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Patients undergoing oncology-related gynecologic surgical procedures experience substantial symptom burden and distress. Support from specialist palliative care teams may benefit these patients and their families; however, an evidence-informed approach to the integration of palliative care and gynecologic oncology is needed. To inform such an approach, a scoping review synthesizing current evidence on the palliative care needs of patients and families in gynecologic surgical oncology was performed. Reviewers performed a structured search of online databases CINAHL, Scopus, PsycINFO, MEDLINE, and PubMed in addition to the grey literature to identify relevant studies published between 2011 and June 11th, 2021. The original search identified 993 articles, which were dually screened for study inclusion, resulting in a final sample of articles from which data were systematically extracted and synthesized. This review of 59 publications predominantly consisted of European studies (n=26, 44.1%), described quantitative study methods (n=47, 79.6%), followed an observational study design (n=49, 83.1%), and focused on psychological impact of treatment as a major topic of study (n=21, 35.6%). The dataset also described sexual function of women post treatment (n= 15, 25.4%), quality of life (n=10, 16.9%), therapeutic decision making (n= 9, 15.2%), pain assessment (n=2, n=3.6%), and medication for symptom management (n=2, 3.6%). Explicit discussion of specialist palliative care involvement was rare. The needs of patients and families in gynecologic surgical oncology are well-suited to palliative care collaboration; however, the body of literature on palliative care services provided to this unique population is underdeveloped.

Multispecies models have existed in a fisheries context since at least the 1970s, but despite much exploration, advancement, and consideration of multispecies models, there remain limited examples of their operational use in fishery management. Given that species and fleet interactions are inherently multispecies problems and the push towards ecosystem-based fisheries management, the lack of more regular operational use is both surprising and compelling. We identify impediments hampering the regular operational use of multispecies models and provide recommendations to address those impediments. These recommendations are: (1) engage stakeholders and managers early and often; (2) improve messaging and communication about the various uses of multispecies models; (3) move forward with multispecies management under current authorities while exploring more inclusive governance structures and flexible decision-making frameworks for handling tradeoffs; (4) evaluate when a multispecies modelling approach may be more appropriate; (5) tailor the multispecies model to a clearly defined purpose; (6) develop interdisciplinary solutions to promoting multispecies model applications; (7) make guidelines available for multispecies model review and application; and (8) ensure code and models are well documented and reproducible. These recommendations draw from a global assemblage of subject matter experts who participated in a workshop entitled “Multispecies Modeling Applications in Fisheries Management”.

Background: Evidence suggests the usefulness of complementary and alternative medicine approaches, like neurofeedback and virtual reality, for the management of cancer-related pain and mood. It is not well-understood whether neurofeedback delivered through virtual reality is feasible and acceptable to patients actively undergoing cancer treatment. Objective: The purpose of this study was to explore the feasibility and acceptability of a nature-based virtual reality combined with neurofeedback as a non-pharmacologic strategy for managing cancer-related pain and anxiety. Methods: This study utilized a mixed-methods approach. Participants included 15 cancer patients undergoing treatment. Patients engaged in a 22-minute nature-based virtual reality experience, wearing a virtual reality headset with a Brainlink headband measuring EEG activity. Participants were asked to complete the Edmonton Symptom Assessment System revised version (ESAS-r) before (T1) and after (T3) the experience to measure pain and anxiety. They were asked their level of pain midway through the experience (T2) and completed a follow-up interview afterward. Results: This study revealed feasible delivery of a virtual reality intervention combined with neurofeedback for patients seeking cancer treatment. All participants (100%) completed the intervention experience. Patients report this is an acceptable approach to managing cancer-related pain and anxiety. Comparisons between patients’ pain scores at T1, T2, and T3 reveal statistically significant reductions in pain (p .001). Patients also report decreased depression and anxiety. Conclusion: This is the first study examining virtual reality combined with neurofeedback as a non-pharmacologic intervention for managing cancer symptoms during treatment. The study reveals it is a promising for managing cancer-symptoms.

supplemental figure legends

Figure S1. Components of EnCore-A; Figure S2. Silencing of CTNNB1 mRNA after single-dose or multiple-dose regimens; Figure S3: Comparable activity achieved with a payload with 2'F modifications; Figure S4. Tumor growth inhibition in multiple subcutaneous xenograft models; Figure S5. No efficacy observed in APC/CTNNB1 wild-type RKO tumors; Figure S6. ApoE-independent DsiRNA delivery to primary and metastatic tumors; Figure S7. Detection of cleaved CTNNB1 mRNA by 5'RACE-Seq; Figure S8. EnCore-mediated delivery to CTNNB1/YAP-driven hepatoblastoma; Figure S9: Tolerability profile of EnCore-R/CTNNB1 DsiRNA in nonhuman primates.

