Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy.

We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., "dead" Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1×1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.).

Shedding light on sperm pHertility.

The acquisition of fertilization capacity by sperm is regulated by intracellular pH (pH(i)), but the transport pathways that regulate pH(i) are not well understood. Lishko et al. (2010) now report that Hv1, the voltage-sensitive proton channel, is present in human sperm and is an important regulator of the functional maturation of sperm.

Suicide-related crisis presentations to a rural emergency department: A retrospective cohort study.

OBJECTIVE: The study sought to investigate the profile and characteristics of suicide-related crisis presentations and factors associated with repeat presentations to a rural hospital Emergency Department (ED). METHOD: This retrospective cohort study examined suicide-related crisis presentation data from a rural ED for the years 2008-2018 inclusive. Descriptive statistical analyses included demographic characteristics and trends over time. Factors associated with increased likelihood to re-present to the ED for suicide-related crisis were identified using Odds Ratio analyses. RESULTS: First Nations People, adolescents and young adults were at increased risk of presentation. Suicidal crisis presentations had increased well beyond that which might be accorded to the catchment's population increase and almost a third of presentations involved individuals re-presenting in suicide-related crisis. Repeat presentation was positively associated with younger age, less acute triage category, discharge to the community and leaving the ED before/during treatment. CONCLUSIONS: This study illustrates the importance of flagging, follow-up and support of rural repeat presenters to reduce further suicidal behaviours and presentation. Findings support the need for culturally safe and appropriate interventions and follow-up services. It is recommended to extend approach this to non-ED settings.

Correlates of anxiety and depression in a community cohort of people who smoke methamphetamine.

OBJECTIVE: Anxiety and depression are the most common mental health disorders experienced by Australians. These disorders are commonly found in people who use methamphetamine; however, much of this research has involved participants recruited from treatment settings who inject methamphetamine. We therefore explored (1) the prevalence of moderate to severe anxiety and depression in a community-recruited cohort who smoked methamphetamine and (2) examined potential factors associated with moderate to severe anxiety or depression in this cohort. METHOD: Data were derived from baseline surveys of 725 participants of the prospective 'VMAX' study, recruited from metropolitan and non-metropolitan areas of Victoria, Australia, via snowball and respondent-driven sampling. Anxiety and depression were measured using the Generalized Anxiety Disorder-7 and the Patient Health Questionnaire-9 instruments. Independent associations between moderate to severe scores on these measures and demographic, socio-economic, substance use and other health and social characteristics were examined using multivariable logistic regression. RESULTS: More than half (60%) of the participants were classified as experiencing moderate to severe anxiety and/or depression. In the multivariable models, having poor/very poor self-rated health, methamphetamine dependence and being unemployed were associated with higher odds of experiencing both moderate to severe depression and moderate to severe anxiety. Living in a large rural town, identifying as Aboriginal and Torres Strait Islander and smoking methamphetamine were associated with lower odds of experiencing moderate to severe depression. Being female was associated with higher odds of experiencing moderate to severe anxiety. CONCLUSION: The high rates of anxiety and/or depression found in the VMAX cohort were associated with demographic, socio-economic, substance use and other health and social factors. The prevalence of moderate to severe anxiety is a novel finding that warrants further study. Further work is needed to determine how anxiety and depression change over time among people who smoke methamphetamine, to help identify key intervention points.

Rural health service leaders co-design state-wide research addressing an emerging health issue: A case report.

AIMS: This commentary aims to describe a case of how meaningful co-design between rural health service leaders and a health service-embedded research unit can identify emerging research priorities and optimise translation. CONTEXT: The challenges facing rural health services are unique, and the important role of health service leaders in the research response is increasingly recognised. Poorly-designed research can contribute to research waste through reduced applicability of results to rural communities, and an opportunity exists to increase research co-designed with rural health services through the involvement of research users during study planning. APPROACH: In early 2020, leaders at a rural Victorian health service approached the embedded health service research unit to request research be conducted on an emerging issue: rural staff well-being in the face of the COVID-19 pandemic. This was based on their concern regarding the lack of available COVID-19-specific evidence to inform organisational policy. In collaboration with the rural health service executive, a translation-focused study of staff well-being with nine rural Victorian health services was developed. Key co-design activities of the project included involving research end-users as study investigators and conducting formal stakeholder engagement regarding study design and outcomes. CONCLUSION: Meaningful co-design of research with health services is a multifaceted process that can assist researchers and end-users alike in identifying and responding to emerging health issues. In the rural setting where there is a vital need for impactful health research, we recommend that researchers should consider employing co-design processes in order to minimise research waste and optimise the translatability of research findings.

