An implementation science approach to geriatric screening in an emergency department.

BACKGROUND: The Geriatric Emergency Department (ED) Guidelines recommend screening older adults during their ED visit for delirium, fall risk/safe mobility, and home safety needs. We used the Consolidated Framework for Implementation Research (CFIR) and the Expert Recommendations for Implementation Change (ERIC) tool for preimplementation planning. METHODS: The cross-sectional survey was conducted among ED nurses at an academic medical center. The survey was adapted from the CFIR Interview Guide Tool and consisted of 21 Likert scale questions based on four CFIR domains. Potential barriers identified by the survey were mapped to identify recommended implementation strategies using ERIC. RESULTS: Forty-six of 160 potential participants (29%) responded. Intervention Characteristics: Nurses felt geriatric screening should be standard practice for all EDs (76.1% agreed some/very much) and that there was good evidence (67.4% agreed some/very much). Outer setting: The national and regional practices such as the existence of guidelines or similar practices in other hospitals were unknown to many (20.0%). Nurses did agree some/very much (64.4%) that the intervention was good for the hospital/health system. Inner Setting: 67.4% felt more staff or infrastructure and 63.0% felt more equipment were needed for the intervention. When asked to pick from a list of potential barriers, the most commonly chosen were motivational (I often do not remember (n = 27, 58.7%) and It is not a priority (n = 14, 30.4%)). The identified barriers were mapped using the ERIC tool to rate potential implementation strategies. Strategies to target culture change were identifying champions, improve adaptability, facilitate the nurses performing the intervention, and increase demand for the intervention. CONCLUSION: CFIR domains and ERIC tools are applicable to an ED intervention for older adults. This preimplementation process could be replicated in other EDs considering implementing geriatric screening.

Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells.

PURPOSE: Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BMI1 in our patient-derived GBM BTICs and its relationship with CD133, a well-established marker of BTICs. METHODS: Using gain and loss-of-function studies for Bmi1 in neural stem cells (NSCs) and patient-derived GBM BTICs respectively, we assessed in vitro self-renewal and in vivo tumor formation in these two cell populations. We further explored the BMI1 transcriptional regulatory network through RNA sequencing of different GBM BTIC populations that were knocked down for Bmi1. RESULTS: There is a differential role of BMI1 in CD133-positive cells, notably involving cell metabolism. In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties. CONCLUSIONS: Our work sheds light on the association of three genes with CD133-BMI1 circuitry, their importance as downstream effectors of the BMI1 signalling pathway, and their potential as future targets for tackling GBM treatment-resistant cell populations.

Objective-subjective disparity in cancer-related cognitive impairment: does the use of change measures help reconcile the difference?

OBJECTIVE: Studies to date have found little correlation between subjective and objective measures of cognitive function in cancer patients, making it difficult to interpret the significance of their cognitive complaints. The purpose of this study was to determine if a stronger correlation would be obtained using measures of cognitive change rather than static scores. METHODS: Sixty women with early stage breast cancer underwent repeated cognitive assessment over the course of chemotherapy with a neuropsychological test battery (objective measure) and with the FACT-Cog (subjective measure). Their results were compared to 60 healthy women matched on age and education and assessed at similar intervals. We used multilevel modeling, with FACT-Cog as the dependent measure and ordinary least squares slopes of a neuropsychological summary score as the independent variable, to evaluate the co-variation between the subjective and objective measures over time RESULTS: Measures of both objective and subjective cognitive function declined over the course of chemotherapy in the breast cancer patients but there was no significant relationship between them, even when using change measures. Change in objective cognitive function was not related to change in anxiety or fatigue scores but the decline in perceived cognitive function was associated with greater anxiety and fatigue. CONCLUSIONS: The discrepancy in objective and subjective measures of cognition in breast cancer patients cannot be accounted for in terms of a failure to use change measures. Although the results are negative, we contend that this is the more appropriate methodology for analyzing cancer-related changes in cognition.