Despite wide recognition as a disease of pandemic proportions, effective treatments for nonalcoholic fatty liver disease (NAFLD) remain elusive. Most of the current clinical programs aim to reduce hepatic fat accumulation and, thus, prevent downstream inflammation and fibrosis. To date, this therapeutic approach has helped identify a potential disconnect between steatosis reduction and disease resolution. Mounting preclinical evidence indicates liver inflammation may play a major role in steatosis development and fibrosis but has not garnered the same clinical representation. This may be owing to deficiencies in standard therapeutic modalities that limit their application in NAFLD. RNA interference (RNAi) is an attractive approach to targeting liver inflammation owing to its clinical safety profile, target specificity, and limited biodistribution. In this study, we characterize a simple cholesterol-short-interfering RNA (siRNA) conjugate system targeting

The translation of evidence-based interventions into routine hospice care is impeded by numerous barriers, including a disconnect between research priorities and clinical care. To inform the development of a more practice-informed agenda for hospice intervention research, our team conducted a qualitative descriptive study, posing the following research questions: 1) How do hospice staff members describe their most significant work-related challenges? and 2) What regulatory changes do hospice staff members report would most improve hospice care? To answer these research questions, we interviewed 22 hospice staff members and then conducted a template analysis of the interview content. In doing so, we identified themes that described challenges in 5 key areas: time, documentation, professional roles, recruitment and retention, and burn-out. In addition, we identified a perceived need among hospice staff members for more regulatory flexibility and clarity. Based on our findings, we conclude that a practice-informed agenda for hospice intervention research includes the development and testing of interventions that increase efficiency, explicitly speak to the humanity of hospice care, and elevate the roles of all members of the interdisciplinary team.

Mechatronic system design is multidisciplinary and integration among the mechanical, sensor, actuator, electronic, computer, and control elements is essential. The integration is done simultaneously from the start of the design process and the design is model-based. Modeling, physical and mathematical, is the key in modern engineering practice. Accurate motion control and energy efficiency in industrial machines heavily depend on trajectory planning and the appropriate selection of the motors controlling the axes of the machine. A model-based design approach is proposed for (1) trajectory planning that leads to accurate positioning and energy efficiency and (2) optimized selection of motors prior to building a prototype. As planar positioning is an important task in industrial applications, a two-axis, single-beltdriven, H-frame planar positioning robot called an H-Bot was built. The proposed approach is demonstrated via modeling, analysis, control-design simulation using MatLab / Simulink, and hardware implementation using the Arduino and LabVIEW MyRIO.

Context : Hospitalization provides an opportunity to address end-of-life care (EoLC) preferences if patients at risk of death can be accurately identified while in the hospital. The modified Hospital One-Year Mortality Risk (mHOMR) uses demographic and admission data in a logistic regression algorithm to identify patients at risk of death one year from admission. Objective : This project sought to validate mHOMR and identify superior models. Methods : The mHOMR model was validated using historical data from an academic health system. Alternative logistic regression and random forest (RF) models were developed using the same variables. Receiver operating characteristic (ROC) and precision recall curves were developed, and sensitivity, specificity, and positive and negative predictive values were compared over a range of model thresholds. Results : The RF model demonstrated higher area under the ROC curve (0.950, 95% CI 0.947-0.954) as compared to the logistic regression models (0.818 [95% CI 0.812-0.825] and 0.841 [95% CI 0.836-0.847]). Area under the precision recall curve was higher with the random forest model compared to the logistic regression models (0.863 versus 0.458 and 0.494, respectively). Across a range of thresholds, the RF model demonstrated superior sensitivity, equivalent specificity, and higher positive and negative predictive values. Conclusion : A machine learning RF model, using common demographic and utilization data available on hospital admission, identified inpatients at risk of death more effectively than logistic regression models using the same variables. Machine learning models have promise for identifying admitted patients with elevated one-year mortality risk, increasing opportunities to prompt discussion of EoLC preferences.

