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e17567 Background: Platinum-taxane chemotherapy and surgical debulking are the optimal treatment for patients with advanced ovarian cancer. While initial response rates are above 80%, tumor recurrence occurs in about 70 to 80% of patients. Cells with defects in homologous recombination repair (HRR) are susceptible to cell death induced by Poly (ADP-ribose) polymerase inhibitors (PARPi). These drugs are used to treat recurrent neoplasms that have BRCA1 or BRCA2 mutations or homologous recombination deficiency (HRD). Low tumor percentage in test samples, which is common in clinical practice, is often overlooked when addressing HRD tests. The goal of this study was to determine the optimal tumor content rate needed to detect HRD changes. Methods: A total of sixteen ovarian neoplasms were studied. These samples were sequenced using Illumina TSO500 NGS and interpreted using NxClinical software 6.1. In all cases, HRD scores were evaluated. A score of ≥42 was determined to be HR-deficient and a score < 42 was considered HR-proficient. We aimed to identify the optimal tumor percentage needed for detection of HRD alterations. HRD scores were calculated with tumor percentages of 70%, 60%, 40%, and 20%. Additionally, chemotherapy response scores (CRS) were available in 8 of 16 cases. We correlated the CRS with HRD scores. Results: In this project, visualization of a 523-gene cancer exome panel was shown to be 66.7% sensitive and 100% specific for detecting genomic scars (HRD score). 68.75% of cases showed low HRD score and 31.25% of cases showed a high HRD score. Next generation sequencing (NGS) results for most specimens are adequate with a tumor content rate of 70%. CRS1 cases were HR-proficient. For CRS2 and CRS3 we had mixed results. Conclusions: HRD correlates with platinum sensitivity in epithelial ovarian tumors, which has clinical significance as a predictor of sensitivity to PARPi. During treatment, tissue samples are obtained at different times points and sources, some at diagnosis/surgical debulking and some after neoadjuvant therapy. After neoadjuvant treatment, tumor volume is reduced. Cytology specimens are convenient for obtaining tumoral cells, but tumor volumes are usually small. Profiling tumors of low volume decrease the chances of detecting a patient’s eligibility for targeted maintenance. Our next steps will evaluate the performance of tissue microarrays using the Infinium CytoSNP-850K array compared to NGC cytogenomics at low tumor volumes.

As one of the oldest known human diseases, leprosy or Hansen's disease remains a public health concern around the world with over 200 000 new cases in 2018. Most human leprosy cases are caused by Mycobacterium leprae , but a small number of cases are now known to be caused by Mycobacterium lepromatosis , a sister taxon of M. leprae . The global pattern of genomic variation in M. leprae is not well defined. Particularly, in the Pacific Islands, the origins of leprosy are disputed. Historically, it has been argued that leprosy arrived on the islands during nineteenth century colonialism, but some oral traditions and palaeopathological evidence suggest an older introduction. To address this, as well as investigate patterns of pathogen exchange across the Pacific Islands, we extracted DNA from 39 formalin-fixed paraffin-embedded biopsy blocks dating to 1992–2016. Using whole-genome enrichment and next-generation sequencing, we produced nine M. leprae genomes dating to 1998–2015 and ranging from 4-63× depth of coverage. Phylogenetic analyses indicate that these strains belong to basal lineages within the M. leprae phylogeny, specifically falling in branches 0 and 5. The phylogeographical patterning and evolutionary dating analysis of these strains support a pre-modern introduction of M. leprae into the Pacific Islands. This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.

