Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers

Dendrimers have potential for delivering chemotherapeutic drugs to solid tumours via the enhanced permeation and retention (EPR) effect. The impact of conjugation of hydrophobic anticancer drugs to hydrophilic PEGylated dendrimer surfaces, however, has not been fully investigated. The current study has therefore characterised the effect on dendrimer disposition of conjugating α-carboxyl protected methotrexate (MTX) to a series of PEGylated 3H-labelled poly-L-lysine dendrimers ranging in size from generation 3 (G3) to 5 (G5) in rats. Dendrimers contained 50% surface PEG and 50% surface MTX. Conjugation of MTX generally increased plasma clearance when compared to conjugation with PEG alone. Conversely, increasing generation reduced clearance, increased metabolic stability and reduced renal elimination of the administered radiolabel. For constructs with molecular weights >20 kDa increasing the molecular weight of conjugated PEG also reduced clearance and enhanced metabolic stability but had only a minimal effect on renal elimination. Tissue distribution studies revealed retention of MTX conjugated smaller (G3-G4) PEG570 dendrimers (or their metabolic products) in the kidneys. In contrast, the larger G5 dendrimer was concentrated more in the liver and spleen. The G5 PEG1100 dendrimer was also shown to accumulate in solid Walker 256 and HT1080 tumours and comparative disposition data in both rats (1 to 2% dose/g in tumour) and mice (11% dose/g in tumour) are presented. The results of this study further illustrate the potential utility of biodegradable PEGylated poly-L-lysine dendrimers as long circulating vectors for the delivery and tumour-targeting of hydrophobic drugs.

NT-ProBNP levels in saliva and its clinical relevance to heart failure

Background: Current blood based diagnostic assays to detect heart failure (HF) have large intra-individual and inter-individual variations which have made it difficult to determine whether the changes in the analyte levels reflect an actual change in disease activity. Human saliva mirrors the body's health and well being and similar to 20% of proteins that are present in blood are also found in saliva. Saliva has numerous advantages over blood as a diagnostic fluid which allows for a non-invasive, simple, and safe sample collection. The aim of our study was to develop an immunoassay to detect NT-proBNP in saliva and to determine if there is a correlation with blood levels. Methods: Saliva samples were collected from healthy volunteers (n = 40) who had no underlying heart conditions and HF patients (n = 45) at rest. Samples were stored at -80 degrees C until analysis. A customised homogeneous sandwich AlphaLISA((R)) immunoassay was used to quantify NT-proBNP levels in saliva. Results: Our NT-proBNP immunoassay was validated against a commercial Roche assay on plasma samples collected from HF patients (n = 37) and the correlation was r(2) = 0.78 (p<0.01, y = 1.705 x +1910.8). The median salivary NT-proBNP levels in the healthy and HF participants were <16 pg/mL and 76.8 pg/mL, respectively. The salivary NT-proBNP immunoassay showed a clinical sensitivity of 82.2% and specificity of 100%, positive predictive value of 100% and negative predictive value of 83.3%, with an overall diagnostic accuracy of 90.6%. Conclusion: We have firstly demonstrated that NT-proBNP can be detected in saliva and that the levels were higher in heart failure patients compared with healthy control subjects. Further studies will be needed to demonstrate the clinical relevance of salivary NT-proBNP in unselected, previously undiagnosed populations.

Saliva as an emerging biofluid for clinical diagnosis and applications of MEMS/NEMS in salivary diagnostics

Saliva as a biological fluid is gaining wider acceptance for diagnosing diseases. The growing interest in saliva as a biological fluid is due to its noninvasiveness, ease of use, cost-effectiveness, and multiple sample collection possibilities as well as minimal risk to health care professionals of contracting infectious organisms such as HIV and Hep B. However, the clinical translation of saliva is hampered by our lack of understanding of the biomolecular transportation from blood into saliva, the diurnal variations of biomolecules present in saliva, and relatively low levels of analytes (100th to a 1000th fold less than in blood). We provide information on the current status of salivary research, salivary diagnostics empowered by nanotechnology, and future prospects in this emerging field of saliva diagnostics.

Choice impulsivity: Definitions, measurement issues, and clinical implications

Background Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. Method The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Results Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. Conclusions The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.

Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma : results from the European Thoracic Oncology Platform Lungscape Project

PURPOSE: The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. METHODS: Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. RESULTS: Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS). CONCLUSION: In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.

