Physical activity coaching for adults with mobility limitations: protocol for the ComeBACK pragmatic hybrid effectiveness-implementation type 1 randomised controlled trial

INTRODUCTION: Mobility limitation is common and often results from neurological and musculoskeletal health conditions, ageing and/or physical inactivity. In consultation with consumers, clinicians and policymakers, we have developed two affordable and scalable intervention packages designed to enhance physical activity for adults with self-reported mobility limitations. Both are based on behaviour change theories and involve tailored advice from physiotherapists. METHODS AND ANALYSIS: This pragmatic hybrid effectiveness-implementation type 1 randomised control trial (n=600) will be undertaken among adults with self-reported mobility limitations. It aims to estimate the effects on physical activity of: (1) an enhanced 6-month intervention package (one face-to-face physiotherapy assessment, tailored physical activity plan, physical activity phone coaching from a physiotherapist, informational/motivational resources and activity monitors) compared with a less intensive 6-month intervention package (single session of tailored phone advice from a physiotherapist, tailored physical activity plan, unidirectional text messages, informational/motivational resources); (2) the enhanced intervention package compared with no intervention (6-month waiting list control group); and (3) the less intensive intervention package compared with no intervention (waiting list control group). The primary outcome will be average steps per day, measured with the StepWatch Activity Monitor over a 1-week period, 6 months after randomisation. Secondary outcomes include other physical activity measures, measures of health and functioning, individualised mobility goal attainment, mental well-being, quality of life, rate of falls, health utilisation and intervention evaluation. The hybrid effectiveness-implementation design (type 1) will be used to enable the collection of secondary implementation outcomes at the same time as the primary effectiveness outcome. An economic analysis will estimate the cost-effectiveness and cost-utility of the interventions compared with no intervention and to each other. ETHICS AND DISSEMINATION: Ethical approval has been obtained by Sydney Local Health District, Royal Prince Alfred Zone. Dissemination will be via publications, conferences, newsletters, talks and meetings with health managers. TRIAL REGISTRATION NUMBER: ACTRN12618001983291

National, clinical cohort study of late effects among survivors of acute lymphoblastic leukaemia:The ALL-STAR study protocol

Introduction More than 90% of patients diagnosed with childhood acute lymphoblastic leukaemia (ALL) today will survive. However, half of the survivors are expected to experience therapy-related chronic or late occurring adverse effects, reducing quality of life. Insight into underlying risk trajectories is warranted. The aim of this study is to establish a Nordic, national childhood ALL survivor cohort, to be investigated for the total somatic and psychosocial treatment-related burden as well as associated risk factors, allowing subsequent linkage to nation-wide public health registers.Methods and analysis This population-based observational cohort study includes clinical follow-up of a retrospective childhood ALL survivor cohort (n=475), treated according to a common Nordic ALL protocol during 2008–2018 in Denmark. The study includes matched controls. Primary endpoints are the cumulative incidence and cumulative burden of 197 health conditions, assessed through self-report and proxy-report questionnaires, medical chart validation, and clinical examinations. Secondary endpoints include organ-specific outcome, including cardiovascular and pulmonary function, physical performance, neuropathy, metabolic disturbances, hepatic and pancreatic function, bone health, oral and dental health, kidney function, puberty and fertility, fatigue, and psychosocial outcome. Therapy exposure, acute toxicities, and host genome variants are explored as risk factors.Ethics and dissemination The study is approved by the Regional Ethics Committee for the Capital Region in Denmark (H-18035090/H-20006359) and by the Danish Data Protection Agency (VD-2018–519). Results will be published in peer-reviewed journals and are expected to guide interventions that will ameliorate the burden of therapy without compromising the chance of cure

Multiple Roles of Staphylococcus aureus Enterotoxins: Pathogenicity, Superantigenic Activity, and Correlation to Antibiotic Resistance

