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OBJECTIVES/SPECIFIC AIMS: Glioblastoma (GBM) is a brain cancer with a devastatingly short overall survival of under two years. The poor prognosis of GBM is largely due to cell invasion and maintenance of cancer initiating cells that evade the brain’s innate and adaptive immune responses which enables escape from surgical resection and drives inevitable recurrence. While targeting the brain’s immune microenvironment has long been proposed as a strategy for treating GBM, translational progress has been slow, underscoring the need to investigate the brain’s immune microenvironment for therapeutic avenues. METHODS/STUDY POPULATION: Recent advancements in tunable synthetic immunomodulatory gene circuits targeting metastatic cancers has demonstrated the novel ability to use engineering principles to induce infiltrative cancer cells to express combinatorial immunomodulatory outputs that enable T-cell killing4. Our central hypothesis is: we will be able to significantly improve survival with a lasting immune-mediated control of GBM by using synthetic immunomodulatory gene circuits driving GBM cells to express a local combination of immunomodulatory proteins: human IL15, a surface T-cell engager, PD-L1-CD3 bispecific antibody, and the protein, LIGHT (TNFRSF14). Importantly, the co-expression of LIGHT and anti-PD-L1 therapies was recently shown to rescue PD-L1 checkpoint blockage in the preclinical models of brain tumors and significant enhance survival outcomes highlighting the benefits of novel combinations of immunomodulatory proteins for treatment of GBM. To identify genes whose expression is dramatically upregulated in GBM compared to normal human brain cells, a pooled of six thousand lentiviral oncogene promoters that drive expression of a red-fluorescent protein has been infected into three human GBM cell lines. RESULTS/ANTICIPATED RESULTS: We have successfully infected our GBM cells and are preparing samples for next generation DNA sequencing to determine highly active promoters in GBM that are not expressed in multiple normal brain cells types, astrocytes and neurons. These chosen promoters will then be used to drive an AND gate logic gene circuit immunotherapy outputs which is currently under development for both in-vitro and in-vivo experiments. DISCUSSION/SIGNIFICANCE OF IMPACT: We anticipate that local expression of multiple immune effectors proteins will significantly enhance tumor control and survival in both synergistic murine and human-murine xenograft pre-clinical models of GBM. Ultimately, our goal is to rapidly translate this technology advance into the clinical trial for adult GBM patients.
The construction of future technological systems in work domains that do not yet exist, known as the envisioned world problem, is an increasingly important topic for designers, particularly given the rapid rate of technological advancement in the modern era. This paper first discusses the theoretical underpinnings of using cognitive work analysis (CWA) for developing a decision support system (DSS) situated within the envisioned world problem and recasts the problem as pathway-dependent processes. Using this pathway-dependent framework, each stage of the envisioning process is described to reveal how human factors experts can link existing work domains to envisioned instances. Finally, a case study example of the envisioning process that incorporates CWA modelling is demonstrated as it pertains to the advancement of the human spaceflight domain. As a result, this paper provides a unified treatment of the envisioned world problem with an end-to-end example of one approach to designing future technologies for future work domains.
The US Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) program sponsors the development of systematic reviews to inform clinical policy and practice. The EPC program sought to better understand how health systems identify and use this evidence.
Representatives from eleven EPCs, the EPC Scientific Resource Center, and AHRQ developed a semi-structured interview script to query a diverse group of nine Key Informants (KIs) involved in health system quality, safety and process improvement about how they identify and use evidence. Interviews were transcribed and qualitatively summarized into key themes.
All KIs reported that their organizations have either centralized quality, safety, and process improvement functions within their system, or they have partnerships with other organizations to conduct this work. There was variation in how evidence was identified, with larger health systems having medical librarians and central bureaus to gather and disseminate information and smaller systems having local chief medical officers or individual clinicians do this work. KIs generally prefer guidelines, especially those with treatment algorithms, because they are actionable. They like systematic reviews because they efficiently condense study results and reconcile conflicting data. They prefer information from systematic reviews to be presented as short digestible summaries with the full report available on demand. KIs preferred systematic reviews from reputable entities and those without commercial bias. Some of the challenges KIs reported include how to resolve conflicting evidence, the generalizability of evidence to local needs, determining whether the evidence is up-to-date, and the length of time required to generate reviews. The topics of greatest interest included predictive analytics, high-value care, advance care planning, and care coordination. To increase awareness of AHRQ EPC reviews, KIs suggest alerting people at multiple levels in a health-system when new evidence reports are available and making reports easier to find in common search engines.
