Costs and healthcare use of patients with chronic kidney disease in the Northern Territory, Australia.

BACKGROUND: The burden of chronic kidney disease (CKD) is high in the Northern Territory (NT), Australia. This study aims to describe the healthcare use and associated costs of people at risk of CKD (e.g. acute kidney injury, diabetes, hypertension, and cardiovascular disease) or living with CKD in the NT, from a healthcare funder perspective. METHODS: We included a retrospective cohort of patients at risk of, or living with CKD, on 1 January 2017. Patients on kidney replacement therapy were excluded from the study. Data from the Territory Kidney Care database, encompassing patients from public hospitals and primary health care services across the NT was used to conduct costing. Annual healthcare costs, including hospital, primary health care, medication, and investigation costs were described over a one-year follow-up period. Factors associated with high total annual healthcare costs were identified with a cost prediction model. RESULTS: Among 37,398 patients included in this study, 23,419 had a risk factor for CKD while 13,979 had CKD (stages 1 to 5, not on kidney replacement therapy). The overall mean (± SD) age was 45 years (± 17), and a large proportion of the study cohort were First Nations people (68%). Common comorbidities in the overall cohort included diabetes (36%), hypertension (32%), and coronary artery disease (11%). Annual healthcare cost was lowest in those at risk of CKD (AUD$7,958 per person) and highest in those with CKD stage 5 (AUD$67,117 per person). Inpatient care contributed to the majority (76%) of all healthcare costs. Predictors of increased total annual healthcare cost included more advanced stages of CKD, and the presence of comorbidities. In CKD stage 5, the additional cost per person per year was + $53,634 (95%CI 32,769 to 89,482, p < 0.001) compared to people in the at risk group without CKD. CONCLUSION: The total healthcare costs in advanced stages of CKD is high, even when patients are not on dialysis. There remains a need for effective primary prevention and early intervention strategies targeting CKD and related chronic conditions.

Optimising remote health workforce retention: protocol for a program of research.

BACKGROUND: Nowhere is optimising healthcare staff retention more important than in primary health care (PHC) settings in remote Australia, where there are unacceptably high rates of staff burnout and turnover. Ensuing consequences for the remote health services and the community are acute - staffing shortfalls in clinics; organisational instability; excessive costs associated with frequent staff recruitment and orientation; diminished access to PHC for patients in need; and lack of continuity of patient care; all of which further entrench poor health outcomes for the community. Optimising remote healthcare staff retention is critical in order to provide high quality and continued PHC. Currently, however, there is paucity of knowledge to inform targeted and effective retention strategies in remote health services. This research program seeks to develop a stronger evidence base to understand (i) what retention strategies are effective in improving morale, job satisfaction, intention to remain in the job, and consequent length of service for remote healthcare staff; (ii) how best to 'bundle' these strategies for different health workforce groups; and (iii) how these 'bundles' work in different service contexts. METHODS: This paper describes a five-year implementation research program in partnership with twelve remote Aboriginal and Torres Strait Islander Community Controlled Health Services (ATSICCHS) in the Northern Territory and Queensland, Australia. Overall methodology follows a participatory action research approach which incorporates co-design and realist elements. The program comprises two broad phases involving evidence consolidation and synthesis (Phase 1), and co-design, implementation, and prospective evaluation of 'bundles' of retention strategies (Phase 2) to improve retention of healthcare staff in participating ATSICCHSs. DISCUSSION: This innovative research program has the potential to develop a comprehensive evidence base required to optimise health workforce retention in remote health services. This new evidence will strengthen understanding of what 'bundles' of retention strategies are effective, for which groups of employees, and how they work to improve staff retention.

Identifying barriers and facilitators to physical activity and perceptions of Traditional Indigenous Games among Aboriginal and Torres Strait Islander women: a qualitative study.

