Barriers and enablers to participation in the National Cervical Screening Program experienced by young women and people with a cervix aged between 25 and 35.

ISSUE ADDRESSED: Cervical screening rates for young women aged between 25 and 35 are lower than older Australian women, however, little research has been conducted to understand why. This study aimed to identify and explore the barriers and enablers faced by young Victorians with a cervix to regular cervical screening. METHODS: This study used a mixed method exploratory design consisting of qualitative focus groups and a quantitative online survey. Four focus groups were conducted with 24 Victorians with a cervix aged between 25 and 35. Barriers, enablers and knowledge of cervical screening were explored. Focus groups were recorded and transcribed for thematic analysis of common themes. A supporting online survey was completed by 98 respondents. Summary statistics were analysed for differences in age. RESULTS: Focus groups and the online survey revealed four main factors that influence young people's cervical screening behaviour. These include past negative screening experiences, practitioner factors, priority placed on cervical screening, and cervical screening knowledge. These factors differ to the opinions of people older than 35, with young people focusing more on the psychological elements of cervical screening compared with practical factors. CONCLUSIONS: This research provides a unique insight into cervical screening barriers faced by women and people with a cervix aged between 25 and 35 as well as what factors motivate them to screen. SO WHAT?: These findings should be utilised to inform the design of public health campaign messaging targeting this age demographic. Findings can also assist practitioners to improve how they communicate with young people in a clinical setting.

A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness.

BACKGROUND: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown. METHODS: Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology. RESULTS: We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability. CONCLUSIONS: A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.

Zebrafish as a model for kidney function and disease.

Kidney disease is a global problem with around three million people diagnosed in the UK alone and the incidence is rising. Research is critical to develop better treatments. Animal models can help to better understand the pathophysiology behind the various kidney diseases and to screen for therapeutic compounds, but the use especially of mammalian models should be minimised in the interest of animal welfare. Zebrafish are increasingly used, as they are genetically tractable and have a basic renal anatomy comparable to mammalian kidneys with glomerular filtration and tubular filtration processing. Here, we discuss how zebrafish have advanced the study of nephrology and the mechanisms underlying kidney disease.

Self-harm prevalence and ideation in a community sample of cis, trans and other youth.

Background: Trans youth have been reported to have high rates of self-harm, depression and bullying, and find it difficult to seek support. However, much of this research comes from gender identity clinics; non-clinical samples and those who reject gender binaries remain under-researched. Aims: This study investigated the experiences of a community school-based sample of Trans, identifying youth, Other, and cis-gendered adolescents in relation to their experiences of low mood, bullying, associated support, self-harm ideation and peer-related self-harm. Methods: An online survey was completed by 8440 13-17 year olds (3625 male, 4361 female, 227 Other, and 55 Trans). Results: Trans and Other students had significantly higher rates of self-harm ideation and peer self-harm, in comparison to cis-gendered students. These Trans and Other students reported significantly higher rates of bullying and self-reported depression and significantly less support from teachers and staff at school, in fact these students did not know where to go to access help. Discussion: This community sample confirms findings of high rates of self-harm ideation, self-reported depression and bullying for Trans youth as previously reported in clinic-based samples. However, by accessing a community sample, the salience of the category "Other" was established for young people today. While Other and Trans identified students both struggled to find support, those who identified as Trans were more likely to have been bullied, and have experienced self-reported depression and thoughts of self-harm. Thus, those who identify as transgender represent a high-risk group that needs targeted support within schools and by statutory and nonstatutory community services. Unpacking the category of Other would be beneficial for future research, as well as exploring resilience within this group and intersecting identities such as sexuality, Autism, or experiences such as earlier abuse.

Combined tissue and fluid proteomics with Tandem Mass Tags to identify low-abundance protein biomarkers of disease in peripheral body fluid: An Alzheimer's Disease case study.

