Medicinal Cannabis Use in Sickle Cell Anemia

Approximately 100,000 Americans suffer from sickle cell anemia (SCA), a severe hereditary form of anemia in which red blood cells can mutate into a sickled shape causing severe pain crises that can lead to ED visits, hospitalization, and negatively impact multiple organ systems. Pain crises greatly impact the quality of life for SCA patients. Living with SCA can be stressful and often affects patients’ mental health, causing anxiety or depression (National Heart, Lung, and Blood Institute, 2016). Opioids have been a treatment mainstay for the severe pain caused by SCA but the side effects of opioids, plus the risk of dependence, are issues that have led both patients and researchers to consider medicinal cannabis as a treatment option. While there is limited research addressing the treatment of sickle cell pain with cannabis some research does suggest that cannabis could have a beneficial effect on the management of both chronic pain and acute pain (Choo, Feldstein Ewing, & Lovejoy, 2016; Kroenke & Cheville, 2017). The aim of this study is to evaluate the association between medicinal cannabis use and quality of life for individuals with SCA. The primary goal of this pilot study is to gather a cohort of participants and administer a baseline survey that will be used in a larger study. The goal of the larger study is to assess the impact of medicinal cannabis available through Pennsylvania’s Department of Health-approved dispensaries in Philadelphia on the quality of life for individuals with sickle cell anemia (SCA)

Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.

Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit

E5501: phase II study of topotecan sequenced with etoposide/cisplatin, and irinotecan/cisplatin sequenced with etoposide for extensive-stage small-cell lung cancer.

PURPOSE: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC). METHODS: Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m(2)) on days 1, 2 and 3, etoposide (70 mg/m(2)) and cisplatin (20 mg/m(2)) (PET) on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m(2)) and cisplatin (20 mg/m(2)) on days 1 and 8 followed by etoposide (85 mg/m(2) PO bid) on days 3 and 10 (PIE) in a 3-week cycle. RESULTS: We enrolled 140 patients and randomized 66 eligible patients to each arm. Only 54.5 % of all patients completed the planned maximum 6 cycles. There were grade ≥3 treatment-related adverse events in approximately 70 % of the patients on both arms including 6 treatment-related grade 5 events. The overall response rates (CR + PR) were 69.7 % (90 % CI 59.1-78.9, 95 % CI 57.1-80.4 %) for arm A and 57.6 % (90 % CI 46.7-67.9, 95 % CI 44.8-69.7 %) for arm B. The median progression-free survival and overall survival were 6.4 months (95 % CI 5.4-7.5 months) and 11.9 months (95 % CI 9.6-13.7 months) for arm A and 6.0 months (95 % CI 5.4-7.0 months) and 11.0 months (95 % CI 8.6-13.1 months) for arm B. CONCLUSION: Sequential administration of topoisomerase inhibitors did not improve on the historical efficacy of standard platinum-doublet chemotherapy for extensive-stage SCLC

Racial Disparities in Head and Neck Cancers in an Urban Hospital

Introduction: Head and neck cancer incidence rates are higher for white residents in Philadelphia, while related mortality rates are highest for black residents. It is unclear how risk factors like HPV and smoking contribute to these disparities. The goal of this study is to determine which factors are associated with head and neck cancers in a diverse patient population from a Philadelphia hospital. Methods: Cancer registry data from Thomas Jefferson University was used to obtain records from 922 head and neck cancer patients. One patient of other race was excluded. Twenty in-situ cancer cases were excluded. Chi-square tests were used to examine categorical variables. Logistic and Cox regression models were designed to examine associations with advanced disease and time to mortality. Results: Our sample included 901 patients (769 white, 96 black, 36 Asian). Positive HPV status was most prevalent for white patients (p\u3c 0.0001). Oral cancers were most common among Asians (p\u3c.0001). In univariate analysis, black patients were most likely to die from their cancer. In multivariate analysis, time to death was shorter for current smokers (HR=1.95, CI=1.311-2.901) and former smokers (HR=2.94, CI=1.949-4.387). Positive HPV status was protective (HR=0.34, CI=.244-.481). No significant race effects were observed in multivariate analysis. Conclusions: Results suggest that race is not independently associated with head and neck cancer associated mortality. These results also suggest that some risk factors for head and neck cancer and outcomes may be modified by educational and behavioral interventions

