Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons.

Alzheimer's disease is linked to increased levels of amyloid beta (Aß) in the brain, but the mechanisms underlying neuronal dysfunction and neurodegeneration remain enigmatic. Here, we investigate whether organizational characteristics of functional presynaptic vesicle pools, key determinants of information transmission in the central nervous system, are targets for elevated Aß. Using an optical readout method in cultured hippocampal neurons, we show that acute Aß42 treatment significantly enlarges the fraction of functional vesicles at individual terminals. We observe the same effect in a chronically elevated Aß transgenic model (APPSw,Ind) using an ultrastructure-function approach that provides detailed information on nanoscale vesicle pool positioning. Strikingly, elevated Aß is correlated with excessive accumulation of recycled vesicles near putative endocytic sites, which is consistent with deficits in vesicle retrieval pathways. Using the glutamate reporter, iGluSnFR, we show that there are parallel functional consequences, where ongoing information signaling capacity is constrained. Treatment with levetiracetam, an antiepileptic that dampens synaptic hyperactivity, partially rescues these transmission defects. Our findings implicate organizational and dynamic features of functional vesicle pools as targets in Aß-driven synaptic impairment, suggesting that interventions to relieve the overloading of vesicle retrieval pathways might have promising therapeutic value.

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.

Defects in DNA single-strand break repair (SSBR) are linked with neurological dysfunction but the underlying mechanisms remain poorly understood. Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan. Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1Nes-Cre mice is greatly extended. This is the first demonstration that lethal seizures can be triggered by aberrant Parp1 activity at unrepaired SSBs, highlighting PARP inhibition as a possible therapeutic approach in hereditary neurological disease.

Efficacy of a telephone outcall program to reduce caregiver burden among caregivers of cancer patients [PROTECT]: a randomised controlled trial.

BACKGROUND: Informal caregivers provide extended support to people with cancer but they receive little support from the health care system to assist them in their caring role. The aim of this single-blind, multi-centre, randomised controlled trial was to test the efficacy of a telephone outcall program to reduce caregiver burden and unmet needs, and improve psychological well-being among cancer caregivers, as well as evaluating the potential impact on patient outcomes. METHODS: Cancer patient/caregiver dyads (N = 216) were randomised to a telephone outcall program (n = 108) or attention control group (n = 108). The primary outcome was self-reported caregiver burden. Secondary endpoints included depressive symptoms, unmet needs, self-esteem, self-empowerment, and health literacy. Data were collected at baseline and at both 1 and 6 months post-intervention. An intention to treat analysis was performed. RESULTS: The intervention had no effect on the primary outcome (caregiver burden), but reduced the number of caregiver unmet needs (intervention group baseline, mean = 2.66, 95% confidence interval (CI) [1.91-3.54]; intervention group 1 month post intervention, mean = 0.85, 95%CI [0.42-1.44]; control group baseline, mean = 1.30 95%CI [0.80-1.94], control group 1 month post intervention, mean = 1.02 95%CI [0.52-1.69]; p = 0.023). For caregivers at risk for depression, the intervention had a significant effect on caregivers' confidence in having sufficient information to manage their health (p = 0.040). No effects were found for patients' depressive symptoms, unmet needs, self-empowerment, and other health literacy domains. CONCLUSIONS: While caregiver burden was not reduced, the outcall program was effective in reducing unmet needs in caregivers. Provision of cancer information and support via a telephone service may represent a feasible approach to reducing unmet needs among cancer caregiver populations. TRIAL REGISTRATION: ACTRN12613000731796 ; prospectively registered on 02/07/2013.

A telephone outcall program to support caregivers of people diagnosed with cancer: utility, changes in levels of distress, and unmet needs.

