An exploration of the impact of ethanol diluent on breath alcohol concentration in patients receiving paclitaxel chemotherapy.

PURPOSE: This study aimed to provide a better understanding of the impact of paclitaxel chemotherapy on breath alcohol in an Irish population. METHODS: Patients attending the Oncology Day Unit at Beaumont Hospital were invited to participate on the day of their treatment. The brand of paclitaxel used was Actavis Pharma Inc and contained 6 mg/mL paclitaxel in 50% Ethanol/ 50% Cremophor EL. Breath alcohol concentration was measured using the AlcoSense ™ Breathalyser on three separate visits. The primary end-point was the number of patients who were above the legal threshold for drink driving in Ireland. RESULTS: In total, 50 patients were recruited. 36 (68%) were female. The most common diagnosis was breast cancer (56%). Ten (20%) patients had metastatic disease and 4 (8%) had liver metastases. The mean paclitaxel dose administered was 118 mg. The mean amount of ethanol infused was 7.7 g. 27 patients had a detectable breath alcohol level on at least one visit. The mean breath alcohol concentration was 2 mcg/100 mL or 0.02 mg/L of breath. The maximum concentration of ethanol in exhaled breath was 11 mcg/100 mL or 0.11 mg/L which is 50% of the statutory limit for drink driving in Ireland. A weak correlation was observed between ethanol concentration in exhaled breath and the total amount of ethanol administered. Although no patient exceeded the general limit for drink driving in Ireland, three (6%) participants had a breath alcohol concentration above the threshold for professional, learner or novice drivers. CONCLUSION: Although definitive conclusions are limited by relatively small numbers, it seems unlikely that weekly paclitaxel infusions pose any significant risk to patients driving.

Marked differences in local bone remodelling in response to different marrow stimulation techniques in a large animal.

Marrow stimulation, including subchondral drilling and microfracture, is the most commonly performed cartilage repair strategy, whereby the subchondral bone plate is perforated to release marrow-derived cells into a cartilage defect to initiate repair. Novel scaffolds and therapeutics are being designed to enhance and extend the positive short-term outcomes of this marrow stimulation. However, the translation of these newer treatments is hindered by bony abnormalities, including bone resorption, intralesional osteophytes, and bone cysts, that can arise after marrow stimulation. In this study, three different marrow stimulation approaches - microfracture, subchondral drilling and needle-puncture - were evaluated in a translationally relevant large-animal model, the Yucatan minipig. The objective of the study was to determine which method of marrow access (malleted awl, drilled Kirschner wire or spring-loaded needle) best preserved the underlying subchondral bone. Fluorochrome labels were injected at the time of surgery and 2 weeks post-surgery to capture bone remodelling over the first 4 weeks. Comprehensive outcome measures included cartilage indentation testing, histological grading, microcomputed tomography and fluorochrome imaging. Findings indicated that needle-puncture devices best preserved the underlying subchondral bone relative to other marrow access approaches. This may relate to the degree of bony compaction occurring with marrow access, as the Kirschner wire approach, which consolidated bone the most, induced the most significant bone damage with marrow stimulation. This study provided basic scientific evidence in support of updated marrow stimulation techniques for preclinical and clinical practice.

Motivation for participating in phase 1 vaccine trials: Comparison of an influenza and an Ebola randomized controlled trial.

INTRODUCTION/HYPOTHESIS: Recruitment of participants into phase 1 vaccine clinical trials can be challenging since these vaccines have not been used in humans and there is no perceived benefit to the participant. Occasionally, as was the case with a phase 1 clinical trial of an Ebola vaccine in Halifax, Canada, during the 2014-2016 West African Ebola virus outbreak, recruitment is less difficult. In this study, we explored the motivations of participants in two phase 1 vaccine trials that were concurrently enrolling at the same centre and compared the motivations of participants in a high-profile phase 1 Ebola vaccine trial to those in a less high-profile phase 1 adjuvanted seasonal influenza vaccine study. METHODS: An online survey which included participants' prior experience with clinical trials, motivations to participate (including financial incentives), and demographic information was developed to examine the motivations of healthy participants in two phase 1 clinical vaccine trials conducted at the Canadian Center for Vaccinology in Halifax, Nova Scotia. Participants were invited via email to complete the online survey. Readability and clarity were assessed through pilot testing. RESULTS: A total of 49 (55.7%) of 88 participants of the two studies completed the survey (22 [55%] of 40 participants from the Ebola vaccine study and 27 [56.3%] of 48 from the adjuvanted influenza vaccine study). Motivations that were most frequently ranked among participants' top three in both trials were (1) wanting to contribute to the health of others, (2) wanting to participate in something important, (3) wanting to contribute to the advancement of science, and (4) wanting to receive an incentive such as money or a tablet. CONCLUSIONS/RECOMMENDATIONS: Although media attention and financial compensation were more often cited by Ebola vaccine trial participants as a reason to participate, both altruistic and self-interested factors were important motivations for participants in their decision to participate in a phase 1 vaccine clinical trial.

