First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults.

VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus, including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC24) and maximum concentration (Cmax). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.

Ten guiding principles for youth mental health services.

AIMS: Guiding principles are arguably central to the development of any health service. The aim of this article is to report on the outcomes of a youth mental health (YMH) community of practice (CoP), which identified a range of guiding principles that provide a clear point of comparison for the only other set of principles for YMH service delivery proposed to date. METHODS: A YMH CoP was established in 2010 as part of the Victorian State Government approach to improving YMH care. An initial literature search was undertaken to locate articles on YMH service delivery. A number of common themes were identified, which the YMH community of practice (YMHCoP) members then elaborated upon by drawing from their collective experience of the YMH sector. The resultant themes were then refined through subsequent group discussions to derive a definitive set of guiding principles. These principles were then augmented by a second literature search conducted in July 2015. RESULTS: Fifteen key themes were derived from the initial literature search and YMH CoP discussions. These were refined by the YMH CoP to produce 10 guiding principles for YMH service development. These are discussed through reference to the relevant literature, using the only other article on principles of YMH service delivery as a notable point of comparison. CONCLUSION: The 10 principles identified may be useful for quality improvement and are likely to have international relevance. We suggest the timely pursuit of an international consensus on guiding principles for service delivery under the auspices of a peak body for YMH.

Development of an implementation guide to facilitate the roll-out of early intervention services for psychosis.

AIM: Our aim was to develop an implementation guide that was informed by an analysis of context-specific barriers and enablers, behaviour change theory, as well as evidence about the effects of implementation interventions, for the establishment and scaling up of an early intervention model for psychosis (called Early Psychosis Prevention and Intervention Centre (EPPIC)). METHODS: We used a systematic approach involving four steps. First, the target behaviours of the EPPIC model for implementation were specified. Second, a consultation was undertaken to explore the barriers and enablers to undertaking these priority minimum standard clinical behaviours. Third, an implementation strategy that included a range of behaviour change techniques tailored to address the identified barriers was developed. Finally, a tool to assess whether those implementing the EPPIC model maintained fidelity to the implementation strategy was designed. RESULTS: We identified a range of barriers that could act to dilute the core components of the EPPIC model and compromise its implementation. An implementation strategy using theory and evidence-based strategies for behaviour change was designed to address these barriers. CONCLUSIONS: The process we used in the development of the implementation strategy provided a unique opportunity to consider the essential areas to cover, how to make information easily understandable and accessible while noting the complexity of issues involved in not only implementation, but also the scaling up of the EPPIC model for services.

At the heart of an early psychosis centre: the core components of the 2014 Early Psychosis Prevention and Intervention Centre model for Australian communities.

OBJECTIVE: To describe the core components of the Early Psychosis Prevention and Intervention Centre service model as the template agreed with the Australian Federal Government for national upscaling. The Early Psychosis Prevention and Intervention Centre model of early intervention has two main goals: to reduce the period of time between the onset of psychosis and the commencement of treatment and to bring about symptomatic recovery and restore the normal developmental trajectory as early as possible. CONCLUSIONS: The Early Psychosis Prevention and Intervention Centre comprises three elements of service provision for young people experiencing a first episode of psychosis: (i) early detection; (ii) acute care during and immediately following a crisis; (iii) recovery-focused continuing care, featuring multimodal interventions to enable the young person to maintain or regain their social, academic and/or career trajectory during the critical first 2-5 years following the onset of a psychotic illness. It does this via a combination of 16 core components, which provide a flexible, comprehensive, integrated service that is able to respond quickly, appropriately and consistently to the individual needs of the young person and their family. Innovative service reforms, such as Early Psychosis Prevention and Intervention Centre, that recognise the value of early intervention are crucial to reducing the impact of serious mental illness on young people and their families and, ultimately, on our society.

Pharmacist-led workshops to enhance pharmacotherapy knowledge for medical students.

BACKGROUND: Graduating medical students have reported concern regarding inadequate training in pharmacotherapy. Teaching by clinical pharmacists may improve medical students' pharmacotherapy knowledge. PURPOSE: To assess the impact of pharmacist led workshops on 4th year medical students' knowledge of pharmacotherapy and satisfaction. METHODS: Senior medical students enrolled in intensive care unit rotations at a US medical school were randomized to an intervention of pharmacist led case-based workshops or a control group without an explicit pharmacotherapy curriculum. Intervention group students attended four weekly 1-hour workshops that covered topics in pharmacokinetics, pharmacodynamics, drug interactions and toxicity. A multiple-choice test of clinical vignettes assessed students' knowledge of pharmacotherapy. An end of clerkship survey assessed student satisfaction with teaching. RESULTS: Of 176 medical students eligible, 148 agreed to participate and were randomized to the intervention (n = 63) or control groups (n = 85). Student satisfaction with pharmacist led workshops was high. End of clerkship performance on clinical vignettes (minimum score 0, maximum 100) was similar between the groups (mean score 47 (SD = 12.2) for intervention vs 44 (SD = 13.0) for control group, p = 0.16). On end of clerkship survey, only 8% of control group students agreed or strongly agreed that the standard curriculum provided sufficient teaching in pharmacotherapy. The majority of students (82%) felt that pharmacotherapy should be taught formally in the clinical years. CONCLUSION: Pharmacist led workshops on pharmacotherapy were well received by senior medical students but did not improve performance on a test of pharmacotherapy knowledge. Further study is needed to define optimal strategies for improving medical students' pharmacotherapy knowledge.