Aboriginal and Torres Strait Islander women are key members of the community who have specific roles within their families that may result in lower levels of physical activity (PA) undertaken. Clearly identifying barriers for women to engage with PA, and exploring culturally based activities (i.e. Traditional Indigenous Games), may help to improve long-term health benefits. Subsequently, the aim of this study was to identify the barriers and facilitators for Aboriginal and Torres Strait Islander women engaging in PA, and their interest in participating in Traditional Indigenous Games. Seventeen Aboriginal and Torres Strait Islander women (34.3 ±â€…10.2 years) participated in focus groups. Through thematic analysis, participants experienced a range of common barriers such as lack of time due to family commitments, limited finances, ageing and poor physical and/or mental health. Common facilitators were also identified such as fun, access and improving mental and/or physical health. Importantly, unique themes were identified for Aboriginal and Torres Strait Islander women including barriers (e.g. racism, shame) and facilitators (e.g. culture, interactions with other Aboriginal and Torres Strait Islander women) that influenced PA participation. Notably, Traditional Indigenous Games were considered as an appealing PA mode to engage with their culture, experience nostalgia and be around other Aboriginal and Torres Strait Islander women. These key findings will guide future PA programs including Traditional Indigenous Games to improve health outcomes of Aboriginal and Torres Strait Islander women, vital members of the community.

Comparison of two ferritin assay platforms to assess their level of agreement in measuring serum and plasma ferritin levels in patients with chronic kidney disease.

BACKGROUND: Ferritin levels are used to make decisions on therapy of iron deficiency in patients with chronic kidney disease (CKD). Hyperferritinaemia, common among patients with CKD from the Northern Territory (NT) of Australia, makes use of ferritin levels as per clinical guidelines challenging. No gold standard assay exists for measuring ferritin levels. Significant variability between results from different assays creates challenges for clinical decision-making regarding iron therapy. In the NT, different laboratories use different methods. In 2018, Territory Pathology changed the assay from Abbott ARCHITECT i1000 (AA) to Ortho-Clinical Diagnostics Vitros 7600 (OCD). This was during the planning of the INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis (INFERR) clinical trial. The trial design was based on AA assay ferritin levels. We compared the two assays' level of agreement in measuring ferritin levels in CKD patients. METHODS: Samples from INFERR clinical trial participants were analysed. Other samples from patients whose testing were completed the same day on OCD analyzers and run within 24 h on AA analyzers were added to ensure wide range of ferritin levels, adding statistical strength to the comparison. Ferritin levels from both assays were compared using Pearson's correlation, Bland-Altman, Deming and Passing-Bablok regression analyses. Differences between sample types, plasma and serum were assessed. RESULTS: Sixty-eight and 111 (179) samples from different patients from Central Australia and Top End of Australia, respectively, were analyzed separately and in combination. The ferritin levels ranged from 3.1 µg/L to 3354 µg/L and 3 µg/L to 2170 µg/L for AA and OCD assays respectively. Using Bland-Altman, Deming and Passing-Bablok regression methods for comparison, ferritin results were consistently 36% to 44% higher with AA than OCD assays. The bias was up to 49%. AA ferritin results were the same in serum and plasma. However, OCD ferritin results were 5% higher in serum than plasma. CONCLUSIONS: When making clinical decisions, using ferritin results from the same assay in patients with CKD is critical. If the assay is changed, it is essential to assess agreement between results from the new and old assays. Further studies to harmonize ferritin assays are required.

"The most culturally safe training I've ever had": the co-design of a culturally safe Managing hepatitis B training course with and for the Aboriginal health workforce of the Northern Territory of Australia.

BACKGROUND: The Aboriginal health workforce provide responsive, culturally safe health care. We aimed to co-design a culturally safe course with and for the Aboriginal health workforce. We describe the factors which led to the successful co-design, delivery, and evaluation of the "Managing hepatitis B" course for the Aboriginal health workforce. METHODS: A Participatory Action Research approach was used, involving ongoing consultation to iteratively co-design and then develop course content, materials, and evaluation tools. An Aboriginal and Torres Strait Islander research and teaching team received education in chronic hepatitis B and teaching methodologies. Pilot courses were held, in remote communities of the Northern Territory, using two-way learning and teach-back methods to further develop the course and assess acceptability and learnings. Data collection involved focus group discussions, in-class observations, reflective analysis, and use of co-designed and assessed evaluation tools. RESULTS: Twenty-six participants attended the pilot courses. Aboriginal and Torres Strait Islander facilitators delivered a high proportion of the course. Evaluations demonstrated high course acceptability, cultural safety, and learnings. Key elements contributing to success and acceptability were acknowledging, respecting, and integrating cultural differences into education, delivering messaging and key concepts through an Aboriginal and Torres Strait Islander lens, using culturally appropriate approaches to learning including storytelling and visual teaching methodologies. Evaluation of culturally safe frameworks and findings from the co-design process led to the creation of a conceptual framework, underpinned by meeting people's basic needs, and offering a safe and comfortable environment to enable productive learning with attention to the following: sustenance, financial security, cultural obligations, and gender and kinship relationships. CONCLUSIONS: Co-designed education for the Aboriginal health workforce must embed principles of cultural safety and meaningful community consultation to enable an increase in knowledge and empowerment. The findings of this research can be used to guide the design of future health education for First Nations health professionals and to other non-dominant cultures. The course model has been successfully transferred to other health issues in the Northern Territory.

