIG is not “low dose”, the concomitant use of prednisone 0.5mg/kg/d may protect against development of a greater degree of anemia in these patients. IVIG is the standard of care treatment for AIT; however 1 g/kg/wk is known not sufficiently effective in severely thrombocytopenic fetuses (Berkowitz, OB-GYN 2006). Therefore we believe appropriate treatment of women whose previous babies did not have an ICH needs to be > 1g/kg/wk. Our study found that hemolytic anemia in non-O blood types may be an important side effect of 2g/kg/wk IVIG treatment, indicating that patient blood type should be considered when deciding which IVIG regimen to use. Disclosures: Bussel: Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.

Over the past decade, the introduction of robotics in the field of medicine has provided a new approach to patients requiring surgery, and both its advantages and disadvantages are currently under study by many groups worldwide. The use of robotics has especially been considered by the urological community as a treatment option in radical prostatectomy. The current case report is one in which the da Vinci Surgical System™, with fourth arm use was employed in radical prostatectomy. This case presents a unique occurrence in which a bolt of the Prograsper forcep became loose during an operation, leading to diminished device functionality and later impedance of its removal. A circumstance such as this has not previously been reported, so we introduce for other robotic surgeons our unique instrumental malfunction case during a robotic prostatectomy.