The role and activities of the Traveller mental health liaison nurse: Findings from a multi-stakeholder evaluation.

Irish Travellers are a minority ethnic group within the Irish state with a distinct culture and set of traditions. Travellers experience mental health inequalities, high rates of mental ill health, and structural and individual barriers to mental health supports. A Traveller Mental Health Liaison Nurse (TMHLN) was introduced in a healthcare region in Ireland to provide greater mental health-related support to Travellers. This paper presents a description of the TMHLN role following a multi-stakeholder evaluation. The research design was descriptive qualitative and the findings are reported using COREQ criteria. Thirty-four key stakeholders were interviewed individually or as part of focus groups. Thematic analysis generated two broad themes: the role context, and the specific activities of the role. Mental health nursing experience and understanding of local issues and services were key, as was use of language, building trusting relations, creating the metaphorical, and having the physical, space for working. Specific activities involved in-reach and outreach work, including one-to-one mental health support provision, delivery of education/training sessions to Travellers and service providers, (re)establishing links to specialist services, integrated and interagency working, and promoting cultural competency. The findings set out a role with a greater emphasis on the use of recovery technologies, having an emphasis on psychosocial interventions and self-care, and less focus on biomedical technologies, signs and symptoms, and clinical outcomes. This study contributes to knowledge on the role of a MHLN as this relates to working with marginalized minority groups.

Evaluation of a Traveller Mental Health Liaison Nurse: Service User Perspectives.

Irish Travellers are a small indigenous minority group with a distinctive lifestyle and culture which sets them apart from the general population. Travellers are vulnerable to significant mental distress which is exacerbated by the social disadvantage that they experience. A Traveller Mental Health Liaison Nurse (TMHLN) was introduced in one health care region in Ireland to provide support for Travellers and increase their access to mental health services. The aim of this paper is to present the findings from an evaluation which explored Travellers access to and reasons for accessing the TMHLN, the interventions provided and their experiences of and perceptions of the role of the TMHLN. A descriptive qualitative approach was used. Ten Travellers who used the service were interviewed. Following data analysis, three themes emerged: factors affecting Traveller mental health; accessing the TMHLN and the Travellers experiences and perceptions of the TMHLN. The participants were extremely positive about the TMHLN and valued the support provided. The findings highlight how the interpersonal skills associated with mental health nursing set against recovery orientated and culturally congruent practices are suitable approaches when working with Travellers.

How hedge woody species diversity and habitat change is a function of land use history and recent management in a European agricultural landscape.

European hedged agricultural landscapes provide a range of ecosystem services and are an important component of cultural and biodiversity heritage. This paper investigates the extent of hedges, their woody species diversity (including the influence of historical versus recent hedge origin) and dynamics of change. The rationale is to contribute to an ecological basis for hedge habitat management. Sample sites were allocated based on a multivariate classification of landscape attributes. All field boundaries present in each site were mapped and surveyed in 1998 and 2007. To assess diversity, a list of all woody species was recorded in one standard 30 m linear plot within each hedge. There was a net decrease in hedge habitat extent, mainly as a result of removal, and changes between hedges and other field boundary types due to the development and loss of shrub growth-form. Agricultural intensification, increased rural building, and variation in hedge management practices were the main drivers of change. Hedges surveyed at baseline, which were lost at resurvey, were more species rich than new hedges gained. Hedges coinciding with historical land unit boundaries of likely Early Medieval origin were found to be more species rich. The most frequent woody species in hedges were native, including a high proportion with Fraxinus excelsior, a species under threat from current and emerging plant pests and pathogens. Introduced species were present in circa 30% of hedges. We conclude that since hedge habitat distribution and woody species diversity is a function of ecology and anthropogenic factors, the management of hedges in enclosed agricultural landscapes requires an integrated approach.

Comparison of rechargeable versus battery-operated insulin pumps: temperature fluctuations.

The role of continuous subcutaneous insulin infusion (insulin pumps) has become increasingly important in diabetes management, and many different types of these systems are currently available. This exploratory study focused on the reported heating issues that lithium-ion battery-powered pumps may have during charging compared with battery-operated pumps. It was found that pump temperature increased by 6.4°C during a long charging cycle of a lithiumion battery-operated pump under ambient temperatures. In an environmental-chamber kept at 35°C, the pump temperature increased by 4.4°C, which indicates that the pump temperature was above that of the recommended safety limit for insulin storage of 37°C. When designing new pumps, and when using currently available rechargeable pumps in warmer climates, the implications of these temperature increases should be taken into consideration. Future studies should also further examine insulin quality after charging.

