APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation

Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus – Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT;ApcMin/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT;ApcMin/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT;ApcMin/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance

Rethinking zoning for people: Utilizing the concept of the village

In this chapter, we propose it is time to re-think and re-imagine how we approach zoning. This is especially true for suburban developments. Today, especially in the United States, zoning in suburban areas is being used to segregate and separate the component parts of our communities into distinct zones which are spread out geographically and in most cases require the daily use of an automobile. The negative consequences of this form of development for health, community and the environment are discussed. Using a study of neighborhoods in Dublin, Ireland and its suburbs we examine how professionals and the public view the places they live and connect these perspectives to the manner in which zoning has changed over the course of the twentieth century. Insights from these professionals and the public lead us to propose that planners, engineers and developers be expected to think more about the kinds of walkable village neighborhoods that people seem to be drawn to almost instinctively. We urge that zoning laws be re-purposed to enable the building of communities that people prefer to live in

Impact of using commercially prepared specialty exams as clinical course final exams

The presentation will describe a pilot study on the use of commercially prepared specialty exams as course final exams to improve students\u27 scores. Positive results led to a policy change regarding the use of these commercially prepared exams as final exams in clinical courses

Nursing student simulation: A three-tiered model approach

Introduction: Simulation has long been used as training in nonmedical facilities1. In nursing, it has had many definitions. The oldest definition found is using models to teach basic skills 1. As simulation technology grows, changes, and improves, so does the need to clearly define terms and how we use them. Simulation, presently, includes varying degrees of interaction. Examples include low-fidelity models (LFM) which has limited function/interaction (task-trainer intravenous (IV) arms for IV insertion); medium-fidelity mannequin (MFM), (chest model illustrating heart rhythms); high-fidelity mannequin (HFM), (full-bodied mannequin, fully functioning, mimicking a living patient)2,3; and standardized patients (SP), (live persons participating in a scenario)4. Technologically-enriched learning through simulation lab activity enhances personal and professional confidence. Simulations promote teamwork through communication and collaboration5. Students stated they enjoy the simulation lab activity and prepares them for the real world clinical environment. Students enter their roles with explored senses of patient care needs, and clinical expectations. This produces confidence and decreases situational anxiety6. Patient safety has improved since the seeds of critical thinking skills have been planted and sprouted in the real clinical environment. Medication errors are identified and corrected during simulation learning7. Usefulness of differing simulation mediums in student education needs to be fully explored, well-documented, and clearly defined. Recommendations for use of differing simulation methods are dependent on learning objectives and the level of the student 8. The purpose of this research is to disseminate how one baccalaureate-nursing program in a highly diverse, liberal-arts university with novice simulation technicians and faculty defined various methods of simulation, students response to various methods, and recommendations for use. Background: Partnership with a senior baccalaureate-nursing program with expert simulation technicians and faculty occurred so lab facilitators/faculty could shadow simulations and explore laboratory function to enhance simulation development and experience with novice users. A hospital clinical rotation preparation simulation was developed in Fall 2015, it was well received by students; however, technical limitations warranted close examination for modifications. High-intensity simulations were used in Spring 2016. Categorization, definitions, and learning objectives for simulation was needed for clarity across the program. Methods: Faculty developed an introductory simulation, Fall 2015 for the adult/older adult medical surgical course, in addition to already existing laboratory skills with LFM. Introductory simulation included students assigned to one-on-one care to HFM with adult/older adult medical/surgical scenarios. This simulation mimicked a general medical/surgical hospital unit. Objectives included hospital unit preparation, setting expectations, understanding the routine of a hospital unit, beginning clinical reasoning, and effective communication to facilitate patient care. One student acted as charge nurse, other students assessed, medicated, and called the provider if needed and performed many other tasks, critical thinking, and prioritizing orders. Students carried out orders, documented findings, called laboratory and radiology for results, if needed. Students performed this simulation over 6-hour periods with pre- and post-briefing. Debriefing included asking the students to describe how they can use this experience going forward to their clinical experience, discuss their perceived limitations, and their perceived needs for clinical success. Faculty extended simulation Spring 2016 for the Pediatric course. This simulation was increased in intensity and performed in a shorter period in small groups of 2-3 students and completed in phases. This simulation included two higher acuity patient scenario and a focus on clinical reasoning. Students participated in two scenarios. Pre- and post-simulation testing completed to measure effectiveness and meeting of learner objectives. Students positive feedback and request for more simulations prompted the faculty to develop a step-approach to simulation in courses. Resources and technological restrictions needed to be