Protocol of trans-Tasman feasibility randomised controlled trial of the Younger Women's Wellness After Breast Cancer (YWWACP) lifestyle intervention.

BACKGROUND: Younger women (defined as those < 50 years who are likely pre-menopausal at time of diagnosis) with breast cancer often experience persistent treatment-related side effects that adversely affect their physical and psychological wellbeing. The Women's Wellness After Cancer Program (WWACP) was adapted and piloted in Australia to address these outcomes in younger women. The aims of this feasibility study are to determine (1) the potential to translate the Younger WWACP (YWWACP) intervention to a broader population base in Aotearoa/New Zealand and Australia, and (2) the potential for success of a larger, international, phase ΙΙΙ, randomised controlled trial. METHODS: This bi-national, randomised, single-blinded controlled trial involves two main study sites in Aotearoa/New Zealand (Kowhai study) and Australia (EMERALD study). Young women aged 18 to 50 years who completed intensive treatment (surgery, chemotherapy, and/or radiotherapy) for breast cancer in the previous 24 months are eligible. The potential to translate the YWWACP to women in these two populations will be assessed according to several feasibility outcomes. These include examining intervention accessibility, acceptability and uptake; intervention sustainability and adherence; the prevalence components of the intervention in the control group; intervention efficacy; participants' perception of measurement burden; the effectiveness of planned recruitment strategies; and trial methods and procedures. The studies collectively aim to enrol 60 participants in the intervention group and 60 participants in the control group (total = 120 participants). DISCUSSION: Ethical approval has been received from the Southern Health and Disability Ethics Committee (Kowhai ref: 19/STH/215), and UnitingCare Human Research Ethics Committee (EMERALD ref: 202103). This study will provide important data on the feasibility of the refined YWWACP in the trans-Tasman context. This study will account for and harmonise cross-country differences to ensure the success of a proposed international grant application for a phase ΙΙΙ randomised controlled trial of this program to improve outcomes in younger women living with breast cancer. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): Kowhai ACTRN12620000260921 , registered on 27 February 2020. EMERALD ACTRN12621000447853 , registered on 19 April 2021.

Benchmarking nurse outcomes in Australian Magnet® hospitals: cross-sectional survey.

BACKGROUND: Positive reports of nursing-related outcomes such as quality nursing care, nursing engagement with work and good practice environment are crucial in attaining and maintaining Magnet® designation. The majority of Magnet®-designated organisations (N = 482) are in the USA, with their aggregate nursing outcomes widely published as benchmark data. Australian Magnet® outcomes have not been aggregated or published to date. METHODS: The aims are to benchmark educational preparation, occupational burnout, job satisfaction, intention to leave and working environment of nurses in Australian Magnet®-designated facilities and to determine the reliability of the Practice Environment Scale-Australia.The design is a cross-sectional multisite survey set in all three Australian Magnet®-designated organisations.The demographics included age, gender, level of education, years in practice, level of seniority and position title. Two items measured job satisfaction and intent to stay in current employment. The Maslach Burnout Inventory explored the three domains of nursing engagement: depersonalisation, personal achievement and emotional exhaustion. The Australian version of the Practice Environment Scale interrogated participants' perceptions of their work environments. RESULTS: 2004 nurses participated (response rate 45.9%). Respondents' mean age was 39.2 years (range 20-72). They were predominantly female and had worked in their current facility for more than 5 years. Eighty five percent had a minimum of a Bachelor's degree. Eighty-six percent of respondents were satisfied or very satisfied with their current position. Eighty eight percent had no intention of leaving their current employer within the next 12 months. Participants rated their hospitals highly in all domains of the practice environment. Respondents reported less burnout in the personal accomplishment and depersonalisation domains than in the emotional exhaustion domain, in which they reported average levels of burnout. The internal consistency of the Practice Environment Scale-Australia was confirmed in this sample (Cronbach α's 0.87-0.9 for subscales and 0.89 for composite score). CONCLUSION: In this paper, we present nursing outcome data from all Australian Magnet® hospitals for the first time. This provides a benchmark that facilitates comparison with nursing outcomes published by Australian non-Magnet® hospitals and with international Magnet® organisations.