Differentiating benign blue nevi from blue nevus-like melanoma can be diagnostically challenging. We aimed to determine the utility of immunohistochemical staining for p16 and cyclin D1 in distinguishing benign blue nevi and malignant melanoma.Thirty-two biopsy specimens taken between 2007 and 2015 were obtained from the Department of Pathology at the Queen's Medical Center in Honolulu, HI. These included 9 common blue nevi, 8 cellular blue nevi (2 with atypical features), and 15 malignant melanomas (3 blue nevus-like melanoma). The primary outcome was the difference in p16 and cyclin D1 staining between benign blue nevi and malignant melanoma. Staining of specimens for p16 and cyclin D1 was graded on the strength of staining, and the percent of tumor that stained positive. A specimen was deemed positive if it showed 2+ staining in ≥50% of the tumor.The majority (82%) of blue nevi stained negative for p16. There was not a significant difference between p16 staining in benign blue nevi and melanoma (P=0.06). Eleven (73%) melanomas stained positive for cyclin D1 with a sensitivity of 0.73 and positive predictive value of 1.0. All blue nevi were negative for cyclin D1, making its specificity 1.0 and its negative predictive value 0.8. This difference in cyclin D1 staining in blue nevi and melanoma was significant (P=0.0001).Cyclin D1 may be useful in differentiating benign blue nevi from melanoma.

Understanding the aerodynamic impact of swept-wing ice accretions is a crucial component of the design of modern aircraft. Computer-simulation tools are commonly used to approximate ice shapes, so the necessary level of detail or fidelity of those simulated ice shapes must be understood relative to high-fidelity representations of the ice. Previous tests were performed in the NASA Icing Research Tunnel to acquire high-fidelity ice shapes. Some of those ice shapes are based on aircraft certification requirements. From this database, full-span artificial ice shapes were designed and manufactured for both an 8.9%-scale and 13.3%-scale semispan wing model of the CRM65 which has been established as the full-scale baseline for this swept-wing project. These models were tested in the Walter H. Beech wind tunnel at Wichita State University and at the ONERA (Office national d'etudes et de recherches aerospatiales) F1 facility, respectively. The data collected in the Wichita State University wind tunnel provided a low-Reynolds number baseline study while the pressurized F1 facility produced data over a wide range of Reynolds and Mach numbers with the highest Reynolds number studied being approximately Re = 11.9 by 10 (sup 6). Three different fidelity representations were created based on three different icing conditions. Lower-fidelity ice shapes were created by lofting a smooth ice shape between cross-section cuts of the high-fidelity ice shape. Grit roughness was attached to this smooth ice shape as another fidelity variant. The data indicates that the geometric fidelity of the ice shapes resulted in significant differences in lift and drag. These results were similar at both facilities over the wide range of test conditions utilized.

Artificial ice shapes of various geometric fidelity were tested on a wing model based on the Common Research Model. Low Reynolds number tests were conducted at Wichita State University's Beech Memorial Wind Tunnel, and high Reynolds number tests were conducted at ONERA's F1 wind tunnel. The aerodynamic performance data from the two facilities were compared at matched or similar Reynolds and Mach number to ensure that the results and trends observed at low Reynolds number could be applied and continued to high Reynolds number. For both clean and iced configurations, the data from Wichita State University and F1 agreed well at matched or similar Reynolds and Mach numbers. The lift and pitching moment curves agreed very well for most configurations. There appeared to be 0.2-0.3deg offset in the angle of attack between the Wichita State University and F1 data, possibly due to different flow angularities in the test sections of the two facilities. There was also an offset in the drag values between the two facilities from an unknown cause. Overall, the data compared very well between the low Reynolds number test at Wichita State University tunnel and the high Reynolds number test at F1. This indicated that data from the low Reynolds number tests could be used to understand iced-swept-wing aerodynamics at high Reynolds number.

This paper studied the aerodynamic effects of a single scalloped ice accretion and two lower fidelity ice-shape simulations. These data were compared to the aerodynamics of a clean 8.9% scale CRM65 semispan wing model at a Reynolds number of 1.6 x 10(exp 6). The clean wing experienced an aggressive, tip-first stall and showed a small, strong leading-edge vortex at lower angle-of-attack while the iced cases showed larger, seemingly weaker leading-edge vortices at similar angles. The size of these vortices is larger for the low-fidelity ice shape. The stall pattern for the iced cases was also tip-first, but more gradual than the clean wing. The high-fidelity ice shape produced streamwise flow features over the upper surface of the wing due to flow moving through gaps that exist in the ice shape geometry that disrupted the formation of the leading-edge vortices, changing the aerodynamics of the wing. These gaps do not exist in the low-fidelity shape. The low-fidelity scallop ice shape was non-conservative in its aerodynamic penalties compared to the full high-fidelity case.