PURPOSE: To evaluate the utility of a telephone outcall program for cancer caregivers and to examine longitudinal changes in their distress levels and supportive care needs. METHODS: As part of the PROTECT trial, caregivers assigned to the intervention arm (N = 108) received three telephone outcalls from a Cancer Council 13 11 20 nurse at three time points (7-10 days post-randomization, 1 and 4 months later). During each call, caregivers were screened for distress using the Distress Thermometer (range: 0-10) then six supportive care issues were raised for discussion. Participants completed a utility survey 1 month post-intervention. RESULTS: The outcall program was highly acceptable and perceived as beneficial by caregivers. Overall, 95% reported it was worth their time to take part in the outcall program and 82% stated that the program was very relevant to them. Level of distress and impact of distress decreased over time (p = 0.0031, p < 0.0001, respectively). Average call duration decreased over time (p < 0.0001) and was longer for female than male caregivers (p = 0.0009). The frequency of caregivers discussing issues related to psychological distress (p = 0.0003), health literacy (p < 0.0001), financial (p = 0.0014), and practical concerns (p = 0.0121) decreased over time. Psychological distress was more often discussed by female than male caregivers (p = 0.0153), and family issues more often by younger (< 55 years) than older caregivers (p = 0.0071). CONCLUSIONS: Utility of this outcall program was high. Caregivers' level of distress and unmet needs decreased over time. Gender and age differences emerged, which warrants the need for tailored support. Further research is necessary to identify the best method of improving access to 13 11 20 services for caregivers.

A comparison of barriers to accessing services for mental and physical health conditions in a sample of rural Australian adults.

INTRODUCTION: The prevalence of chronic disease, mortality and suicide rates is higher in rural Australia than in urban centres. Understanding rural Australians' barriers to accessing health services requires urgent attention. The purpose of this study was to compare barriers to help-seeking for physical and mental health issues among rural South Australian adults. METHODS: A total of 409 people from three rural and remote regions in South Australia completed a computer-assisted telephone interview. They were presented a physical or mental health scenario and rated the extent to which barriers would prevent them from seeking help for that condition. Responses ranged from 1 ('strongly disagree') to 5 ('strongly agree') and were averaged to form domain scores (higher scores representing stronger barriers to seeking support), in addition to being examined at the item level. RESULTS: Men reported higher barriers for the mental compared with physical health scenario across four domains ('need for control and self-reliance', 'minimising the problem, resignation and normalisation', 'privacy' and 'emotional control'). Women reported higher barriers for the mental compared to physical health scenario in two domains ('need for control and self-reliance' and 'privacy'). Both men and women endorsed many items in the mental health context (eg 'I don't like feeling controlled by other people', 'I wouldn't want to overreact to a problem that wasn't serious', 'Problems like this are part of life; they're just something you have to deal with', 'I'd prefer just to put up with it rather than dwell on my problems', 'Privacy is important to me, and I don't want other people to know about my problems' and 'I don't like to get emotional about things') but in the physical health context, barriers were endorsed only by men (eg 'I wouldn't want to overreact to a problem that wasn't serious',' I'd prefer just to put up with it rather than dwell on my problems', 'Problems like this are part of life; they're just something you have to deal with', 'I like to make my own decisions and not be too influenced by others'). CONCLUSIONS: Both rural men and rural women report more barriers to help seeking for mental health issues than physical health issues across a range of domains. There is a need to educate the current and future rural health and mental health workforce about these barriers and to encourage them to test evidence-based strategies to address them, in particular to facilitate more widespread mental health help-seeking in rural Australia.

A comparison of barriers to mental health support-seeking among farming and non-farming adults in rural South Australia.