The Hypoglycaemia-Hyperglycaemia Minimizer System in the Management of Type 1 Diabetes.

Living with type 1 diabetes (T1D) presents many challenges in terms of daily living. Insulin users need to frequently monitor their blood glucose levels and take multiple injections per day and/or multiple boluses through an insulin infusion pump, with the consequences of failing to match the insulin dose to the body's needs resulting in hypoglycaemia and hyperglycaemia. The former can result in seizures, coma and even death; the latter can have both acute and long-term health implications. Many patients with T1D also fail to meet their treatment goals. In order to reduce the burdens of self-administering insulin, and improve efficacy and safety, there is a need to at least partially remove the patient from the loop via a closed-loop 'artificial pancreas' system. The Hypoglycaemia-Hyperglycaemia Minimizer (HHM) System, comprising a continuous, subcutaneous insulin infusion pump, continuous glucose monitor (CGM) and closed-loop insulin dosing algorithm, is able to predict changes in blood glucose and adjust insulin delivery accordingly to help keep the patient at normal glucose levels. Early clinical data indicate that this system is feasible, effective and safe, and has the potential to dramatically improve the therapeutic outcomes and quality of life for people with T1D.

Sensitivity of the Predictive Hypoglycemia Minimizer System to the Algorithm Aggressiveness Factor.

BACKGROUND: The Predictive Hypoglycemia Minimizer System ("Hypo Minimizer"), consisting of a zone model predictive controller (the "controller") and a safety supervision module (the "safety module"), aims to mitigate hypoglycemia by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The "aggressiveness factor," a pivotal variable in the system, governs the speed and magnitude of the controller's insulin dosing characteristics in response to changes in CGM levels. METHODS: Twelve adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 24 hours. This analysis focused primarily on the effect of the aggressiveness factor on the automated insulin-delivery characteristics of the controller, and secondarily on the glucose control results. RESULTS: As aggressiveness increased from "conservative" to "medium" to "aggressive," the controller recommended less insulin (-3.3% vs -14.4% vs -19.5% relative to basal) with a higher frequency (5.3% vs 14.4% vs 20.3%) during the critical times when the CGM was reading 90-120 mg/dl and decreasing. Blood glucose analyses indicated that the most aggressive setting resulted in the most desirable combination of the least time spent <70 mg/dl and the most time spent 70-180 mg/dl, particularly in the overnight period. Hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia did not occur with any of the aggressiveness values. CONCLUSION: The Hypo Minimizer's controller took preemptive action to prevent hypoglycemia based on predicted changes in CGM glucose levels. The most aggressive setting was quickest to take action to reduce insulin delivery below basal and achieved the best glucose metrics.

A practical approach to interpreting lower extremity noninvasive physiologic studies.

Peripheral arterial disease (PAD) is an important manifestation of atherosclerosis, with an estimated age-adjusted prevalence of approximately 13% in people older than 50 years. Noninvasive vascular laboratory physiologic studies are indispensable tools in the initial evaluation and workup and postintervention follow-up. In this review, we describe a practical approach to the technique, interpretation, pitfalls, and limitations of these physiologic studies. We also provide an algorithmic approach for using these studies in the initial workup of patients with suspected PAD. Noninvasive techniques that primarily provide anatomic information have not been included in this review.

Gastric pneumatosis: Laboratory and imaging findings associated with mortality in adults.

AIM: To describe laboratory and imaging findings associated with mortality in patients with gastric pneumatosis. MATERIALS AND METHODS: Institution review board approval was obtained for this retrospective study. Using radiology report databases, all patients with "gastric pneumatosis" or "emphysematous gastritis" in their CT reports were identified from two institutions during 12 or 9 year periods. Clinical parameters and laboratory values [lactic acid, white blood cell (WBC) count, and serum creatinine] were obtained from medical records and images were reviewed in consensus by two readers. Bivariate associations between continuous variables were tested by Mann-Whitney tests. Fisher's exact test was used to evaluate bivariate associations between categorical variables. RESULTS: Of the 24 patients identified, there were five (21%) deaths. Median serum lactic acid and creatinine levels were significantly higher in patients who died compared to surviving patients [median (interquartile range, IQR): 1.95 (1.45-4.15) versus 1.5 (1.3-2.6), p = 0.001; 1.2 (1-2.8) versus 1 (0.8-1.4), p = 0.005, respectively). There was no significant difference in WBC levels between the groups. Coexistent small bowel pneumatosis and colonic pneumatosis were significantly more common in patients who died compared to surviving patients (80% versus 0%, p < 0.001; 40% versus 0%, p = 0.04, respectively). There was no significant difference for portal or mesenteric venous gas, free intraperitoneal gas, or dilated bowel. CONCLUSIONS: When the imaging finding of gastric pneumatosis was associated with elevated serum lactic acid, elevated serum creatinine, or concomitant small bowel or colonic pneumatosis, an association with mortality was observed. These findings suggest that more aggressive treatment may be warranted in patients with these laboratory or imaging abnormalities.