Aerodynamic assessment of icing effects on swept wings is an important component of a larger effort to improve three-dimensional (3D) icing simulation capabilities. An understanding of ice-shape geometric fidelity and Reynolds and Mach number effects on the iced-wing aerodynamics is needed to guide the development and validation of ice-accretion simulation tools. To this end, wind tunnel testing was carried out for a 13.3-percent-scale semispan wing based upon the Common Research Model airplane configuration. The wind tunnel testing was conducted at the Office National d’Etudes et de Recherches Aerospatiales (ONERA) F1 pressurized wind tunnel with Reynolds numbers of 1.6 x 10(exp 6) to 11.9 x 10(exp 6 ) and Mach numbers of 0.09 to 0.34. Five different configurations were investigated using fully 3D, high-fidelity artificial ice shapes that maintain nearly all of the 3D ice-accretion features documented in prior icing wind tunnel tests. These large, leading-edge ice shapes were nominally based upon airplane holding in icing conditions scenarios. For three of these configurations, lower fidelity simulations were also built and tested. The results presented in this paper show that while Reynolds and Mach number effects are important for quantifying the clean-wing performance, there is very little to no effect for an iced wing with 3D, high-fidelity artificial ice shapes or 3D smooth ice shapes with grit roughness. These conclusions are consistent with the large volume of past research on iced airfoils. However, some differences were also noted for the associated stalling angle of the iced swept wing and for various lower fidelity versions of the leading-edge ice accretion. More research is planned to further investigate the key features of ice-accretion geometry that must be simulated in lower fidelity versions in order to capture the essential aerodynamics.

Low-Reynolds number testing was conducted at the 7 ft. x 10 ft. Walter H. Beech Memorial Wind Tunnel at Wichita State University to study the aerodynamic effects of ice shapes on a swept wing. A total of 17 ice shape configurations of varying geometric detail were tested. Simplified versions of an ice shape may help improve current ice accretion simulation methods and therefore aircraft design, certification, and testing. For each configuration, surface pressure, force balance, and fluorescent mini-tuft data were collected and for a selected subset of configurations oil-flow visualization and wake survey data were collected. A comparison of two ice shape geometries and two configurations with simplified geometric detail for each ice shape geometry is presented in this paper.

Cutaneous manifestations associated with myelodysplastic syndromes (MDS) are uncommon and can occur as specific or nonspecific lesions. Recognizing these cutaneous manifestations is important as they can precede blood or bone marrow transformation to leukemia. Granulomatous reactions have rarely been described as nonspecific lesions of MDS. These rare cases histologically resembled granuloma annulare, sarcoid, and a generalized dermal interstitial granulomatous dermatitis (IGD) which were not associated with leukemic infiltration. The authors report an interesting case of an IGD-like eruption evolving over the course of MDS with eventual progression to systemic leukemia. IGD is an inflammatory reaction that refers to a varied spectrum of histologic patterns and is associated with a variety of systemic illnesses and hypersensitivity reactions, including lymphoma and leukemia. In patients with MDS, surveillance for leukemia is a critical component of their follow-up care. Normally, this surveillance occurs through serial peripheral blood smears and bone marrow studies. IGD-like eruptions are a cutaneous reaction pattern that may serve as an additional clinical indicator of leukemic progression in patients with MDS. Although primarily a reactive pattern, this entity can rarely harbor leukemic blasts.

In order to achieve safe and successful operation of unmanned aerial systems (UAS), one must have a thorough understanding of the reliability of the system as well as the risks involved with its operation. This chapter describes a model and methodology to assess and estimate the risk associated with a given UAS mission. Motivations for risk analysis as well as risk factors associated with UAS operation are also described. The risk model estimates threats to human safety that result from midair collisions and ground strikes. This framework aims to assist in determining applications that leverage the strengths of current unmanned aircraft technology while mitigating the weaknesses to meet or exceed the safety of manned aircraft. The intended use of the proposed risk framework is discussed and risk assessments are presented for several example scenarios. Keywords: unmanned aerial vehicle; unmanned aircraft system; reliability; risk; risk assessment; safety