Evolution of cooperation without reciprocity

A long-standing problem in biological and social sciences is to understand the conditions required for the emergence and maintenance of cooperation in evolving populations. For many situations, kin selection(1) is an adequate explanation, although kin-recognition may still be a problem. Explanations of cooperation between non-kin include continuing interactions that provide a shadow of the future (that is, the expectation of an ongoing relationship) that can sustain reciprocity(2-4), possibly supported by mechanisms to bias interactions such as embedding the agents in a two-dimensional space(4-6) or other context-preserving networks(7). Another explanation, indirect reciprocity(8), applies when benevolence to one agent increases the chance of receiving help from others. Here we use computer simulations to show that cooperation can arise when agents donate to others who are sufficiently similar to themselves in some arbitrary characteristic. Such a characteristic, or 'tag', can be a marking, display, or other observable trait. Tag-based donation can lead to the emergence of cooperation among agents who have only rudimentary ability to detect environmental signals and, unlike models of direct(3,4) or indirect reciprocity(9,10), no memory of past encounters is required.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62686/1/414441a0.pd

A Computational Approach for Designing Tiger Corridors in India

Wildlife corridors are components of landscapes, which facilitate the movement of organisms and processes between intact habitat areas, and thus provide connectivity between the habitats within the landscapes. Corridors are thus regions within a given landscape that connect fragmented habitat patches within the landscape. The major concern of designing corridors as a conservation strategy is primarily to counter, and to the extent possible, mitigate the effects of habitat fragmentation and loss on the biodiversity of the landscape, as well as support continuance of land use for essential local and global economic activities in the region of reference. In this paper, we use game theory, graph theory, membership functions and chain code algorithm to model and design a set of wildlife corridors with tiger (Panthera tigris tigris) as the focal species. We identify the parameters which would affect the tiger population in a landscape complex and using the presence of these identified parameters construct a graph using the habitat patches supporting tiger presence in the landscape complex as vertices and the possible paths between them as edges. The passage of tigers through the possible paths have been modelled as an Assurance game, with tigers as an individual player. The game is played recursively as the tiger passes through each grid considered for the model. The iteration causes the tiger to choose the most suitable path signifying the emergence of adaptability. As a formal explanation of the game, we model this interaction of tiger with the parameters as deterministic finite automata, whose transition function is obtained by the game payoff.Comment: 12 pages, 5 figures, 6 tables, NGCT conference 201

Learning and innovative elements of strategy adoption rules expand cooperative network topologies

Cooperation plays a key role in the evolution of complex systems. However, the level of cooperation extensively varies with the topology of agent networks in the widely used models of repeated games. Here we show that cooperation remains rather stable by applying the reinforcement learning strategy adoption rule, Q-learning on a variety of random, regular, small-word, scale-free and modular network models in repeated, multi-agent Prisoners Dilemma and Hawk-Dove games. Furthermore, we found that using the above model systems other long-term learning strategy adoption rules also promote cooperation, while introducing a low level of noise (as a model of innovation) to the strategy adoption rules makes the level of cooperation less dependent on the actual network topology. Our results demonstrate that long-term learning and random elements in the strategy adoption rules, when acting together, extend the range of network topologies enabling the development of cooperation at a wider range of costs and temptations. These results suggest that a balanced duo of learning and innovation may help to preserve cooperation during the re-organization of real-world networks, and may play a prominent role in the evolution of self-organizing, complex systems.Comment: 14 pages, 3 Figures + a Supplementary Material with 25 pages, 3 Tables, 12 Figures and 116 reference

The politics of regulatory enforcement and compliance: Theorizing and operationalizing political influences