Closed-Loop Control Performance of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System in a Feasibility Study.

BACKGROUND: This feasibility study investigated the insulin-delivery characteristics of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System-an automated insulin delivery device-in participants with type 1 diabetes. METHODS: Thirteen adults with type 1 diabetes were enrolled in this nonrandomized, uncontrolled, clinical-research-center-based feasibility study. The HHM System comprised a continuous subcutaneous insulin infusion pump, a continuous glucose monitor (CGM), and a model predictive control algorithm with a safety module, run on a laptop platform. Closed-loop control lasted approximately 20 hours, including an overnight period and two meals. RESULTS: When attempting to minimize glucose excursions outside of a prespecified target zone, the predictive HHM System decreased insulin infusion rates below the participants' preset basal rates in advance of below-zone excursions (CGM < 90 mg/dl), and delivered 80.4% less insulin than basal during those excursions. Similarly, the HHM System increased infusion rates above basal during above-zone excursions (CGM > 140 mg/dl), delivering 39.9% more insulin than basal during those excursions. Based on YSI, participants spent a mean ± standard deviation (SD) of 0.2 ± 0.5% of the closed-loop control time at glucose levels < 70 mg/dl, including 0.3 ± 0.9% for the overnight period. The mean ± SD glucose based on YSI for all participants was 164.5 ± 23.5 mg/dl. There were nine instances of algorithm-recommended supplemental carbohydrate administrations, and there was no severe hypoglycemia or diabetic ketoacidosis. CONCLUSIONS: Results of this study indicate that the current HHM System is a feasible foundation for development of a closed-loop insulin delivery device.

Effect of algorithm aggressiveness on the performance of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System.

The Hypoglycemia-Hyperglycemia Minimizer (HHM) System aims to mitigate glucose excursions by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The "aggressiveness factor" is a key parameter in the HHM System algorithm, affecting how readily the system adjusts insulin infusion in response to changing CGM levels. Twenty adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 26 hours. This analysis focused on the effect of the aggressiveness factor on the insulin dosing characteristics of the algorithm and, to a lesser extent, on the glucose control results observed. As the aggressiveness factor increased from conservative to medium to aggressive: the maximum observed insulin dose delivered by the algorithm­which is designed to give doses that are corrective in nature every 5 minutes­increased (1.00 vs 1.15 vs 2.20 U, respectively); tendency to adhere to the subject's nominal basal dose decreased (61.9% vs 56.6% vs 53.4%); and readiness to decrease insulin below basal also increased (18.4% vs 19.4% vs 25.2%). Glucose analyses by both CGM and Yellow Springs Instruments (YSI) indicated that the aggressive setting of the algorithm resulted in the least time spent at levels >180 mg/dL, and the most time spent between 70-180 mg/dL. There was no severe hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia for any of the aggressiveness values investigated. These analyses underscore the importance of investigating the sensitivity of the HHM System to its key parameters, such as the aggressiveness factor, to guide future development decisions.

Temporal molecular and biological assessment of an erlotinib-resistant lung adenocarcinoma model reveals markers of tumor progression and treatment response.

Patients with lung cancer with activating mutations in the EGF receptor (EGFR) kinase, who are treated long-term with tyrosine kinase inhibitors (TKI), often develop secondary mutations in EGFR associated with resistance. Mice engineered to develop lung adenocarcinomas driven by the human EGFR T790M resistance mutation are similarly resistant to the EGFR TKI erlotinib. By tumor volume endpoint analysis, these mouse tumors respond to BIBW 2992 (an irreversible EGFR/HER2 TKI) and rapamycin combination therapy. To correlate EGFR-driven changes in the lung with response to drug treatment, we conducted an integrative analysis of global transcriptome and metabolite profiling compared with quantitative imaging and histopathology at several time points during tumor progression and treatment. Responses to single-drug treatments were temporary, whereas combination therapy elicited a sustained response. During tumor development, metabolomic signatures indicated a shift to high anabolic activity and suppression of antitumor programs with 11 metabolites consistently present in both lung tissue and blood. Combination drug treatment reversed many of the molecular changes found in tumored lung. Data integration linking cancer signaling networks with metabolic activity identified key pathways such as glutamine and glutathione metabolism that signified response to single or dual treatments. Results from combination drug treatment suggest that metabolic transcriptional control through C-MYC and SREBP, as well as ELK1, NRF1, and NRF2, depends on both EGFR and mTORC1 signaling. Our findings establish the importance of kinetic therapeutic studies in preclinical assessment and provide in vivo evidence that TKI-mediated antiproliferative effects also manifest in specific metabolic regulation.