Are adult carpal angle measurements applicable to the pediatric population in the trauma setting?

OBJECTIVE: The aim of this study is to assess the applicability of standard adult carpal angle measurements, specifically the scapholunate and capitolunate angles, in the assessment of the pediatric wrist. MATERIALS AND METHODS: The study cohort comprised male and female children who underwent a wrist radiograph for the evaluation of suspected wrist injuries following trauma. A gender- and indication-matched adult cohort was also assessed. To ensure an accurate carpal angle measurement, only individuals with a sufficiently ossified carpus and an adequately positioned lateral wrist radiograph were included. RESULTS: Carpal angle measurements were performed on the lateral wrist radiographs of 256 individuals between the ages of 5 and 17 years (mean 11.2 years, SD ± 2.5 years) and 256 individuals between the ages of 18 and 40 years (mean 28.8 years, SD ± 6.2 years). The mean pediatric scapholunate angle was 47° (SD ± 8) and the mean pediatric capitolunate angle was 11° (SD ± 7). The mean adult scapholunate and capitolunate angles were 48° (SD ± 8°) and 10° (SD ± 6°) respectively. No statistically significant difference was observed between the scapholunate or capitolunate angle measurements in the two groups (p = 0.26 and p = 0.36). CONCLUSION: The study data supports the applicability of standard adult carpal angle values to the pediatric population provided the carpus is sufficiently ossified.

The differences between sex offenders who victimise older women and sex offenders who offend against children.

OBJECTIVES: Within the literature on sex offending, much attention is paid to the distinction between those sex offenders who offend against adults and those who offend against children. In contrast, there is a paucity of research into sex offenders who offend specifically against elderly or older victims. METHOD: A detailed interview and psychometric tests were conducted with a sample of 28 sex offenders who had been convicted of a sexually motivated offence against an older female. These data were compared to a sample of 23 child sex offenders. RESULTS: Results indicate that amongst other significant differences between these sub-groups, men who offend against older women are generally younger, are more violent, and are more likely to use a weapon and cause injury and death compared to child sex offenders. The men who offended against children were more likely to think about and plan their offending, spend more time with the victim pre and post offence, admit sexual arousal during the offence, and admit to a sexual motivation for the offence. CONCLUSIONS: This study suggests that men who sexually offend against older women and men who sexually offend against children are distinct groups. Treatment and risk management strategies should take this into account. Further exploration of this sub-group of offenders is recommended to help inform treatment and risk management strategies for sex offenders who offend against older people.

Chronic Disease Management - The Patient's Perspective.

A paucity of data exists on Irish patients' perspective of chronic disease management. This study explores patients' views on what is the most appropriate setting for their chronic disease management, the advantages and disadvantages of these settings, and where they get information on their condition. Semi-structured qualitative interviews were carried out with 24 patients. Three main themes emerged: Current Care Model, Health Literacy and Treatment Burden. Patients believe that the GP-patient relationship plays a pivotal role in the provision of chronic disease management. Health literacy and psychosocial burden were found to impact significantly on the lives of patients with chronic disease(s).

A Cu(ii) complex targeting the translocator protein: in vitro and in vivo antitumor potential and mechanistic insights.

A new Cu-based anticancer metallodrug which targets the translocator protein is reported. [CuBr2(TZ6)] elicits a remarkable in vitro cytotoxicity in sensitive and multidrug resistant cell lines and induces a 98% reduction of tumor mass in a murine tumor model. Target binding was studied by experimental and computational methods.

Proliferative Capacity and Phenotypical Alteration of Multipotent Ecto-Mesenchymal Stem Cells from Human Exfoliated Deciduous Teeth Cultured in Xenogeneic and Allogeneic Media.