Recreational fishing is increasingly recognised as an important source of mortality for marine fish populations. In the United States, estimates of marine recreational catch and effort were recently revised for the time period 1981 and beyond, and for many species, the revised estimates were substantially higher than the original values. Here, the proportion of total landings that came from the recreational sector in the Southeast US Atlantic was quantified. The proportions for 22 oceanic species and for all species combined were computed, using a full time series of landings (1981–2016) and a more recent time series (1999–2016). For the full and recent time series, landings of most species (15/22 and 17/22, respectively) were dominated by the recreational sector. For all species combined, 71% of landings in the full time series were from the recreational sector, and 76% in the recent time series. Trend analysis indicated that most species had a stable or increasing proportion of landings from the recreational sector. In addition, stock assessments were conducted on four species, and the catch revisions increased the estimated scale of abundance and, in some cases, affected stock or fishery status. This work underscores the importance of recreational fishing for marine resource management.

As individuals’ relationships with information technology (IT) grow more complex and personal, our understanding of the problem of resistance to IT continues to evolve. Current approaches to resist...

Mechatronic system design is multidisciplinary and integration among the mechanical, sensor, actuator, electronic, computer, and control elements is essential. The integration is done simultaneously from the beginning and the design is model-based. Modeling, physical and mathematical, is the key in modern engineering practice. Before any hardware is purchased or built, a complete, computer virtual prototype is created to meet all performance specifications. Only then can an actual hardware prototype be built. Mechatronics students need to perform, need to experience, this process before graduation. It is all about the process, as they will be asked to apply the process to challenging problems. Modern machines are complex and computer-controlled, but most are made up of mechanisms. In this course, senior mechanical engineering students choose a mechanism to perform a certain task. They then apply the process to create the virtual and hardware prototypes to meet performance specifications, just like real mechatronics engineers.

Coastal acidification in southeastern U.S. estuaries and coastal waters is influenced by biological activity, run-off from the land, and increasing carbon dioxide in the atmosphere. Acidification can negatively impact coastal resources such as shellfish, finfish, and coral reefs, and the communities that rely on them. Organismal responses for species located in the U.S. Southeast document large negative impacts of acidification, especially in larval stages. For example, the toxicity of pesticides increases under acidified conditions and the combination of acidification and low oxygen has profoundly negative influences on genes regulating oxygen consumption. In corals, the rate of calcification decreases with acidification and processes such as wound recovery, reproduction, and recruitment are negatively impacted. Minimizing the changes in global ocean chemistry will ultimately depend on the reduction of carbon dioxide emissions, but adaptation to these changes and mitigation of the local stressors that exacerbate global acidification can be addressed locally. The evolution of our knowledge of acidification, from basic understanding of the problem to the emergence of applied research and monitoring, has been facilitated by the development of regional Coastal Acidification Networks (CANs) across the United States. This synthesis is a product of the Southeast Coastal and Ocean Acidification Network (SOCAN). SOCAN was established to better understand acidification in the coastal waters of the U.S. Southeast and to foster communication among scientists, resource managers, businesses, and governments in the region. Here we review acidification issues in the U.S. Southeast, including the regional mechanisms of acidification and their potential impacts on biological resources and coastal communities. We recommend research and monitoring priorities and discuss the role SOCAN has in advancing acidification research and mitigation of and adaptation to these changes.

Since the underutilization of technology often prevents organizations from reaping expected benefits from IT investments, an increasing body of literature studies how to elicit value-added, post-adoptive IT use behaviors. Such behaviors include extended and innovative feature use, both of which are exploratory in nature and can lead to improved work performance. Since these exploratory behaviors can be risky, research has directed attention to trust in technology as an antecedent to post-adoptive IT use. In parallel, research has examined how computer self-efficacy relates to post-adoptive IT use. While such research has found that both trust and efficacy can lead to value-added IT use and that they might do so interdependently, scant research has examined the interplay between these antecedents to post-adoptive IT use. Drawing on the Model of Proactive Work Behavior with a focus on its predictions about trust and efficacy, we develop a research model that integrates trust in technology and computer self-efficacy in the post-adoption context. Our model suggests that the two concepts are interdependent such that trust-related impacts on post-adoptive use behaviors unfold via computer-related self-efficacy beliefs. Contemporary tests of mediation on data from more than 350 respondents provided support for our model. Hence, our findings begin to open the black box by which trust-related impacts on post-adoptive behaviors unfold, revealing computer self-efficacy as an important mediating factor. In doing so, this study furthers understanding of how, and why, trust matters in post-adoptive usage, enabling strategic change management by elucidating the “fit” between technological characteristics and post-adoptive usage.