The deleterious effect of ice accretion on aircraft is often assessed through dry-air flight and wind tunnel testing with artificial ice shapes. This paper describes a method to create fullspan swept-wing artificial ice shapes from partial span ice segments acquired in the NASA Glenn Icing Reserch Tunnel for aerodynamic wind-tunnel testing. Full-scale ice accretion segments were laser scanned from the Inboard, Midspan, and Outboard wing station models of the 65% scale Common Research Model (CRM65) aircraft configuration. These were interpolated and extrapolated using a weighted averaging method to generate fullspan ice shapes from the root to the tip of the CRM65 wing. The results showed that this interpolation method was able to preserve many of the highly three dimensional features typically found on swept-wing ice accretions. The interpolated fullspan ice shapes were then scaled to fit the leading edge of a 8.9% scale version of the CRM65 wing for aerodynamic wind-tunnel testing. Reduced fidelity versions of the fullspan ice shapes were also created where most of the local three-dimensional features were removed. The fullspan artificial ice shapes and the reduced fidelity versions were manufactured using stereolithography.

Treatment-resistant depression (TRD) may be implicated in 33–57% of depression cases. The currently available effective treatments include electroconvulsive therapy (ECT) or augmentation of serotonin selective reuptake inhibitors (SSRIs) with antipsychotics. ECT and antipsychotics are both associated with safety and tolerability concerns. Depression is hypothesized to result from a dysregulation of monoamine neurotransmitters, although the source of the dysregulation has been unclear. However, recent studies have revealed that an enzyme that degrades the neurotransmitters, known as monamine oxidase-A (MAO-A), may be overactive in patients with depression. Thus, treatments for depression that modulate MAO-A could act upstream relative to current antidepressant treatments. Monoamine oxidase inhibitors (MAOIs) can be highly effective therapeutic agents for depression and some anxiety disorders. Some evidence suggests that MAOIs may act by reversing excessive neurotransmitter depletion within the neuron and the synapse. MAOIs tend to be underutilized in clinical practice, due in part to misinformation and mythology about their dietary and drug interactions. The new class of reversible monoamine oxidase inhibitors (RIMAs) has shown efficacy in depression, with safety and tolerability comparable to SSRIs. This article discusses recent progress in RIMAs toward the treatment of TRD. Dietary and drug interactions of MAOIs will be covered, as well as guidelines for integrating these agents into clinical practice.

Background Several reports have shown expression of cyclooxygenase-2 (COX-2) in malignant skin tumors. COX-2 has also recently been reported as a marker of malignant melanoma (MM). Objective Our aim was to investigate whether there is a difference in the immunohistochemical expression of COX-2 between malignant and benign melanocytic lesions of the skin. Methods We selected 40 archival cases of MM including 10 cases of superficial spreading melanoma, 10 of lentigo maligna melanoma, 10 of nodular melanoma, and 10 of acral lentiginous melanoma. For comparison, we also selected 35 benign melanocytic lesions, which included 15 nonatypical nevi and 10 atypical nevi. The remaining 10 cases were Spitz nevi. COX-2 immunohistochemical staining was performed, and intensities were assessed quantitatively. Results The MM group and the benign melanocytic nevi group showed a highly statistically significant difference in the intensity of COX-2 expression (P

Introduction: COPD has significant morbidity and incurs heavy utilization of healthcare resources. Objectives: To assess whether a comprehensive care programme can decrease hospital admissions and length of hospital (LOS) for COPD patients. Methods: In a RCT of patients discharged from hospital after an episode of acute exacerbation of COPD, patients were randomised to an Intervention Group (IG) or Usual Care Group (UG). The IG received a comprehensive, individualized care plan which included optimization of medication, nurse-led education, physiotherapist support for pulmonary rehabilitation, monthly telephone calls by a respiratory nurse for a period of 1 year, and followed up in respiratory clinic by a respiratory specialist once every 3 months for 1 year. The UG were managed according to standard practice. All patients had assessments (spirometry, 6 minute walk test, dyspnoea score [Modified Medical Research Council Dyspnoea Scale {MMRC}], and quality of life [QOL] [St. Georges Respiratory Questionnaire {SGRQ}]) at baseline and at 12 months. The primary outcome was 12-month hospital readmission. Results: 180 patients were recruited (IG N=90,UG N=90; mean age 74.7±8.2yrs,172(95.6%)males; mean FEV1 45.4±16.6% predicted). At 12 months, the IG had fewer readmissions (1.56±2.13vs2.38±2.14times,p=0.0008) and shorter LOS (7.41±11.29vs12.21±12.87days,p=0.0003) for COPD than UG. IG at 12 months had improved mean MMRC(-0.1±0.7vs0.2±0.6,p=0.033) and SGRQ score (-8.5±16.6vs-0.1±15.7,p=0.002) compared with UG. Conclusion: Comprehensive COPD programme can reduce hospital readmissions for COPD and LOS, and improve symptoms and QOL of the patients.