The use of fluorescent proteins for developing cancer-specific target imaging probes.

Target-specific imaging probes represent a promising tool in the molecular imaging of human cancer. Fluorescently-labeled target-specific probes are useful in imaging cancers because of their ability to bind a target receptor with high sensitivity and specificity. The development of probes relies upon preclinical testing to validate the sensitivity and specificity of these agents in animal models. However, this process involves both conventional histology and immunohistochemistry, which require large numbers of animals and samples with costly handling. In this chapter, we describe a novel validation tool that takes advantage of genetic engineering technology, whereby cell lines are transfected with genes that induce the target cell to produce fluorescent proteins with characteristic emission spectra, thus enabling their easy identification as cancer cells in vivo. Combined with multicolor fluorescence imaging, this can provide rapid validation of newly-developed exogenous probes that fluoresce at different wavelengths. For example, the plasmid containing the gene encoding red fluorescent protein (RFP) was transfected into cell lines previously developed to either express or not express specific cell surface receptors. Various antibody-based or ligand-based optical-contrast agents, with green fluorophores were developed to concurrently target cancer cells and validate their positive and negative controls, such as the ß-D: -galactose receptor, HER1, and HER2 in a single animal/organ. Spectrally-resolved multicolor fluorescence imaging was used to detect separate fluorescence emission spectra from the exogenous green fluorophore and RFP. Here, we describe the use of "co-staining" (matching the exogenous fluorophore and the endogenous fluorescent protein to the positive control cell line) and "counter-staining" (matching the exogenous fluorophore to the positive control and the endogenous fluorescent protein to the negative control cell line) to validate the sensitivity and specificity of target-specific probes. Using these in vivo imaging techniques, we are able to determine the sensitivity and specificity of target-specific optical contrast agents in several distinct animal models of cancer in vivo, thus exemplifying the versatility of our technique, while reducing the number of animals needed to conduct these experiments.

Activatable optical imaging with a silica-rhodamine based near infrared (SiR700) fluorophore: a comparison with cyanine based dyes.

Optical imaging is emerging as an important tool to visualize tumors. However, there are many potential choices among the available fluorophores. Optical imaging probes that emit in the visible range can image superficial tumors with high quantum yields; however, if deeper imaging is needed then near-infrared (NIR) fluorophores are necessary. Most commercially available NIR fluorophores are cyanine based and are prone to nonspecific binding and relatively limited photostability. Silica-containing rhodamine (SiR) fluorophores represent a new class of NIR fluorophores, which permit photoactivation via H-dimer formation as well as demonstrate improved photostability. This permits higher tumor-to-background ratios (TBRs) to be achieved over longer periods of time. Here, we compared an avidin conjugated with SiR700 (Av-SiR700) to similar compounds based on cyanine dyes (Av-Cy5.5 and Av-Alexa Fluor 680) in a mouse tumor model of ovarian cancer metastasis. We found that the Av-SiR700 probe demonstrated superior quenching, enabling activation after binding-internalization to the target cell. As a result, Av-SiR700 had higher TBRs compared to Av-Cy5.5 and better biostability compared to Av-Alexa Fluor 680.

Molecular imaging of tumor invasion and metastases: the role of MRI.

The processes of tumor invasion and metastasis have been well characterized at the molecular level, and numerous biomarkers of tumor aggressiveness have been discovered. Molecular imaging offers the opportunity to depict specific cell markers relevant to tumor aggressiveness. Here, we describe the role of MRI in identifying tumor invasiveness and metastasis with reference to other methods. Target-specific molecular imaging probes for tumor invasiveness have been developed for positron emission tomography and optical imaging, but progress in MRI has been slower. For example, proteases associated with tumor invasion, such as specific matrix metalloproteinases or cathepsins, can be targeted in vivo using optical and positron emission tomography methods, but have not yet been successful with MRI. In addition, we describe the use of MRI to detect metastases. Novel MR contrast agents based on iron oxide and dendrimer nanomaterials allow for better characterization of tumor metastases. Organ-specific MR contrast agents are used to identify metastatic disease in the liver. Finally, diffusion-weighted whole-body MRI is discussed as an alternative offered by MRI that does not require the use of molecular probes to screen distant metastases.