OBJECTIVE: To assess the differences between farming and non-farming rural adults in perceived barriers to mental health service use. DESIGN: A cross-sectional survey, modified from the Barriers to Help-Seeking Scale (BHSS), was conducted using a computer-assisted telephone interview. SETTING: Respondents (age 52.6 ± 11.6 years) were recruited from three rural regions of South Australia. PARTICIPANTS: Approximately, 78 non-farmers and 45 farmers were included in analyses. 78 retired and two unemployed participants were excluded from the analyses. MAIN OUTCOME MEASURE: Farmers and non-farmers were compared on domain scores and individual item responses from the adapted BHSS that represent 'agrarian' attitudes to support-seeking for mental health: stoicism, self-reliance, minimisation of the problem, stigma and distrust of health professionals. RESULTS: In the analysis of domain scores, 'Need for Control and Self-Reliance' was a stronger barrier for farmers than non-farmers (P = 0.009) with a trend (P = 0.07) towards stronger barriers among farmers in the 'Minimising Problem and Resignation' domain. In the analysis of item-level responses, there was a difference (P = 0.03) between farmers and non-farmers in responses to 'I find it difficult to understand my doctor/health professional', with 24.4% of the farmers agreeing that this is a barrier compared with 15.3% of the non-farmers. CONCLUSION: Long-held stereotypes of stoicism and self-reliance among farmers were somewhat supported, in the context of mental health. Mental health services and professionals in rural Australia might need to adapt their practices to successfully engage this population.

How calls from carers, friends and family members of someone affected by cancer differ from those made by people diagnosed with cancer; analysis of 4 years of South Australian Cancer Council Helpline data.

PURPOSE: The purpose of this study is to determine how people diagnosed with cancer who call the Cancer Council Helpline in South Australia differ from carers/family/friends (caregivers) who call. METHOD: Descriptive, retrospective audit of calls from people who contacted Cancer Council Helpline in South Australia between 16 April 2009 and 16 April 2013 who were diagnosed with cancer (n = 5766) or were the caregivers (n = 5174) of a person with cancer. RESULTS: Caregivers were more likely to be female (p < 0.001); younger in age (p < 0.001); call regarding cancer that was metastasised/widespread/advanced, terminal or at an unknown stage (p < 0.001) and phone requesting general cancer information or emotional support (p < 0.001). This group was more distressed (p < 0.001) but less likely (p = 0.02) to be offered and/or accept referrals to counselling than people diagnosed with cancer who called. Follow-up care was required by 63.5 % of caregivers and 73.1 % of people with cancer according to distress management guidelines; 8.5 and 15.3 %, respectively, accepted referrals to internal services. The most frequently discussed topic for both groups was emotional/psychological concerns. There were no differences in remoteness of residence or call length between groups. CONCLUSIONS: Caregivers represented different demographic groups than people diagnosed with cancer who called this helpline. The two groups phoned for different issues, at different stages of disease progression, displayed different levels of distress and, therefore, may benefit from services being tailored to meet their unique needs. These results also demonstrate the capacity of helplines to complement other health services and confirm that callers to cancer helplines exhibit high levels of distress.

Conceptualisations of Leadership and Relevance to Health and Human Service Workforce Development: A Scoping Review.

PURPOSE: This scoping review was undertaken to determine leadership definitions and approaches relevant to health and human service (H&HS) workforce development. This review provides a preliminary analysis of the potential size and scope of available research literature to inform ongoing research with the ultimate aim to inform a future systematic review in relation to leadership development interventions. METHODS: Following the methodology proposed by Arksey and O'Malley and using PRISMA-ScR, a systematic search was conducted using seven databases (PubMed, Health Business Elite, Medline, CINAHL, Ovid, Scopus, and Web of Science). Articles were screened and assessed for eligibility. From eligible studies, data were extracted to summarize, collate, and make a narrative account of the findings. RESULTS: Employing pre-selected criteria, a total of 424 records were identified and 171 full-text articles were assessed. The majority of the papers were studies undertaken by researchers based in North America. Leadership in the H&HS sector was addressed in 35% of the articles. The narrow disciplinary or workforce fields of the nursing and medical professions in hospitals and acute care settings dominated the literature. CONCLUSION: The findings suggest that while leadership has been studied extensively in the health system, there is a paucity of leadership development research specific to the broader H&HS sector. This review emphasises the need for further research, including a more critical examination of leadership development interventions and their application to the H&HS sector.