Systematic reviews are valued by health system leaders. To be most useful they should be easy to locate and available in different formats targeted to the needs of different audiences.
A low resting heart rate across development from infancy to young adulthood relates to greater aggression/hostility. Adult aggression and a high heart rate relate to health risk. Do some aggressive individuals retain low heart rate and less health risk across development while others show high heart rate and more risk? A longitudinal sample of 203 men assessed as teens (age 16.1) and adults (mean age 32.0) permitted us to assess (a) stability of heart rate levels and reactivity, (b) stability of aggression/hostility, and (c) whether change or stability related to health risk. Adults were assessed with Buss–Perry measures of aggression/hostility; teens with the Zuckerman aggression/hostility measure. Mean resting heart rate, heart rate reactivity to speech preparation, and aggression/hostility were moderately stable across development. Within age periods, mean heart rate level, but not reactivity, was negatively related to hostility/aggression. Maintaining low heart rate into adulthood was related to better health among aggressive individuals relative to those with increasing heart rate into adulthood. Analyses controlled for weight gain, socioeconomic status, race, health habits, and medication. Low heart rate as a characteristic of hostile/aggressive individuals may continue to relate to better health indices in adulthood, despite possible reversal of this relationship with aging.
Limited research exists examining the biopsychosocial experience of patients diagnosed with metastatic renal cell carcinoma (mRCC), a disease commonly associated with a poor prognosis. The purpose of this study was to describe rates and types of distress in mRCC patients and explore the relationship between distress and overall survival.
A cohort of 102 patients with mRCC treated at a single institution was assessed by a touch screen–based instrument comprising 22 core items spanning physical, practical, functional, and emotional domains. Association between biopsychosocial distress and clinicopathologic criteria was interrogated. Overall survival was compared between patients with low distress versus high distress.
High rates of distress (20.7%) were found among patients newly diagnosed with mRCC. Among those domains contributing to distress, pain, fatigue, and financial comorbidity were the most commonly reported by patients with mRCC. A trend toward poorer overall survival in those patients with high distress versus low distress was observed among mRCC patients.
Significance of results
Based on data from a relatively large sample of patients, this study provides the first specific insights into the potential impact of biopsychosocial distress and outcomes among patients with mRCC.
Psychosocial and health-related risk factors for depressive symptoms are known. It is unclear if these are associated with depressive symptom patterns over time. We identified trajectories of depressive symptoms and their risk factors among midlife women followed over 15 years.
Participants were 3300 multiracial/ethnic women enrolled in a multisite longitudinal menopause and aging study, Study of Women's Health Across the Nation. Biological, psychosocial, and depressive symptom data were collected approximately annually. Group-based trajectory modeling identified women with similar longitudinal patterns of depressive symptoms. Trajectory groups were compared on time-invariant and varying characteristics using multivariable multinomial analyses and pairwise comparisons.
Five symptom trajectories were compared (50% very low; 29% low; 5% increasing; 11% decreasing; 5% high). Relative to whites, blacks were less likely to be in the increasing trajectory and more likely to be in the decreasing symptom trajectory and Hispanics were more likely to have a high symptom trajectory than an increasing trajectory. Psychosocial/health factors varied between groups. A rise in sleep problems was associated with higher odds of having an increasing trajectory and a rise in social support was associated with lower odds. Women with low role functioning for 50% or more visits had three times the odds of being in the increasing symptom group.
Changes in psychosocial and health characteristics were related to changing depressive symptom trajectories. Health care providers need to evaluate women's sleep quality, social support, life events, and role functioning repeatedly during midlife to monitor changes in these and depressive symptoms.
A novel freeze-cast porous chitosan conduit for peripheral nerve repair with highly-aligned, double layered porosity, which provides the ideal mechanical and chemical properties was designed, manufactured, and assessed in vivo. Efficacies of the conduit and the control inverted nerve autograft were evaluated in bridging 10-mm Lewis rat sciatic nerve gap at 12 weeks post-implantation. Biocompatibility and regenerative efficacy of the porous chitosan conduit were evaluated through the histomorphometric analysis of longitudinal and transverse sections. The porous chitosan conduit was found to have promising regenerative characteristics, promoting the desired neovascularization, and axonal ingrowth and alignment through a combination of structural, mechanical and chemical cues.