Oligonucleotide therapeutics have the potential to change the way disease is treated due to their ability to modulate gene expression of any therapeutic target in a highly specific and potent manner. Unfortunately, this drug class is plagued with inherently poor pharmacological characteristics, which need to be overcome. The development of a chemical modification library for oligonucleotides has addressed many of the initial challenges, but delivery of these payloads across plasma membranes remains difficult. The latest technological advances in oligonucleotide therapeutics utilizes direct conjugation to targeting ligands, which has improved bioavailability and target tissue exposure many-fold. The success of this approach has resulted in numerous clinical programs over the past 5 years.We review the literature on oligonucleotide conjugate strategies which have proven effective preclinically and clinically. We summarize the chemical modifications which allow parenteral administration as well as evaluate the efficacy of a multitude of conjugate approaches including lipids, peptides, carbohydrates, and antibodies.The success of future conjugate strategies will likely rely on the effective combination of characteristics from earlier technologies. High-affinity ligand-receptor interactions can be critical to achieving meaningful accumulation in target tissues, but pharmacokinetic modulators which increase the circulating half-life may also be necessary. Synthesis of these approaches has the potential to bring the next breakthrough in oligonucleotide therapeutics.

Context Shared decisions between health care providers and patients and families are replacing the traditional physician-driven plans of care. Hospice philosophy recognizes the patient and family as a unit of care and embraces their role in decision making. Objective The goal of this study was to evaluate the shared decisions between hospice nurses and patients and family members. Methods A secondary analysis of audio recordings of 65 home hospice nurse visits from 65 home hospice nurse visits in 11 different U.S. hospice programs. Results To varying degrees, hospice nurses used all the recommended elements of shared decision making during home visits with patients and families; however, not all elements were used in every visit. The most commonly used element was defining a problem, and the least used element was the assessment of patient and family understanding. Conclusions Hospice staff can benefit from a more purposeful shared decision-making process and a greater focus on assessment of patient and family understanding and ability to implement plans of care.

Fish demography and the behavior of fishing fleets can vary across fine spatial and temporal scales, generating dynamic patterns of harvest that can impact both fishery yield and the conservation of stock biomass. We conducted a paired tag return experiment in spatially distinct estuarine fisheries during two consecutive years to examine temporal and spatial variation in harvest of a commercially exploited flatfish, the Southern Flounder Paralichthys lethostigma, in North Carolina. Monthly rates of instantaneous fishing mortality (F) varied across the fishing season in different ways, thus generating differences in total F between the two systems despite the fact that the fishery was concentrated in the warmer months and was dominated by the same gear in both systems. Recent patterns in fishing effort among gears and water bodies throughout the state illustrated seasonal and spatial variation that was produced mainly by gear type. Although current regulations in the Southern Flounder fishery recog...

Quantifying the population-level effects of hypoxia on coastal fish species has been challenging. In the companion paper (part 1), we described an individual-based population model (IBM) for Atlantic croaker in the northwestern Gulf of Mexico (NWGOM) designed to quantify the long-term population responses to low dissolved oxygen (DO) concentrations during the summer. Here in part 2, we replace the idealized hypoxia conditions with realistic DO concentrations generated from a 3-dimensional water quality model. Three years were used and randomly arranged into a time series based on the historical occurrence of mild, intermediate, and severe hypoxia year types. We also used another water quality model to generate multipliers of the chlorophyll concentrations to reflect that croaker food can be correlated to the severity of hypoxia. Simulations used 100 years under normoxia and hypoxia conditions to examine croaker population responses to the following: (1) hypoxia with food uncoupled and coupled to the severity of hypoxia, (2) hypoxia reducing benthos due to direct mortality, (3) how much hypoxia would need to be reduced to offset decreased croaker food expected under 25 and 50% reduction in nutrient loadings, and (4) key assumptions about avoidance movement. Direct mortality on benthos had no effect on long-term simulated croaker abundance, and the effect of hypoxia (about a 25% reduction in abundance) was consistent whether chlorophyll (food) varied with hypoxia or not. Reductions in hypoxia needed with a 25% reduction in nutrient loadings to result in minimal loss of croaker is feasible, and the croaker population will likely do as well as possible (approach abundance under normoxia) under the 50% reduction in nutrient loadings. We conclude with a discussion of why we consider our simulation-based estimates of hypoxia causing a 25% reduction the long-term population abundance of croaker in the NWGOM to be realistic and robust.