Correction: Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65.

The authors originally published this article under the incorrect license type; this has now been corrected and is published under the CC-BY license.

Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65.

Leber congenital amaurosis is a group of inherited retinal dystrophies that cause severe sight impairment in childhood; RPE65-deficiency causes impaired rod photoreceptor function from birth and progressive impairment of cone photoreceptor function associated with retinal degeneration. In animal models of RPE65 deficiency, subretinal injection of recombinant adeno-associated virus (AAV) 2/2 vectors carrying RPE65 cDNA improves rod photoreceptor function, and intervention at an early stage of disease provides sustained benefit by protecting cone photoreceptors against retinal degeneration. In affected humans, administration of these vectors has resulted to date in relatively modest improvements in photoreceptor function, even when retinal degeneration is comparatively mild, and the duration of benefit is limited by progressive retinal degeneration. We conclude that the demand for RPE65 in humans is not fully met by current vectors, and predict that a more powerful vector will provide more durable benefit. With this aim we have modified the original AAV2/2 vector to generate AAV2/5-OPTIRPE65. The new configuration consists of an AAV vector serotype 5 carrying an optimized hRPE65 promoter and a codon-optimized hRPE65 gene. In mice, AAV2/5-OPTIRPE65 is at least 300-fold more potent than our original AAV2/2 vector.

High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides.

The therapeutic use of antisense and siRNA oligonucleotides has been constrained by the limited ability of these membrane-impermeable molecules to reach their intracellular sites of action. We sought to address this problem using small organic molecules to enhance the effects of oligonucleotides by modulating their intracellular trafficking and release from endosomes. A high-throughput screen of multiple small molecule libraries yielded several hits that markedly potentiated the actions of splice switching oligonucleotides in cell culture. These compounds also enhanced the effects of antisense and siRNA oligonucleotides. The hit compounds preferentially caused release of fluorescent oligonucleotides from late endosomes rather than other intracellular compartments. Studies in a transgenic mouse model indicated that these compounds could enhance the in vivo effects of a splice-switching oligonucleotide without causing significant toxicity. These observations suggest that selected small molecule enhancers may eventually be of value in oligonucleotide-based therapeutics.

'Broken Heart' syndrome in Scotland: a case of Takotsubo cardiomyopathy in a recently widowed lady.

Takotsubo cardiomyopathy (TCM), first described in Japan in the early 1990s, is a reversible non-ischaemic cardiomyopathy of unclear aetiology characterised by transient left ventricular dysfunction. It mimics acute myocardial infarction with ST segment changes (STEMI), although evidence of occlusive coronary artery disease is absent. TCM is typically triggered by an intense physical or emotional stress event. We report a case of TCM diagnosed in a recently widowed lady in whom a myocardial infarction was initially suspected. This case illustrates the importance of an awareness of this unique clinical entity. Without appreciation of differentiating features, TCM can easily be misdiagnosed as an acute coronary syndrome. Misdiagnosis and the subsequent inappropriate and potentially harmful use of fibrinolytic therapy can be avoided through careful history-taking, clinical examination and appropriate investigations. Although well reported in the medical literature, this case of TCM provides the basis of a timely summary and update on current understanding of this perplexing condition.

Health care providers' perspectives on patient delay for seeking care for symptoms of acute myocardial infarction.

To inform intervention development in a multisite randomized community trial, the Rapid Early Action for Coronary Treatment (REACT) project formative research was undertaken for the purpose of investigating the knowledge, beliefs, perceptions, and usual practice of health care professionals. A total of 24 key informant interviews of cardiologists and emergency physicians and 15 focus groups (91 participants) were conducted in five major geographic regions: Northeast, Northwest, Southeast, Southwest, and Midwest. Transcript analyses revealed that clinicians are somewhat unaware of the empirical evidence related to the problem of patient delay, are concerned about the practice constraints they face, and would benefit from concrete suggestions about how to improve patient education and encourage fast action. Findings provide guidance for selection of educational strategies and messages for health providers as well as patients and the public.

