Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

Addressing childcare as a barrier to healthcare access through community partnerships in a large public health system.

OBJECTIVE: In our public health system, a survey of reproductive-aged women identified lack of childcare as the most common reason for missing or delaying healthcare. Community-based organisations (CBOs) in our county identified a similar need, so we partnered to develop a hospital-based childcare centre for patients to use during appointments. METHODS: In a large academic public health system, a partnership with a non-profit childcare CBO was formed to address lack of childcare as a barrier to accessing healthcare. Pilot clinics where no-cost childcare would be offered included obstetrics, gynaecology and medical oncology. Transparent communication from the CBO within the electronic medical record was built to minimally impact clinic workflows. Visual and electronic outreach, including patient portal questionnaires, were created to introduce patients to the services. Personalised clinic staff in-services were performed to introduce the service to clinics and leadership. Continual assessments of workflow were conducted and adjusted based on patient and staff feedback and quality checks. At 12 months, overall utilisation of the service was collected. RESULTS: In the first 12 months that no-cost childcare was offered, 175 patients enrolled 271 children into the programme. Ninety-seven percent were women, primarily Hispanic (87/175 (50%)) or black (64/175 (37%)), with an average age of 31.8 years. Of the enrollees, 142/175 (81%) patients made 637 childcare appointments and 119/175 (68%) patients used at least one reservation for 191 children. Most patients were verbally referred by clinic staff for childcare or self-referred for childcare from clinic signage or paperwork. Childcare was requested most frequently for obstetrics and gynaecology appointments.

Neoadjuvant therapy or upfront surgery in advanced endometrial cancer: a systematic review protocol.

INTRODUCTION: There is no consensus on the optimal treatment strategy for people with advanced endometrial cancer. Neoadjuvant therapies such as chemotherapy and radiotherapy have been employed to try to reduce the morbidity of surgery, improve its feasibility and/or improve functional performance in people considered unfit for primary surgery. The objective of this review is to assess whether neoadjuvant chemotherapy or radiotherapy improves health outcomes in people with advanced endometrial cancer when compared with upfront surgery. METHODS AND ANALYSIS: This review will consider both randomised and non-randomised studies that compare health outcomes associated with the neoadjuvant therapy and upfront surgery in advanced endometrial cancer. Potential studies for inclusion will be collated from electronic searches of OVID Medline, Embase, international trial registries and conference abstract lists. Data collection and extraction will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodological quality of the studies will be assessed using the Risk of Bias 2 and Risk of Bias in Non-randomised Studies of Interventions tools. If appropriate, we will perform a meta-analysis and provide summary statistics for each outcome. ETHICS AND DISSEMINATION: Ethics approval was not required for this study. Once complete, we will publish our findings in peer-reviewed publications, via conference presentations and to update relevant practice guidelines.

Comparative evaluation of a low-cost solar powered otoscope with a traditional device among health care workers in Malawi.

OBJECTIVES: To comparatively evaluate a low-cost otoscope with a traditional device among health care workers in Malawi. METHODS: The study is a prospective, comparative, qualitative observational survey of health care worker's opinions using 5-point Likert rating scales and tick box categories in a 10-item survey questionnaire. Twenty-five mixed cadre health care workers from the Ear, Nose, and Throat Department of the Queen Elizabeth Hospital, Blantyre in Malawi were recruited. Outcomes measures used were ease of speculum attachment, handling, insertion, stability, the quality of view, color, build, brightness, overall ease of use, and their suitability for local work. RESULTS: The low-cost otoscope scored statistically higher in overall combined performance, as well as in the remaining four out of the nine attributes. Notably, 54.2% of users rated the low-cost device more suitable than the traditional device for use in low-middle income countries, 25% were equivocal, and 20.8% preferred the traditional device. CONCLUSION: This study found the Arclight otoscope to be an appropriate and practical substitute for more expensive traditional otoscopes for the delivery of ENT services in low resource settings. LEVEL OF EVIDENCE: N/A.

The impact of algorithmic decision-making processes on young people's well-being.

This study aims to capture the online experiences of young people when interacting with algorithm mediated systems and their impact on their well-being. We draw on qualitative (focus groups) and quantitative (survey) data from a total of 260 young people to bring their opinions to the forefront while eliciting discussions. The results of the study revealed the young people's positive as well as negative experiences of using online platforms. Benefits such as convenience, entertainment and personalised search results were identified. However, the data also reveals participants' concerns for their privacy, safety and trust when online, which can have a significant impact on their well-being. We conclude by recommending that online platforms acknowledge and enact on their responsibility to protect the privacy of their young users, recognising the significant developmental milestones that this group experience during these early years, and the impact that algorithm mediated systems may have on them. We argue that governments need to incorporate policies that require technologists and others to embed the safeguarding of users' well-being within the core of the design of Internet products and services to improve the user experiences and psychological well-being of all, but especially those of children and young people.

