A Stoichiometric Haloform Coupling for Ester Synthesis with Secondary Alcohols.

The haloform reaction from methyl ketones to carboxylic acids is one of the oldest known synthetic organic reactions, which has been used in myriad applications over the decades. The corresponding reaction to produce esters is, however, less developed, as the reaction is generally limited to simple, primary alcohols that are used in solvent-level quantities, thereby restricting the complexity of esters that can be directly formed. Herein, we detail the development of a general ester-forming haloform coupling reaction using one equivalent of alcohol. Mechanistic and kinetic modelling studies demonstrated that the key intermediates are formed under equilibrium, which facilitated the development of conditions that are amenable to secondary alcohols.

Navigating the care of families with a child or children with autistic spectrum disorder.

The aim of this project was to better understand nurse navigators work with children and families who are living with severe autism spectrum disorder to achieve improved health and wellbeing outcomes. Nurse navigators were introduced into the public health sector in Queensland in 2016, with 400 navigators currently working across 16 health services in diverse geographic and demographic settings. Narrative inquiry was used to explore one nurse navigator's journey working with children and families living with severe Autism. The challenges of rigid health systems to adapt to the requirements of children with special needs, particularly in relation to care in the emergency department and where interventional procedures are necessary were apparent. Nurse navigators can effectively co-ordinate the care of an extremely vulnerable patient cohort and provide essential advocacy in a health system that is rigid and lacking the flexibility to deal with individual needs.

Electrochemical Benzylic C(sp3)-H Acyloxylation.

The development of sustainable C(sp3)-H functionalization methods is of great interest to the pharmaceutical and agrochemical industries. Anodic oxidation is an efficient means of producing benzylic cations that can undergo subsequent in situ nucleophilic attack to afford functionalized benzylic products. Herein, we demonstrate the suitability of carboxylic acids as nucleophiles to yield benzylic esters. This method employs a series of secondary benzylic substrates and functionalized carboxylic acids and is demonstrated on a gram scale in flow.

Dichloromeldrum's Acid (DiCMA): A Practical and Green Amine Dichloroacetylation Reagent.

Dichloromeldrum's acid is introduced as a bench-stable, nonvolatile reagent for the dichloroacetylation of anilines and alkyl amines to produce α,α-dichloroacetamides, which are important motifs for medicinal chemistry. Products are formed in good to excellent yields with reagent grade solvents, and, as the only byproducts are acetone and CO2, no column chromatography is required. Thus, this reagent is practical, efficient, and green for the dichloroacetylation of primary amines.

Understanding the impact and causes of 'failure to attend' on continuity of care for patients with chronic conditions.

AIM: To understand the impact and causes of 'Failure to Attend' (FTA) labelling, of patients with chronic conditions. BACKGROUND: Nurse navigators are registered nurses employed by public hospitals in Queensland, Australia, to coordinate the care of patients with multiple chronic conditions, who frequently miss hospital appointments. The role of the nurse navigator is to improve care management of these patients. Evidence for this is measured through improvement in patient self-management of their conditions, a reduction in preventable hospital admissions and compliance with attendance at outpatient clinics. Failure to attend (FTA) is one measure of hospital utilisation, identifying outpatient appointments that are cancelled or not attended. METHOD: The cohort for this study was patients with multiple chronic conditions, and nurse navigators coordinating their care. Data describing the concept of FTA were thematically analysed twelve months into this three year evaluation. RESULTS: Although the patient is blamed for failing to attend appointments, the reasons appear to be a mixture of systems error/miscommunication between the patient and the health services or social reasons impacting on patient's capacity to attend. Themes emerging from the data were: access barriers; failure to recognise personal stigma of FTA; and bridging the gap. CONCLUSION: The nurse navigators demonstrate their pivotal role in engaging with outpatient services to reduce FTAs whilst helping patients to become confident in dealing with multiple appointments. There are many reasons why a patient is unable to attend a scheduled appointment. The phrase 'Failure to Attend' has distinctly negative connotations and can lead to a sense of blame and shame for those with complex chronic needs. We propose the use of the neutral phrase "appointment did not proceed" to replace FTA. IMPLICATIONS FOR NURSING MANAGEMENT: This article advocates for further consideration of collaborative models that engage the patient in their care journey and for consideration of the language used within the outpatient acute hospital setting, proposing the term 'appointment did not proceed.'

Examining the hurdles in defining the practice of Nurse Navigators.