Prevalence of mental illness among parents of children receiving treatment within child and adolescent mental health services (CAMHS): a scoping review.

People affected by mental illness often come from families with patterns of mental illness that span across generations. Hence, child and adolescent mental health services (CAMHS) likely provide treatment to many children with parents who also experience mental illness. The aim of this scoping review was to: (1) identify the prevalence of mental illness among parents of children in CAMHS; (2) identify and appraise the methodologies that have been implemented to assess the prevalence of parental mental illness in CAMHS; (3) identify additional circumstances associated with families where both parent and child experience mental illness; and (4) present recommendations that have been made for CAMHS practice based on these findings. English language, peer-reviewed studies (2010-2018) that had investigated the mental health of parents in CAMHS were included in the review. Literature searching yielded 18 studies which were found to have utilised diverse methodologies to assess parental mental health. Overall, reported prevalence of parental mental illness ranged from 16 to 79%; however, a single study that was deemed to be comprehensive reported prevalence rates of 36% for mothers and 33% for fathers. Across studies, parent and child mental illness was found to be associated with additional adversities impacting family functioning and wellbeing. For children who receive treatment for mental illness, having a parent who also experiences mental illness is a frequent family circumstance that has implications for their prospects for recovery. Accordingly, the mental health of parents should be an important consideration within the mental health care CAMHS provide to children.

Building a rural workforce through identifying supports for rural, mature-aged nursing and allied health students: A systematic scoping review.

INTRODUCTION: There is a long-standing undersupply of nursing and allied health professionals in rural Australia. Rural, mature-aged people form an untapped section of rural communities that could help to address these workforce needs. There is little understanding of the supports required to assist rural, mature-aged nursing and allied health students to complete their studies and enter the rural health workforce. OBJECTIVE: To scope factors influencing rural, mature-aged nursing and allied health students' ability to access, participate, and succeed in higher education. DESIGN: A scoping review of the international rural nursing and allied health and education literature was undertaken. Five databases (CINAHL Complete, MEDLINE, Education Resources Information Center [ERIC], Embase, and Education Research Complete), key peer-reviewed journals, and Australian grey literature were searched. FINDINGS: Fourteen articles were included in the review. Ten studies described rural, mature-aged nursing and allied health student characteristics, 6 described barriers to students participating and succeeding in higher education, and 4 described student supports. DISCUSSION: This review found limited evidence to guide higher education providers in attracting, supporting and retaining rural, mature-aged nursing and allied health students. In particular, evidence of student supports is required beyond those manifested by students themselves or their family, to include offerings from university and government sources. CONCLUSION: Substantially more research attention is needed to understand the experiences of rural, mature-aged nursing and allied health students, and supports required for this cohort to access, participate and successfully complete higher education.

Investigating first-year graduate paramedics' reason for current work location: A cross-sectional, data linkage study.

OBJECTIVE: This study aims to describe the demographic and employment characteristics of first-year graduates from a Victorian-based paramedicine course and investigate factors that influenced their choice in place of practice. DESIGN: Cross-sectional study using data from the Nursing and Allied Health Graduate Outcomes Tracking study. SETTING: Victoria, Australia. PARTICIPANTS: First-year graduates (2019) from the Monash University range of paramedicine programs. MAIN OUTCOME MEASURES: Variables of interest included principal place of practice and the reasons for working in the current location. RESULTS: Over half of the 2018 paramedicine course graduates responded to the 2019 Graduate Outcomes Survey. Nearly all were registered as paramedics (including double registrants as nurses), and over a fifth were from a rural background; however, less than that were working in a rural area. Of those with complete data, the most cited reasons for current work location were 'spouse/partner's employment or career', 'opportunity for career advancement' and 'scope of practice within the role'. CONCLUSION: This study provides important insight into the factors associated with rural practice location amongst paramedicine graduates, specifically rural origin or personal, lifestyle and professional influences. The study adds to the sparse literature about paramedic practice location decision-making and highlights the need for further systematic longitudinal research examining the 'where' and 'why'.