RATIONALE: Ideal biomarkers are present in readily accessible samples including plasma and cerebrospinal fluid (CSF), and are directly derived from diseased tissue, therefore likely to be of relatively low abundance. Traditional unbiased proteomic approaches for biomarker discovery have struggled to detect low-abundance markers due to the high dynamic range of proteins, the predominance of hyper-abundant proteins, and the use of data-dependent acquisition mass spectrometry (MS). To overcome these limitations and improve biomarker discovery in peripheral fluids, we have developed TMTcalibrator™; a novel MS workflow combining isobarically labelled diseased tissue digests in parallel with an appropriate set of labelled body fluids to increase the chance of identifying low-abundance, tissue-derived biomarkers. METHODS: A disease relevant cell line was labelled with TMT® in a range of concentrations generating a multi-point calibration curve. Peripheral biofluid samples were labelled with the remaining tags and quantitative analysis was performed using an Orbitrap Fusion Tribrid mass spectrometer with a Top10 CID-HCD MS3 synchronous precursor selection (SPS) method. SPS allowed direct analysis of non-depleted, unfractionated CSF samples with complete profiling of six individual samples requiring only 15 hours of MS time, equivalent to 1.5 h per sample. RESULTS: Using the TMTcalibrator™ workflow allowed the identification of several markers of microglia activation that are differentially quantified in the CSF of patients with Alzheimer's disease (AD). We report peptides from 41 proteins that have not previously been detected in the CSF, that appear to be regulated by at least 60% in AD. CONCLUSIONS: This study has demonstrated the benefits of the new TMTcalibrator™ workflow and the results suggest this is a suitable and efficient method of detecting low-abundance peptides within biological fluids. The use of TMTcalibrator™ in further biomarker discovery studies should be considered to overcome some of the limitations commonly associated with more conventional approaches. Copyright © 2016 John Wiley & Sons, Ltd.

Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1.

The mitochondrial ATPase Inhibitory Factor 1 (hereafter referred to as IF1) blocks the reversal of the F1Fo-ATPsynthase to prevent detrimental consumption of cellular ATP and associated demise. Herein, we infer further its molecular physiology by assessing its protective function in neurons during conditions of challenged homeostatic respiration. By adopting in vitro and in vivo protocols of hypoxia/ischemia and re-oxygenation, we show that a shift in the IF1:F1Fo-ATPsynthase expression ratio occurs in neurons. This increased IF1 level is essential to induce accumulation of the PTEN-induced putative kinase 1 (PINK-1) and recruitment of the mitophagic ubiquitin ligase PARK-2 to promote autophagic "control" of the mitochondrial population. In IF1 overexpressing neurons ATP depletion is reduced during hypoxia/ischemia and the mitochondrial membrane potential (ΔYm) resilient to re-oxygenation as well as resistant to electrogenic, Ca(2+) dependent depolarization. These data suggest that in mammalian neurons mitochondria adapt to respiratory stress by upregulating IF1, which exerts a protective role by coordinating pro-survival cell mitophagy and bioenergetics resilience.

Palladium(II)-Catalyzed Synthesis of Sulfinates from Boronic Acids and DABSO: A Redox-Neutral, Phosphine-Free Transformation.

A redox-neutral palladium(II)-catalyzed conversion of aryl, heteroaryl, and alkenyl boronic acids into sulfinate intermediates, and onwards to sulfones and sulfonamides, has been realized. A simple Pd(OAc)2 catalyst, in combination with the sulfur dioxide surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO), is sufficient to achieve rapid and high-yielding conversion of the boronic acids into the corresponding sulfinates. Addition of C- or N-based electrophiles then allows conversion into sulfones and sulfonamides, respectively, in a one-pot, two-step process.

Glycosylation of Human Plasma Clusterin Yields a Novel Candidate Biomarker of Alzheimer's Disease.