HIV-Associated Alterations of the Biophysical Features of Maternal Antibodies Correlate With Their Reduced Transfer Across the Placenta.

BACKGROUND: Human immunodeficiency virus (HIV) infection during pregnancy is associated with reduced transplacental transfer of maternal antibodies and increased risk of severe infections in children who are exposed and uninfected with HIV. The basis of this reduced transfer of maternal immunity has not yet been defined but could involve modifications in the biophysical features of antibodies. The objective of this study was to assess the impact of maternal HIV infection on the biophysical features of serum IgG and transplacental antibody transfer. METHODS: Maternal serum IgG subclass levels, Fc glycosylation, Fc receptor (FcR) binding, and transplacental transfer of pathogen-specific maternal IgG were measured in pregnant women with HIV (WWH) and pregnant women testing negative for HIV (WNH) in Cape Town, South Africa. RESULTS: Maternal antibody profiles were strikingly different between pregnant WWH and WNH. Antibody binding to FcγR2a and FcγR2b, IgG1 and IgG3 antibodies, and agalactosylated antibodies were all elevated in WWH, whereas digalactosylated and sialylated antibodies were reduced compared to pregnant WNH. Antibody features that were elevated in WWH were also correlated with reduced transplacental transfer of vaccine antigen-specific antibodies. CONCLUSIONS: HIV infection is associated with marked alterations of biophysical features of maternal IgG and reduced placental transfer, potentially impairing antimicrobial immunity.

Vehicular Platoon Communication: Architecture, Security Threats and Open Challenges.

The emerging technology that is vehicular platooning is an exciting technology. It promises to save space on congested roadways, improve safety and utilise less fuel for transporting goods, reducing greenhouse gas emissions. The technology has already been shown to be vulnerable to attack and exploitation by attackers. Attackers have several attack surfaces available for exploitation to achieve their goals (either personal or financial). The goal of this paper and its contribution to the area of research is to present the attacks and defence mechanisms for vehicular platoons and put risks of existing identified attacks forwards. Here the variety of attacks that have been identified in the literature are presented and how they compromise the wireless communications of vehicle platoons. As part of this, a risk assessment is presented to assess the risk factor of the attacks. Finally, this paper presents the range of defence and countermeasures to vehicle platooning attacks and how they protect the safe operations of vehicular platoons.

Systematic Review of Clinical Practice Guidelines for Oral Health in Children With Cleft Lip and Palate.

OBJECTIVE: Clinical practice guidelines (CPGs) exist to present recommendations and policies aimed at optimizing the oral health of children and adolescents born with cleft lip and/or palate. The aim of this review is to identify and assess the scope, quality, adequacy, and consistency of CPGs related to oral health in children and adolescents with clefts, along with reporting any differences and shortcomings. METHODS: A systematic review of the literature of CPGs following Preferred Reporting Items for Systematic Reviews guidelines was conducted. Assessment of selected CPGs was performed using the Appraisal of Guidelines for Research & Evaluation II methodological quality instrument. RESULTS: Only 7 CPGs fulfilled the criteria. Of these, 4 were from the American Cleft Palate-Craniofacial Association, and 1 each from the American Academy of Pediatrics, the Academy of Breastfeeding Medicine, and the American Academy of Pediatric Dentistry. The lowest overall mean scores were in the domain "Rigor of Development" (mean 29.58%, SD 17.11), revealing lower quality in methodology of the guideline. The domain "Clarity of Presentation" (mean 73.80%, SD 7.87) revealed the best score. CONCLUSIONS: Our review results reveal a lack of integrated high-quality CPGs that can be used as universal guidelines by health workers in a range of disciplines for improving oral health in children and adolescents with cleft problems.