Poor physiological self-regulation has been proposed as a potential biological vulnerability for adolescent suicidality. This study tested this hypothesis by examining the effect of parasympathetic stress responses on future suicide ideation. In addition, drawing from multilevel developmental psychopathology theories, the interplay between parasympathetic regulation and friendship support, conceptualized as an external source of regulation, was examined. At baseline, 132 adolescent females (M age = 14.59, SD = 1.39) with a history of mental health concerns participated in an in vivo interpersonal stressor (a laboratory speech task) and completed self-report measures of depressive symptoms and perceived support within a close same-age female friendship. Respiratory sinus arrhythmia (RSA) was measured before and during the speech task. Suicide ideation was assessed at baseline and at 3, 6, and 9 months follow-up. The results revealed that females with greater relative RSA decreases to the laboratory stressor were at higher risk for reporting suicide ideation over the subsequent 9 months. Moreover, parasympathetic responses moderated the effect of friendship support on suicide ideation; among females with mild changes or higher relative increases in RSA, but not more pronounced RSA decreases, friendship support reduced risk for future suicide ideation. Findings highlight the crucial role of physiological and external regulation sources as protective factors for youth suicidality.
The population growth of endangered whooping cranes (Grus americana) is not consistent with species recovery goals, and the impact of parasite infection on whooping crane populations is largely unknown. Disease ecology and epidemiology research of endangered species is often hindered by limited ability to conduct invasive sampling on the target taxa. Accordingly, we hypothesized that sandhill cranes (Grus canadensis) would be a useful surrogate species to investigate the health impacts of Haemosporida infection in whooping cranes. Our goal was to compare the prevalence and diversity of Haemosporida infection between whooping cranes and sandhill cranes. We detected an overall infection prevalence of 83·6% (n = 61) in whooping cranes and 59·6% (n = 47) and 63·6 (n = 22) in two sympatric sandhill crane populations captured in Texas. Prevalence was significantly lower in allopatric sandhill cranes captured in New Mexico (12·1%, n = 33). Haemoproteus antigonis was the most abundant haemoparasite in cranes, present in 57·4% of whooping cranes and 39·2% of sandhill cranes; Plasmodium and Leucocytozoon were present at significantly lower levels. The high prevalence of Haemosporida in whooping cranes and sympatric sandhill cranes, with shared parasite lineages between the two species, supports sandhill cranes as a surrogate species for understanding health threats to endangered whooping cranes.
I had the good fortune of beginning graduate school when my major professor, David Glass, began his theoretical work on the Type A behavior pattern as a coping style aimed at maintaining control over stressful circumstances. Two cardiologists, Meyer Friedman and Ray Rosenman, described the Type A pattern as a constellation of characteristics: competitiveness, excessive achievement striving, time urgency, hypervigilance, and easily angered and hostile. They demonstrated that initially healthy men classified as Type A were at higher risk for subsequent coronary heart disease (CHD) compared to non-Type As (called Type Bs). As one who had vacillated between becoming a physician versus becoming a psychologist, I thought that investigating Type A behavior would be an optimal way to combine my interests in both psychology and health. Little did I realize at the time that a focus on Type A would launch my own career in investigating more broadly the psychological underpinnings of risk for cardiovascular disease (CVD). My primary research questions were two-fold: Who is at psychological risk for CVD? How does psychological risk for CVD develop over the life span? Before I describe how we addressed those questions, I briefly describe cardiovascular diseases, and I conclude by describing next steps for these research questions.
Cardiovascular disease (CVD) refers to a number of diseases of the heart and circulation. Underlying many types of CVD is atherosclerosis, the accumulation of plaque in the arterial wall. Plaque is composed of fat, cholesterol, and other substances. Over time, the build-up of plaque and potential for rupture can partially or completely block blood flow to tissues, resulting in ischemia (i.e., inadequate blood supply) and tissue death. Depending on which arteries are blocked by plaque, different conditions occur. Heart attacks and chest pain (angina) result from inadequate blood flow to the coronary arteries, stroke from inadequate blood flow to carotid arteries, and peripheral artery disease from inadequate blood flow to the arteries in the legs. Atherosclerosis develops slowly over the life-span, beginning in adolescence and young adulthood and accelerating in women after the menopause and in men in midlife. These facts suggest that investigations of psychological risk for CVD should take a life-span approach.
Healthcare provider hands are an important source of intraoperative bacterial transmission events associated with postoperative infection development.
To explore the efficacy of a novel hand hygiene improvement system leveraging provider proximity and individual and group performance feedback in reducing 30-day postoperative healthcare-associated infections via increased provider hourly hand decontamination events.
Randomized, prospective study.
Dartmouth-Hitchcock Medical Center in New Hampshire and UMass Memorial Medical Center in Massachusetts.