Clinical outcomes, not clinical utility, should be the major consideration for saxagliptin with or without metformin

A recent review by Panagoulias and Doupis, published in Patient Preference and Adherence, concerned the saxagliptin/metformin fixed combination (SAXA/MET FDC), and was titled "Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination."1 This review concluded that "The SAXA/MET FDC is a patient-friendly, dosage-flexible, and hypoglycemia-safe regimen with very few adverse events and a neutral or even favorable effect on body weight. It achieves significant glycosylated hemoglobin A1c reduction helping the patient to achieve his/her individual glycemic goals."1

Clinical perceptions of radiation therapy undergraduate competency standards

Introduction The multifactorial nature of clinical skills development makes assessment of undergraduate radiation therapist competence level by clinical mentors challenging. A recent overhaul of the clinical assessment strategy at Queensland University of Technology has moved away from the high-stakes Observed Structured Clinical Examination (OSCE) to encompass a more continuous measure of competence. This quantitative study aimed to gather stakeholder evidence to inform development of standards by which to measure student competence for a range of levels of progression. Methods A simple anonymous questionnaire was distributed to all Queensland radiation therapists. The tool asked respondents to assign different levels of competency with a range of clinical tasks to different levels of student. All data were anonymous and was combined for analysis using Microsoft Excel. Results Feedback indicated good agreement with tasks that specified amount of direction required and this has been incorporated into the new clinical achievements record that the students need to have signed off. Additional puzzling findings suggested higher expectations with planning tasks than with treatment-based tasks. Conclusion The findings suggest that the amount of direction required by students is a valid indicator of their level and has been adopted into the clinical assessment scheme. Further work will build on this to further define standards of competency for undergraduates.

Clinical data warehousing : a business analytics approach for managing health data

Heterogeneous health data is a critical issue when managing health information for quality decision making processes. In this paper we examine the efficient aggregation of lifestyle information through a data warehousing architecture lens. We present a proof of concept for a clinical data warehouse architecture that enables evidence based decision making processes by integrating and organising disparate data silos in support of healthcare services improvement paradigms.

The visual and functional impacts of astigmatism and its clinical management

Purpose: To provide a comprehensive overview of research examining the impact of astigmatism on clinical and functional measures of vision, the short and longer term adaptations to astigmatism that occur in the visual system, and the currently available clinical options for the management of patients with astigmatism. Recent findings: The presence of astigmatism can lead to substantial reductions in visual performance in a variety of clinical vision measures and functional visual tasks. Recent evidence demonstrates that astigmatic blur results in short-term adaptations in the visual system that appear to reduce the perceived impact of astigmatism on vision. In the longer term, uncorrected astigmatism in childhood can also significantly impact on visual development, resulting in amblyopia. Astigmatism is also associated with the development of spherical refractive errors. Although the clinical correction of small magnitudes of astigmatism is relatively straightforward, the precise, reliable correction of astigmatism (particularly high astigmatism) can be challenging. A wide variety of refractive corrections are now available for the patient with astigmatism, including spectacle, contact lens and surgical options. Conclusion: Astigmatism is one of the most common refractive errors managed in clinical ophthalmic practice. The significant visual and functional impacts of astigmatism emphasise the importance of its reliable clinical management. With continued improvements in ocular measurement techniques and developments in a range of different refractive correction technologies, the future promises the potential for more precise and comprehensive correction options for astigmatic patients.

Clinical trials in pediatrics

“Children are not little adults.” Almost all aspects of children's health including clinical trials and drug development are poor cousins of adult health. Over the years, pediatricians worldwide caution against blind extrapolation of adult data to children as it may result in considerable harm [1,2]. Also, it is increasingly recognized that the roots of many chronic diseases in adulthood stem from childhood and tackling health issues in children lead to improved health in adults [3,4]. Furthermore, investment in early childhood has long-term benefits in adults not only in health but also in other aspects of life such as education and crime reduction [4,5]. Arguably, health at birth is the single most important predictor of health in adulthood as the inequality of an infant at birth has intergenerational effects [5]. The Carolina Abecedarian Project showed that early childhood programs that are of high quality result in substantial societal benefits (e.g., reduction of crime, increased earnings, better education) [4,5]. A recent publication from this project found that this benefit also translated into improved adult health outcomes [4]. In a randomized trial, Campbell and colleagues described that disadvantaged children who were randomized to the intervention group (early education, health screenings and nutrition program) had significantly lower rates of metabolic syndrome, obesity and hypertension, when aged in their mid-30s, compared with the control group [4]...