A New SARS-CoV-2 Dual-Purpose Serology Test: Highly Accurate Infection Tracing and Neutralizing Antibody Response Detection.

Many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology tests have proven to be less accurate than expected and do not assess antibody function as neutralizing, correlating with protection from reinfection. A new assay technology measuring the interaction of the purified SARS-CoV-2 spike protein receptor binding domain (RBD) with the extracellular domain of the human angiotensin-converting enzyme 2 (hACE2) receptor detects these important antibodies. The cPass surrogate virus neutralization test (sVNT), compared directly with eight SARS-CoV-2 IgG serology and two live-cell neutralization tests, gives similar or improved accuracy for qualitative delineation between positive and negative individuals in a fast, scalable, and high-throughput assay. The combined data support the cPass sVNT as a tool for highly accurate SARS-CoV-2 immunity surveillance of infected/recovered and/or vaccinated individuals as well as drug and convalescent-phase donor screening. The data also preview a novel application for the cPass sVNT in calibrating the stringency of live-cell neutralization tests and its use in longitudinal testing of recovered and/or vaccinated patients.

Trivalent Glycoprotein Subunit Vaccine Prevents Neonatal Herpes Simplex Virus Mortality and Morbidity.

Herpes simplex virus (HSV) can cause severe infection in neonates leading to mortality and lifelong morbidity. Prophylactic approaches, such as maternal immunization, could prevent neonatal HSV (nHSV) infection by providing protective immunity and preventing perinatal transmission. We previously showed that maternal immunization with a replication-defective HSV vaccine candidate, dl5-29, leads to transfer of virus-specific antibodies into the neonatal circulation and protects against nHSV neurological sequela and mortality (C. D. Patel, I. M. Backes, S. A. Taylor, Y. Jiang, et al., Sci Transl Med, 11:eaau6039, 2019, https://doi.org/10.1126/scitranslmed.aau6039). In this study, we evaluated the efficacy of maternal immunization with an experimental trivalent (gC2, gD2, and gE2) subunit vaccine to protect against nHSV. Using a murine model of nHSV, we demonstrated that maternal immunization with the trivalent vaccine protected offspring against nHSV-disseminated disease and mortality. In addition, offspring of immunized dams were substantially protected from behavioral pathology following HSV infection. This study supports the idea that maternal immunization is a viable strategy for the prevention of neonatal infections.IMPORTANCE Herpes simplex virus is among the most serious infections of newborns. Current antiviral therapies can prevent mortality if infection is recognized early and treated promptly. Most children who survive nHSV develop lifelong neurological and behavioral deficits, despite aggressive antiviral treatment. We propose that maternal immunization could provide protection against HSV for both mother and baby. To this end, we used a trivalent glycoprotein vaccine candidate to demonstrate that offspring are protected from nHSV following maternal immunization. Significantly, this approach protected offspring from long-term behavioral morbidity. Our results emphasize the importance of providing protective immunity to neonates during this window of vulnerability.

Herpes Simplex Virus 1 ICP34.5 Alters Mitochondrial Dynamics in Neurons.

Expression of viral genes and activation of innate antiviral responses during infection result in an increase in reactive oxygen species (ROS) and toxic by-products of energy metabolism which can lead to cell death. The mitochondrion and its associated proteins are crucial regulators of these responses and related pathways such as autophagy and apoptosis. Through a mass spectrometry approach, we have shown that the herpes simplex virus 1 (HSV-1) neurovirulence- and autophagy-modulating protein ICP34.5 interacts with numerous mitochondrion-associated factors. Specifically, we showed that amino acids 68 to 87 of ICP34.5, the domain that binds beclin1 and controls neurovirulence, are necessary for interactions with PGAM5, KEAP1, and other regulators of the antioxidant response, mitochondrial trafficking, and programmed cell death. We further show that while this domain interacts with multiple cellular stress response factors, it does not alter apoptosis or antioxidant gene expression. That said, the attenuated replication of a recombinant virus lacking residues 68 to 87 (termed Δ68-87) in primary human fibroblasts was restored by addition of ferric nitrate. Furthermore, in primary mouse neurons, the perinuclear localization of mitochondria that follows infection with HSV-1 was notably absent following Δ68-87 infection. Through this 20-amino-acid domain, ICP34.5 significantly reduces mitochondrial motility in axons of neurons. We propose the hypothesis that ICP34.5 promotes perinuclear mitochondrial localization by modulating transport of mitochondria through interaction with PGAM5. These data expand upon previous observations of altered mitochondrial dynamics following alphaherpesvirus infections and identify a key determinant of this activity during HSV-1 infections.IMPORTANCE Herpes simplex virus persists lifelong in neurons and can reactivate to cause recurrent lesions in mucosal tissues. A key determinant of virulence is the viral protein ICP34.5, of which residues 68 to 87 significantly contribute to neurovirulence through an unknown mechanism. Our report provides evidence that residues 68 to 87 of ICP34.5 are required for binding mitochondrion-associated factors. These interactions alter mitochondrial dynamics in neurons, thereby facilitating viral replication and pathogenesis.

