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Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas secondary to loss of heterozygosity of NF2 in Schwann cells or their precursors. While these tumors are largely benign, they can cause considerable morbidity due to compromised auditory, vestibular, facial, and vertebral nerve function. This may result in deafness, vertigo, facial muscle weakness, chronic neuropathic pain, and even death.There are currently no pharmacotherapies for VS, and surgical resection remains the standard of care, which is associated with significant morbidity. Thus, there is an urgent need to develop pharmaceutical approaches to halt or reverse the progression of tumor growth in NF2 patients who develop VS. Our lab previously identified the receptor tyrosine kinase inhibitors brigatinib and dasatinib as potentially efficacious agents for the treatment of VS and demonstrated that both agents targeted the Ephrin A2 receptor (EPHA2). EPHA2is a transmembrane receptor tyrosine kinase thatis involved in cell contact-mediated motility, adhesion,and migration. Additionally, EPHA2 modulates axon guidance, and synaptogenesis in developing brain. Here we demonstrate that EPHA2expression is increased in NF2-/-Schwanncells and NF2-/-cancers. We identify ponatinib, a receptor tyrosine kinase inhibitor targeting ABL1 that is FDA-approved for CML, as an additional agent that targets EPHA2. We demonstrate that ponatinib treatment impairs the viability of both human and murine NF2-/-Schwanncells in vitro and decreases EPHA2 protein expression. Accordingly, pharmacologic,and siRNA-mediated inhibition of EPHA2 also impaired the growth of human NF2-/-Schwann cells in vitro. Lastly, we demonstrate that both ponatinib and EPHA2 inhibition induce morphological changes in NF2-/-Schwann cells. Our findings suggest that ponatinib or the direct targeting of EPHA2 may be efficacious for the treatment of NF2-associated vestibular schwannoma. Future in vivo efficacystudies are warranted.

BACKGROUND Vagus nerve stimulation (VNS) therapy was first approved in the mid-1990s in the USA, Europe and Australia, with demonstrable efficacy in paediatric populations. Benefit in seizure frequency reduction can be observed up to 2 years post-intervention; however, few studies assess outcomes beyond this period. Furthermore, paediatric cohort sizes are small, limiting generalisability of outcome assessments. We evaluate VNS insertion outcomes and complications or side-effects in a large paediatric cohort, over a 20-year period from Queensland's first VNS insertion. METHODS A retrospective review was conducted of all paediatric VNS insertions at the Queensland Children's Hospital (QCH) and the Mater Children's Hospital/Mater Children's Private Hospital (MCH/MCPH) Brisbane. A minimum of 1-year follow-up from 1999 to 2020 was required for inclusion. Patients were assessed on demographics, epilepsy details, seizure outcomes and complications or side-effects. RESULTS In this extended follow-up cohort (76 patients, 7.2 ± 5.3 years), 51.3% of patients had ≥ 50% seizure frequency reduction, while 73.7% experienced an Engel III outcome (worthwhile benefit) or better. Eleven patients (14.9%) were seizure-free at follow-up, and 81.6% retained long-term therapy. Stimulation-related side-effects are common (17.1%) but rarely result in stimulation cessation (3.9%). Cessation occurred in 14 patients (18.4%) and most commonly related to minimal benefit (13.2%). Demographics, aetiology, seizure nature and surgical factors did not influence outcomes. CONCLUSION Over extended treatment periods, a large proportion of patients will benefit significantly from VNS therapy. Approximately 4 of 5 patients will retain VNS therapy, and in cases of cessation, this is most commonly related to minimal benefit. Underlying demographics, aetiology or seizure nature do not influence outcomes. This 20-year Queensland assessment of VNS therapy outcomes informs long-term expectation of VNS therapy.