Breast cancer is the second leading cause of cancer mortality amongst American women. The HER2 gene encodes a cell surface receptor that affects cell proliferation and has been recognized as a diagnostic factor in treatment selection for invasive breast cancer. Examine accuracy in HER2 detection between manual count, computer assisted, and automated tiling algorithm. 42 randomly selected invasive breast cancer specimens were enumerated by fluorescence in situ hybridization (FISH)for HER2 and CEP17 markers using the Vysis HER2 assay (AbbotLaboratory, North Chicago, IL). Specimens were tested using three methods: Manual, computer assisted nuclei selection (Tissue FISH MetaSystems, Newton, MA), and automated enumeration (MetaSystems, Newton, MA). The greatest bias and widest agreement limits for HER2 and CEP17 were seen in Automatic versus Manual, the gold standard. HER2 values greater than 6 possessed the greatest bias and widest agreement limits. CEP17 comparison showed similar bias and agreement limits for each comparison. Kappa values indicated good agreement for all methods although Tissue FISH and Manual possessed better agreement. Higher agreement at lower HER2 & CEP17 count maybe due to fewer chromosomal aberrations, in which selection of field of views has less variation between methods. Alternatively, increased background signals seen in polyploidy may be responsible for the variations in signal count. Manual and Tissue FISH demonstrated good agreement amongst by both Altman Bland and Cohen’s Kappa. While the automatic method has good agreement at lower HER2, the sharp increase in variability at higher HER2 counts illustrates a limitation of the automatic method.

As the Federal Aviation Administration (FAA) prepares to integrate Unmanned Aerial Systems (UAS) into the National Airspace System (NAS), developing technologies that mitigate the risk associated with UAS collisions have become a top priority. Despite advances in detect and avoid technologies, the UAS operator remains the primary controller responsible for maintaining inter-vehicle separation and ensuring conflicts do not occur. This paper examines a collision awareness system which increases the operator's situational awareness by spatially and temporally predicting conflicts between the UAS and entities such as other aviation traffic or restricted airspaces. By modeling entities as 3D point masses, the system can be implemented for various, dissimilar UASs. Furthermore, the system supports aircraft engaged in different flight modes such as free flight, following a flight path, and orbit/loiter behavior. Mixed Gaussian distributions model each entity's future position, where the mean is determined by 3D kinematic motion and the covariance is determined by a continuous time error propagation model. Convolving these mixed distribution with another entity or airspace yields mathematically conservative future conflict estimates. Scenarios are presented to demonstrate the algorithm's capabilities.

We examined the proliferative characteristics of 20 basal-cell carcinomas (BCCs) and 16 trichoepitheliomas (TEps) in an effort to understand and explore possible differences in their tumorigenic cell-cycle properties. These tumors were first compared for their expression of the nuclear proliferative protein Ki-67 and the tumor suppressor protein p53. We also compared the p53 downstream effector, p21(waf-1/cip-1), an inhibitor of cyclin-dependent kinases. The other p53-dependent, cyclin-dependent kinase inhibitor, p27(kip-1), has shown to be increased in TEps, which is consistent with this benign neoplasm's better-differentiated state. In our findings, we confirmed through immunohistochemical staining for Ki-67 that BCCs qualitatively showed a greater proliferative fraction compared to TEps (50.0 vs. 13.0%, p < 0.00001) as well as over-expression of p53 (2+ vs. 1+, p < 0.0008). BCCs marked by p21 demonstrated scattered nuclear positivity compared to the virtual absence of staining in the TEps (p < 0.019). In studying their cell-cycle properties, our findings suggest that abnormalities in the p53 pathway allow BCCs to obtain a growth advantage. We show that Ki-67 and p53 staining both appear useful in resolving challenging differential diagnoses and thereby help in directing appropriate treatment strategies.