Specific glycosylated peptides of clusterin are found associated with hippocampal atrophy. The glycosylation of clusterin from human plasma was comprehensively analyzed and characterized using mass spectrometry (MS)-based glycoproteomics analysis. All six known N-glycosylation sites are covered, three in the alpha subunit (α64N, α81N and α123N) and three in the beta subunit (ß64N, ß127N, and ß147N). More detailed structural characterization of clusterin glycopeptides was also performed, demonstrating the presence of glycosylated peptides and their corresponding glycans. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we have determined the differences in the glycoforms associated at each of the different glycosylation sites in plasma clusterin obtained from subjects of low hippocampal atrophy (n = 13) and high hippocampal atrophy (n = 14). In our pilot study, the ß64N site shows the most significant regulations between clinical groups. Eight ß64N glycoforms are significantly reduced in patients with high atrophy compared with those with low atrophy, which demonstrates the utility of clusterin isoforms as diagnostic and prognostic Alzheimer's disease (AD) markers. These results provide a novel and robust workflow suitable for rapid verification of specific clusterin glycoforms with utility as AD biomarkers.

New zebrafish models of neurodegeneration.

In modern biomedicine, the increasing need to develop experimental models to further our understanding of disease conditions and delineate innovative treatments has found in the zebrafish (Danio rerio) an experimental model, and indeed a valuable asset, to close the gap between in vitro and in vivo assays. Translation of ideas at a faster pace is vital in the field of neurodegeneration, with the attempt to slow or prevent the dramatic impact on the society's welfare being an essential priority. Our research group has pioneered the use of zebrafish to contribute to the quest for faster and improved understanding and treatment of neurodegeneration in concert with, and inspired by, many others who have primed the study of the zebrafish to understand and search for a cure for disorders of the nervous system. Aware of the many advantages this vertebrate model holds, here, we present an update on the recent zebrafish models available to study neurodegeneration with the goal of stimulating further interest and increasing the number of diseases and applications for which they can be exploited. We shall do so by citing and commenting on recent breakthroughs made possible via zebrafish, highlighting their benefits for the testing of therapeutics and dissecting of disease mechanisms.

Combining organometallic reagents, the sulfur dioxide surrogate DABSO, and amines: a one-pot preparation of sulfonamides, amenable to array synthesis.

We describe a method for the synthesis of sulfonamides through the combination of an organometallic reagent, a sulfur dioxide equivalent, and an aqueous solution of an amine under oxidative conditions (bleach). This simple reaction protocol avoids the need to employ sulfonyl chloride substrates, thus removing the limitation imposed by the commercial availability of these reagents. The resultant method allows access to new chemical space, and is also tolerant of the polar functional groups needed to impart favorable physiochemical properties required for medicinal chemistry and agrochemistry. The developed chemistry is employed in the synthesis of a targeted 70 compound array, prepared using automated methods. The array achieved a 93% success rate for compounds prepared. Calculated molecular weights, lipophilicities, and polar surface areas are presented, demonstrating the utility of the method for delivering sulfonamides with drug-like properties.

Use of model organisms for the study of neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses are a group of fatal progressive neurodegenerative diseases predominantly affecting children. Identification of mutations that cause neuronal ceroid lipofuscinosis, and subsequent functional and pathological studies of the affected genes, underpins efforts to investigate disease mechanisms and identify and test potential therapeutic strategies. These functional studies and pre-clinical trials necessitate the use of model organisms in addition to cell and tissue culture models as they enable the study of protein function within a complex organ such as the brain and the testing of therapies on a whole organism. To this end, a large number of disease models and genetic tools have been identified or created in a variety of model organisms. In this review, we will discuss the ethical issues associated with experiments using model organisms, the factors underlying the choice of model organism, the disease models and genetic tools available, and the contributions of those disease models and tools to neuronal ceroid lipofuscinosis research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

Modelling inborn errors of metabolism in zebrafish.