Clearing the air: a review of our current understanding of "chemo fog".

An increasing number of cancer survivors has led to a greater interest in the long-term side effects of cancer treatments and their impact on quality of life. In particular, cognitive impairments have been frequently reported by cancer survivors as an adverse effect which they attribute to the neurotoxicity of chemotherapy and have dubbed "chemobrain" or "chemo fog." Research within the past 15-20 years has explored the many factors thought to contribute to cancer-related cognitive decline in an attempt to determine a potential cause. In spite of many confounding factors, there is growing evidence that the neurotoxicity of chemotherapy does contribute to cognitive changes. This review examines the evolution of "chemo fog" research with a look at methodological issues, the status of our current understanding, and suggestions for future research.

Antimicrobial resistance in Enterococcus spp. isolated from environmental samples in an area of intensive poultry production.

Enterococcus spp. from two poultry farms and proximate surface and ground water sites in an area of intensive poultry production were tested for resistance to 16 clinical antibiotics. Resistance patterns were compared to assess trends and possible correlations for specific antimicrobials and levels of resistance. Enterococci were detected at all 12 surface water sites and three of 28 ground water sites. Resistance to lincomycin, tetracycline, penicillin and ciprofloxacin in poultry litter isolates was high (80.3%, 65.3%, 61.1% and 49.6%, respectively). Resistance in the surface water to the same antibiotics was 87.1%, 24.1%, 7.6% and 12.9%, respectively. Overall, 86% of litter isolates, 58% of surface water isolates and 100% of ground water isolates were resistant to more than one antibiotic. Fifty-four different resistance patterns were recognised in isolates obtained from litter and environmental samples and several E. faecium and E. faecalis isolates from litter and environment samples shared the same resistance pattern. Multiple antibiotic resistant (MAR) indices calculated to assess health risks due to the presence of resistant enterococci suggested an increased presence of antibiotics in surface water, likely from poultry sources as no other wastewater contributions in the area were documented.

A cancer stem cell model for studying brain metastases from primary lung cancer.

BACKGROUND: Brain metastases are most common in adults with lung cancer, predicting uniformly poor patient outcome, with a median survival of only months. Despite their frequency and severity, very little is known about tumorigenesis in brain metastases. METHODS: We applied previously developed primary solid tumor-initiating cell models to the study of brain metastases from the lung to evaluate the presence of a cancer stem cell population. Patient-derived brain metastases (n = 20) and the NCI-H1915 cell line were cultured as stem-enriching tumorspheres. We used in vitro limiting-dilution and sphere-forming assays, as well as intracranial human-mouse xenograft models. To determine genes overexpressed in brain metastasis tumorspheres, we performed comparative transcriptome analysis. All statistical analyses were two-sided. RESULTS: Patient-derived brain metastasis tumorspheres had a mean sphere-forming capacity of 33 spheres/2000 cells (SD = 33.40) and median stem-cell frequency of 1/60 (range = 0-1/141), comparable to that of primary brain tumorspheres (P = .53 and P = .20, respectively). Brain metastases also expressed CD15 and CD133, markers suggestive of a stemlike population. Through intracranial xenotransplantation, brain metastasis tumorspheres were found to recapitulate the original patient tumor heterogeneity. We also identified several genes overexpressed in brain metastasis tumorspheres as statistically significant predictors of poor survival in primary lung cancer. CONCLUSIONS: For the first time, we demonstrate the presence of a stemlike population in brain metastases from the lung. We also show that NCI-H1915 tumorspheres could be useful in studying self-renewal and tumor initiation in brain metastases. Our candidate genes may be essential to metastatic stem cell populations, where pathway interference may be able to transform a uniformly fatal disease into a more localized and treatable one.

A comparison of BOX-PCR and pulsed-field gel electrophoresis to determine genetic relatedness of enterococci from different environments.