The safety evaluation of food flavoring substances: the role of genotoxicity studies.

The Flavor and Extract Manufacturers Association (FEMA) Expert Panel relies on the weight of evidence from all available data in the safety evaluation of flavoring substances. This process includes data from genotoxicity studies designed to assess the potential of a chemical agent to react with DNA or otherwise cause changes to DNA, either in vitro or in vivo. The Panel has reviewed a large number of in vitro and in vivo genotoxicity studies during the course of its ongoing safety evaluations of flavorings. The adherence of genotoxicity studies to standardized protocols and guidelines, the biological relevance of the results from those studies, and the human relevance of these studies are all important considerations in assessing whether the results raise specific concerns for genotoxic potential. The Panel evaluates genotoxicity studies not only for evidence of genotoxicity hazard, but also for the probability of risk to the consumer in the context of exposure from their use as flavoring substances. The majority of flavoring substances have given no indication of genotoxic potential in studies evaluated by the FEMA Expert Panel. Examples illustrating the assessment of genotoxicity data for flavoring substances and the consideration of the factors noted above are provided. The weight of evidence approach adopted by the FEMA Expert Panel leads to a rational assessment of risk associated with consumer intake of flavoring substances under the conditions of use.

Cross-sectional association of seafood consumption, polyunsaturated fatty acids and depressive symptoms in two Torres Strait communities.

Background Dietary intake of long-chain omega 3 (n-3) polyunsaturated fatty acids (LCPUFA) represents a putative modifiable risk factor for depression, and a high ratio of omega 6 (n-6) to n-3 LCPUFA is frequently observed in patients with major depressive disorder. Recent reports suggest that the availability of fish and seafood may be associated with lower depression rates. The aim of this study was to investigate associations of fish consumption and LCPUFA levels with depressive symptoms.Methods Participants for this cross-sectional study (n=206) were recruited at a community screening programme in two Torres Strait Islander communities (Mer and Waiben). Depressive symptoms were assessed with the adapted Patient Health Questionnaire-9 (aPHQ-9) and diet with a structured questionnaire. LCPUFA concentrations were measured with a capillary dried blood spot system (PUFAcoat). Logistic and quantile regression modelling was used to test the relationship between seafood consumption, membrane LCPUFAs and depression scores.Results A higher blood n-6/3 LCPUFA ratio was associated with moderate/severe depression scores across both study sites (OR=1.59 (95%CI 1.09-2.34), P = .017). Seafood consumption was higher and the proportion of participants with aPHQ-9 scores above the cut-off for depression was lower on Mer (n = 100) compared with Waiben (n = 106). Higher seafood consumption was associated with lower depression scores on Waiben (B = -0.57 (95%CI -0.98 - -0.16), P = .006) but not on Mer.Conclusions Our findings support an association of n-3 LCPUFA from natural sources with depressive symptoms. The availability of fresh seafood in the local diet may represent a protective factor for depression in this setting.

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Hair cortisol, allostatic load, and depressive symptoms in Australian Aboriginal and Torres Strait Islander people.