Foetal calf serum (FCS) is a standard supplement used in media for in vitro stem cell cultivation. This xenogeneic supplement remains widely used for its favourable growth-promoting properties and ease of accessibility; however, it is inherently not fit for human medicine due to its capacity to temper with the cultured cell quality. For this reason, the international community encourages research and development of allogeneic sera, which would expunge this issue. This study aims to investigate the differences in proliferative capacity, phenotype, and differentiation capacity of ecto-mesenchymal stem cells from human exfoliated deciduous teeth (SHED) cultured in vitro in media supplemented with allogeneic and xenogeneic sera. To address these aims, we cultured three lineages of stem cells in media supplemented with FCS in a concentration of 2% + growth factors; human blood plasma and platelet-rich plasma in concentrations of 2% + growth factors, and 10%. Here, the xenogeneic cultivation was considered as a basis for comparison because this serum is commonly used in studies concerning ecto-mesenchymal stem cells. The study shows that multipotent ecto-mesenchymal SHED can be feasibly cultivated in media where the xenogeneic FCS is substituted by allogeneic platelet-rich plasma, considering the cultured cell proliferative and differentiation capacities. We have also proved that different sera impact the cultured cells' phenotype differently, which has major implications for previous and future stem cell research and regenerative therapy.

The palmaris profundus, a rare sight during carpal tunnel release.

Palmaris profundus is a rare anatomical anomaly that may complicate carpal tunnel release. We discuss a recent case of carpal tunnel syndrome and its surgical release, whilst reviewing the published anatomical and surgical literature.

The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents.

The cytolytic protein perforin is a key component of the immune response and is implicated in a number of human pathologies and therapy-induced conditions. A novel series of small molecule inhibitors of perforin function have been developed as potential immunosuppressive agents. The pharmacokinetics and metabolic stability of a series of 16 inhibitors of perforin was evaluated in male CD1 mice following intravenous administration. The compounds were well tolerated 6 h after dosing. After intravenous administration at 5 mg/kg, maximum plasma concentrations ranged from 532 ± 200 to 10,061 ± 12 ng/mL across the series. Plasma concentrations were greater than the concentrations required for in vitro inhibitory activity for 11 of the compounds. Following an initial rapid distribution phase, the elimination half-life values for the series ranged from 0.82 ± 0.25 to 4.38 ± 4.48 h. All compounds in the series were susceptible to oxidative biotransformation. Following incubations with microsomal preparations, a tenfold range in in vitro half-life was observed across the series. The data suggests that oxidative biotransformation was not singularly responsible for clearance of the compounds and no direct relationship between microsomal clearance and plasma clearance was observed. Structural modifications however, do provide some information as to the relative microsomal stability of the compounds, which may be useful for further drug development.

An unequivocal good? Acknowledging the complexities of advance care planning.

Over the past few decades advance care planning (ACP) has become the subject of debate, research and legislation in many countries. Encouraging people to express their preference for treatment in advance, ideally in written form, seems a natural way to identify what someone might have wanted when they can no longer participate in decision-making. The notion of ACP as an unequivocal good permeates much of the research and policy work in this area. For example, ACP is now actively encouraged in Australian federal and state government policies and the Victorian Government has recently published a practical ACP strategy for Victorian health services (2014-2018). However, advance care plan is ethically complex and the introduction of the Victorian health services strategy provides an opportunity to reflect on this complexity, particularly on the benefits and risks of ACP.

The tin whistle: a rare and serious cause of penetrating oropharyngeal trauma in children.

Impalement injuries of the oral cavity are common in children and the potential for serious complications including internal carotid artery thrombosis can be unnoticed. We present a patient who sustained a penetrating injury in which a "tin whistle" caused herniation of the parotid gland which was not detected on clinical examination. We discuss the challenging clinical examination, the role of investigations, and consequences of these injuries aiming at increasing awareness and optimizing patient management.

Clinical observed performance evaluation: a prospective study in final year students of surgery.

We report a prospective study of clinical observed performance evaluation (COPE) for 197 medical students in the pre-qualification year of clinical education. Psychometric quality was the main endpoint. Students were assessed in groups of 5 in 40-min patient encounters, with each student the focus of evaluation for 8 min. Each student had a series of assessments in a 25-week teaching programme. Over time, several clinicians from a pool of 16 surgical consultants and registrars evaluated each student by direct observation. A structured rating form was used for assessment data. Variance component analysis (VCA), internal consistency and inter-rater agreement were used to estimate reliability. The predictive and convergent validity of COPE in relation to summative OSCE, long case, and overall final examination was estimated. Median number of COPE assessments per student was 7. Generalisability of a mean score over 7 COPE assessments was 0.66, equal to that of an 8 × 7.5 min station final OSCE. Internal consistency was 0.88-0.97 and inter-rater agreement 0.82. Significant correlations were observed with OSCE performance (R = 0.55 disattenuated) and long case (R = 0.47 disattenuated). Convergent validity was 0.81 by VCA. Overall final examination performance was linearly related to mean COPE score with standard error 3.7%. COPE permitted efficient serial assessment of a large cohort of final year students in a real world setting. Its psychometric quality compared well with conventional assessments and with other direct observation instruments as reported in the literature. Effect on learning, and translation to clinical care, are directions for future research.