Heat-stable enterotoxins are the most notable virulence factors associated with Staphylococcus aureus, a common pathogen associated with serious community and hospital acquired diseases. Staphylococcal enterotoxins (SEs) cause toxic shock-like syndromes and have been implicated in food poisoning. But SEs also act as superantigens that stimulate T-cell proliferation, and a high correlation between these activities has been detected. Most of the nosocomial S. aureus infections are caused by methicillin-resistant S. aureus (MRSA) strains, and those resistant to quinolones or multiresistant to other antibiotics are emerging, leaving a limited choice for their control. This review focuses on these diverse roles of SE, their possible correlations and the influence in disease progression and therapy

Measures of Association for Identifying MicroRNA-mRNA Pairs of Biological Interest

MicroRNAs are a class of small non-protein coding RNAs that play an important role in the regulation of gene expression. Most studies on the identification of microRNA-mRNA pairs utilize the correlation coefficient as a measure of association. The use of correlation coefficient is appropriate if the expression data are available for several conditions and, for a given condition, both microRNA and mRNA expression profiles are obtained from the same set of individuals. However, there are many instances where one of the requirements is not satisfied. Therefore, there is a need for new measures of association to identify the microRNA-mRNA pairs of interest and we present two such measures. The first measure requires expression data for multiple conditions but, for a given condition, the microRNA and mRNA expression may be obtained from different individuals. The new measure, unlike the correlation coefficient, is suitable for analyzing large data sets which are obtained by combining several independent studies on microRNAs and mRNAs. Our second measure is able to handle expression data that correspond to just two conditions but, for a given condition, the microRNA and mRNA expression must be obtained from the same set of individuals. This measure, unlike the correlation coefficient, is appropriate for analyzing data sets with a small number of conditions. We apply our new measures of association to multiple myeloma data sets, which cannot be analyzed using the correlation coefficient, and identify several microRNA-mRNA pairs involved in apoptosis and cell proliferation

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming.

Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence of a positive feedback loop. In line with this, we found that siRNA knockdown of eIF4E3 decreased Nrf2 protein levels. On the other hand, elevated SQSTM1/p62 levels were due at least in part to activation of the PERK-eIF2α pathway. LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Genetic and pharmacologic inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2α pathway, disruption of redox homeostasis or inhibition of fatty acid oxidation or autophagy conferred sensitivity to carfilzomib. Our findings were supported by clinical data where increased EIF4E3 expression was predictive of Nrf2 target gene upregulation in a subgroup of patients with chemoresistant minimal residual disease and relapsed/refractory MM. Thus, our data offer a preclinical rationale for including inhibitors of the SQSTM1/p62-Nrf2 pathway to the treatment regimens for certain advanced stage MM patients

Lack of evidence of disease contamination in ovarian tissue harvested for cryopreservation from patients with Hodgkin lymphoma and analysis of factors predictive of oocyte yield

Ovarian cryopreservation is a promising technique to preserve fertility in women with Hodgkin lymphoma (HL) treated with chemotherapy. Thus, the aim of this study was to examine harvested ovarian tissue for subclinical involvement by HL by morphology/immunohistochemistry, and to define patient and treatment factors predictive of oocyte yield. This was a retrospective analysis of 26 ovarian tissue samples harvested for cryopreservation from women with HL. Histology, immunohistochemistry and follicle density (number mm−3) was examined. Disease status and preharvest chemotherapy details were obtained on 24 patients. The median age was 22 years (range 13–29). Seven of 24 patients had infradiaphragmatic disease at time of harvest. Nine of 20 patients had received chemotherapy preharvest (ABVD (Adriamycin®, Bleomycin, Vinblastine and Dacarbazine)=7, other regimens=2). The seven receiving ABVD showed no difference in follicle density compared to patients not receiving treatment (n=14); (median=1555 vs 1620 mm3 P=0.97). Follicle density measurement showed no correlation with patient age (R2=0.0001, P=0.99). There was no evidence of HL involvement in the 26 samples examined (95% CI=0–11%). In conclusion, subclinical involvement of HL has not been identified in ovarian tissue, even when patients have infradiaphragmatic disease. Furthermore, the quality of tissue harvested does not appear to be adversely affected by patient's age or prior ABVD chemotherapy