Loss of CD26 protease activity in recipient mice during hematopoietic stem cell transplantation results in improved transplant efficiency.

BACKGROUND: A firm understanding of the biology of hematopoietic stem and progenitor cell (HSC/HPC) trafficking is critical to improve transplant efficiency and immune reconstitution during hematopoietic stem cell transplantation (HSCT). Our earlier findings suggested that suppression of CD26 (dipeptidyl peptidase IV) proteolytic activity in the donor cell population can be utilized as a method for increasing transplant efficiency. However, factors in the recipient should not be overlooked, given the potential for the bone marrow (BM) microenvironment to regulate HSCT. STUDY DESIGN AND METHODS: We first evaluated CD26 expression and then investigated the effects of the CD26 inhibitor diprotin A and the absence of CD26 (CD26-/-) in recipient mice on HSC/HPC homing and engraftment using an in vivo congenic mouse model of HSCT. RESULTS: A significant increase in donor cell engraftment into the peripheral blood (PB), and to a lesser extent homing into the BM, was observed in CD26-/- mice or CD26 inhibitor-treated mice. Increased PB engraftment of CD26-/- mice was significant at 3 and 6 months, but not 1 month, after transplant. It was noted that the increased homing was statistically greater with donor cell manipulation (CD26-/- donor cells) than with recipient manipulation (CD26-/- recipient mice). Conversely, donor and recipient manipulation both worked well to increase PB engraftment at 6 months. CONCLUSION: These results provide preclinical evidence of CD26, in the HSCT recipient, as a major regulator of HSC/HPC engraftment with minor effects on HSC/HPC homing and suggest the potential use of CD26 inhibitors in HSCT patients to improve transplant efficiency.

Targeted intervention to improve monitoring of antipsychotic-induced weight gain and metabolic disturbance in first episode psychosis.

OBJECTIVE: International guidelines recommend monitoring for weight gain and metabolic disturbance in patients prescribed second generation antipsychotics. We aimed to investigate whether a targeted intervention could improve levels of monitoring in a first episode psychosis clinic. METHOD: A pre-intervention audit of both metabolic screening rates and specific monitoring of weight and metabolic indices following the initiation of antipsychotic medication was performed in our first episode psychosis clinic. This was repeated 18 months later, following an intervention that included a number of targeted improvement strategies based on an analysis of barriers and enablers to performing monitoring within the clinic. The intervention included provision of monitoring equipment, interactive educational events, reminders and prompts and embedding processes for monitoring within team structure. RESULTS: There were significant improvements in both the screening of metabolic indices and the monitoring of indices following initiation of antipsychotic medications. There were also improvements in the number of active interventions offered to clients by clinicians. However, the level of guideline concordant monitoring remains low within our service. CONCLUSIONS: A comprehensive programme of implementation strategies can improve both screening and monitoring of the metabolic side-effects of antipsychotic medications. Further focused strategies are necessary to continue to improve monitoring to guideline concordant levels.

Promoting physical health in youth mental health services: ensuring routine monitoring of weight and metabolic indices in a first episode psychosis clinic.

OBJECTIVE: Clinicians are increasingly being asked to implement guideline recommendations into their practice, but are given little practical guidance on this complex task. In this paper we outline a promising theory-driven approach we took to implementing guideline recommendations about routine monitoring of weight gain and metabolic disturbance in our first-episode psychosis clinic. While there is significant psychological and physical morbidity associated with weight gain and metabolic disturbance, routine monitoring was not being undertaken according to guideline recommendations. We examined the factors that make it difficult to undertake routine monitoring by interviewing psychiatrists. This barrier analysis allowed us to develop and introduce feasible and acceptable strategies to address these barriers, increasing the likelihood that routine monitoring would take place. CONCLUSION: This paper advocates for undertaking an analysis of the barriers clinicians face to undertaking evidence-based practice in order to develop more sophisticated approaches to address areas where clinical practice and evidence are divergent. Such an approach is more likely to ensure that measures to improve practice are successful, are meaningful for the clinicians involved, and become imbedded in the clinical practice of the service.

Intracranial metastatic disease spares the limbic circuit: a review of 697 metastatic lesions in 107 patients.