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-ß Intermediates Revealing that Self-Assembly Is Required for Aß-Induced Cytotoxicity.

Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-ß (Aß) forms DiY in vitro and DiY-cross-linked Aß is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of Aß42 results in an increase in DiY cross-links. Using DiY as a marker of oxidation, we compare the self-assembly propensity and DiY cross-link formation for a non-assembly competent variant of Aß42 (vAß) with wild-type Aß42. Oxidation results in the formation of trapped wild-type Aß assemblies with increased DiY cross-links that are unable to elongate further. Assembly-incompetent vAß and trapped Aß assemblies are non-toxic to neuroblastoma cells at all stages of self-assembly, in contrast to oligomeric, non-cross-linked Aß. These findings point to a mechanism of toxicity that necessitates dynamic self-assembly whereby trapped Aß assemblies and assembly-incompetent variant Aß are unable to result in cell death.

Good training, systems and funding, not good luck: what hematologists and oncologists believe would make it easier for them to refer their cancer patients to psychosocial care.

Rates of referral of patients to psychosocial services are low in most cancer treatment centers, while rates of distress are high. The purpose of this study is to identify clinicians' barriers to referring cancer patients to psychosocial services and strategies that could increase rates of referral. A purposive sampling method ensured data were gathered in two large public teaching hospitals from seven oncologists and five hematologists with varying levels of experience, of whom five were female. Data were collected using semistructured interviews guided by the Capability, Opportunity, Motivation and Behavior model (Michie S, Atkins L, West R. The Behaviour Change Wheel: A Guide to Designing Interventions. United Kingdom: Silverback Publishing; 2014.). This helped us to identify modifiable variables associated with referral likelihood and associated evidence-based strategies using the Behavior Change Wheel. Data were analyzed using Thematic Analysis. Barriers relating to capability, opportunity, and motivation to refer to psychosocial services were identified, including lack of knowledge of available services, how to refer to them, and the types of patients who would benefit. Other barriers included the following: lack of time to discuss and refer, convoluted referral pathways, long waiting times, and fear of patient reluctance due to stigma. Respondents identified numerous strategies for overcoming barriers, including training on referral best practice, role-plays, the provision of lists of services with referral and contact details, and increasing service capacity via additional funding. Findings inform the development of acceptable, evidence-based strategies, to improve rates of referral to psychosocial services by oncologists and hematologists. Without implementation, a substantial number of people affected by cancer will continue to suffer from potentially treatable distress.

The information needs of adult cancer survivors across the cancer continuum: A scoping review.

OBJECTIVE: To provide an updated synthesis of the literature that investigates the self-reported information needs of people diagnosed with cancer across the cancer continuum. METHODS: We conducted a scoping review of the literature published from August 2003 to June 2015 and expanded an existing typology summarizing the information needs of people diagnosed with cancer. RESULTS: The majority of the included studies (n=104) focused on questions relevant to the diagnosis/active treatment phase of the cancer continuum (52.9%) and thus the most frequently identified information needs related to this phase (33.4%). Information needs varied across the continuum and the results highlight the importance of recognising this fact. CONCLUSION: People diagnosed with cancer experience discrete information needs at different points from diagnosis to survival. Much of the research conducted in this area has focused on their information needs during the diagnosis and treatment of cancer, and literature relating to information needs following completion of treatment is sparse. PRACTICE IMPLICATIONS: Further research is needed to discern the specific nature of the treatment concerns and identify the information needs that survivors experience during recurrence of cancer, metastasis or changes in diagnosis, and the end of life phase of the cancer continuum.

Use of the Distress Thermometer in a cancer helpline context: Can it detect changes in distress, is it acceptable to nurses and callers, and do high scores lead to internal referrals?