BAcTrace, a tool for retrograde tracing of neuronal circuits in Drosophila.

Animal behavior is encoded in neuronal circuits in the brain. To elucidate the function of these circuits, it is necessary to identify, record from and manipulate networks of connected neurons. Here we present BAcTrace (Botulinum-Activated Tracer), a genetically encoded, retrograde, transsynaptic labeling system. BAcTrace is based on Clostridium botulinum neurotoxin A, Botox, which we engineered to travel retrogradely between neurons to activate an otherwise silent transcription factor. We validated BAcTrace at three neuronal connections in the Drosophila olfactory system. We show that BAcTrace-mediated labeling allows electrophysiological recording of connected neurons. Finally, in a challenging circuit with highly divergent connections, BAcTrace correctly identified 12 of 16 connections that were previously observed by electron microscopy.

Allosteric Inhibitor of KRas Identified Using a Barcoded Assay Microchip Platform.

Protein catalyzed capture agents (PCCs) are synthetic antibody surrogates that can target a wide variety of biologically relevant proteins. As a step toward developing a high-throughput PCC pipeline, we report on the preparation of a barcoded rapid assay platform for the analysis of hits from PCC library screens. The platform is constructed by first surface patterning a micrometer scale barcode composed of orthogonal ssDNA strands onto a glass slide. The slide is then partitioned into microwells, each of which contains multiple copies of the full barcode. Biotinylated candidate PCCs from a click screen are assembled onto the barcode stripes using a complementary ssDNA-encoded cysteine-modified streptavidin library. This platform was employed to evaluate candidate PCC ligands identified from an epitope targeted in situ click screen against the two conserved allosteric switch regions of the Kirsten rat sarcoma (KRas) protein. A single microchip was utilized for the simultaneous evaluation of 15 PCC candidate fractions under more than a dozen different assay conditions. The platform also permitted more than a 10-fold savings in time and a more than 100-fold reduction in biological and chemical reagents relative to traditional multiwell plate assays. The best ligand was shown to exhibit an in vitro inhibition constant (IC50) of ∼24 µM.

Development of the major trauma case review tool.

BACKGROUND: As many as half of all patients with major traumatic injuries do not receive the recommended care, with variance in preventable mortality reported across the globe. This variance highlights the need for a comprehensive process for monitoring and reviewing patient care, central to which is a consistent peer-review process that includes trauma system safety and human factors. There is no published, evidence-informed standardised tool that considers these factors for use in adult or paediatric trauma case peer-review. The aim of this research was to develop and validate a trauma case review tool to facilitate clinical review of paediatric trauma patient care in extracting information to facilitate monitoring, inform change and enable loop closure. METHODS: Development of the trauma case review tool was multi-faceted, beginning with a review of the trauma audit tool literature. Data were extracted from the literature to inform iterative tool development using a consensus approach. Inter-rater agreement was assessed for both the pilot and finalised versions of the tool. RESULTS: The final trauma case review tool contained ten sections, including patient factors (such as pre-existing conditions), presenting problem, a timeline of events, factors contributing to the care delivery problem (including equipment, work environment, staff action, organizational factors), positive aspects of care and the outcome of panel discussion. After refinement, the inter-rater reliability of the human factors and outcome components of the tool improved with an average 86% agreement between raters. DISCUSSION: This research developed an evidence-informed tool for use in paediatric trauma case review that considers both system safety and human factors to facilitate clinical review of trauma patient care. CONCLUSIONS: This tool can be used to identify opportunities for improvement in trauma care and guide quality assurance activities. Validation is required in the adult population.

Paediatric trauma systems and their impact on the health outcomes of severely injured children: protocol for a mixed methods cohort study.

BACKGROUND: Injury is a leading cause of death and disability for children. Regionalised trauma systems have improved outcomes for severely injured adults, however the impact of adult orientated trauma systems on the outcomes of severely injured children remains unclear. The objective of this study is to review the processes of care and describe the impacts of a regionalised trauma system on the outcomes of severely injured children. METHODS: This article describes the design of a mixed methods cohort study evaluating the paediatric trauma system in New South Wales (NSW), the most populous state in Australia. Recommendations and an implementation strategy will be developed for aspects of the paediatric trauma care system that require change. All injured children (aged <16 years) requiring intensive care, or with an Injury Severity Score (ISS) ≥ 9 treated in NSW, or who died following injury in NSW in the 2015-16 financial year, will be eligible for participation. Injury treatment and processes will be examined via retrospective medical record review. Quality of care will be measured via peer review and staff interviews, utilising a human factors framework. Health service and cost outcomes will be calculated using activity based funding data provided by the Ministry of Health. Health-related quality of life (HRQoL) proxy measures will occur at baseline, 6 and 12 months to measure child HRQoL and functional outcomes. DISCUSSION: This will be the first comprehensive analysis undertaken in Australia of the processes and systems of care for severe paediatric injury. The collaborative research method will encourage clinician, consumer and clinical networks to lead the clinical reform process and will ultimately enable policy makers and service providers to ensure that children seriously injured in Australia have the best opportunity for survival, improved functional outcome and long-term quality of life.