Profile and rural exposure for nursing and allied health students at two Australian Universities: A retrospective cohort study.

OBJECTIVE: Linking enrolment and professional placement data for students' from 2 universities, this study compares characteristics across universities and health disciplines. The study explores associations between students' location of origin and frequency, duration and type of placements. DESIGN: Retrospective cohort data linkage. SETTING: Two Australian universities, Monash University and the University of Newcastle. PARTICIPANTS: Students who completed medical radiation science, nursing, occupational therapy, pharmacy or physiotherapy at either university between 2 February 2017 and 28 February 2018. INTERVENTIONS: Location of origin, university and discipline of enrolment. MAIN OUTCOME MEASURE(S): Main measures were whether graduates had multiple rural placements, number of rural placements and cumulative rural placement days. Location of origin, discipline and university of enrolment were the main explanatory variables. Secondary dependent variables were age, sex, socio-economic indices for location of origin, and available placements. RESULTS: A total of 1,315 students were included, of which 22.1% were of rural origin. The odds of rural origin students undertaking a rural placement was more than 4.5 times greater than for urban origin students. A higher proportion of rural origin students had multiple rural placement (56.0% vs 14.9%), with a higher mean number of rural placement days. Public hospitals were the most common placement type, with fewer in primary care, mental health or aged care. CONCLUSIONS: There is a positive association between rural origin and rural placements in nursing and allied health. To help strengthen recruitment and retention of graduates this association could be further exploited, while being inclusive of non-rural students.

Destinations of nursing and allied health graduates from two Australian universities: A data linkage study to inform rural placement models.

OBJECTIVE: Combined, nursing and allied health constitute most of the Australian health workforce; yet, little is known about graduate practice destinations. University Departments of Rural Health have collaborated on the Nursing and Allied Health Graduate Outcomes Tracking to investigate graduate entry into rural practice. DESIGN: Data linkage cohort study. SETTING: Monash University and the University of Newcastle. PARTICIPANTS: Graduates who completed their degree in 2017 across seven disciplines. MAIN OUTCOME MEASURE(S): The outcome variable was Australian Health Practitioner Regulation Agency principal place of practice data. Explanatory variables included discipline, age, gender, location of origin, and number and duration of rural placements. RESULT: Of 1130 graduates, 51% were nurses, 81% females, 62% under 21 years at enrolment, 23% of rural origin, 62% had at least one rural student placement, and 23% had over 40 cumulative rural placement days. At the time of their second Australian Health Practitioner Regulation Agency registration, 18% worked in a 'Rural principal place of practice.' Compared to urban, rural origin graduates had 4.45 times higher odds ratio of 'Rural principal place of practice.' For graduates who had <20 cumulative rural placement days, compared to zero the odds ratio of 'Rural principal place of practice' was the same (odds ratio = 1.10). For those who had 20-40 rural placement days, the odds ratio was 1.93, and for >40 rural placement days, the odds ratio was 4.54). CONCLUSION: Rural origin and more rural placement days positively influenced graduate rural practice destinations. Outcomes of cumulative placements days may compare to immersive placements.

Rationale and protocol for the Nursing and Allied Health Graduate Outcomes Tracking (NAHGOT) study: a large-scale longitudinal investigation of graduate practice destinations.