Patients undergoing surgery.
Operating room environments were randomly assigned to usual intraoperative hand hygiene or to a personalized, body-worn hand hygiene system. Anesthesia and circulating nurse provider hourly hand decontamination events were continuously monitored and reported. All patients were followed prospectively for the development of 30-day postoperative healthcare-associated infections.
A total of 3,256 operating room environments and patients (1,620 control and 1,636 treatment) were enrolled. The mean (SD) provider hand decontamination event rate achieved was 4.3 (2.9) events per hour, an approximate 8-fold increase in hand decontamination events above that of conventional wall-mounted devices (0.57 events/hour); P<.001. Use of the hand hygiene system was not associated with a reduction in healthcare-associated infections (odds ratio, 1.07 [95% CI, 0.82–1.40], P=.626).
The hand hygiene system evaluated in this study increased the frequency of hand decontamination events without reducing 30-day postoperative healthcare-associated infections. Future work is indicated to optimize the efficacy of this hand hygiene improvement strategy.
We replicated a 1994 study that surveyed the state of supportive care services due to changes in the field and the increased need for such services. We provide an updated assessment, comparing the changes that have occurred and describing the current status of supportive care services in comprehensive cancer settings.
We used Coluzzi and colleague's 60-question survey from their 1995 Journal of Clinical Oncology article to frame the 98-question survey employed in the current study. Medical and palliative care directors for the 2011 National Cancer Institute (NCI) comprehensive cancer centers were surveyed regarding their supportive care services and their subjective review of the overall effectiveness of the services provided.
We achieved a 76% response rate (n = 31). The data revealed increases in the number of cancer beds in the hospitals, the degree of integration of supportive care services, the availability of complementary services, and the number of pain and palliative care services offered. There was also an overall shift toward centers becoming more patient centered, as 65% reported now having a patient and family advisory council. Our findings revealed a growing trend to offer distress screening for both outpatients and inpatients. Medical and palliative care directors' evaluations of the supportive care services they offered also significantly improved. However, the results revealed an ongoing gap in services for end-of-life care and timely referrals for hospice services.
Significance of results:
Overall, both the quantity and quality of supportive care services in the surveyed NCI-designated cancer centers has improved.
A high-resolution pollen record from Path Lake in Port Joli Harbour, Nova Scotia, Canada, provides a paleo-ecological perspective on Holocene climate and vegetation variability within the context of local archaeological research. Pollen assemblages in the early Holocene reflect a post-glacial forest dominated by Pinus, Tsuga, Betula and Quercus. During this time, a lower frequency of radiocarbon dated cultural material suggests lower human settlement intensity. Shallow water aquatic (Isoetes) and wetland (Alnus, Sphagnum) taxa increased after 3400 cal yr BP in response to a transition towards wetter climatic conditions. Culturally significant periods, where settlement intensity increased in the Maritimes and Maine, coincide with maximum values of reconstructed total annual precipitation, suggesting that environmental conditions may have influenced prehistoric human activity. European settlement, after 350 cal yr BP, was marked by a rise in Ambrosia. The impact of anthropogenic fire disturbances on the landscape was evidenced by peak charcoal accumulations after European settlement.
The aim of our study was to explore the impact of gender and hematological cancer grade on distress, anxiety, and depression in patients receiving chemotherapy.
A prospective study was done in a cohort of 104 patients with hematological cancer. We employed the (1) Distress Thermometer (DT) and the Problem List (PL) and (2) the Hospital Anxiety and Depression Scale (HADS) for assessments at baseline (T1), the halfway timepoint (T2), and completion of chemotherapy (T3).
The proportion of patients experiencing significant distress (DT ≥ 4) decreased from the first to the last timepoint; the proportion experiencing anxiety and depression (as assessed by HADS) also decreased. Specifically, 50% of participants reported significant distress levels, 47.1% anxiety, and 26% depression at T1. At T2, the proportion of patients experiencing distress was reduced by 60.8%, by 76% for anxiety, and by 48.5% for depression; at T3, the reduction was close to 80% for all assessments compared with T1. Emotional and physical problems were most commonly reported. Significant reductions were discovered for distress and problem-related distress levels over time, and a significant interaction was found between gender and practical and physical problems (p < 0.05).
Significance of results:
Our findings suggest that female patients reported more distress, anxiety, and depression than male patients. Gender differences were related to problem-related distress but not to grade of neoplasm. We observed that, over the course of chemotherapy, the distress levels of patients with hematological cancer decrease over time.