Chronic stress and adversity are associated with poor mental health and are thought to contribute to the existing mental health gap between Aboriginal and Torres Strait Islander people and other Australians. Hair cortisol and allostatic load (AL) are indices of sustained stress and may be mediators of the effects of stress on health. The aim of this study was to examine the relationship between hair cortisol, AL, and depressive symptoms. This cross-sectional study comprised 329 Aboriginal and Torres Strait Islander adolescents and adults recruited at two health screening programs operating in three communities in north Queensland. We measured hair cortisol and calculated an AL index from 10 biomarkers. We assessed depressive symptoms with a version of the Patient Health Questionnaire-9 adapted for Aboriginal and Torres Strait Islander people (aPHQ-9). We found differences in cortisol and AL between the screening programs and communities, which were not explained by depressive symptoms. Overall aPHQ-9 scores were unrelated to hair cortisol (p = .25 and p = .94) and AL (p = .30 and p = .88) when age, gender and smoking were taken into account. However, anhedonia (p = .007) and insomnia (p = .006) sub-scores were each significantly associated with AL in one study site. Our present data did not demonstrate overall associations of stress biomarkers and multisystem dysregulation with depressive symptoms, which suggests that the relationship between cumulative stress and depression may be better explained by other factors in this population. The specific association between anhedonia and insomnia with AL indicates that chronic multisystem dysregulation plays a role in these features of depression in this population. Lay summary Our study investigated the relationship between symptoms of depression and two biological pathways thought to mediate depression risk - the stress hormone cortisol and allostatic load (AL) - in an Australian Aboriginal and Torres Strait Islander population. Overall, cortisol and AL were unrelated to depression. However, AL was selectively associated with anhedonia (lack of motivation or drive) and sleep disturbances. These results suggest that metabolic dysregulation measured as AL may be relevant to the depression risk in this population.

Assessment of FD&C Yellow No. 6 (Sunset Yellow FCF) effects on sperm count, motility and viability in the rat in a 28-day toxicity study.

Sunset Yellow FCF was tested for 28-days in male Hsd:SD® rats for its potential effect on sperm quality parameters at dietary concentrations of 6,000, 12,000 and 18,000 ppm, corresponding to target doses of 500, 1000, and 1500 mg/kg bw/day. The measured average daily intake was 490, 944, and 1,475 mg/kg bw/day, based on feed consumption and stability of Sunset Yellow FCF in the diet. The animals fed diets with Sunset Yellow FCF presented no clinical signs of toxicity and no differences in feed consumption, body weights, organ weights, ophthalmology, hematology, clinical chemistry, urinalysis, or coagulation parameters that were considered adverse. No mortality or abnormalities were observed at necropsy, and no microscopic changes were observed in histopathology. Increased testes weights relative to body weight in animals of the middle and high intake groups were not associated with any abnormal findings in histopathology. Sperm quality evaluation presented no adverse effects on sperm motility, epididymal sperm count, homogenization-resistant spermatid count, or sperm morphological development. Therefore, in the absence of any adverse effects under the conditions of this study, the NOAEL for Sunset Yellow FCF was 1,475 mg/kg bw/day in male rats, corresponding to 18,000 ppm in the diet.

"We are everything to everyone": a systematic review of factors influencing the accountability relationships of Aboriginal and Torres Strait Islander health workers (AHWs) in the Australian health system.

BACKGROUND: Health policy in Australia positions Aboriginal and Torres Strait Islander Health Workers (AHWs) as central to improving Aboriginal and Torres Strait Islander peoples' health, with high expectations of their contribution to closing the gap between Indigenous and non-Indigenous health outcomes. Understanding how AHWs' governance and accountability relationships influence their ability to address such health inequities has policy, programme and ethical significance. We sought to map the evidence of AHWs' experiences of accountability in the Australian health system. METHODS: We followed an adapted qualitative systematic review process to map evidence on accountability relations in the published literature. We sought empirical studies or first-person accounts describing AHWs' experiences of working in government or Aboriginal community-controlled services anywhere in Australia. Findings were organised according to van Belle and Mayhew's four dimensions of accountability - social, political, provider and organisational. RESULTS: Of 27 included studies, none had a primary focus on AHW governance or AHWs' accountability relationships. Nonetheless, selected articles provided some insight into AHWs' experiences of accountability across van Belle and Mayhew's four dimensions. In the social dimension, AHWs' sense of connection and belonging to community was reflected in the importance placed on AHWs' cultural brokerage and advocacy functions. But social and cultural obligations overlapped and sometimes clashed with organisational and provider-related accountabilities. AHWs described having to straddle cultural obligations (e.g. related to gender, age and kinship) alongside the expectations of non-Indigenous colleagues and supervisors which were underpinned by 'Western' models of clinical governance and management. Lack of role-clarity stemming from weakly constituted (state-based) career structures was linked to a system-wide misunderstanding of AHWs' roles and responsibilities - particularly the cultural components - acting as a barrier to AHWs working to their full capacity for the benefit of patients, broader society and their own professional satisfaction. CONCLUSIONS: In literature spanning different geographies, service domains and several decades, this review found evidence of complexity in AHWs' accountability relationships that both affects individual and team performance. However, theoretically informed and systematic investigation of accountability relationships and related issues, including the power dynamics that underpin AHW governance and performance in often diverse settings, remains limited and more work in this area is required.