We developed a spatially explicit, individual-based model to analyze how hypoxia effects on reproduction, growth, and mortality of Atlantic croaker in the northwestern Gulf of Mexico lead to population-level responses. The model follows the hourly growth, mortality, reproduction, and movement of individuals on a 300 × 800 spatial grid of 1-km2 cells for 140 years. Chlorophyll-a concentration, water temperature, and dissolved oxygen (DO) were specified daily for each grid cell and repeated for each year of the simulation. A bioenergetics model was used to represent growth, mortality was assumed stage- and age-dependent, and the movement behavior of juveniles and adults was modeled based on temperature and avoidance of low DO. Hypoxia effects were imposed using exposure effect submodels that converted time-varying exposures to low DO to reduced hourly growth, increased hourly mortality, and reduced annual fecundity. Results showed that 100 years of either mild or intermediate hypoxia produced small reductions in population abundance, while repeated severe hypoxia caused a 19% reduction in long-term population abundance. Relatively few individuals were exposed to low DO each hour, but many individuals experienced some exposure. The response was dominated by a 5% average reduction in annual fecundity of individuals. Under conditions of random sequences of mild, intermediate, and severe hypoxia years occurring in proportion to their historical frequency, the model predicted a 10% decrease in the long-term population abundance of croaker. A companion paper substitutes hourly DO values from a three-dimensional water quality model for the idealized hypoxia and results in a more realistic population reduction of about 25%.

The macrobenthos and megabenthos responses to long-term, recurring hypoxia on the Louisiana continental shelf were compared at four locations with different historical (2000-2010) episodes of annual exposure to bottom-water hypoxia. Measurements of abundance, biomass, species diversity, and community composition of the two size classes of benthos suggested that the macrobenthic response is driven chiefly by tolerance to hypoxia, whereas the megabenthic response was affected by the ability to migrate and the availability/unavailability of macrobenthos prey at the sediment surface. The site exposed to the historically lowest average bottom-water dissolved oxygen (BWDO) concentration exhibited the lowest species diversity for macrobenthos and the highest species diversity for megabenthos, exemplifying the differential effects of hypoxia on different size classes. The high diversity and smaller average size of the megabenthos at the lowest DO site was due to high abundance of invertebrates and a preponderance of small, less vagile fishes that appeared to remain in the area after larger dominant sciaenids had presumably emigrated. The average size and the depth of habitation in the sediment of macrobenthos prey may have also influenced the abundance and biomass of megabenthos foragers.

The aim of this retrospective study was to determine whether an inpatient approach and the use of regional anaesthesia techniques can accelerate the recovery to normal functions in children with Complex Regional Pain Syndrome (CRPS). This study looked at the data of patients admitted to the rehabilitation unit with a diagnosis of CRPS from January 2010 to April 2015. Variables such as hospital stay, medications administered, regional anaesthesia procedures, changes in functional status prior to treatment and at the time of discharge, psychological evaluation and diagnosis were evaluated. A total of 31 patients (21 females and 10 males) were admitted with a diagnosis of CRPS 1 and 2. In all, 97% of the patients received a peripheral or central nerve catheter for an average of 4 days with pain scores of Verbal Numeric Scale (VNS) score = 1.0 ± 0.7 and an average length of hospital stay of 8.2 ± 2.6 days. The modified Functional Independence Measure for Children (WeeFIM) scores and Canadian Association of Occupational Therapists tests significantly improved at the time of hospital discharge, as well as their pain scores, which decreased from 8.2 ± 2 to 1.6 ± 3. In conclusion, these data suggest that the use of regional anaesthesia techniques and an intensive inpatient rehabilitation programme could accelerate the recovery of children with CRPS.

Objective:Researchers sought to determine the extent to which burden related to patients' symptom subtypes could predict informal hospice caregiver depression, and to illustrate the differences between caregivers who experience suicidal ideation and those who do not.Method:Informal caregivers recruited from a not-for-profit community-based hospice agency participated in a cross-sectional survey. Self-report questionnaires assessed caregiver burden associated with patient symptomatology (via a modified version of the Memorial Symptom Assessment Scale–Short Form) and caregiver depressive symptoms, including suicidal ideation (measured by the Patient Health Questionnaire–9). Multiple regressions evaluated the unique predictability of patients' symptom subtypes on caregiver depression. Exploratory analyses examined mean differences of study variables between participants who did and did not endorse suicidal ideation.Results:Caregiver burden related to patients' psychological symptoms accounted for significant variance in caregiver depression scores when controlling for burden related to physical symptoms. Among 229 caregivers (M age = 61.4 years), 12 reported suicidal ideation, where 6 of the 12 were male, despite male caregivers comprising less than 20% of the total sample.Significance of results:Burden associated with patients' psychological symptoms uniquely contributed to caregiver depression, further highlighting the clinical utility and necessity for hospice providers to address the emotional needs of patients and their caregivers alike. Developing clinical procedures to identify and respond to such needs would not only behoove hospice agencies, but it would likely enhance the caregiving experience holistically, which might be particularly imperative for male caregivers.