BACKGROUND: Nurse navigators are an emerging workforce providing care to people with multiple chronic conditions. The role of the navigators is to identify patients requiring support in negotiating their health care. PURPOSE: A critical discourse analysis was used to examine qualitative data collected from nurse navigators and consenting navigated patients to identify key indicators of how nurse navigators do their work and where the success of their work is most evident. DISCUSSION: Nurse navigators help patients who have lost trust in the health system to re-engage with their interdisciplinary health care team. This re-engagement is the final step in a journey of addressing unmet needs, essential to hospital avoidance. CONCLUSION: Nurse navigators provide a continuum of authentic and holistic care. To acknowledge the true value of nurse navigators, their performance indicators need to embrace the value-added care they provide.

Correction to: ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease.

Unfortunately, the acknowledgement section was not included in the original publication.

Exploring the role of nurses in after-hours telephone services in regional areas; A scoping review.

INTRODUCTION: The management of patients who need chronic and complex care is a focus of attention internationally, brought about by an increase in chronic conditions, requiring significantly more care over longer periods of time. The increase in chronic conditions has placed pressure on health services, financially and physically, bringing about changes in the way care is delivered, with hospital avoidance and home-based care encouraged. In this environment, nurses play an important role in co-ordinating care across services. This review formed one part of a funded project that explored the nurse navigator role within a proposed 24-hour telephone-call service in one regional area that has a diverse population in terms of cultural identity and geographical location in relation to service access. AIM: The review reports on the extant literature on the nurse's role in the provision of afterhours telephone services for patients with chronic and complex conditions. The specific aim was to explore the effectiveness of services for patients in geographically isolated locations. METHODS: The methodological approach to the review followed the Preferred Reporting System for Meta-Analyses (PRISMA) guidelines. A thematic analysis was used to identify themes with chronic care models underpinning analysis. RESULTS: Three themes were identified; nurse-led decision making; consumer profile; and program outcomes. Each theme was divided into two sub-themes. The two sub-themes for decision making were: the experience of the staff who provided the service and the tool or protocol used. The two sub-themes for consumers profile were; the geographic/demographic identity of the consumers, and consumer satisfaction. The final theme of outcomes describes how the effectiveness of the service is measured, broken into two sub-themes: the economic/workforce outcomes and the consumer outcomes. DISCUSSION: The provision of an after-hours telephone service, in whatever model used should align with a Chronic Care Model. In this way, after-hours telephone services provided by experienced nurses, supported by ongoing professional development and relevant protocols, form part of the ongoing improvement for chronic and complex care management as a health priority.

Electrode Materials in Modern Organic Electrochemistry.

The choice of electrode material is critical for achieving optimal yields and selectivity in synthetic organic electrochemistry. The material imparts significant influence on the kinetics and thermodynamics of electron transfer, and frequently defines the success or failure of a transformation. Electrode processes are complex and so the choice of a material is often empirical and the underlying mechanisms and rationale for success are unknown. In this review, we aim to highlight recent instances of electrode choice where rationale is offered, which should aid future reaction development.

Exploring the nurse navigator role: A thematic analysis.

BACKGROUND: Patients with complex chronic conditions experience fragmentation of care, unnecessary hospitalization and reduced quality of life, with an increased incidence of poor health outcomes. AIM(S): The aim of this paper was to explore how nurse navigators manage client care. This was achieved through an examination of narratives provided by the nurse navigator that evaluated their scope of practice. METHOD(S): All nurse navigators employed by Queensland Health were invited to participate in a study evaluating the effectiveness of the service. Eighty-four self-reported vignettes were thematically analysed to understand the work from the nurses' perspectives. RESULTS: Two themes emerged from the vignettes. Theme 1, the layers of complexity, is comprised of three sub-themes: the complex patient, the complex system and patient outcomes. Theme 2, professional attributes, has two sub-themes: person-centred care and clinical excellence. CONCLUSION: Navigators innovatively integrate services and address the fragmented nature of the health system. They apply expert clinical and social skills, through consistent and robust communication, to meet the needs of those with multiple chronic conditions. IMPLICATIONS FOR NURSING MANAGEMENT: Results provide insight into the new role, illuminating the work they achieve, despite system complexities.

Person-centred rhetoric in chronic care: a review of health policies.

PURPOSE: The purpose of the paper is to explore how the national, state and organisational health policies in Australia support the implementation of person-centred care in managing chronic care conditions. DESIGN/METHODOLOGY/APPROACH: A qualitative content analysis was performed regarding the national, state and organisational Queensland Health policies using Elo and Kyngas' (2008) framework. FINDINGS: Although the person-centred care as an approach is well articulated in health policies, there is still no definitive measure or approach to embedding it into operational services. Complex funding structures and competing priorities of the governments and the health organisations carry the risk that person-centred care as an approach gets lost in translation. Three themes emerged: the patient versus the government; health care delivery versus the political agenda; and health care organisational processes versus the patient. RESEARCH LIMITATIONS/IMPLICATIONS: Given that person-centred care is the recommended approach for responding to chronic health conditions, further empirical research is required to evaluate how programs designed to deliver person-centred care achieve that objective in practice. PRACTICAL IMPLICATIONS: This research highlights the complex environment in which the person-centred approach is implemented. Short-term programmes created specifically to focus on person-centred care require the right organisational infrastructure, support and direction. This review demonstrates the need for alignment of policies related to chronic disease management at the broader organisational level. ORIGINALITY/VALUE: Given the introduction of the nurse navigator program to take up a person-centred care approach, the review of the recent policies was undertaken to understand how they support this initiative.

