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.

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.

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.

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.

Comparison of two yttrium-90 regimens in inflammatory and osteoarthropathies.

Two yttrium-90 (90Y) radiosynovectomy procedures were compared. One procedure, performed at the Royal Perth Rehabilitation Hospital (RPRH) required a shorter immobilisation time than that performed at the Sir Charles Gardiner Hospital (SCGH). There were no significant differences in outcome between the two procedures for the groups with inflammatory and osteoarthropathy. Thirty two patients (45 joints) with inflammatory arthropathy were treated (25 with rheumatoid arthritis, three with psoriatic arthritis, two with ankylosing spondylitis, and two with unspecified inflammatory arthropathy) and 40 patients (58 joints) with osteoarthropathy. A separate assessment of local lymph node spread in patients treated by the RPRH showed a minor spread of 90Y in one of 37 joints assessed. A marked improvement in the patient evaluation scores in the inflammatory arthropathy group at three months persisted at 12 months. Good lasting responses were more common in patients with inflammatory arthropathy with a normal joint or early radiological disease. A marked improvement in the pain and evaluation scores occurred at three months in the group with osteoarthropathy but had disappeared by six months after treatment.

Hydroxyapatite crystals are a frequent finding in osteoarthritic synovial fluid, but are not related to increased concentrations of keratan sulfate or interleukin 1 beta.

Synovial fluid (SF) was obtained from 40 patients with varying grades of osteoarthritis (OA) of the knee and examined by transmission electron microscopy to ascertain how frequently hydroxyapatite crystals (HA) were present and whether they were related to disease severity or putative markers or promoters of cartilage resorption. HA crystals were conspicuous and abundant in specimens from 21 of the 40 patients studied. Patients in whom HA was present had significantly larger effusions (13.0 +/- 8.9 vs 8.7 +/- 6.1 ml, p less than 0.05). They also tended to have radiologically more severe disease (radiological grade: 2.91 +/- 0.92 vs 2.39 +/- 0.85, p = 0.056). No difference in keratan sulfate (KS) concentrations was observed. Moreover, despite the presence in some specimens of numerous free histiocytes which were actively phagocytosing HA aggregates, the concentrations of interleukin 1 beta (IL-1 beta), a monocyte product with cartilage and bone resorbing activity, were below the limit of detection (20 pg/ml). Our results confirm that HA crystals are a common finding in patients with OA of the knee and show that HA is associated with larger effusions, but not increased SF concentrations of cartilage proteoglycan substituents (KS) or IL-1 beta.

Management of enterocutaneous fistulas and problem stomas with silicone casting of the abdominal wall defect.

Silicone casting of abdominal wall defects around enteric fistulas in six patients and problem stomas in three patients proved to be an effective means of controlling the output of the fistulas, reducing wound care time, and reducing or eliminating parenteral nutrition needs. Outpatient management was possible in seven of the nine patients. It is observed that the wounds healed rapidly with this method of fistula control. Epithelialization occurred more rapidly than expected. This method of management may tend to make the fistulas remain open longer than by other means of care, but the significant increase in patient comfort, the financial savings, and the relative safety warrant continued utilization and observation of this method of management.