Relationship between subjective fall risk assessment and falls and fall-related fractures in frail elderly people

<p>Abstract</p> <p>Background</p> <p>Objective measurements can be used to identify people with risks of falls, but many frail elderly adults cannot complete physical performance tests. The study examined the relationship between a subjective risk rating of specific tasks (SRRST) to screen for fall risks and falls and fall-related fractures in frail elderly people.</p> <p>Methods</p> <p>The SRRST was investigated in 5,062 individuals aged 65 years or older who were utilized day-care services. The SRRST comprised 7 dichotomous questions to screen for fall risks during movements and behaviours such as walking, transferring, and wandering. The history of falls and fall-related fractures during the previous year was reported by participants or determined from an interview with the participant's family and care staff.</p> <p>Results</p> <p>All SRRST items showed significant differences between the participants with and without falls and fall-related fractures. In multiple logistic regression analysis adjusted for age, sex, diseases, and behavioural variables, the SRRST score was independently associated with history of falls and fractures. Odds ratios for those in the high-risk SRRST group (≥ 5 points) compared with the no risk SRRST group (0 point) were 6.15 (p < 0.01) for a single fall, 15.04 (p < 0.01) for recurrent falls, and 5.05 (p < 0.01) for fall-related fractures. The results remained essentially unchanged in subgroup analysis accounting for locomotion status.</p> <p>Conclusion</p> <p>These results suggest that subjective ratings by care staff can be utilized to determine the risks of falls and fall-related fractures in the frail elderly, however, these preliminary results require confirmation in further prospective research.</p

The design of a purpose-built exergame for fall prediction and prevention for older people

Background Falls in older people represent a major age-related health challenge facing our society. Novel methods for delivery of falls prevention programs are required to increase effectiveness and adherence to these programs while containing costs. The primary aim of the Information and Communications Technology-based System to Predict and Prevent Falls (iStoppFalls) project was to develop innovative home-based technologies for continuous monitoring and exercise-based prevention of falls in community-dwelling older people. The aim of this paper is to describe the components of the iStoppFalls system. Methods The system comprised of 1) a TV, 2) a PC, 3) the Microsoft Kinect, 4) a wearable sensor and 5) an assessment and training software as the main components. Results The iStoppFalls system implements existing technologies to deliver a tailored home-based exercise and education program aimed at reducing fall risk in older people. A risk assessment tool was designed to identify fall risk factors. The content and progression rules of the iStoppFalls exergames were developed from evidence-based fall prevention interventions targeting muscle strength and balance in older people. Conclusions The iStoppFalls fall prevention program, used in conjunction with the multifactorial fall risk assessment tool, aims to provide a comprehensive and individualised, yet novel fall risk assessment and prevention program that is feasible for widespread use to prevent falls and fall-related injuries. This work provides a new approach to engage older people in home-based exercise programs to complement or provide a potentially motivational alternative to traditional exercise to reduce the risk of falling