Genetic relatedness of enterococci from poultry litter to enterococci from nearby surface water and groundwater in the Lower Fraser Valley regions of British Columbia, Canada was determined. A new automated BOX-PCR and Pulsed-Field Gel Electrophoresis (PFGE) were used to subtype enterococcal isolates from broiler and layer litter and surface and groundwater. All surface water samples (n = 12) were positive for enterococci, as were 11% (3/28) of groundwater samples. Enterococcus faecium (n = 90) was isolated from all sources, while Enterococcus faecalis (n = 59) was isolated from all sources except layer litter. The majority of E. faecalis originated from broiler litter (28/59; 47.5%) while the majority of E. faecium were isolated from layer litter (29/90; 32.2%). E. faecalis grouped primarily by source using BOX-PCR. Isolates from water samples were dispersed more frequently among PFGE groups containing isolates from poultry litter. E. faecium strains were genetically diverse as overall clustering was independent of source by both molecular methods. Subgroups of E. faecium isolates based upon source (layer litter) were present in BOX-PCR groups. Three individual E. faecalis groups and two individual E. faecium groups were 100% similar using BOX-PCR; only one instance of 100% similarity among isolates using PFGE was observed. Although enterococci from litter and water sources were grouped together using BOX-PCR and PFGE, isolates originating from water could not be definitively identified as originating from poultry litter. Automation of BOX-PCR amplicon separation and visualization increased the reproducibility and standardization of subtyping using this procedure.

An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity.

Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.

In vitro grown human ovarian follicles from cancer patients support oocyte growth.

BACKGROUND: Young female adult and adolescent cancer patients facing life-preserving but fertility-threatening chemo- or radiation-therapy are increasingly seeking options to protect their reproductive potential. Ovarian tissue cryopreservation with transplantation is a promising technique to safeguard fertility in cancer patients. However, this method may risk re-introduction of the original cancer to the survivor of the disease. Thus, developing a method for in vitro growth of immature follicles may provide a method for fertility restoration in the future. METHODS: Human secondary follicles were isolated from ovarian tissues obtained from cancer patients and grown in vitro within a bio-engineered culture system for 30 days. RESULTS: Human ovarian follicles became steroidogenically active, and developed from the early secondary to antral stage in vitro. The follicles contained healthy, growing oocytes that were connected by transzonal projections between the somatic cells and oocyte. CONCLUSIONS: Our data support the notion that human follicle development can be achieved in vitro in a bio-engineered culture system. More studies are required to investigate whether the fully sized oocytes obtained from in vitro grown follicle are competent to resume meiosis and be fertilized.

Encapsulated three-dimensional culture supports development of nonhuman primate secondary follicles.

In vitro ovarian follicle cultures may provide fertility-preserving options to women facing premature infertility due to cancer therapies. An encapsulated three-dimensional (3-D) culture system utilizing biomaterials to maintain cell-cell communication and support follicle development to produce a mature oocyte has been developed for the mouse. We tested whether this encapsulated 3-D system would also support development of nonhuman primate preantral follicles, for which in vitro growth has not been reported. Three questions were investigated: Does the cycle stage at which the follicles are isolated affect follicle development? Does the rigidity of the hydrogel influence follicle survival and growth? Do follicles require luteinizing hormone (LH), in addition to follicle-stimulating hormone (FSH), for steroidogenesis? Secondary follicles were isolated from adult rhesus monkeys, encapsulated within alginate hydrogels, and cultured individually for

The mouse follicle microenvironment regulates antrum formation and steroid production: alterations in gene expression profiles.