Substantial evidence exists describing differences between paediatric and adult Chiari 1 malformation (CM1) patients. Differences in clinical presentation between very young (0–6 years old) and older (7–18 years old) paediatric patients is similarly well-established. However, progression on these findings with regard to surgical outcomes is limited. We aimed to establish whether inter-paediatric age group modifies surgical outcome for CM1 decompression. Retrospective chart review was conducted for 65 patients receiving posterior fossa decompression between 2006 and 2018. Presenting features, surgical management, and outcome were evaluated and stratified into very young patients (0–6 years) or older patients (7–18 years). Outcomes were assessed using the Chicago Chiari Outcome Scale (CCOS), a validated 16-point framework for comparison. Very young patients (21 patients) scored significantly lower in surgical outcome overall compared with older patients (44 patients) (12.1 ± 3.2/16 vs 14.2 ± 1.6/16, p = 0.011), and across 3/4 CCOS subscores: non-pain symptoms, functionality, and complications. Very young patients also returned to theatre more commonly (47.6% vs 13.6%, p = 0.003), primarily for re-do decompression (7/10 patients, 70%). Finally, the presentation of very young patients differed to older patients with significantly more oropharyngeal (38.1% vs 9.0%, p = 0.014) and motor symptoms (47.6% vs 22.7%, p = 0.042). Very young patients (0–6 years) do not appear to respond as well to standard posterior fossa decompression, as their older (7–18 years) paediatric counterparts, in the absence of several baseline cohort characteristic differences. We hypothesise underlying anatomical differences may contribute to this finding.

With the intensification and frequency of heat waves and periods of water deficit stress, along with rising atmospheric carbon dioxide [CO2], understanding the seasonal leaf-gas-exchange responses to combined abiotic factors will be important in predicting crop performance in semi-arid production systems. In peanut (Arachis hypogaea L.), the availability of developmental stage physiological data on the response to repeated water deficit stress periods in an elevated [CO2] (EC) environment is limited and necessary to improve crop model predictions. Here, we investigated the effects of season-long EC (650 µmol CO2 m−2 s−1) on the physiology and productivity of peanut in a semi-arid environment. This study was conducted over two-growing seasons using field-based growth chambers to maintain EC conditions, and impose water-stress at three critical developmental stages. Our results showed that relative to ambient [CO2] (AC), long-term EC during water-stress episodes, increased leaf-level light-saturated CO2 assimilation (Asat), transpiration efficiency (TE), vegetative biomass, and pod yield by 58%, 73%, 58%, and 39%, respectively. Although leaf nitrogen content was reduced by 16%, there was 41% increase in maximum Rubisco carboxylation efficiency in EC, indicating that there was minimal photosynthetic down-regulation. Furthermore, long-term EC modified the short-term physiological response (Asat) to rapid changes in [CO2] during the water-stress episodes, generating a much greater change in EC (54%) compared to AC (10%). Additionally, long-term EC generated a 23% greater Asat compared to the short-term EC during the water-stress episodes. These findings indicate high levels of physiological adjustment in EC, which may increase drought resilience. We concluded that EC may reduce the negative impacts of repeated water-stress events at critical developmental stages on rain-fed peanut in semi-arid regions. These results can inform current models to improve the projections of peanut response to future climates.

Opisthotonus as a presenting feature in neurosurgical patients is rare, with few reports describing such presentations. Only four reports of opisthotonos secondary to posterior fossa mass were identified. An unclear pathophysiology, and broad aetiology contribute to clinical misdirection. While posterior fossa lesions commonly present with signs of raised intracranial pressure, or cerebellar dysfunction, this case describes the presentation of an infant with opisthotonic posturing, ataxia and autonomic dysfunction secondary to a large pilocytic astrocytoma. Despite initial treatment of hydrocephalus, opisthotonus only resolved with complete surgical resection of the posterior fossa mass. At follow-up, the child remains well and without signs of hypertonicity or other signs or symptoms. Presentations involving opisthotonus are rare, and active exclusion of posterior fossa pathology is necessary. In this case, urgent surgical resection allowed for a positive patient outcome. Description of such a case may contribute to understanding of similar presentations in the neurosurgical context.

Quadriparesis and cardiovascular instability are not symptoms commonly associated with Chiari I malformation diagnoses, less so in a 3-month-old toddler. Chiari I malformations have a wide array of symptoms, varying with regard to both the nature of onset and the age of the patient presenting. This variation is illustrated in this report, presenting a novel description of a set of symptoms in a particularly young patient, a case lacking the common insidious nature of Chiari I malformation symptoms. Acute onset of cardiovascular instability, global hypertonia, hyperreflexia, and proximal upper limb weakness in a 3-month-old toddler are discussed. Parallels between the presented case and previous case reports are few, however some key features are distinguishable among similar cases. A successful posterior fossa craniectomy allowed the acutely unwell toddler to become a healthy, fully functional child. We believe this case contributes to elucidating the rare presentations of a curious pathology.