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer's disease.

Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aß and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aß and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aß42 and IL1-ß levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

The use of telephone communication between nurse navigators and their patients.

BACKGROUND: Hospitals and other health care providers frequently experience difficulties contacting patients and their carers who live remotely from the town where the health service is located. In 2016 Nurse Navigator positions were introduced into the health services by Queensland Health, to support and navigate the care of people with chronic and complex conditions. One hospital in Far North Queensland initiated an additional free telephone service to provide another means of communication for patients and carers with the NNs and for off-campus health professionals to obtain details about a patient utilising the service. Calls made between 7am and 10pm, seven days per week are answered by a nurse navigator. AIM: To report utilisation of the service by navigated clients and remotely located clinicians compared to use of navigators' individual work numbers and direct health service numbers. We report the reason for calls to the free number and examine features of these calls. METHODS: Statistical analysis examined the call reason, duration of calls, setting from where calls originated and stream of calls. Interactions between the reasons for calls and the features of calls, such as contact method, were examined. RESULTS: The major reason for calls was clinical issues and the source of calls was primarily patients and carers. Clinical calls were longer in duration. Shorter calls were mainly non-clinical, made by a health professional. Setting for calls was not related to the reason. The most frequent number used was the individual mobile number of the NN, followed by the hospital landline. Although the free number was utilised by patients and carers, it was not the preferred option. CONCLUSION: As patients and carers preferred to access their NN directly than via the 1800 number, further research should explore options best suited to this group of patients outside normal business hours.

Uncovering biosynthetic relationships between antifungal nonadrides and octadrides.

Maleidrides are a class of bioactive secondary metabolites unique to filamentous fungi, which contain one or more maleic anhydrides fused to a 7-, 8- or 9- membered carbocycle (named heptadrides, octadrides and nonadrides respectively). Herein structural and biosynthetic studies on the antifungal octadride, zopfiellin, and nonadrides scytalidin, deoxyscytalidin and castaneiolide are described. A combination of genome sequencing, bioinformatic analyses, gene disruptions, biotransformations, isotopic feeding studies, NMR and X-ray crystallography revealed that they share a common biosynthetic pathway, diverging only after the nonadride deoxyscytalidin. 5-Hydroxylation of deoxyscytalidin occurs prior to ring contraction in the zopfiellin pathway of Diffractella curvata. In Scytalidium album, 6-hydroxylation - confirmed as being catalysed by the α-ketoglutarate dependent oxidoreductase ScyL2 - converts deoxyscytalidin to scytalidin, in the final step in the scytalidin pathway. Feeding scytalidin to a zopfiellin PKS knockout strain led to the production of the nonadride castaneiolide and two novel ring-open maleidrides.

Using max standardized uptake value from positron emission tomography to assess tumor responses after lung stereotactic body radiotherapy for different prescriptions.

PURPOSE: To retrospectively investigate tumor responses of lung SBRT patients for different prescriptions. To analyze the relation between optimal biologically equivalent dose (BED) and tumor responses. METHODS AND MATERIALS: Tumor responses after lung SBRT were compared by examining 48 treatments used four prescriptions. This study used simplified tumor response criteria: (a) Complete Response (CR) - post max SUV (SUVpost ) after SBRT in the treated tumor region was almost the same as the SUVs in the surrounding regions; (b) Partial Response (PR) - SUVpost was smaller than previous max SUV (SUVpre ), but was greater than the SUVs in the surrounding regions; (c) No Response (NR) - SUVpost was the same as or greater than SUVpre . Some SUVpost reported as mild or favorable responses were classified as CR/PR. BED calculated using α/ß of 10 Gy were analyzed with assessments of tumor responses for SBRT prescriptions. RESULTS: For the prescriptions (9 Gy × 5, 10 Gy × 5, 11 Gy × 5, and 12 Gy × 4) historically recommended by RTOG, we observed that higher BED10 and lower tumor volume would achieve a higher complete response rate. The highest complete response rate was observed for smallest tumor volume (PTVave  = 6.8 cc) with higher BED10 (105.6) of 12 Gy × 4 prescription. For 11 Gy × 5 prescription, the BED10 (115.5) was the highest, but its complete response rate (58%) was lower than 79% of 12 Gy × 4 prescription. We observed the PTVave of 11 Gy × 5 prescription was more than double of the PTVave of 12 Gy × 4 prescription. For the same lung SBRT prescription (BED10  > 100) earlier staging tumor had more favorable local control. CONCLUSION: We demonstrated post max SUV read from PET/CT could efficiently and accurately assess tumor response after lung SBRT. Although SBRT with prescriptions resulting in a BED10  > 100 experienced favorable tumor responses for early staging cancer, escalation of BED10 to higher levels would be beneficial for lung cancer patients with later staging and larger volume tumors.