There is broad consensus in the literature on regulatory enforcement and compliance that politics matters. However, there is little scholarly convergence on what politics is or rigorous theorization and empirical testing of how politics matters. Many enforcement and compliance studies omit political variables altogether. Among those that address political influences on regulatory outcomes, politics has been defined in myriad ways and, too often, left undefined. Even when political constructs are explicitly operationalized, the mechanisms by which they influence regulatory outcomes are thinly hypothesized or simply ignored. If politics is truly as important to enforcement and compliance outcomes as everyone in the field seems to agree, regulatory scholarship must make a more sustained and systematic effort to understand their relationship, because overlooking this connection risks missing what is actually driving regulatory outcomes. This article examines how the construct of “politics” has been conceptualized in regulatory theory and analyzes how it has been operationalized in empirical studies of regulatory enforcement and compliance outcomes. It brings together scholarship across disciplines that rarely speak but have much to say to one another on this subject in order to constitute a field around the politics of regulation. The goal is to sharpen theoretical and empirical understandings of when and how regulation works by better accounting for the role politics plays in its enforcement

Payer leverage and hospital compliance with a benchmark: a population-based observational study

<p>Abstract</p> <p>Background</p> <p>Since 1976, Medicare has linked reimbursement for hospitals performing organ transplants to the attainment of certain benchmarks, including transplant volume. While Medicare is a stakeholder in all transplant services, its role in renal transplantation is likely greater, given its coverage of end-stage renal disease. Thus, Medicare's transplant experience allows us to examine the role of payer leverage in motivating hospital benchmark compliance.</p> <p>Methods</p> <p>Nationally representative discharge data for kidney (<it>n </it>= 29,272), liver (<it>n </it>= 7,988), heart (<it>n </it>= 3,530), and lung (<it>n </it>= 1,880) transplants from the Nationwide Inpatient Sample (1993 – 2003) were employed. Logistic regression techniques with robust variance estimators were used to examine the relationship between hospital volume compliance and Medicare market share; generalized estimating equations were used to explore the association between patient-level operative mortality and hospital volume compliance.</p> <p>Results</p> <p>Medicare's transplant market share varied by organ [57%, 28%, 27%, and 18% for kidney, lung, heart, and liver transplants, respectively (<it>P </it>< 0.001)]. Volume-based benchmark compliance varied by transplant type [85%, 75%, 44%, and 39% for kidney, liver, heart, and lung transplants, respectively (<it>P </it>< 0.001)], despite a lower odds of operative mortality at compliant hospitals. Adjusting for organ supply, high market leverage was independently associated with compliance at hospitals transplanting kidneys (OR, 143.00; 95% CI, 18.53 – 1103.49), hearts (OR, 2.84; 95% CI, 1.51 – 5.34), and lungs (OR, 3.24; 95% CI, 1.57 – 6.67).</p> <p>Conclusion</p> <p>These data highlight the influence of payer leverage–an important contextual factor in value-based purchasing initiatives. For uncommon diagnoses, these data suggest that at least 30% of a provider's patients might need to be "at risk" for an incentive to motivate compliance.</p

The PDZ Protein Canoe/AF-6 Links Ras-MAPK, Notch and Wingless/Wnt Signaling Pathways by Directly Interacting with Ras, Notch and Dishevelled

Over the past few years, it has become increasingly apparent that signal transduction pathways are not merely linear cascades; they are organized into complex signaling networks that require high levels of regulation to generate precise and unique cell responses. However, the underlying regulatory mechanisms by which signaling pathways cross-communicate remain poorly understood. Here we show that the Ras-binding protein Canoe (Cno)/AF-6, a PDZ protein normally associated with cellular junctions, is a key modulator of Wingless (Wg)/Wnt, Ras-Mitogen Activated Protein Kinase (MAPK) and Notch (N) signaling pathways cross-communication. Our data show a repressive effect of Cno/AF-6 on these three signaling pathways through physical interactions with Ras, N and the cytoplasmic protein Dishevelled (Dsh), a key Wg effector. We propose a model in which Cno, through those interactions, actively coordinates, at the membrane level, Ras-MAPK, N and Wg signaling pathways during progenitor specification