Effects of magnetic stimulation over supplementary motor area on movement in Parkinson's disease.

Movement execution can be delayed by transcranial magnetic stimulation delivered over primary motor cortical areas, resulting in transient inhibition of cortico-motor output. Inhibition or disruption of higher-order motor planning and preparatory processes, such as are thought to occur in the supplementary motor area (SMA), would allow an examination of processes at other stages of the motor control system. In this study, six subjects with Parkinson's disease and six healthy control subjects performed a non-cued sequential finger movement task. At various times relative to movement, high-intensity single-pulse magnetic stimulation was delivered over the region of the SMA, with minimal current spread to primary motor areas. When magnetic stimulation was given at early stages during the movement for parkinsonian subjects, movement times were significantly increased, indicating disrupted movements. Supplementary motor area stimulation had no effect when delivered during later stages of the movement or immediately prior to movement onset, and had no apparent effect on control subjects at any time. It is therefore suggested that the SMA is important in motor planning and preparatory processes, since SMA stimulation has no effect on movements in their later stages when planning may be complete, but may disrupt movements in their early stages, when preparation for later stages may still be in progress. Further, possible instability of motor planning/preparation processes in Parkinson's disease is suggested, since these processes appeared more susceptible to disruption by magnetic stimulation in parkinsonian subjects than controls.

Apolipoprotein E epsilon 4 in inclusion body myositis.

The genetic predisposition to inclusion body myositis (IBM) is probably multifactorial. The deposition of the beta-amyloid protein is a characteristic histological feature of both IBM and Alzheimer's disease (AD). The epsilon 4 allele of apolipoprotein E (APO E) has been strongly associated with familial and late-onset AD. We therefore compared the APO E allele frequencies in a group of 14 patients with IBM with those in a group of patients with other inflammatory muscle diseases and in the general population. The frequency of the epsilon 4 allele in IBM was increased (0.29) compared with that in patients with other inflammatory muscle diseases (0.15) and the general population (0.13) (p < 0.05). These data suggest that APO E genotype may be one of the factors involved in determining the predisposition to the development of IBM.

Lifestyle intervention: results of the Treatment of Mild Hypertension Study (TOMHS).

BACKGROUND: Questions regarding the efficacy of nonpharmacologic approaches for the treatment of stage 1 hypertension were addressed as part of the Treatment of Mild Hypertension Study (TOMHS), a 4-year, randomized clinical trial (N = 902). This report describes the lifestyle intervention program used in TOMHS, presents data on the lifestyle changes observed, and focuses on the effect of weight loss on blood pressure and blood lipid levels. METHODS: Participants were randomly assigned to receive either placebo or one of five different antihypertensive medications. All took part in a lifestyle intervention program to reduce weight and sodium and alcohol intake and to increase physical activity. RESULTS: Substantial changes from baseline levels were achieved for all lifestyle intervention variables. Mean weight change was -10.5 lb (-5.6%) at 1 year, -8.5 lb (-4.5%) at 2 years, -7.4 lb (-4.0%) at 3 years, and -5.7 lb (-3.0%) at 4 years. At 4 years, 70% of participants remained below baseline weight and 34% maintained a weight loss of 10 lb or greater. Mean change in urinary sodium excretion was -12.5 mmol/8 hr (-23%) at 1 year, -10.7 mmol/8 hr (-20%) at 2 years, -8.4 mmol/8 hr (-16%) at 3 years, and -4.6 mmol/8 hr (-9%) at 4 years. Alcohol intake declined by 1.6 drinks/week among drinkers at 4 years. Reported leisure physical activity increased by 86% at 1 year and remained 50% above baseline at 4 years. Beneficial changes in blood pressure and serum lipids were associated with these changes. CONCLUSIONS: These results support a role for lifestyle interventions as the initial treatment for stage 1 hypertension and demonstrate that such interventions can be successfully implemented in the clinical setting.