Paediatric trauma systems and their impact on the health outcomes of severely injured children: An integrative review.

BACKGROUND: Injury is a leading cause of death and disability for children. Regionalised trauma systems have improved outcomes for severely injured adults, however the impact of adult orientated trauma systems on the outcomes of severely injured children remains unclear. AIMS: This research aims to identify the impact of trauma systems on the health outcomes of children following severe injury. METHODS: Integrative review with data sourced from Medline, Embase, CINAHL, Scopus and hand searched references. Abstracts were screened for inclusion/exclusion criteria with fifty nine articles appraised for quality, analysed and synthesised into 3 main categories. RESULTS: The key findings from this review include: (1) a lack of consistency of prehospital and inhospital triage criteria for severely injured children leading to missed injuries, secondary transfer and poor utilisation of finite resources; (2) severely injured children treated at paediatric trauma centres had improved outcomes when compared to those treated at adult trauma centres, particularly younger children; (3) major causes of delays to secondary transfer are unnecessary imaging and failure to recognise the need for transfer; (4) a lack of functional or long term outcomes measurements identified in the literature. CONCLUSIONS: Research designed to identify the best processes of care and describe the impacts of trauma systems on the long term health outcomes of severely injured children is required. Ideally all phases of care including prehospital, paediatric triage trauma criteria, hospital type and interfacility transfer should be included, focusing on timeliness and appropriateness of care. Outcome measures should include long term functional outcomes in addition to mortality.

A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands.

We describe a general synthetic strategy for developing high-affinity peptide binders against specific epitopes of challenging protein biomarkers. The epitope of interest is synthesized as a polypeptide, with a detection biotin tag and a strategically placed azide (or alkyne) presenting amino acid. This synthetic epitope (SynEp) is incubated with a library of complementary alkyne or azide presenting peptides. Library elements that bind the SynEp in the correct orientation undergo the Huisgen cycloaddition, and are covalently linked to the SynEp. Hit peptides are tested against the full-length protein to identify the best binder. We describe development of epitope-targeted linear or macrocycle peptide ligands against 12 different diagnostic or therapeutic analytes. The general epitope targeting capability for these low molecular weight synthetic ligands enables a range of therapeutic and diagnostic applications, similar to those of monoclonal antibodies.

The use of high-fidelity simulation for rapid response team training: a community hospital's story.

The authors describe how simulation training was used to improve rapid response team activation in a nonteaching, nonprofit community hospital. Goals were established, and a scenario was developed to educate the healthcare team on the importance of early activation of the rapid response ream. Organizing and implementing a large-scale simulation required a solid commitment from the staff development department. The education from the simulation has led to increased knowledge and comfort levels of clinical staff, resulting in an increased use of the rapid response team.

Assessing the impact of cue exposure on craving to gamble in university students.

We recruited a sample of university student gamblers (n = 48) to complete a web-based battery of instruments in a study designed to assess the impact of imagery-based versus photographic cue exposure on acute craving to gamble using the multi-item Gambling Urge Scale (GUS; Raylu and Oei 2004). Although self-reported craving increased following both forms of cue exposure, the imagery script had a more pronounced impact than did examination of photographs of gambling-related stimuli. We also evaluated the association of the post-cue exposure GUS with other relevant measures, and found it correlated highly both with other questionnaires assessing craving to gamble and with other gambling-relevant characteristics (e.g., gambling-related problems, preoccupation with gambling, distorted gambling beliefs, gambling refusal self-efficacy, sensation seeking), but was not associated with social desirability bias. These findings support the use of the GUS-a brief multi-item scale that shows several key elements of construct, convergent, criterion and discriminant validity-to study the experience of craving in university student gamblers.

Connecting hospitalized patients with their families: case series and commentary.

The overall aim of this project was to ascertain the utilization of a custom-designed telemedicine service for patients to maintain close contact (via videoconference) with family and friends during hospitalization. We conducted a retrospective chart review of hospitalized patients (primarily children) with extended hospital length of stays. Telecommunication equipment was used to provide videoconference links from the patient's bedside to friends and family in the community. Thirty-six cases were managed during a five-year period (2006 to 2010). The most common reasons for using Family-Link were related to the logistical challenges of traveling to and from the hospital-principally due to distance, time, family commitments, and/or personal cost. We conclude that videoconferencing provides a solution to some barriers that may limit family presence and participation in care for hospitalized patients, and as a patient-centered innovation is likely to enhance patient and family satisfaction.