Background BRCA1–associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma. Methods Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher’s exact test). Results Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call “melanocytic BAP1-mutated atypical intradermal tumors” (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001). Conclusions Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.

In order to operate in the national airspace, an aircraft system must have documentation and analysis to show that it can operate at a satisfactory level of safety. For traditional manned aircraft systems, this is equivalent to operating a reliable system. However with Unmanned Aerial Systems (UAS), a relatively unreliable system can safely be operated provided that the risk to bystanders on the ground is sufficiently low. This paper presents a set of design tools and methodologies which can be used to assess the risk associated with operating an UAS in a potentially populated area. The intended use of the tool is discussed and a risk assessment is provided for an existing UAS.

A major focus of current unmanned systems operations is assessing the inherent risk associated with a mission. Efforts to integrate unmanned systems into the national airspace require manufacturers be able to calculate the risk of a mission in terms of human safety. Threats to human safety from midair collisions and ground strikes are the focus of the risk model. The projects intent is to assist in determining applications that leverage the strengths of current unmanned aircraft technology while mitigating the weaknesses so as to meet or exceed the safety and economic viability of manned aircraft. The validity of the risk model is demonstrated by comparison to historical data when available. The intended use of the tool is discussed and risk assessments are presented for several example scenarios. Resources for gathering the required information are surveyed and material is developed to aid a general audience in performing a risk assessment.

Several reports have shown expression of cyclooxygenase-2 (COX-2) in malignant skin tumors. COX-2 has also recently been reported as a marker of malignant melanoma (MM).Our aim was to investigate whether there is a difference in the immunohistochemical expression of COX-2 between malignant and benign melanocytic lesions of the skin.We selected 40 archival cases of MM including 10 cases of superficial spreading melanoma, 10 of lentigo maligna melanoma, 10 of nodular melanoma, and 10 of acral lentiginous melanoma. For comparison, we also selected 35 benign melanocytic lesions, which included 15 nonatypical nevi and 10 atypical nevi. The remaining 10 cases were Spitz nevi. COX-2 immunohistochemical staining was performed, and intensities were assessed quantitatively.The MM group and the benign melanocytic nevi group showed a highly statistically significant difference in the intensity of COX-2 expression (P0.0001). Staining intensity in the dermal component of MM cases also showed a tendency to increase with increasing tumor depth. By contrast, the intensity of the dermal component in the melanocytic nevi group decreased with increasing depth as the nevus cells matured from type A to type C cells. No statistical difference was noted between the MM and Spitz nevi cases (P = 0.20).Malignant melanoma shows stronger immunohistochemical expression of COX-2 than benign melanocytic nevi. Although COX-2 cannot be used alone to differentiate MM from melanocytic nevi, it may serve as an aid in the differential diagnosis of melanocytic skin lesions.

Searching a complex environment for a hidden target is a common problem encountered by many autonomous systems. Many modern autonomous systems use a hierarchical structure for mission management where different algorithms perform different tasks to give agents desired behavior. This work investigates a search policy that guarantees both an exhaustive search of the map and conflict free paths of all agents. Agents formulate control decisions for a fixed number of time steps using a modular algorithm that allows parameterizations of agent capabilities. High fidelity simulation and flight test data using multiple autonomous vehicles are used to verify and validate the algorithms in real time.

Searching for a target in a complex environment is a common problem encountered by many autonomous systems. This work considers the problem of searching for targets using a team of heterogeneous agents. The system maintains a grid-based world model which contains information about the probability that a target is located in any given cell of the map. Agents formulate control decisions for a fixed number of time steps using a modular algorithm that allows for individual capabilities and characteristics of individual agents to be encoded in several parameters. This paper investigates one aspect of the search strategy and presents a solution that guarantees total map coverage. The resulting search patterns executed by agents guarantee an exhaustive search of the map in the sense that all cells will be searched sufficiently to ensure that the probability of a target being located in any given cell is driven to zero.