PURPOSE: To improve understanding about; (1) the validity of the Distress Thermometer (DT) as a measure of changes in distress after a cancer helpline call, (2) the impact of a helpline call on callers' distress, (3) caller and helpline nurses' comfort with use of the DT, and (4) the extent to which DT scores over the critical threshold, are associated with referral to internal support services for follow-up psychosocial care. METHODS: Callers (people diagnosed with cancer and their family/friends: N = 100) completed a questionnaire that included DT ratings (three time-points), the Depression Anxiety and Stress Scale-21 (DASS-21) and measures of comfort with the DT tool. Nurses recorded referrals to internal services and their comfort in using the DT in each call. RESULTS: The DT correlated with the DASS-21 depression (r = 0.45, p < 0.001), anxiety (r = 0.56, p < 0.001) and stress (r = 0.64, p < 0.001) subscales demonstrating validity. Callers' self-rated distress was significantly lower after the call, regardless of gender or caller type (F(2, 97) = 63.67, p < 0.01, partial eta squared = 0.57). Over 74% of people diagnosed with cancer, 80% family/friends and 89.3% of nurses felt comfortable with DT use. Only 16% of participants were referred on to follow-up internal support services despite 90% of people with cancer and 75% of family/friends' DT scores' suggesting they required follow-up care. CONCLUSIONS: The DT is a valid and acceptable tool for use by cancer helplines. Improved documentation of referrals is required to better understand referral patterns.

Demographic characteristics, call details and psychosocial support needs of the family/friends of someone diagnosed with cancer who access Australian Cancer Council telephone information and support services.

PURPOSE: Community-based cancer organizations provide telephone-based information and support services to assist people diagnosed with cancer and their family/friends. We investigated the demographic characteristics and psychosocial support needs of family/friends who contacted Australian Cancer Council 13 11 20 information and support helplines. METHODS: Data collected on 42,892 family/friends who contacted a 13 11 20 service across Australia from January 2010 to December 2012 were analyzed. Chi-square analysis was used to examine associations between caller groups and reasons for calling, logistic regression to examine age and gender interaction effects. RESULTS: The majority of calls received were from women (81%) of middle- (40%) and high-socio-economic backgrounds (41%), aged 40-59 years (46%); 52% phoned for information on cancer diagnosis (including early detection, risk factors), 22% on treatment/disease management, and 26% phoned seeking psychological/emotional support. Information on a diagnosis was significantly more often the reason older males called, compared to female callers of any age. Overall, 32% found out about the service through Cancer Council resources or events, 20% from the media, 18% from the internet; 11% from health professionals. CONCLUSIONS: Family/friends of persons diagnosed with cancer have specific information and support needs. This study identifies groups of family/friends to whom the promotion of this service could be targeted. Within Australia and internationally, clinicians and oncology nurses as well as allied health professionals can provide an important role in increasing access to cancer telephone support services to ensure the needs of the family and friends of people affected by cancer are being met.

Barriers to Seeking Help for Skin Cancer Detection in Rural Australia.

This study explores rural South Australians' barriers to help-seeking for skin cancer detection. A total of 201 randomly selected rural adults (18-94 years, 66% female) were presented with a skin-cancer-related scenario via telephone and were asked the extent to which various barriers would impede their help-seeking, based on an amended version of the Barriers to Help-Seeking Scale. Older (≥63 years) and less educated participants endorsed barriers more strongly than their younger, more educated counterparts in the following domains; "Concrete barriers and distrust of caregivers", "Emotional control", "Minimising problem and Normalisation", "Need for control and self-reliance" (every domain other than "Privacy"). Socioeconomic disadvantage, gender, and farmer status did not predict stronger overall barriers, but some gender and occupation-related differences were detected at the item level. Farmers were also more likely to endorse the "Minimising problem and normalization" domain than their non-farmer working rural counterparts. Widely endorsed barriers included the tendency to minimise the problem, a desire to remain in control/not be influenced by others, reluctance to show emotion or complain, and having concerns about privacy or waiting times.