INTRODUCTION: Inequitable distribution of health workforce limits access to healthcare services and contributes to adverse health outcomes. WHO recommends tracking health professionals from their points of entry into university and over their careers for the purpose of workforce development and planning. Previous research has focused on medical students and graduates' choice of practice location. Few studies have targeted nursing and allied health graduates' practice intentions and destinations. The Nursing and Allied Health Graduate Outcomes Tracking (NAHGOT) study is investigating factors affecting Australian nursing and allied health students and graduates' choice of graduate practice location over the course of their studies and up to 10 years after graduation by linking multiple data sources, including routinely collected university administrative and professional placement data, surveys of students and graduates, and professional registration data. METHODS: By using a prospective cohort study design, each year a new cohort of about 2000 students at each participating university (Deakin University, Monash University and the University of Newcastle) is tracked throughout their courses and for 10 years after graduation. Disciplines include medical radiation practice, nursing and midwifery, occupational therapy, optometry, paramedicine, pharmacy, physiotherapy, podiatry and psychology. University enrolment data are collected at admission and professional placement data are collected annually. Students' practice destination intentions are collected via questions added into the national Student Experience Survey (SES). Data pertaining to graduates' practice destination, intentions and factors influencing choice of practice location are collected in the first and third years after graduation via questions added to the Australian Graduate Outcomes Survey (GOS). Additionally, participants may volunteer to receive a NAHGOT survey in the second and fourth-to-tenth years after graduation. Principal place of practice data are accessed via the Australian Health Practitioner Regulation Agency (Ahpra) annually. Linked data are aggregated and analysed to test hypotheses comparing associations between multiple variables and graduate practice location. RESULTS: This study seeks to add to the limited empirical evidence about factors that lead to rural practice in the nursing and allied health professions. This prospective large-scale, comprehensive study tracks participants from eight different health professions across three universities through their pre-registration education and into their postgraduate careers, an approach not previously reported in Australia. To achieve this, the NAHGOT study links data drawn from university enrolment and professional placement data, the SES, the GOS, online NAHGOT graduate surveys, and Ahpra data. The prospective cohort study design enables the use of both comparative analysis and hypothesis testing. The flexible and inclusive study design is intended to enable other universities, as well as those allied health professions not regulated by Ahpra, to join the study over time. CONCLUSION: The study demonstrates how the systematic, institutional tracking and research approach advocated by the WHO can be applied to the nursing and allied health workforce in Australia. It is expected that this large-scale, longitudinal, multifactorial, multicentre study will help inform future nursing and allied health university admission, graduate pathways and health workforce planning. Furthermore, the project could be expanded to explore health workforce attrition and thereby influence health workforce planning overall.

Supervision training in healthcare: a realist synthesis.

Supervision matters: it serves educational, supportive and management functions. Despite a plethora of evidence on the effectiveness of supervision, scant evidence for the impact of supervision training exists. While three previous literature reviews have begun to examine the effectiveness of supervision training, they fail to explore the extent to which supervision training works, for whom, and why. We adopted a realist approach to answer the question: to what extent do supervision training interventions work (or not), for whom and in what circumstances, and why? We conducted a team-based realist synthesis of the supervision training literature focusing on Pawson's five stages: (1) clarifying the scope; (2) determining the search strategy; (3) study selection; (4) data extraction; and (5) data synthesis. We extracted contexts (C), mechanisms (M) and outcomes (O) and CMO configurations from 29 outputs including short (n = 19) and extended-duration (n = 10) supervision training interventions. Irrespective of duration, interventions including mixed pedagogies involving active and/or experiential learning, social learning and protected time served as mechanisms triggering multiple positive supervisor outcomes. Short-duration interventions also led to positive outcomes through mechanisms such as supervisor characteristics, whereas facilitator characteristics was a key mechanism triggering positive and negative outcomes for extended-duration interventions. Disciplinary and organisational contexts were not especially influential. While our realist synthesis builds on previous non-realist literature reviews, our findings extend previous work considerably. Our realist synthesis presents a broader array of outcomes and mechanisms than have been previously identified, and provides novel insights into the causal pathways in which short and extended-duration supervision training interventions produce their effects. Future realist evaluation should explore further any differences between short and extended-duration interventions. Educators are encouraged to prioritize mixed pedagogies, social learning and protected time to maximize the positive supervisor outcomes from training.

PERSPECTIVES: Recovery Oriented Services for Persons with Severe Mental Illness Can Focus on Meeting Needs Through Care Coordination.