The majority of human inborn errors of metabolism are fatal multisystem disorders that lack proper treatment and have a poorly understood mechanistic basis. Novel technologies are required to address this issue, and the use of zebrafish to model these diseases is an emerging field. Here we present the published zebrafish models of inborn metabolic diseases, discuss their validity, and review the novel mechanistic insights that they have provided. We also review the available methods for creating and studying zebrafish disease models, advantages and disadvantages of using this model organism, and successful examples of the use of zebrafish for drug discovery and development. Using a zebrafish to model inborn errors of metabolism in vivo, although still in its infancy, shows promise for a deeper understanding of disease pathomechanisms, onset, and progression, and also for the development of specific therapies.

A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation.

Tripeptidyl peptidase 1 (TPP1) deficiency causes CLN2 disease, late infantile (or classic late infantile neuronal ceroid lipofuscinosis), a paediatric neurodegenerative disease of autosomal recessive inheritance. Patients suffer from blindness, ataxia, epilepsy and cognitive defects, with MRI indicating widespread brain atrophy, and profound neuron loss is evident within the retina and brain. Currently there are no effective therapies for this disease, which causes premature death in adolescence. Zebrafish have been successfully used to model a range of neurological and behavioural abnormalities. The aim of this study was to characterize the pathological and functional consequences of Tpp1 deficiency in zebrafish and to correlate these with human CLN2 disease, thereby providing a platform for drug discovery. Our data show that homozygous tpp1(sa0011) mutant (tpp1(sa0011)(-/-)) zebrafish display a severe, progressive, early onset neurodegenerative phenotype, characterized by a significantly small retina, a small head and curved body. The mutant zebrafish have significantly reduced median survival with death occurring 5 days post-fertilization. As in human patients with CLN2 disease, mutant zebrafish display storage of subunit c of mitochondrial ATP-synthase, hypertrophic lysosomes as well as localized apoptotic cell death in the retina, optic tectum and cerebellum. Further neuropathological phenotypes of these mutants provide novel insights into mechanisms of pathogenesis in CLN2 disease. Secondary neurogenesis in the retina, optic tectum and cerebellum is impaired and axon tracts within the spinal cord, optic nerve and the posterior commissure are disorganized, with the optic nerve failing to reach its target. This severe neurodegenerative phenotype eventually results in functional motor impairment, but this is preceded by a phase of hyperactivity that is consistent with seizures. Importantly, both of these locomotion phenotypes can be assayed in an automated manner suitable for high-throughput studies. Our study provides proof-of-principle that tpp1(sa0011)(-/-) mutants can utilize the advantages of zebrafish for understanding pathogenesis and drug discovery in CLN2 disease and other epilepsies.

Relations among optimism, perceived health vulnerability, and academic, self-regulatory, and social self-efficacy in adolescent survivors of childhood cancer.

This study investigated relations among optimism, perceived health vulnerability, treatment intensity, and academic, self-regulatory, and social self-efficacy in adolescent survivors of childhood cancer. Fifty-six adolescent survivors (Mage = 16.19 years, SD = 2.48) completed questionnaires. Compared to a previously published sample of adolescents without a history of cancer, survivors reported similar academic, higher self-regulatory, and lower social self-efficacy. Optimism and health vulnerability were associated with changes in academic, self-regulatory, and social self-efficacy. Cancer-specific variables (e.g., treatment intensity, time since treatment ended) were unrelated to self-efficacy. Interventions aimed at enhancing self-efficacy may benefit from exploring optimism and health vulnerabilities as mechanisms for change.

Understanding the costs and economic impact of mental disorders in South Asia: A systematic review.