ObjectiveHospice nurses frequently encounter patients and families under tremendous emotional distress, yet the communication techniques they use in emotionally charged situations have rarely been investigated. In this study, researchers sought to examine hospice nurses’ use of validation communication techniques, which have been shown in prior research to be effective in supporting individuals experiencing emotional distress.MethodResearchers performed a directed content analysis of audiorecordings of 65 hospice nurses’ home visits by identifying instances when nurses used validation communication techniques and rating the level of complexity of those techniques.ResultAll nurses used validation communication techniques at least once during their home visits. Use of lower level (i.e., more basic) techniques was more common than use of higher level (i.e., more complex) techniques.Significance of ResultsAlthough hospice nurses appear to use basic validation techniques naturally, benefit may be found in the use of higher level techniques, which have been shown to result in improved clinical outcomes in other settings.

PURPOSE/OBJECTIVES: Family caregivers of individuals living with cancer are often highly involved in communication with healthcare teams, yet little is known about their experiences, needs, and preferences in this role. To address this gap in the knowledge base, researchers sought to explore family caregivers’ perspectives on communication with oncology care providers. DESIGN AND METHODS: Researchers conducted a secondary inductive thematic analysis of qualitative interviews originally collected as part of a randomized clinical trial of a supportive intervention for family caregivers of patients with cancer (N = 63). PARTICIPANTS: Participants were family caregivers of adult patients with cancer. Most were patients’ spouses/long-term partners (52.3%) or adult children/grandchildren (29.2%). Caregivers of patients with all cancer types and stages of disease progression were eligible for study enrollment. FINDINGS: Caregivers valued communication with healthcare providers who were attentive, genuine, broadly focused on patients and caregivers’ experiences, sensitive to unmet information needs, and responsive to the potentially different communication preferences of patients and caregivers. INTERPRETATION: Family caregivers expressed a strong preference for person-centered communication, conceptualized as communication that helps healthcare providers meet the needs of patients and caregivers both as individuals and as an interdependent unit of care, and that acknowledges individuals’ experiences beyond their prescribed roles of “cancer patient” and “caregiver.” IMPLICATIONS FOR PSYCHOSOCIAL ONCOLOGY PRACTICE: Psychosocial oncology providers’ strong orientation to the biopsychosocial and spiritual aspects of cancer care delivery make them uniquely positioned to support family caregivers. Findings suggest that providers should explicitly communicate their commitment to both patient and family care, involve family caregivers in psychosocial assessment activities and subsequent intervention, and strive to honor patients and caregivers’ potentially different communication preferences.

Catchability relates fishing effort to fishing mortality, and is an important component in fishery stock assessment models. Mis-specifying catchability can lead to inaccurate estimation of model parameters and bias in the determination of stock status. The Gulf of Mexico has one of the largest seasonal occurrences of hypoxia in the world and it overlaps in time and space with the Gulf menhaden Brevoortia patronus fishery, potentially leading to temporal and spatial patterns in stock distribution and thus catchability. These patterns are not currently modeled in the Gulf menhaden stock assessment. To better understand the implications of spatial and temporal patterns in catchability due to hypoxia, we constructed an operating model of Gulf menhaden fishery dynamics under various assumptions of spatial coverages and temporal patterns, and used the output from the operating model as input into estimation models with alternative approaches on modeling catchability. Under the most extreme assumptions about the spatial coverage and magnitude of variation in catchability, median absolute error in estimates of fishing mortality and spawning stock reference points (F30% and S30%) was 73% and 29%, respectively, and median absolute error in estimates of fishing mortality and spawning stock based stock status was 23% and 79%, supporting the notion that errors in catchability are important. Under more reasonable assumptions, median absolute error declined to 20% and 2.9% for F30% and S30%, respectively, and to 3.8% and 2.4% for fishing mortality and spawning stock-based stock status, respectively. Modeling catchability as a random walk further reduced median absolute error to 5.0% for F30% and 1.4% for S30%, but slightly increased median absolute error for stock status indicators to 4.0% and 3.3%. Our results show generally that the spatial coverage, temporal pattern, and estimation approach of catchability affects the influence of mis-specifying catchability; and show specifically that the Gulf menhaden stock assessment is robust to the effects of hypoxia on catchability if assuming random-walk catchability.