evaluated. Limitations: HFM require the most consideration. HFM are manufactured and programed by commercial companies and try to resemble life-like situations. Battery life varies between brand, gender, and mass. Males are more efficient because of automated features. The power source is located below the waist. Females use more power. They are used for general simulations and maternity. In maternity simulations, automation requires total body manipulation which requires greater power. Longevity of the mannequin s battery life may determine scenario length. Learning objectives may depend on mannequin type. Power source can be a great limitation, as well as varying sizes of simulation laboratories. When the lab size is small, the radioactivity space is limited. This causes a voided transfer of data between mannequins. This cancels programmed scenario data and will not allow use of multiple mannequins in one setting; this can create limited teaching capabilities at one time. Instructors must monitor mannequin vitals at all times. If abnormal vital signs are set in a scenario and go untreated by the student, mannequins will decompensate like live patients would. Mannequins will overheat and shut down. Facilitator knowledge and ability varies and facilitators must learn the technology in order to allow the student to gather the most benefit. This facility uses an ultraportable recording system, so the ideal simulation includes one-facilitator recording/annotating student observations, one facilitator changing mannequin settings, vital signs, one answering the students questions as the patient , and one facilitator acting as the provider on-call, laboratory, or other departments the student may need to call upon. Implementation: In Fall 2016, faculty developed a three-tiered model approach to simulation for students entering the adult/older adult medical surgical clinical rotation in order to classify and define simulation exercises for students. The first tier, coined Sim-Skill , included needed laboratory skills training. The second tier, Sim-Shift , is an introduction into the hospital unit and patient care during a shift. The third tier, Sim-Care , is a high-acuity patient scenario. Sim-Skill included learning new skills on LFM. For example, nasogastric tube insertion, central line dressing change, and injections were a few of the skills learned. In addition, students view equipment orientation and procedures via faculty-made videos. Sim-Shift included students assigned to HFM as if in a general medical/surgical nursing unit, like in the previous year. However, shifts were shortened to morning and afternoon sessions allowing for technical considerations, and the students to report to one another between shifts. Session changes allowed the students to develop their communication skills nurse-to-nurse while giving report on the patient. Students in both sessions reported to the class on the following day their experience. These changes allowed the mannequins to reset between sessions. Most importantly, it allowed the students to transfer patient care and learn what was essential in communicating for transfer of care. Students got a sense of what it is like to work on a medical/surgical unit, fully manage patient care, communicate for continuation of care, and be accountable to others for that patient. Furthermore, students were able to put into practice fundamental safety concerns. For example, if a student left a side-rail down, simulation facilitators would place mannequin on the floor for the student to find. Sim-Shift was useful in identifying immediate safety and prioritization student needs. Sim-Care included HFM and SP (acting as mannequin s family member) with high-acuity adult/older adult and pediatric scenarios performed in groups of 2-3 students. Expectations included assessment, prioritization, and interventions appropriate to scenario stages. The simulated patient s family may also be in the scenario adding another dimension to the simulation. They were also expected to communicate findings to the patient s provider. Learning objectives in this tier include synthesizing theory learned in classroom and skills learned in the previous tiers. In addition, faculty assessment of students included clinical judgment and critical indicators. Pre-/post-simulation testing occurred. Results: Students consistently request more time spent in the lab to develop technique and facilitate practice for the clinical setting. Students report a freedom in lab practice without risk of causing harm to a live patient. Students participating in Sim-Shift reported better understanding of clinical expectations/role and helped to link theory to actual patient care. They reported seeing symptoms displayed by mannequins helped make disease clinical manifestations concrete. Learning these elements in simulated environment helped students feel safe in practice when clinical began. Students especially liked mannequins who were placed on contact/respiratory isolation. This helped make aware of needing to prioritize and prepare nursing interventions. Students learned importance of communication and preparedness before talking to the simulated-provider of the patient in order to receive orders or request the patient to be seen. Students reported an over-all positive experience and a desire for more Sim-Shifts. Students participating in Sim-Care reported positive, stressful experiences. Post-simulation testing improved knowledge base in 57% of students for both scenarios and 83% of students for one scenario. One student had poor performance in post testing of both scenarios. All students identified own needs in order to think, prioritize, communicate, and implement patient care. All students requested more Sim-Care scenarios to translate didactic content into practical environment. Conclusion: Simulation definitions helped facilitators communicate needs and student expectations to faculty and students. In addition, the clear definitions helped students understand a step-approach to clinical preparedness. This three-tiered model approach assists faculty in deciding simulation levels appropriate to student ability of for meeting set objectives. Technical limitations help form simulation type, length, and intensity. Faculty will continue to use this three-tier model to facilitate learning