PURPOSE: We report the incidence of metastatic involvement of the limbic circuit in a retrospective review of patients treated at our institution. This review was performed to assess the feasibility of selectively sparing the limbic system during whole-brain radiotherapy and prophylactic cranial irradiation. METHODS AND MATERIALS: We identified 697 intracranial metastases in 107 patients after reviewing contrast-enhanced CT and/or MR image sets for each patient. Lesions were localized to the limbic circuit or to the rest of the brain/brain stem. Patients were categorized by tumor histology (e.g., non-small-cell lung cancer, small-cell lung cancer, breast cancer, and other) and by total number of intracranial metastases (1-3, oligometastatic; 4 or more, nonoligometastatic). RESULTS: Thirty-six limbic metastases (5.2% of all metastases) were identified in 22 patients who had a median of 16.5 metastases/patient (limbic metastases accounted for 9.9% of their lesions). Sixteen metastases (2.29%) involved the hippocampus, and 20 (2.86%) involved the rest of the limbic circuit; 86.2% of limbic metastases occurred in nonoligometastatic patients, and 13.8% occurred in oligometastatic patients. The incidence of limbic metastases by histologic subtype was similar. The incidence of limbic metastases in oligometastatic patients was 4.9% (5/103): 0.97%, hippocampus; 3.9%, remainder of the limbic circuit. One of 53 oligometastatic patients (1.9%) had hippocampal metastases, while 4/53 (7.5%) had other limbic metastases. CONCLUSIONS: Metastatic involvement of the limbic circuit is uncommon and limited primarily to patients with nonoligometastatic disease, supporting our hypothesis that it is reasonable to selectively exclude or reduce the dose to the limbic circuit when treating patients with prophylactic cranial irradiation or whole-brain radiotherapy for oligometastatic disease not involving these structures.

Community-acquired pneumonia due to pandemic A(H1N1)2009 influenzavirus and methicillin resistant Staphylococcus aureus co-infection.

BACKGROUND: Bacterial pneumonia is a well described complication of influenza. In recent years, community-onset methicillin-resistant Staphylococcus aureus (cMRSA) infection has emerged as a contributor to morbidity and mortality in patients with influenza. Since the emergence and rapid dissemination of pandemic A(H1N1)2009 influenzavirus in April 2009, initial descriptions of the clinical features of patients hospitalized with pneumonia have contained few details of patients with bacterial co-infection. METHODOLOGY/PRINCIPAL FINDINGS: Patients with community-acquired pneumonia (CAP) caused by co-infection with pandemic A(H1N1)2009 influenzavirus and cMRSA were prospectively identified at two tertiary hospitals in one Australian city during July to September 2009, the period of intense influenza activity in our region. Detailed characterization of the cMRSA isolates was performed. 252 patients with pandemic A(H1N1)2009 influenzavirus infection were admitted at the two sites during the period of study. Three cases of CAP due to pandemic A(H1N1)2009/cMRSA co-infection were identified. The clinical features of these patients were typical of those with S. aureus co-infection or sequential infection following influenza. The 3 patients received appropriate empiric therapy for influenza, but inappropriate empiric therapy for cMRSA infection; all 3 survived. In addition, 2 fatal cases of CAP caused by pandemic A(H1N1)2009/cMRSA co-infection were identified on post-mortem examination. The cMRSA infections were caused by three different cMRSA clones, only one of which contained genes for Panton-Valentine Leukocidin (PVL). CONCLUSIONS/SIGNIFICANCE: Clinicians managing patients with pandemic A(H1N1)2009 influenzavirus infection should be alert to the possibility of co-infection or sequential infection with virulent, antimicrobial-resistant bacterial pathogens such as cMRSA. PVL toxin is not necessary for the development of cMRSA pneumonia in the setting of pandemic A( H1N1) 2009 influenzavirus co-infection.

Optic nerve dysfunction in a mouse model of neurofibromatosis-1 optic glioma.

Individuals with neurofibromatosis type 1 (NF1) are prone to develop optic pathway gliomas that can result in significant visual impairment. To explore the cellular basis for the reduced visual function resulting from optic glioma formation, we used a genetically engineered mouse model of Nf1 optic glioma (Nf1+/-(GFAP)CKO mice). We performed multimodal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, before obvious glioma formation, Nf1+/-(GFAP)CKO mice had decreased visual-evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/-(GFAP)CKO mice exhibited pronounced optic nerve axonopathy and apoptosis of neurons in the retinal ganglion cell layer. Magnetic resonance diffusion tensor imaging showed a progressive increase in radial diffusivity between 6 weeks and 6 months of age in the optic nerve proximal to the tumor indicating ongoing deterioration of axons. These data suggest that optic glioma formation results in early axonal disorganization and damage, which culminates in retinal ganglion cell death. Collectively, this study shows that Nf1+/-(GFAP)CKO mice can provide a useful model for defining mechanisms of visual abnormalities in children with NF1 and lay the foundations for future interventional studies aimed at reducing visual loss.