The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level and therefore can be applied to previously undruggable targets. Lipid nanoparticles (LNP) represent an elegant solution for the delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens, and identify efficacious combinations with standard-of-care therapeutics. Mol Cancer Ther; 15(9); 2143–54. ©2016 AACR.

Nearly every summer, a large hypoxic zone forms in the northern Gulf of Mexico. Research on the causes and consequences of hypoxia requires reliable estimates of hypoxic extent, which can vary at submonthly time scales due to hydro-meteorological variability. Here, we use an innovative space-time geostatistical model and data collected by multiple research organizations to estimate bottom-water dissolved oxygen (BWDO) concentrations and hypoxic area across summers from 1985 to 2016. We find that 27% of variability in BWDO is explained by deterministic trends with location, depth, and date, while correlated stochasticity accounts for 62% of observational variance within a range of 185 km and 28 days. Space-time modeling reduces uncertainty in estimated hypoxic area by 30% when compared to a spatial-only model, and results provide new insights into the temporal variability of hypoxia. For years with shelf-wide cruises in multiple months, hypoxia is most severe in July in 59% of years, 29% in August, and 12% in June. Also, midsummer cruise estimates of hypoxic area are only modestly correlated with summer-wide (June-August) average estimates ( r

Objective In response to the well-documented need for evidence-based cancer caregiver support, we examined the feasibility of problem-solving therapy for family caregivers of cancer patients receiving outpatient palliative care and investigated the impact of problem-solving therapy on family caregivers' anxiety, depression, and quality of life. Methods We conducted a feasibility study of a structured problem-solving therapy intervention delivered to family caregivers of cancer patients receiving outpatient palliative care from an academic health center in the Midwestern United States. Participants (N = 83) were randomly assigned to receive usual care or usual care plus a problem-solving therapy intervention, which was delivered over three sessions via web-based videoconferencing or telephone. Descriptive statistics were used to determine feasibility relative to recruitment, retention, and fidelity to core intervention components. Outcome data were analyzed using ordinary least squares multiple regression. Results Problem-solving therapy for family caregivers of patients with cancer was found to be highly feasible in the outpatient palliative care setting. Caregivers who received problem-solving therapy reported less anxiety than those who received only usual care (P = 0.03). No statistically significant differences were observed for caregiver depression (P = 0.07) or quality of life (P = 0.06). Conclusions Problem-solving therapy is a feasible and promising approach to reducing cancer family caregivers' anxiety in the outpatient palliative care setting. Further testing in multiple sites is recommended.

Wnt/β-catenin signaling mediates cancer immune evasion and resistance to immune checkpoint therapy, in part by blocking cytokines that trigger immune cell recruitment. Inhibition of β-catenin may be an effective strategy for increasing the low response rate to these effective medicines in numerous cancer populations. DCR-BCAT is a nanoparticle drug product containing a chemically optimized RNAi trigger targeting CTNNB1, the gene that encodes β-catenin. In syngeneic mouse tumor models, β-catenin inhibition with DCR-BCAT significantly increased T cell infiltration and potentiated the sensitivity of the tumors to checkpoint inhibition. The combination of DCR-BCAT and immunotherapy yielded significantly greater tumor growth inhibition (TGI) compared to monotherapy in B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma, and Renca renal adenocarcinoma. Response to the RNAi-containing combination therapy was not dependent on Wnt activation status of the tumor. Importantly, this drug combination was associated with elevated levels of biomarkers of T cell-mediated cytotoxicity. Finally, when CTLA-4 and PD-1 antibodies were combined with DCR-BCAT in MMTV-Wnt1 transgenic mice, a genetic model of spontaneous Wnt-driven tumors, complete regressions were achieved in the majority of treated subjects. These data support RNAi-mediated β-catenin inhibition as an effective strategy to increase response rates to cancer immunotherapy., Graphical Abstract, Immune checkpoint inhibitors including PD-(L)1 antibodies have shown great potential for treating diverse human cancers, but relatively few patients achieve durable responses. Using murine tumor models, Ganesh et al. demonstrate that co-treatment with an optimized β-catenin-targeting RNAi agent increases sensitivity to immunotherapy by promoting the infiltration of cytotoxic T cells.