Dermatitis herpetiformis (DH) is an immune-mediated cutaneous disease occasionally associated with celiac disease, but rarely associated with systemic lupus erythematosus (SLE). The combination of DH and SLE is immunologically mediated and suggests a relationship between the two conditions. We describe a woman with DH and SLE with a novel HLA phenotype.

The goal of most current Unmanned Air Vehicle (UAV) research is to develop algorithms which allow a single agent or possibly a team of agents to operate completely autonomously without human interaction. Most of these autonomous algorithms operate at a high, strategic level and assume that low level tasks such as state stabilization and signal tracking have already been realized. The di‐culty in verifying and validating strategic algorithms in an actual ∞ight test is that implementing these algorithms require the development of many other lower-level subsystems which are not directly related to the strategic algorithms. This paper presents both an architecture and hardware implementation of a ground based, distributed testing environment that is used in the Autonomous Flight System Laboratory to test strategic level algorithms in an e‐cient manner. This system allows human interaction at very speciflc points to avoid developing a fully autonomous system, but still preserves the function and contributions of the strategic algorithm. This architecture and ground based testing facility greatly reduces development time and allows algorithms to be tested with little approximations before implementing them on a fully autonomous system.

This work considers algorithms for maritime search and surveillance missions. During these type of missions, an agent searches for a target using its various sensors. Performing target identiflcation and classiflcation of sensor returns is a crucial component of the mission. This paper investigates a system to process returns from a low dimensional sensor and automatically classify the data. This system uses an algorithm that employs the sensor and motion model of the agent to augment the limited data from the sensor. Several difierentiating features are then extracted and used to train various classiflers and machine learning algorithms.

The term Richter syndrome (RS) describes the transformation of chronic lymphocytic leukemia into a high-grade lymphoma. RS occurs in 3% to 10% of chronic lymphocytic leukemia cases, and its onset is often characterized by the abrupt development of systemic symptoms (eg, fever in the absence of infection, night sweats, and weight loss), progressive lymphadenopathy, and hepatosplenomegaly. RS frequently arises in the lymph nodes or bone marrow, and rarely presents with extranodal involvement, which includes the gastrointestinal tract, eye, testis, central nervous system, lung, kidney, and skin. We review the literature regarding the clinical course and treatment of RS, present a patient with primary cutaneous RS, and discuss the prognostic implications.

In typical search missions, the environment and the targets are not stationary and previous observations become less reliable as time progresses. In addition, the search is often initiated with only a rough idea of target location. In this work we consider a strategy for searching using a team of heterogeneous autonomous vehicles. The team members maintain a world model which includes the estimate of possible target states. The issue of compelling agents to converge on targets and to search unexplored regions is formulated as a model predictive control problem. The world model is propagated in time and strategic decisions are made autonomously based on its prediction. Agents formulate control decisions by optimizing an objective function which allows for control and timing constraints. Individual agents in the team are coupled to one another through the centralized occupancy based map. This coupling, in combination with the outlined search strategy, leads to an e‐cient, autonomous, and cooperative search.

This work considers autonomous coordination between two Unmanned Aerial Vehicles in orbit about a target, with the purpose of geo-locating the target. Wind signican tly aects the relative phase angle between the vehicles. Guidance algorithms are investigated to maintain an approximately constant phase angle in wind. A planar-kinematic aircraft model is proposed in which the eects of attitude dynamics and nonlinearities are considered. 1. NOMENCLATURE Course, [rad] Va Airspeed, [m/s] Vg Inertial speed, [m/s] Vo Nominal inertial speed, [m/s] Vw Windspeed, [m/s] p Clock angle, or bearing from orbit center, [rad] Heading, [rad] w Wind direction (from), [rad] ~ V Velocity, [m/s] xN North position [m] yE East position [m] R Radius of orbit, [m] Subscripts w Wind e Earth xed North-East-Down frame (NED) b Body xed frame 1; 2 Vehicle 1; 2

This work considers algorithms for maritime search and surveillance missions. Search and identiflcation of magnetic anomalies are evaluated. A combination of a particle fllter and a neural network are used to identify and classify anomalies. Communication among vehicles is assumed to update a centralized occupancy based map which represents a discretized belief of target locations. Control decisions are based on a nearest neighbor search of the surrounding cells of the occupancy map. Simulation is performed using a planar kinematic model and actual aeromagnetic data.