India, with its goal of installing 175 GW of new renewable energy capacity by 2022, including 60 GW of wind, is a market which is too big to ignore. Wharton Business School recently ranked India as the best country in the world to invest in. India is progressing an offshore wind regime designed to attract wide interest from developers and the supply chain. In 2015 India adopted an offshore wind policy and two pilot projects are being developed: one in Gujarat and another in Tamil Nadu. The port and power transmission infrastructure in Gujarat is currently far more capable and suited to support offshore wind than for Tamil Nadu; however, the annual average wind speeds are lower in Gujarat and could be close to the limits of economic viability. The tender for the first projects could occur during 2018 and be followed by the developer-led design, procurement and build out of projects. With support from the EU and the British Government, the offshore wind resource is being surveyed, environmental assessments have started, and a policy framework is being crafted to guide and support the development of a pipeline of projects and a local supply chain. In Indian waters with depths of 0–50 m, >800 GW of theoretical wind energy potential exists. A realistic potential, considering technical, environmental and economic viability, will likely offer an extractable resource of many tens of GW.

The digital forensic science for Apple iPods face the challenge of keeping pace with the fast progress of technology. While the popularity and widespread use of Apple iPod have increased the possibility of its being used in crime, sound and legally acceptable procedures of forensic investigation are yet to be developed. Apple iPod Touch device, launched for the first time in 2007 is significantly different than older iPods in many ways. We investigated Apple iPod Touch generation 2 from a digital forensic perspective. In this paper, we describe our investigation techniques and findings.

Librarians are in the recommendation business. Our customers rely on us to recommend what they should read, which database is preferable over another, or which textbook might answer a background question. As digital gate counts increase and outpace traditional face-to-face interactions [1], the need to integrate librarian recommendations into digital systems grows. SmartSearch represents an automated approach to offering digital expert guidance to customers. The Lane Medical Library & Knowledge Management Center provides information access and knowledge management services for the Stanford University School of Medicine, Stanford Hospital, and the Lucile Packard Children's Hospital. Lane's mission is to get the right knowledge, to the right person, at the right time, in the right context to support translational research, innovative education, and advances in patient care. This is largely accomplished via the LaneConnex web interface [2], a library search platform that performs a metasearch across hundreds of licensed and open access knowledge resources. Like many academic health libraries, Lane's clinical collection consists of thousands of electronic journals and textbooks. This wealth of knowledge is daunting to users who are often overwhelmed by the sheer quantity of information. Lane's usage statistics show that clinical users consistently overlook expensive clinical resources (e.g., specialty textbooks from AccessMedicine, MDConsult, and Ovid) that librarians have selected for their high value and clinical relevance. SmartSearch addresses this issue. The goal of the SmartSearch project is to recommend a small number of infrequently consulted, high-value, clinically relevant resources in the context of a standard LaneConnex search. SmartSearch is a resource promotion tool that leverages librarian expertise with the Entrez Programming Utilities (E-Utilities) [3] from the National Center for Biotechnology Information (NCBI) to mimic the information-seeking behavior of a typical reference librarian. System design, development, and an evaluation of its effectiveness will be described.

This paper describes one approach to creating a search application that unlocks heterogeneous content stores and incorporates integrative functionality of Web search engines. LaneConnex is a search interface that identifies journals, books, databases, calculators, bioinformatics tools, help information, and search hits from more than three hundred full-text heterogeneous clinical and bioresearch sources. The user interface is a simple query box. Results are ranked by relevance with options for filtering by content type or expanding to the next most likely set. The system is built using component-oriented programming design. The underlying architecture is built on Apache Cocoon, Java Servlets, XML/XSLT, SQL, and JavaScript. The system has proven reliable in production, reduced user time spent finding information on the site, and maximized the institutional investment in licensed resources.