Folliculogenesis is a coordinated process, and the genes that regulate development are difficult to investigate in vivo. In vitro culture systems permit the assessment of individual follicles during development, thereby enabling gene expression patterns to be monitored during follicle development. Mouse multilayered secondary follicles (150-180 microm in diameter) were cultured in three-dimensional matrices of varying physical properties for up to 8 days. During this period of follicle growth in vitro, antrum formation and steroid production were monitored, and mRNA was isolated. The expression levels of genes (Star, Cyp11a1, Cyp17a1, Hsd3b1, Cyp19a1, Fshr, Lhcgr, Aqp7, Aqp8, Aqp9, and Hif1a) were measured and correlated to follicle developmental status. Follicles that developed an antrum and produced appropriate levels of estrogen and progesterone had unchanging expression of Star, Aqp7, Aqp8, and Hif1a and a 34-fold increase in Cyp19a1 expression at Day 8 of culture and had elevated Lhcgr at Days 6 and 8 of culture. Follicles that were healthy but did not form an antrum or produce appropriate levels of steroids, however, demonstrated increasing levels of Star, Aqp7, Aqp8, and Hif1a and a 15-fold increase in Cyp19a1 at Day 8 of culture, and Lhcgr levels were not elevated until Day 8 of culture. To our knowledge, this study provides the first temporal analysis of gene expression using individual culture in alginate hydrogels that correlates growth and steroidogenesis during follicle development and identifies expression patterns in healthy follicles and in developmentally disadvantaged follicles.

Infliximab-associated Chiasmopathy.

Optic neuropathy has been reported in association with the use of tumor necrosis factor-alpha antagonists such as etanercept, infliximab, and adalimumab. This is a report of a patient who began experiencing decreased vision approximately 1 month after starting infliximab therapy for rheumatoid arthritis. Visual field testing showed bitemporal hemianopic scotomas, indicating involvement of the nerve fibers in the optic chiasm. The infliximab was discontinued, and the patient experienced substantial improvement in her visual acuity and visual field.

Pharmacogenomics and drug development: the impact of US FDA postapproval tracking on clinical pharmacology.

Severe adverse drug reactions to commonly prescribed drugs such as Vioxx® have led to a call for increased scrutiny in deciding which patients are given which drugs, and how much drug they should receive. A personalized approach to medicine offers a larger variety of drugs and doses that would be prescribed only to a subgroup of patients. Pharmacogenomics could help divide patients into these subgroups based on variation in the genes either causing the disease or encoding the principle drug-metabolizing enzymes. Given the cost and infrastructure associated with assembling genetic data, drug sponsors, regulatory agencies and clinicians each play a role in the collection, storage and oversight of pharmacogenetic information. The 110th Congress is in the process of making changes to the drug-approval process and the role of genetics in that process.

In silico and in vitro pharmacogenetic analysis in mice.

Combining the experimental efficiency of a murine hepatic in vitro drug biotransformation system with in silico genetic analysis produces a model system that can rapidly analyze interindividual differences in drug metabolism. This model system was tested by using two clinically important drugs, testosterone and irinotecan, whose metabolism was previously well characterized. The metabolites produced after these drugs were incubated with hepatic in vitro biotransformation systems prepared from the 15 inbred mouse strains were measured. Strain-specific differences in the rate of 16 alpha-hydroxytestosterone generation and irinotecan glucuronidation correlated with the pattern of genetic variation within Cyp2b9 and Ugt1a loci, respectively. These computational predictions were experimentally confirmed using expressed recombinant enzymes. The genetic changes affecting irinotecan metabolism in mice mirrored those in humans that are known to affect the pharmacokinetics and incidence of adverse responses to this medication.

In silico pharmacogenetics of warfarin metabolism.

Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index and a large variation in individual dosing. After quantification of warfarin and nine of its metabolites in plasma from 13 inbred mouse strains, we correlated strain-specific differences in 7-hydroxywarfarin accumulation with genetic variation within a chromosomal region encoding cytochrome P450 2C (Cyp2c) enzymes. This computational prediction was experimentally confirmed by showing that the rate-limiting step in biotransformation of warfarin to its 7-hydroxylated metabolite was inhibited by tolbutamide, a Cyp2c isoform-specific substrate, and that this transformation was mediated by expressed recombinant Cyp2c29. We show that genetic variants responsible for interindividual pharmacokinetic differences in drug metabolism can be identified by computational genetic analysis in mice.