Autosomal dominant distal myopathy: linkage to chromosome 14.

We have studied a family segregating a form of autosomal dominant distal myopathy (MIM 160500) and containing nine living affected individuals. The myopathy in this family is closest in clinical phenotype to that first described by Gowers in 1902. A search for linkage was conducted using microsatellite, VNTR, and RFLP markers. In total, 92 markers on all 22 autosomes were run. Positive linkage was obtained with 14 of 15 markers tested on chromosome 14, with little indication of linkage elsewhere in the genome. Maximum two-point LOD scores of 2.60 at recombination fraction .00 were obtained for the markers MYH7 and D14S64--the family structure precludes a two-point LOD score > or = 3. Recombinations with D14S72 and D14S49 indicate that this distal myopathy locus, MPD1, should lie between these markers. A multipoint analysis assuming 100% penetrance and using the markers D14S72, D14S50, MYH7, D14S64, D14S54, and D14S49 gave a LOD score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a LOD score of 2.8 at this marker. This probable localization of a gene for distal myopathy, MPD1, on chromosome 14 should allow other investigators studying distal myopathy families to test this region for linkage in other types of the disease, to confirm linkage or to demonstrate the likely genetic heterogeneity.

HLA associations with inclusion body myositis.

Inclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8+ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class III region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class I, DR and complement loci along with the C4 and CYP21 RFLP. Ten of the DR3+ subjects had a 6.4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class II and III regions, of the extended haplotype marked by B8/C4A*Q0/C4B1/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11% of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B18/C4A3/C4BW*0/BfF1/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.

Percutaneous fluoroscopic gastrostomy. A safe option?

OBJECTIVE: To assess the safety of percutaneous fluoroscopic gastrostomy (PFG) tube insertion for enteral nutrition. DESIGN AND SETTING: The records of 70 consecutive patients who had a PFG procedure at a tertiary referral hospital (Princess Alexandra Hospital) were analysed retrospectively. MAIN OUTCOME MEASURE: Incidence of morbidity and mortality from PFG. RESULTS: Sixty-nine of 70 procedures were successfully performed. There were two deaths secondary to aspiration pneumonia and a morbidity rate of 13%. These figures are comparable with results from other series. CONCLUSION: PFG is a safe, effective procedure for enteral nutrition.

Treatment of inflammatory myopathies.

Although there have been considerable advances in our understanding of the immunopathogenesis of the different forms of autoimmune inflammatory myopathy, the treatment of these conditions remains largely empirical, being based upon the use of immunosuppressive and immunomodulatory therapies which, for the most part, are non-selective in their actions. Corticosteroids are usually effective in adult and childhood cases of polymyositis and dermatomyositis, but are only rarely helpful in inclusion body myositis, which is usually also unresponsive to other forms of immunosuppressive therapy. Alternate-day corticosteroid therapy has a role in patients with mild disease and as a means of minimizing the side-effects of steroids. This may also be achieved by the early introduction of a second-line agent such as methotrexate or azathioprine, which will allow more rapid steroid withdrawal and may also improve the chances of inducing a remission in more severe cases. In patients who fail to respond adequately to oral corticosteroids, or who relapse after an initial response, intravenous immunoglobulin therapy or pulse therapy with intravenous methylprednisolone are promising approaches which appeal as safer alternatives to cytotoxic drugs. However these forms of treatment will require further evaluation in prospective clinical trials. The same applies to cyclosporin, which has a more selective action on T cells, and which has been reported to be effective in resistant cases of adult and juvenile polymyositis and dermatomyositis. In the longer term, the development of more specific forms of immunotherapy for these myopathies, aimed at blocking autoantigen presentation or its interaction with T cells, awaits the identification of the target antigens and T cells which initiate the autoimmune process.