Exercise for reducing fear of falling in older people living in the community

Background: Fear of falling is common in older people and associated with serious physical and psychosocial consequences. Exercise (planned, structured, repetitive and purposive physical activity aimed at improving physical fitness) may reduce fear of falling by improving strength, gait, balance and mood, and reducing the occurrence of falls. Objectives: To assess the effects (benefits, harms and costs) of exercise interventions for reducing fear of falling in older people living in the community. Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (July 2013), the Central Register of Controlled Trials (CENTRAL 2013, Issue 7), MEDLINE (1946 to July Week 3 2013), EMBASE (1980 to 2013 Week 30), CINAHL (1982 to July 2013), PsycINFO (1967 to August 2013), AMED (1985 to August 2013), the World Health Organization International Clinical Trials Registry Platform (accessed 7 August 2013) and Current Controlled Trials (accessed 7 August 2013). We applied no language restrictions. We handsearched reference lists and consulted experts. Selection criteria: We included randomised and quasi-randomised trials that recruited community-dwelling people (where the majority were aged 65 and over) and were not restricted to specific medical conditions (e.g. stroke, hip fracture). We included trials that evaluated exercise interventions compared with no intervention or a non-exercise intervention (e.g. social visits), and that measured fear of falling. Exercise interventions were varied; for example, they could be 'prescriptions' or recommendations, group-based or individual, supervised or unsupervised. Data collection and analysis: Pairs of review authors independently assessed studies for inclusion, assessed the risk of bias in the studies and extracted data. We combined effect sizes across studies using the fixed-effect model, with the random-effect model used where significant statistical heterogeneity was present. We estimated risk ratios (RR) for dichotomous outcomes and incidence rate ratios (IRR) for rate outcomes. We estimated mean differences (MD) where studies used the same continuous measures and standardised mean differences (SMD) where different measures or different formats of the same measure were used. Where possible, we performed various, usually prespecified, sensitivity and subgroup analyses. Main results: We included 30 studies, which evaluated 3D exercise (Tai Chi and yoga), balance training or strength and resistance training. Two of these were cluster-randomised trials, two were cross-over trials and one was quasi-randomised. The studies included a total of 2878 participants with a mean age ranging from 68 to 85 years. Most studies included more women than men, with four studies recruiting women only. Twelve studies recruited participants at increased risk of falls; three of these recruited participants who also had fear of falling. Poor reporting of the allocation methods in the trials made it difficult to assess the risk of selection bias in most studies. All of the studies were at high risk of performance and detection biases as there was no blinding of participants and outcome assessors and the outcomes were self reported. Twelve studies were at high risk of attrition bias. Using GRADE criteria, we judged the quality of evidence to be 'low' for fear of falling immediately post intervention and 'very low' for fear of falling at short or long-term follow-up and all other outcomes. Exercise interventions were associated with a small to moderate reduction in fear of falling immediately post intervention (SMD 0.37 favouring exercise, 95% confidence interval (CI) 0.18 to 0.56; 24 studies; 1692 participants, low quality evidence). Pooled effect sizes did not differ significantly between the different scales used to measure fear of falling. Although none of the sensitivity analyses changed the direction of effect, the greatest reduction in the size of the effect was on removal of an extreme outlier study with 73 participants (SMD 0.24 favouring exercise, 95% CI 0.12 to 0.36). None of our subgroup analyses provided robust evidence of differences in effect in terms of either the study primary aim (reduction of fear of falling or other aim), the study population (recruitment on the basis of increased falls risk or not), the characteristics of the study exercise intervention or the study control intervention (no treatment or alternative intervention). However, there was some weak evidence of a smaller effect, which included no reduction, of exercise when compared with an alternative control. There was very low quality evidence that exercise interventions may be associated with a small reduction in fear of falling up to six months post intervention (SMD 0.17, 95% CI -0.05 to 0.38; four studies, 356 participants) and more than six months post intervention (SMD 0.20, 95% CI -0.01 to 0.41; three studies, 386 participants). Very low quality evidence suggests exercise interventions in these studies that also reported on fear of falling reduced the risk of falling measured either as participants incurring at least one fall during follow-up or the number of falls during follow-up. Very low quality evidence from four studies indicated that exercise interventions did not appear to reduce symptoms of depression or increase physical activity. The only study reporting the effects of exercise interventions on anxiety found no difference between groups. No studies reported the effects of exercise interventions on activity avoidance or costs. It is important to remember that our included studies do not represent the totality of the evidence of the effect of exercise interventions on falls, depression, anxiety or physical activity as our review only includes studies that reported fear of falling. Authors' conclusions: Exercise interventions in community-dwelling older people probably reduce fear of falling to a limited extent immediately after the intervention, without increasing the risk or frequency of falls. There is insufficient evidence to determine whether exercise interventions reduce fear of falling beyond the end of the intervention or their effect on other outcomes. Although further evidence from well-designed randomised trials is required, priority should be given to establishing a core set of outcomes that includes fear of falling for all trials examining the effects of exercise interventions in older people living in the community