A portable fluorescence camera for testing surgical specimens in the operating room: description and early evaluation.

PURPOSE: Clinical translation of novel optical probes requires testing of human specimens ex vivo to ensure efficacy. However, it may be difficult to remove human tissue from the operating room due to regulatory/privacy issues. Therefore, we designed a portable fluorescence camera to test targeted optical imaging probes on human specimens in the operating room. PROCEDURES: A compact benchtop fluorescence camera was designed and built in-house. A mouse xenograft model of ovarian cancer with an activatable imaging probe based on rhodamine green was used to test the device. Comparison was made to commercially available imaging systems. RESULTS: The prototype camera produced images comparable to images acquired with commercially available, non-portable imaging systems. CONCLUSION: We demonstrate the feasibility of a specimen-based portable fluorescence camera for use in the operating room. Its small size ensures that tissue excised from patients can be tested promptly for fluorescence within the operating room environment, thus expediting the testing of novel imaging probes.

Biodistribution and excretion of monosaccharide-albumin conjugates measured with in vivo near-infrared fluorescence imaging.

Target specific small molecules as modulators of drug delivery may play a significant role in the future development of therapeutics. Small molecules can alter the in vivo pharmacokinetics of therapeutic macromolecules leading to more efficient drug delivery with less systemic toxicity. The potential of creating a more effective drug delivery system through glycosylation has led, for instance, to the addition of galactose to increase drug delivery to the liver. However, there are many other monosaccharides with potentially useful targeting properties that require further characterization. Here, we investigate the potential of glycosylation to guide molecular therapies using five different monosaccharides conjugated to human serum albumin (HSA). Additionally, we investigate how the amount of glycosylation may alter the pharmacokinetic profile of HSA. We introduce the use of in vivo near-infrared optical imaging to characterize the effect of differential glycosylation on the pharmacokinetics of macromolecules.

Real-time optical imaging using quantum dot and related nanocrystals.

Biomedical optical imaging is rapidly evolving because of its desirable features of rapid frame rates, high sensitivity, low cost, portability and lack of radiation. Quantum dots are attractive as imaging agents owing to their high brightness, and photo- and bio-stability. Here, the current status of in vitro and in vivo real-time optical imaging with quantum dots is reviewed. In addition, we consider related nanocrystals based on solid-state semiconductors, including upconverting nanoparticles and bioluminescence resonance energy transfer quantum dots. These particles can improve the signal-to-background ratio for real-time imaging largely by suppressing background signal. Although toxicity and biodistribution of quantum dots and their close relatives remain prime concerns for translation to human imaging, these agents have many desirable features that should be explored for medical purposes.

Length-scale mediated adhesion and directed growth of neural cells by surface-patterned poly(ethylene glycol) hydrogels.

We engineered surfaces that permit the adhesion and directed growth of neuronal cell processes but that prevent the adhesion of astrocytes. This effect was achieved based on the spatial distribution of sub-micron-sized cell-repulsive poly(ethylene glycol) [PEG] hydrogels patterned on an otherwise cell-adhesive substrate. Patterns were identified that promoted cellular responses ranging from complete non-attachment, selective attachment, and directed growth at both cellular and subcellular length scales. At the highest patterning density where the individual hydrogels almost overlapped, there was no cellular adhesion. As the spacing between individual hydrogels was increased, patterns were identified where neurites could grow on the adhesive surface between hydrogels while astrocytes were unable to adhere. Patterns such as lines or arrays were identified that could direct the growth of these subcellular neuronal processes. At higher hydrogel spacings, both neurons and astrocytes adhered and grew in a manner approaching that of unpatterned control surfaces. Patterned lines could once again direct growth at cellular length scales. Significantly, we have demonstrated that the patterning of sub-micron/nano scale cell-repulsive features at microscale lengths on an otherwise cell-adhesive surface can differently control the adhesion and growth of cells and cell processes based on the difference in their characteristic sizes. This concept could potentially be applied to an implantable nerve-guidance device that would selectively enable regrowing axons to bridge a spinal-cord injury without interference from the glial scar.

Chondroitin-4-sulfation negatively regulates axonal guidance and growth.

Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with diversity and complexity based upon the length, composition and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that specific sulfation in the GAG chains of chondroitin sulfate mediates neuronal guidance cues and axonal growth inhibition. Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated chondroitin sulfate GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice. Thus, our findings show that specific sulfation along the carbohydrate backbone carries instructions to regulate neuronal function.