BACKGROUND: The approach to care for persons with an acute illness is different from that for a person with a chronic disease. Whilst the goal of treatment for an acute illness is to cure the disease, a chronic condition has no cure as such, and hence management requires a team approach that is aimed at achieving goals that are jointly set by service users and providers. Severe and persistent mental illness (SPMI) is a chronic disease. However, in many mental health services, the approach to care for persons with SPMI is similar to those who have an acute mental illness. AIM: The aims of this paper are twofold: (i) to make an argument for recovery oriented services to focus on meeting clients' needs rather than on symptom reduction, (ii) to propose a model of service provision where clinical mental health services form a part rather than the mainstay of care for people with SPMI. RESULTS: Using examples from Australia's Partner's in Recovery initiative and other recovery literature, we start by describing how SPMI should be treated as a chronic disease that focuses on recovery. We then highlight how mental health services continue to monitor outcomes based on clinical rather than personal recovery. Next, we diagrammatically illustrate how needs can be aligned with the recovery process and illustrate how care coordination can be the hub of service delivery in a hub and spoke model. We conclude with comments on workforce requirements and costs of a needs-based recovery oriented service. DISCUSSION: In a needs based model, the role of the specialist mental health service will move from being at the centre of care to being one of the components of care and the role of the care coordinator will become central. Although, there are as yet no randomised controlled trials to show that meeting needs of persons with SPMI will significantly contribute to their recovery, preliminary studies show that it is possible. IMPLICATIONS FOR HEALTHCARE PROVISION AND USE: The role of the care coordinator becomes the hub of service provision collaborating with agencies such as family practices, specialist mental health services, legal, housing, employment, education, and community services. IMPLICATIONS FOR HEALTH POLICIES: A shift from the current model of care to a needs based approach requires a revolutionary change in the way we do business and will have to be the largest shake up of the mental health service system since deinstitutionalisation. IMPLICATIONS FOR FURTHER RESEARCH: It is a long journey from the status quo to a needs based approach. The first step would be to gather more evidence on the usefulness of addressing people's needs in achieving recovery.

Concepts, Practices and Advantages of Spirituality Among People with a Chronic Mental Illness in Melbourne.

There is a relative paucity of literature in the field of spirituality among people who have a lived experience of severe mental illness from Australia. Sixteen individuals with a severe mental illness were interviewed on their experiences of spirituality. The three themes that emerged from the data were concepts of spirituality, benefits of intentional spiritual practices and perceived spiritual benefits of recreational pursuits and physical activity. This paper adds to the relatively sparse literature on spirituality among persons with a mental illness in Australia.

The flagellar protein Enkurin is required for mouse sperm motility and for transport through the female reproductive tract.

Enkurin was identified initially in mouse sperm where it was suggested to act as an intracellular adaptor protein linking membrane calcium influx to intracellular signaling pathways. In order to examine the function of this protein, a targeted mutation was introduced into the mouse Enkurin gene. Males that were homozygous for this mutated allele were subfertile. This was associated with lower rates of sperm transport in the female reproductive tract, including reduced entry into the oviduct and slower migration to the site of fertilization in the distal oviduct, and with poor progressive motility in vitro. Flagella from wild-type animals exhibited symmetrical bending and progressive motility in culture medium, and demembranated flagella exhibited the "curlicue" response to Ca2+ in vitro. In contrast, flagella of mice homozygous for the mutated allele displayed only asymmetric bending, nonprogressive motility, and a loss of Ca2+-responsiveness following demembrantion. We propose that Enkurin is part of a flagellar Ca2+-sensor that regulates bending and that the motility defects following mutation of the locus are the proximate cause of subfertility.

Referral patterns and implementation costs of the Partners in Recovery initiative in Gippsland: learnings for the National Disability Insurance Scheme.

OBJECTIVE:: The purpose of this paper is to provide some learnings for the NDIS from the referral pattern and cost of implementing the Partners in Recovery initiative of Gippsland. METHOD:: Information on referral areas made for each consumer was collated from support facilitators. Cost estimates were determined using budget estimates, administrative costs and a literature review and are reported from a government perspective. RESULTS:: Sixty-three per cent of all referrals were made to organisations that provided multiple types of services. Thirty-one per cent were to Mental Health Community Support Services. Eighteen per cent of referrals were made to clinical mental health services. The total cost of providing the service for a consumer per year (set-up and ongoing) was estimated to be AUD$15,755 and the ongoing cost per year was estimated to be AUD$13,434. The cost of doing nothing is likely to cost more in the longer term, with poor mental health outcomes such as hospital admission, unemployment benefits, prison, homelessness and psychiatric residential care. CONCLUSIONS:: Supporting recovery in persons with Severe and Persistent Mental Illness is likely to be economically more beneficial than not doing so. Recovery can be better supported when frequently utilised services are co-located. These might be some learnings for the NDIS.

Health professional students' rural placement satisfaction and rural practice intentions: A national cross-sectional survey.