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This thesis was digitised by the British Library from microfilm. You can acquire a single copy of this thesis for research purposes by clicking on the padlock icon on the thesis file. Please be aware that the text in the supplied thesis pdf file may not be as clear as text in a thesis that was born digital or digitised directly from paper due to the conversion in format. However, all of the theses in Apollo that were digitised from microfilm are readable and have been processed by optical character recognition (OCR) technology which means the reader can search and find text within the document. If you are the author of this thesis and would like to make your work openly available, please contact us: thesis@repository.cam.ac.uk

Colorectal carcinomas harbor well-defined genetic abnormalities, including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. Although the MAPK pathway can be targeted using potent small-molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNAi approaches have advanced to the stage of clinical viability and are especially well suited for transcriptional modulators, such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacologic agents. Using a recently described tumor-selective nanoparticle containing a β-catenin–targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of colorectal cancer, melanoma, and hepatocellular carcinoma. At dose levels that were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing colorectal cancer liver metastases. In addition, pharmacologic silencing of β-catenin mRNA was effective against tumors that are inherently resistant or that acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations. Mol Cancer Ther; 17(2); 544–53. ©2017 AACR.

The next 30 years are going to be challenging for organizations as they need to transition to a workforce that is rapidly growing older. As the workforce is growing older, the age of organizational technology users is an important aspect to examine in the context of organizational information systems (IS). The corresponding IS literature has largely assumed that age is an impediment or disadvantage when using modern information and communication technologies (ICTs) and has, thus, directed attention to the challenges faced by older technology users in the workforce. However, such research has not examined the potential benefits of an older workforce in terms of a possibly higher task performance under certain workplace conditions, such as employees’ subject-area knowledge and the design of the ICT interface. Hence, this paper examines age-related differences in the use of organizational ICTs in terms of the propensity that different age groups have toward performance in the form of mistake-making when searching for information. To do so, the paper forms hypotheses that explain how the combination of age, subject-area knowledge, and system interface lead individuals to make mistakes in a technology-enabled context. Drawing on a laboratory experiment using 107 older and younger technology users, we evaluated the three-way interaction of age, subject-area knowledge, and interface design. Our results demonstrate that—under certain conditions—age is not the detriment that it is widely believed to be. The implications of this finding are explored in relation to the “graying of the workforce” that all OECD countries are currently experiencing.

An improved understanding of the spatial structure and movements of harvested populations can promote more efficient management of marine resources. Conventional tagging is a valuable approach to study the movements of marine fishes due to its relatively low expense and the typically broad spatial extent over which movements can be characterized. We present the findings of multiple tag return studies initiated in the estuaries of North Carolina during the past two decades to better understand habitat residency and migration patterns of Southern Flounder Paralichthys lethostigma, an economically important marine flatfish in the southeastern USA. Tag return data indicated large-scale (>50 km) movements of relatively large fish in the fall, which were presumably associated with offshore winter spawning migrations. Nearly all Southern Flounder that demonstrated large-scale movement were recovered to the south of the system in which they were tagged, suggesting that the spawning activity of fish using ...

Coastal hypoxia (dissolved oxygen ≤ 2 mg/L) is a growing problem worldwide that threatens marine ecosystem services, but little is known about economic effects on fisheries. Here, we provide evidence that hypoxia causes economic impacts on a major fishery. Ecological studies of hypoxia and marine fauna suggest multiple mechanisms through which hypoxia can skew a population’s size distribution toward smaller individuals. These mechanisms produce sharp predictions about changes in seafood markets. Hypoxia is hypothesized to decrease the quantity of large shrimp relative to small shrimp and increase the price of large shrimp relative to small shrimp. We test these hypotheses using time series of size-based prices. Naive quantity-based models using treatment/control comparisons in hypoxic and nonhypoxic areas produce null results, but we find strong evidence of the hypothesized effects in the relative prices: Hypoxia increases the relative price of large shrimp compared with small shrimp. The effects of fuel prices provide supporting evidence. Empirical models of fishing effort and bioeconomic simulations explain why quantifying effects of hypoxia on fisheries using quantity data has been inconclusive. Specifically, spatial-dynamic feedbacks across the natural system (the fish stock) and human system (the mobile fishing fleet) confound “treated” and “control” areas. Consequently, analyses of price data, which rely on a market counterfactual, are able to reveal effects of the ecological disturbance that are obscured in quantity data. Our results are an important step toward quantifying the economic value of reduced upstream nutrient loading in the Mississippi Basin and are broadly applicable to other coupled human-natural systems.