Male circumcision for HIV prevention in Papua New Guinea: a summary of research evidence and recommendations for public health following a national policy forum.

In 2005, a clinical trial in South Africa found that circumcision of young men could reduce their risk of acquiring HIV (human immunodeficiency virus) infection by over 60%. In the following year, two more trials in Africa confirmed this finding, leading the World Health Organization to recommend male circumcision as a public health strategy for HIV prevention in high-incidence countries. In order to inform public health policy in Papua New Guinea (PNG), two major research projects were initiated with the goals of investigating the status of penile cutting practices and assessing understandings, acceptability, feasibility and cost-effectiveness of male circumcision for HIV prevention. In addition, behavioural surveillance surveys systematically asked questions on penile cutting practices and an ethnographic literature review informed historical perspectives of penile cutting in PNG. Key findings from these research activities were presented at a National Policy Forum on Male Circumcision for HIV Prevention held in Port Moresby in November 2011. The Forum made three key recommendations: (1) the formation of a joint National Department of HealthlNational AIDS Council Secretariat Policy Committee on male circumcision; (2) the establishment of an integrated harm reduction program; and (3) that future policy on wide-scale roll-out of male circumcision for HIV prevention in PNG be informed by a combination of data from (a) male circumcision intervention pilot programs and (b) research on the potential protective effect of other forms of penile cutting.

Risk factor characteristics in carers who physically abuse or neglect their elderly dependants.

This study investigates the prevalence of, and differences in, risk factor characteristics in a sample of two select populations of carers, one of which physically abused their elderly dependants and one of which neglected them. Nineteen carers (nine who had physically abused and 10 who had neglected their elderly relatives), who were referred to clinical psychology by either their general practitioner or their psychiatrist, were invited to take part in this study. A detailed history of risk factors was obtained, including history of alcohol dependency, type and history of mental ill health, history of maltreatment earlier in life, who they were caring for, how long they had been a carer and whether they felt isolated as a carer. Subjects were then given five assessments to determine whether there were any differences between the two groups. These were the Conflict Tactic Scale, Strain Scale, Beck Depression Inventory, Beck Anxiety Inventory and Cost of Care Index. An examination of the risk factors suggests that heavy alcohol consumption and past childhood abuse by fathers were likely to lead to physical abuse. Significantly higher conflict and depression scores were also present in the physical abuse group, while the neglect group had significantly higher anxiety scores. It is suggested that these findings should be incorporated into an assessment of future risk of abuse or neglect by the carer.

Unlocking the secrets of cytotoxic granule proteins.

Cytotoxic lymphocytes largely comprise CD8(+) cytotoxic T cells and natural killer cells and form the major defense of higher organisms against virus-infected and transformed cells. A key function of cytotoxic lymphocytes is to detect and eliminate potentially harmful cells by inducing them to undergo apoptosis. This is achieved through two principal pathways, both of which require direct but transient contact between the killer cell and its target. The first, involving ligation of TNF receptor-like molecules such as Fas/CD95 by their cognate ligands, results in mobilization of conventional, programmed cell-death pathways centered on activation of pro-apoptotic caspases. This review concentrates on the second pathway, in which the toxic contents of secretory vesicles of the cytotoxic lymphocyte are secreted toward the target cell, and some toxins penetrate into the target cell cytoplasm and nucleus. In addition to invoking a powerful stimulus to caspase activation, this "granule-exocytosis mechanism" provides a variety of additional strategies for overcoming inhibitors of the caspase cascade that may be elaborated by viruses. The key molecular players in this process are the pore-forming protein perforin and a family of granule-bound serine proteases or granzymes. The molecular functions of perforin and granzymes are under intense investigation in many laboratories including our own, and recent advances will be discussed. In addition, this review discusses the evidence pointing to the importance of perforin and granzyme function in pathophysiological situations as diverse as infection with intracellular pathogens, graft versus host disease, susceptibility to transplantable and spontaneous malignancies, lymphoid homeostasis, and the tendency to auto-immune diseases.