OBJECTIVE: The aim of this study was to profile students undertaking placements at University Departments of Rural Health (UDRHs) and investigate factors affecting students' satisfaction and intention to enter rural practice. DESIGN: Cross-sectional survey comprising 21 core questions used by all UDRHs. SETTING: Eleven UDRHs across Australia that support students' placements in regional, rural and remote locations. PARTICIPANTS: Medical, nursing and allied health students who participated in UDRH placements between July 2014 and November 2015 and completed the questionnaire. MAIN OUTCOME MEASURES: Key dependent variables were placement satisfaction and rural practice intention. Descriptive variables were age, gender, Aboriginal or Torres Strait Islander (ATSI) background, location of placement, healthcare discipline, year of study and type and length of placement. RESULTS: A total of 3328 students responded. The sample was predominantly female (79%), the mean age was 26.0 years and 1.8% identified as ATSI. Most placements (69%) were >2 but ≤12 weeks, 80% were in Modified Monash 3, 4 or 5 geographical locations. Public hospitals and community health made up 63% of placements. Students satisfied with their placement had 2.33 higher odds of rural practice intention. Those satisfied with Indigenous cultural training, workplace supervision, access to education resources and accommodation had higher odds of overall satisfaction and post-placement rural practice intention. CONCLUSIONS: The majority of students were highly satisfied with their placement and the support provided by rural clinicians and the UDRHs. UDRHs are well placed to provide health professional students with highly satisfactory placements that foster rural practice intention.

Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem.

STUDY QUESTION: Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? SUMMARY ANSWER: High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. WHAT IS KNOWN ALREADY: There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform. STUDY DESIGN, SIZE, DURATION: Spermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: A HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 µM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase in fluorescence in the primary screen were rescreened and evaluated further, resulting in 48 hit compounds that produced a concentration-dependent increase in [Ca2+]i. Sperm penetration studies confirmed in vitro exposure to two hit compounds (A and B) resulted in significant improvement in functional motility in spermatozoa from healthy volunteer donors (A: 1 cm penetration index 2.54, 2 cm penetration index 2.49; P < 0.005 and B: 1 cm penetration index 2.1, 2 cm penetration index 2.6; P < 0.005), but crucially, also in patient samples from those undergoing fertility treatment (A: 1 cm penetration index 2.4; P = 0.009, 2 cm penetration index 3.6; P = 0.02 and B: 1 cm penetration index 2.2; P = 0.0004, 2 cm penetration index 3.6; P = 0.002). This was primarily as a result of direct or indirect CatSper channel action, supported by evidence from electrophysiology studies of individual sperm. LIMITATIONS, REASONS FOR CAUTION: Increase and fluxes in [Ca2+]i are fundamental to the regulation of sperm motility and function, including acrosome reaction. The use of calcium signalling as a surrogate for sperm motility is acknowledged as a potential limitation in this study. WIDER IMPLICATIONS OF THE FINDINGS: We conclude that HTS can robustly, efficiently, identify novel compounds that increase [Ca2+]i in human spermatozoa and functionally modify motility, and propose its use as a cornerstone to build and transform much-needed drug discovery for male infertility. STUDY FUNDING/COMPETING INTEREST(S): The majority of the data were obtained using funding from TENOVUS Scotland and Chief Scientist Office NRS Fellowship. Additional funding was provided by NHS Tayside, MRC project grants (MR/K013343/1, MR/012492/1) and University of Abertay. The authors declare that there is no conflict of interest. TRAIL REGISTRATION NUMBER: N/A.

Health workers' views of help seeking and suicide among Aboriginal people in rural Victoria.

OBJECTIVE: To explore Aboriginal health workers' views about help seeking and suicide. DESIGN: One-to-one semi-structured interviews were conducted with participants. Data were analysed thematically. SETTING: Njernda Aboriginal Corporation and the Yorta Yorta Aboriginal Community of Echuca, Victoria. PARTICIPANTS: Twenty seven participants (15 men and 12 women) over the age of 18 years were interviewed, of which 24 were Aboriginal workers employed by Njernda Aboriginal Corporation. RESULTS: Four themes emerged from the data: 'Difficulty in talking about one's problems'; 'Reasons for not talking with family and peers'; 'Lack of access to suitable formal supports' and 'Consequences of not talking about one's problems'. CONCLUSION: This study unpacks the problem of help seeking for psychological distress among rural Aboriginal people and highlights its association with suicide and self-harm. The findings suggest that the barriers faced by Aboriginal people in sharing their traumatic emotions exist from childhood to older age groups and this inability to seek and obtain help can lead to self-harm and suicide. Similar studies on Aboriginal help seeking and suicide will help shed more light on this challenging issue.