The relationship between emotional intelligence and depression in a clinical sample

Background and Objectives: Although depression is a commonly occurring mental illness, research concerning strategies for early detection and prophylaxis has not until now focused on the possible utility of measures of Emotional Intelligence (EI) as a potential predictive factor. The current study aimed to investigate the relationship between EI and a clinical diagnosis of depression in a cohort of adults. Methods: Sixty-two patients (59.70% female) with a DSM-IV-TR diagnosis of a major affective disorder and 39 aged matched controls (56.40% female) completed self-report instruments assessing EI and depression in a cross-sectional study. Results: Significant associations were observed between severity of depression and the EI dimensions of Emotional Management (r = -0.56) and Emotional Control (r = -0.62). The results show a reduced social involvement, an increased prior institutionalization and an increased incidence of "Schizophrenic Psychosis" and "Abnormal Personalities" in the sub-group of repeated admissions. Conclusions: Measures of EI may have predictive value in terms of early identification of those at risk for developing depression. The current study points to the potential value of conducting further studies of a prospective nature.

Australia’s first Allied Health Prescribing Program – exploring participants' understanding and confidence in clinical therapy choices for patient management

BACKGROUND Globally there are emerging trends for non-medical health professionals to expand their scope of practice into prescribing. The NPS Prescribing Competencies Framework and the Health Professionals Prescribing Pathway Program are recent initiatives to assist with implementation of prescribing for allied health professionals (AHPs). For AHPs to become prescribers, training programmes must be designed to extend their knowledge of medicines information and medicine management principles with the aim of optimising medicines related outcomes for patients. AIM To explore the understanding and confidence in clinical therapeutic choices for patient management of those AHPs enrolled in the Allied Health Prescribing Training Program Module One: Introduction to clinical therapeutics for prescribers, delivered by Queensland University of Technology, Brisbane. METHOD A pre-post survey was developed to explore key themes around understanding and confidence in selecting therapeutic choices for patients with varying complexities of conditions. Data were collected from participants in week one and 13 of the module via an online survey using a five-point Likert scale (1 = Strongly Agree (SA) to 5 = Strongly Disagree (SD)). RESULTS In the pre-Module survey the AHPs had a limited degree (D/SD) of understanding and confidence regarding the safe and effective use of medicines and appropriate therapeutic choices for managing patients, particularly with complex patients. This improved significantly in the post Module survey (A/SA).

The clinical utility of the Cornell Scale for Depression in Dementia as a routine assessment in nursing homes

Objective To examine the clinical utility of the Cornell Scale for Depression in Dementia (CSDD) in nursing homes. Setting 14 nursing homes in Sydney and Brisbane, Australia. Participants 92 residents with a mean age of 85 years. Measurements Consenting residents were assessed by care staff for depression using the CSDD as part of their routine assessment. Specialist clinicians conducted assessment of depression using the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders for residents without dementia or the Provisional Diagnostic Criteria for Depression in Alzheimer Disease for residents with dementia to establish expert clinical diagnoses of depression. The diagnostic performance of the staff completed CSDD was analyzed against expert diagnosis using receiver operating characteristic (ROC) curves. Results The CSDD showed low diagnostic accuracy, with areas under the ROC curve being 0.69, 0.68 and 0.70 for the total sample, residents with dementia and residents without dementia, respectively. At the standard CSDD cutoff score, the sensitivity and specificity were 71% and 59% for the total sample, 69% and 57% for residents with dementia, and 75% and 61% for residents without dementia. The Youden index (for optimizing cut-points) suggested different depression cutoff scores for residents with and without dementia. Conclusion When administered by nursing home staff the clinical utility of the CSDD is highly questionable in identifying depression. The complexity of the scale, the time required for collecting relevant information, and staff skills and knowledge of assessing depression in older people must be considered when using the CSDD in nursing homes.

Standardising and assessing digital images for use in clinical trials : a practical, reproducible method that blinds the assessor to treatment allocation

With the increasing availability of high quality digital cameras that are easily operated by the non-professional photographer, the utility of using digital images to assess endpoints in clinical research of skin lesions has growing acceptance. However, rigorous protocols and description of experiences for digital image collection and assessment are not readily available, particularly for research conducted in remote settings. We describe the development and evaluation of a protocol for digital image collection by the non-professional photographer in a remote setting research trial, together with a novel methodology for assessment of clinical outcomes by an expert panel blinded to treatment allocation.