BACKGROUND: Mental disorders remain the most significant contributor to years lived with disability in South Asia, yet governmental health expenditure on mental health in South Asia remains very low with limited strategic policy development. To strengthen the case for action it is important to better understand the profound economic costs associated with poor mental health. METHODS: We conducted a systematic review on the costs of all mental disorders, as well as intentional self-harm and suicide, in the World Bank South Asia Region. Ten global and South Asian databases as well as grey literature sources were searched. RESULTS: 72 studies were identified, including 38 meeting high quality criteria for good reporting of costs. Of these, 27 covered India, five Pakistan, four Nepal and three Bangladesh and Sri Lanka. Most studies focused on depressive disorders (15), psychoses (14) and harmful alcohol use (7); knowledge of economic impacts for other conditions was limited. Profound economic impacts within and beyond health care systems were found. In 15 of 18 studies which included productivity losses to individuals and/or carers, these costs more than outweighed costs of health care. CONCLUSION: Mental disorders represent a considerable economic burden, but existing estimates are conservative as they do not consider long-term impacts or the full range of conditions. Modelling studies could be employed covering longer time periods and more conditions. Clear distinctions should be reported between out-of-pocket and health system costs, as well as between mental health service-specific and physical health-related costs.

An evaluation of treatment integrity in a randomized trial of behavioural therapy for low mood in stroke patients with aphasia.

OBJECTIVE: To assess the treatment integrity of behavioural therapy for low mood in stroke patients with aphasia. DESIGN: Participants were recruited to a multicentre randomized controlled trial (Communication and Low Mood; CALM trial) comparing behavioural therapy with a usual care control group. SUBJECTS: Of the 51 participants randomly allocated to receive behavioural therapy, 44 participants completed treatment. METHODS: Participants were assessed on measures of disability, language and mood. The number and length of therapy sessions, and therapist was recorded. Allocation of time to therapy components was compared across three phases of therapy. Associations between levels of disability, aphasia, mood and the therapy patients received were determined. Therapy content was compared between centres and at the beginning and end of the trial. RESULTS: The mean number of therapy sessions was 9.1 (range 3-18, SD 2.6) and the mean duration of sessions was 58 minutes (range 30-89 minutes, SD 10.7). Allocation of time to each therapy component significantly differed across the three phases of therapy (P < 0.05). There were no significant associations (P > 0.05) between the length and number of sessions and patients' aphasia, mood or disability, suggesting similar levels of therapy were provided regardless of patients' characteristics. The content of therapy showed some differences between centres (P < 0.01) and there was programme drift in some components of therapy. CONCLUSIONS: The results support the ability of the therapists to deliver behavioural therapy according to the treatment manual. However there were differences between centres and over time in some components of therapy.

Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease.

Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102-208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype-phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events.

Thunderstorm-related asthma can occur in New Zealand.

Thunderstorm asthma is induced by specific weather conditions causing breakdown and widespread distribution of allergens. Thunderstorm asthma had previously been considered unlikely to occur in New Zealand (NZ), given its local weather patterns. Storm events on 2 December 2017 led to increased asthma presentations at Waikato Hospital in Hamilton. Analyses of patient presentations led us to conclude that these presentations were similar to international descriptions of thunderstorm asthma. This is the first time such presentations have been reported in NZ. Documenting these events accurately is important as this is the first step to making a plan that would enable paramedics and emergency facilities across NZ to respond to any larger scale thunderstorm asthma events in the future.

The contribution of multicellular model organisms to neuronal ceroid lipofuscinosis research.

The NCLs (neuronal ceroid lipofuscinosis) are forms of neurodegenerative disease that affect people of all ages and ethnicities but are most prevalent in children. Commonly known as Batten disease, this debilitating neurological disorder is comprised of 13 different subtypes that are categorized based on the particular gene that is mutated (CLN1-8, CLN10-14). The pathological mechanisms underlying the NCLs are not well understood due to our poor understanding of the functions of NCL proteins. Only one specific treatment (enzyme replacement therapy) is approved, which is for the treating the brain in CLN2 disease. Hence there remains a desperate need for further research into disease-modifying treatments. In this review, we present and evaluate the genes, proteins and studies performed in the social amoeba, nematode, fruit fly, zebrafish, mouse and large animals pertinent to NCL. In particular, we highlight the use of multicellular model organisms to study NCL protein function, pathology and pathomechanisms. Their use in testing novel therapeutic approaches is also presented. With this information, we highlight how future research in these systems may be able to provide new insight into NCL protein functions in human cells and aid in the development of new therapies.