Provincial Differences in the Diagnosis and Care of Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease resulting in muscle weakness, dysarthria and dysphagia, and ultimately respiratory failure leading to death. Half of the ALS patients survive less than 3 years, and 80% of the patients survive less than 5 years. Riluzole is the only approved medication in Canada with randomized controlled clinical trial evidence to slow the progression of ALS, albeit only to a modest degree. The Canadian Neuromuscular Disease Registry (CNDR) collects data on over 140 different neuromuscular diseases including ALS across ten academic institutions and 28 clinics including ten multidisciplinary ALS clinics. METHODS: In this study, CNDR registry data were analyzed to examine potential differences in ALS care among provinces in time to diagnosis, riluzole and feeding tube use. RESULTS: Significant differences were found among provinces, in time to diagnosis from symptom onset, in the use of riluzole and in feeding tube use. CONCLUSIONS: Future investigations should be undertaken to identify factors contributing to such differences, and to propose potential interventions to address the provincial differences reported.

Targeted single molecule mutation detection with massively parallel sequencing.

Next-generation sequencing (NGS) technologies have transformed genomic research and have the potential to revolutionize clinical medicine. However, the background error rates of sequencing instruments and limitations in targeted read coverage have precluded the detection of rare DNA sequence variants by NGS. Here we describe a method, termed CypherSeq, which combines double-stranded barcoding error correction and rolling circle amplification (RCA)-based target enrichment to vastly improve NGS-based rare variant detection. The CypherSeq methodology involves the ligation of sample DNA into circular vectors, which contain double-stranded barcodes for computational error correction and adapters for library preparation and sequencing. CypherSeq is capable of detecting rare mutations genome-wide as well as those within specific target genes via RCA-based enrichment. We demonstrate that CypherSeq is capable of correcting errors incurred during library preparation and sequencing to reproducibly detect mutations down to a frequency of 2.4 × 10(-7) per base pair, and report the frequency and spectra of spontaneous and ethyl methanesulfonate-induced mutations across the Saccharomyces cerevisiae genome.

Clinical, physiological and pathological characterisation of the sensory predominant peripheral neuropathy in copper deficiency.

INTRODUCTION: Myelopathy is considered the most common neurological complication of copper deficiency. Concurrent peripheral neuropathy has been recognised in association with copper deficiency but has not been well characterised. OBJECTIVES: To characterise the clinical, physiological and pathological features of copper-deficient peripheral neuropathy. METHODS: Patients with simultaneous copper deficiency (<0.78 µg/mL) and peripheral neuropathy seen at the Mayo Clinic from 1985 to 2005 were identified. RESULTS: 34 patients were identified (median age 55 years, range 36-78) including 24 women and 10 men. Myelopathy was found in 21 patients. Median serum copper level was 0.11 µg/mL (range 0-0.58). The most frequent clinical and electrophysiological pattern of neuropathy was a sensory predominant length-dependent peripheral neuropathy (71%). Somatosensory evoked potentials demonstrated central slowing supporting myelopathy (96%). Quantitative sensory testing demonstrated both small and large fibre involvement (100%). Autonomic reflex screens (77%) and thermoregulatory sweat test (67%) confirmed sudomotor dysfunction. 14 cutaneous nerve biopsies revealed loss of myelinated nerve fibres (86%), increased regenerative clusters (50%), increased rates of axonal degeneration (91%) and increased numbers of empty nerve strands (73%). 71% of biopsies demonstrated epineurial perivascular inflammation. CONCLUSIONS: An axonal, length-dependent sensory predominant peripheral neuropathy causing sensory ataxia is characteristic of copper deficiency usually co-occurring with myelopathy. Neurophysiological testing confirms involvement of large, greater than small fibres. The pathological findings suggest axonal degeneration and repair. Inflammatory infiltrates are common but are small and of doubtful pathological significance.