Identifying High and Low Walkable Neighbourhoods Using Multi-disciplinary Walkability Criteria

Neighbourhood features contributing to the walkability (pedestrian friendliness) of a neighbourhood are diverse and depend on both its physical and social attributes. Earlier work in the Cleaner, Greener, Leaner (CGL) Study identified differences in opinion between professional stakeholder groups (planners, designers, engineers, public representatives, and public health and advocacy professionals) on what constitutes a walkable environment [1]. This diversity has implications for neighbourhood design and planning policy. The findings of a multi-disciplinary focus group study were used to generate a list of walkability criteria to select areas for a population study. In this study twenty areas were shortlisted and grouped under four categories: high walkable deprived, high walkable not deprived, low walkable deprived and low walkable not deprived. This paper presents the process undertaken to identify the study sites. International walkability research has favoured macro-scale objective geographic information systems (GIS) information to identify study areas [2]. While these macro scale attributes are important for walkability, alone they were considered insufficient for site selection by the CGL team as street characteristics were not considered and the attributes had a bias towards transportation walking. Also, indications from the focus group participants were that walkability is perceptual and therefore some resulting criteria were subjective, for example ‘a pleasant atmosphere contextual to area characteristics’ and therefore difficult to measure objectively. The CGL site selection process presented a number of challenges including limitations with available GIS information, unrepresentative neighbourhood boundaries on GIS datasets, and only one deprived neighbourhood identified as high walkable by the focus group participants. An investigation of the role of high and low walkable environments on resident’s behaviours and health can be used to inform future planning, transport, public health and neighbourhood design policies

Walkable Neighborhoods: Linkages Between Place, Health, and Happiness in Younger and Older Adults

Problem, research strategy, and findings: We examined whether living in a walkable neighborhood influenced the happiness of younger and older city residents. The data for this study came from a comprehensive household population survey of 1,064 adults living in 16 neighborhoods in Dublin City (Ireland) and its suburbs. We used multigroup structural equation modeling to analyze the direct and indirect effects of walkability on happiness, mediated by health, trust, and satisfaction with neighborhood appearance. We found living in a walkable neighborhood was directly linked to the happiness of people aged 36 to 45 (p¼.001) and, to a lesser extent, those aged 18 to 35 (p¼.07). For older adults, we found that walkable places mattered for happiness indirectly. Such built environments enhanced the likelihood that residents felt more healthy and more trusting of others, and this in turn affected the happiness of older people living in walkable neighborhoods. Takeaway for practice: We found that the way neighborhoods are planned and maintained mattered for happiness, health, and trust. Our findings suggest that mixed-use neighborhood designs that enable residents to shop and socialize within walking distance to their homes have direct and indirect effects on happiness. We call for an ongoing dialogue and evaluation of the way our urban and suburban neighborhoods are planned, designed, and developed, so that people can live in walkable places that better enable health and wellbeing

Characterizing the Causal Pathway From Childhood Adiposity to Right Heart Physiology and Pulmonary Circulation Using Lifecourse Mendelian Randomization

BACKGROUND: Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging. METHODS AND RESULTS: In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization. This approach allowed us to evaluate the effect of childhood body size on 11 measures of right heart and pulmonary circulation independent of other anthropometric traits at various stages in the lifecourse. We found strong evidence that childhood body size has a direct effect on an enlarged right heart structure in later life (eg, right ventricular end-diastolic volume: β=0.24 [95% CI, 0.15-0.33]; P=3×10-7) independent of adulthood body size. In contrast, childhood body size effects on maximum ascending aorta diameter attenuated upon accounting for body size in adulthood, suggesting that this effect is likely attributed to individuals remaining overweight into later life. Effects of childhood body size on pulmonary artery traits and measures of right atrial function became weaker upon accounting for adulthood fat-free mass and childhood height, respectively. CONCLUSIONS: Our findings suggest that, although childhood body size has a long-term influence on an enlarged heart structure in adulthood, associations with the other structural components of the cardiovascular system and their function may be largely attributed to body composition at other stages in the lifecourse