The Musculoskeletal Physiotherapy of Australia position on pre-manipulative testing for the cervical spine

The MPA undertook a survey of its members in 1997 to determine their compliance with and opinion of the APA Protocol for Pre-Manipulative Testing of the Cervical Spine (Magarey et al 2000a, Magarey et al submitted-a). As a result of that survey and a comprehensive literature review, the MPA developed a new set of guidelines for premanipulative procedures for the cervical spine (Magarey et al 2000b, Magarey et al submitted-b)

RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays.

Elevated cytoplasmic [Ca2+] is characteristic in severe skeletal and cardiac myopathies, diabetes, and neurodegeneration, and partly results from increased Ca2+ leak from sarcoplasmic reticulum stores via dysregulated ryanodine receptor (RyR) channels. Consequently, RyR is recognized as a high-value target for drug discovery to treat such pathologies. Using a FRET-based high-throughput screening assay that we previously reported, we identified small-molecule compounds that modulate the skeletal muscle channel isoform (RyR1) interaction with calmodulin and FK506 binding protein 12.6. Two such compounds, chloroxine and myricetin, increase FRET and inhibit [3H]ryanodine binding to RyR1 at nanomolar Ca2+. Both compounds also decrease RyR1 Ca2+ leak in human skinned skeletal muscle fibers. Furthermore, we identified compound concentrations that reduced leak by > 50% but only slightly affected Ca2+ release in excitation-contraction coupling, which is essential for normal muscle contraction. This report demonstrates a pipeline that effectively filters small-molecule RyR1 modulators towards clinical relevance

A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene ‘BRCA3’, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021–0.125%) and of BRCA2 0.068% (95% CI: 0.033–0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families

Health care professionals’ attitudes towards evidence-based medicine in the workers’ compensation setting: a cohort study

Abstract Background Problems may arise during the approval process of treatment after a compensable work injury, which include excess paperwork, delays in approving services, disputes, and allegations of over-servicing. This is perceived as undesirable for injured people, health care professionals and claims managers, and costly to the health care system, compensation system, workplaces and society. Introducing an Evidence Based Medicine (EBM) decision tool in the workers’ compensation system could provide a partial solution, by reducing uncertainty about effective treatment. The aim of this study was to investigate attitudes of health care professionals (HCP) to the potential implementation of an EBM tool in the workers’ compensation setting. Methods The study has a mixed methods design. The quantitative study consisted of an online questionnaire asking about self-reported knowledge, attitudes and behaviour to EBM in general. The qualitative study consisted of interviews about an EBM tool being applied in the workers’ compensation process. Participants were health care practitioners from different clinical specialties. They were recruited through the investigators’ clinical networks and the workers’ compensation government regulator’s website. Results Participants completing the questionnaire (n = 231) indicated they were knowledgeable about the evidence-base in their field, but perceived some difficulties when applying EBM. General practitioners reported having the greatest obstacles to applying EBM. Participants who were interviewed (n = 15) perceived that an EBM tool in the workers’ compensation setting could potentially have some advantages, such as reducing inappropriate treatment, or over-servicing, and providing guidance for clinicians. However, participants expressed substantial concerns that the EBM tool would not adequately reflect the impact of psychosocial factors on recovery. They also highlighted a lack of timeliness in decision making and proper assessment, particularly in pain management. Conclusions Overall, HCP are supportive of EBM, but have strong concerns about implementation of EBM based decision making in the workers’ compensation setting. The participants felt that an EBM tool should not be applied rigidly and should take into account clinical judgement and patient variability and preferences. In general, the treatment approval process in the workers’ compensation insurance system is a sensitive area, in which the interaction between HCP and claims managers can be improved

Testing the theory of immune selection in cancers that break the rules of transplantation

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance

Implementation of a novel stratified PAthway of CarE for common musculoskeletal (MSK) conditions in primary care: Protocol for a multicentre pragmatic randomised controlled trial (the PACE MSK trial)

Introduction Musculoskeletal (MSK) conditions constitute the highest burden of disease globally, with healthcare services often utilised inappropriately and overburdened. The aim of this trial is to evaluate the effectiveness of a novel clinical PAthway of CarE programme (PACE programme), where care is provided based on people's risk of poor outcome. Methods and analysis Multicentre randomised controlled trial. 716 people with MSK conditions (low back pain, neck pain or knee osteoarthritis) will be recruited in primary care. They will be stratified for risk of a poor outcome (low risk/high risk) using the Short Form Örebro Musculoskeletal Pain Screening Questionnaire (SF-ÖMSPQ) then randomised to usual care (n=358) or the PACE programme (n=358). Participants at low risk in the PACE programme will receive up to 3 sessions of guideline based care from their primary healthcare professional (HCP) supported by a custom designed website (mypainhub.com). Those at high risk will be referred to an allied health MSK specialist who will conduct a comprehensive patient-centred assessment then liaise with the primary HCP to determine further care. Primary outcome (SF 12-item PCS) and secondary outcomes (eg, pain self-efficacy, psychological health) will be collected at baseline, 3, 6 and 12 months. Cost-effectiveness will be measured as cost per quality-Adjusted life-year gained. Health economic analysis will include direct and indirect costs. Analyses will be conducted on an intention-To-Treat basis. Primary and secondary outcomes will be analysed independently, using generalised linear models. Qualitative and mixed-methods studies embedded within the trial will evaluate patient experience, health professional practice and interprofessional collaboration. Ethics and dissemination Ethics approval has been received from the following Human Research Ethics Committees: The University of Sydney (2018/926), The University of Queensland (2019000700/2018/926), University of Melbourne (1954239), Curtin University (HRE2019-0263) and Northern Sydney Local Health District (2019/ETH03632). Dissemination of findings will occur via peer-reviewed publications, conference presentations and social media. Trial registration number ACTRN12619000871145

How do women at increased, but unexplained, familial risk of breast cancer perceive and manage their risk? A qualitative interview study

<p>Abstract</p> <p>Background</p> <p>The perception of breast cancer risk held by women who have not had breast cancer, and who are at increased, but unexplained, familial risk of breast cancer is poorly described. This study aims to describe risk perception and how it is related to screening behaviour for these women.</p> <p>Methods</p> <p>Participants were recruited from a population-based sample (the Australian Breast Cancer Family Study - ABCFS). The ABCFS includes women diagnosed with breast cancer and their relatives. For this study, women without breast cancer with at least one first- or second-degree relative diagnosed with breast cancer before age 50 were eligible unless a <it>BRCA1 </it>or <it>BRCA2 </it>mutation had been identified in their family. Data collection consisted of an audio recorded, semi-structured interview on the topic of breast cancer risk and screening decision-making. Data was analysed thematically.</p> <p>Results</p> <p>A total of 24 interviews were conducted, and saturation of the main themes was achieved. Women were classified into one of five groups: don't worry about cancer risk, but do screening; concerned about cancer risk, so do something; concerned about cancer risk, so why don't I do anything?; cancer inevitable; cancer unlikely.</p> <p>Conclusions</p> <p>The language and framework women use to describe their risk of breast cancer must be the starting point in attempts to enhance women's understanding of risk and their prevention behaviour.</p