We examined the proliferative characteristics of 20 basal-cell carcinomas (BCCs) and 16 trichoepitheliomas (TEps) in an effort to understand and explore possible differences in their tumorigenic cell-cycle properties. These tumors were first compared for their expression of the nuclear proliferative protein Ki-67 and the tumor suppressor protein p53. We also compared the p53 downstream effector, p21(waf-1/cip-1), an inhibitor of cyclin-dependent kinases. The other p53-dependent, cyclin-dependent kinase inhibitor, p27(kip-1), has shown to be increased in TEps, which is consistent with this benign neoplasm's better-differentiated state. In our findings, we confirmed through immunohistochemical staining for Ki-67 that BCCs qualitatively showed a greater proliferative fraction compared to TEps (50.0 vs. 13.0%, p0.00001) as well as over-expression of p53 (2+ vs. 1+, p0.0008). BCCs marked by p21 demonstrated scattered nuclear positivity compared to the virtual absence of staining in the TEps (p0.019). In studying their cell-cycle properties, our findings suggest that abnormalities in the p53 pathway allow BCCs to obtain a growth advantage. We show that Ki-67 and p53 staining both appear useful in resolving challenging differential diagnoses and thereby help in directing appropriate treatment strategies.

Metastatic spread of malignancy to the joints is rare and only a few cases of solid tumors have been reported. We describe a patient with inflammatory arthritis of the knee and ankle secondary to metastatic gastric adenocarcinoma to the joints and bone diagnosed by synovianalysis. Arthritis secondary to metastatic cancer is a poor prognostic sign. The diagnosis is based on a strong clinical suspicion, magnetic resonance imaging, and joint fluid cytology or synovial biopsy.

Primary cutaneous infections with Nocardia asteroides are rare and have been reported in immunocompromised patients. Herein, we report a case of primary cutaneous Nocardia asteroides mycetoma of the skin in an immunocompetent individual. The infection was treated successfully with trimethoprim-sulfamethoxazole. Because a prolonged incubation time is required for the cultures and since additional biochemical tests are necessary for identification of this species, the clinician should alert the microbiology laboratory when such an infection is suspected clinically.

A 46-year-old Hispanic woman presented with a 3-year history of a gradually enlarging right upper quadrant abdominal mass. The serum alkaline phosphatase was 2496 IU/L (normal 13 to 126 IU/L). Computed tomography of the chest, abdomen, and pelvis revealed an enormous, densely calcified mass arising from the kidney with no evidence of metastases (Fig. 1). A bone scan demonstrated increased tracer activity in the area of the mass with no evidence of skeletal metastases (Fig. 2). Radical nephrectomy revealed an almost entirely ossified mass measuring 20.5 cm in its greatest dimension. The histopathologic examination revealed a high-grade malignant neoplasm with extensively calcified osteoid that had features of an osteosarcoma. On electron microscopy, the malignant neoplastic cells showed the presence of desmosomes, indicating epithelial derivation (Fig.

e17567 Background: Melanoma is a global problem. Since Caucasians are primarily affected by melanoma, most of the focus is on this cohort. In minorities, melanoma is usually associated with a worse...

Methylation of 5' CpG islands in promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of this study was to determine whether hypermethylation of the adenomatous polyposis coli (APC) gene promoter occurs in primary non-small cell lung cancer (NSCLC), and whether hypermethylated APC has any relationship with survival. APC promoter 1A methylation was determined in normal and corresponding tumor tissue from 91 NSCLC patients and in a control group of 10 patients without cancer, using a quantitative fluorogenic real-time PCR (Taqman) system. APC promoter methylation was detectable in 86 (95%) of 91 tumor samples, but also in 80 (88%) of 91 normal samples of NSCLC patients, and in only two (20%) of 10 normal lung tissues of the control group. The median level of APC promoter methylation was 4.75 in tumor compared to 1.57 in normal lung tissue (P