The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis.

The cycloaspeptides are bioactive pentapeptides produced by various filamentous fungi, which have garnered interest from the agricultural industry due to the reported insecticidal activity of the minor metabolite, cycloaspeptide E. Genome sequencing, bioinformatics and heterologous expression confirmed that the cycloaspeptide gene cluster contains a minimal 5-module nonribosomal peptide synthetase (NRPS) and a new type of trans-acting N-methyltransferase (N-MeT). Deletion of the N-MeT encoding gene and subsequent feeding studies determined that two modules of the NRPS preferentially accept and incorporate N-methylated amino acids. This discovery allowed the development of a system with unprecedented control over substrate supply and thus output, both increasing yields of specific metabolites and allowing the production of novel fluorinated analogues. Furthermore, the biosynthetic pathway to ditryptophenaline, another fungal nonribosomal peptide, was shown to be similar, in that methylated phenylalanine is accepted by the ditryptophenaline NRPS. Again, this allowed the directed biosynthesis of a fluorinated analogue, through the feeding of a mutant strain. These discoveries represent a new paradigm for the production of N-methylated cyclic peptides via the selective incorporation of N-methylated free amino acids.

Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion.

The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for ß-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and ß-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.

Investigative safety science as a competitive advantage for Pharma.

INTRODUCTION: Following a US National Academy of Sciences report in 2007 entitled "Toxicity Testing of the 21st Century: a Vision and a Strategy," significant advances within translational drug safety sciences promise to revolutionize drug discovery and development. The purpose of this review is to outline why investigative safety science is a competitive advantage for the pharmaceutical industry. AREAS COVERED: The article discusses the essential goals for modern investigative toxicologists including: cross-species target biology; molecular pathways of toxicity; and development of predictive tools, models and biomarkers that allow discovery researchers and clinicians to anticipate safety problems and plan ways to address them, earlier than ever before. Furthermore, the article emphasizes the importance of investigating unanticipated clinical safety signals through a combination of mechanistic preclinical studies and/or molecular characterization of clinical samples from affected organs. EXPERT OPINION: The traditional boundaries between pharma industry teams focusing on safety/efficacy and preclinical/clinical development are rapidly disappearing in favor of translational safety science-centric organizations with a vision of bringing more effective medicines forward safely and quickly. Comparative biology and mechanistic toxicology approaches facilitate: i) identifying translational safety biomarkers; ii) identifying new drug targets/indications; and iii) mitigating off-target toxicities. These value-adding safety science contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

A toxicology ontology roadmap.

Foreign substances can have a dramatic and unpredictable adverse effect on human health. In the development of new therapeutic agents, it is essential that the potential adverse effects of all candidates be identified as early as possible. The field of predictive toxicology strives to profile the potential for adverse effects of novel chemical substances before they occur, both with traditional in vivo experimental approaches and increasingly through the development of in vitro and computational methods which can supplement and reduce the need for animal testing. To be maximally effective, the field needs access to the largest possible knowledge base of previous toxicology findings, and such results need to be made available in such a fashion so as to be interoperable, comparable, and compatible with standard toolkits. This necessitates the development of open, public, computable, and standardized toxicology vocabularies and ontologies so as to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. Such ontology development will support data management, model building, integrated analysis, validation and reporting, including regulatory reporting and alternative testing submission requirements as required by guidelines such as the REACH legislation, leading to new scientific advances in a mechanistically-based predictive toxicology. Numerous existing ontology and standards initiatives can contribute to the creation of a toxicology ontology supporting the needs of predictive toxicology and risk assessment. Additionally, new ontologies are needed to satisfy practical use cases and scenarios where gaps currently exist. Developing and integrating these resources will require a well-coordinated and sustained effort across numerous stakeholders engaged in a public-private partnership. In this communication, we set out a roadmap for the development of an integrated toxicology ontology, harnessing existing resources where applicable. We describe the stakeholders' requirements analysis from the academic and industry perspectives, timelines, and expected benefits of this initiative, with a view to engagement with the wider community.