Defining the relationship between cellular and extracellular vesicle (EV) content in breast cancer via an integrative multi-omic analysis.

Much recent research has been dedicated to exploring the utility of extracellular vesicles (EVs) as circulating disease biomarkers. Underpinning this work is the assumption that the molecular cargo of EVs directly reflects the originating cell. Few attempts have been made, however, to empirically validate this on the -omic level. To this end, we have performed an integrative multi-omic analysis of a panel of breast cancer cell lines and corresponding EVs. Whole transcriptome analysis validated that the cellular transcriptome remained stable when cultured cells are transitioned to low serum or serum-free medium for EV collection. Transcriptomic profiling of the isolated EVs indicated a positive correlation between transcript levels in cells and EVs, including disease-associated transcripts. Analysis of the EV proteome verified that HER2 protein is present in EVs, however neither the estrogen (ER) nor progesterone (PR) receptor proteins are detected regardless of cellular expression. Using multivariate analysis, we derived an EV protein signature to infer cellular patterns of ER and HER2 expression, though the ER protein could not be directly detected. Integrative analyses affirmed that the EV proteome and transcriptome captured key phenotypic hallmarks of the originating cells, supporting the potential of EVs for non-invasive monitoring of breast cancers.

Private practice dietetics: A scoping review of the literature.

AIM: Private practice is one of the most rapidly growing, but under-researched employment sectors for graduate dietitians in Australia, limiting evidence-based workforce development. This scoping review examines existing international literature to gain an understanding of the current private practice workforce size, distribution, demography and workforce development considerations, including competencies, supply and demand, remuneration and professional development activities. METHODS: The databases MEDLINE, EMBASE, CINAHL, EMCARE, PsycInfo (Ovid) and grey literature were systematically searched in August 2023 using key search terms to identify studies for inclusion. Articles were included if they related to private practice dietetics and described an aspect of workforce. Original research, government and organisational reports, statements of practice and websites providing governmental or organisational statistics were included. A directed content analysis and qualitative constant comparison technique were used to deductively map intelligence sources against a workforce development framework. A gap analysis was also conducted to provide a focus for future workforce development research. RESULTS: A total of 72 peer-reviewed and grey literature sources were included, with 65% of the studies being Australian-based publications. Private practice dietetics research interest has increased in the last decade. Despite a breadth of published sources, this review found little published data on workforce size, distribution, demography, supply, demand, continued professional development and remuneration, indicating a significant gap in the evidence base. Existing literature focuses on workforce challenges and barriers, the work of private practice dietitians, with limited exploration of competency requirements for graduate private practitioners. CONCLUSIONS: The literature on the private practice dietetics workforce is lacking worldwide, which constrains evidenced-based workforce development initiatives. Workforce development research across all workforce aspects is warranted to address current evidence gaps.

Association of active mobilisation variables with adverse events and mortality in patients requiring mechanical ventilation in the intensive care unit: a systematic review and meta-analysis.

BACKGROUND: Mobilisation during critical illness is now included in multiple clinical practice guidelines. However, a large, randomised trial and systematic review have recently identified an increased probability of adverse events and mortality in patients who received early active mobilisation in the intensive care unit (ICU). We aimed to determine the effects of mobilisation compared with usual care on adverse events and mortality in an acute ICU setting. In subgroup analyses, we specifically aimed to investigate possible sources of harm, including the timing and duration of mobilisation achieved, ventilation status, and admission diagnosis. METHODS: In this systematic review with frequentist and Bayesian analyses, we searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, SPORTDiscus, SCOPUS, Web of Science, and PEDro electronic databases, as well as clinical trial registries (ICTRP and ClinicalTrials.gov), from inception to March 16, 2023, without language restrictions. Eligible studies were randomised controlled trials that examined active mobilisation compared with either no mobilisation or mobilisation commencing later, or at a lower frequency or intensity, in adults who were critically ill during or after a period of mechanical ventilation in an acute ICU setting. Two authors independently screened reports, extracted data, and assessed the risk of bias using the Cochrane risk-of-bias tool (version 1). The primary outcome was the number of adverse events that occurred during the implementation of mobilisation, with the effect of mobilisation on mortality being the secondary outcome. Risk ratios (RRs) with 95% CIs were calculated in R (version 4.0.3) using random-effects modelling, with Bayesian analysis completed to calculate the probability of treatment harm (ie, RR >1). Subgroup analyses were completed to investigate the association of various factors of mobilisation on adverse events and mortality: duration of mobilisation (longer [≥20 min per day] vs shorter [<20 min per day]), timing of commencement (early [≤72 h from ICU admission] vs late [>72 h from ICU admission]), ventilation status at commencement (all patients mechanically ventilated vs all patients extubated), and ICU admission diagnosis (surgical vs medical). This study was registered with PROSPERO, CRD42022369272. FINDINGS: After title and abstract screening of 14 440 studies and review of 466 full texts, 67 trials with 7004 participants met inclusion criteria, with 59 trials contributing to the meta-analysis. Of the 67 included studies, 15 (22%) did not mention adverse events and 13 (19%) reported no adverse events occurring across the trial period. Overall, we found no effect of mobilisation compared with usual care on the occurrence of adverse events (RR 1·09 [95% CI 0·69-1·74], p=0·71; I2 91%; 32 731 events, 20 studies; very low certainty), with a 2·96% occurrence rate (693 events in 23 395 intervention sessions; 25 studies). Mobilisation did not have any effect on mortality (RR 0·98 [95% CI 0·87-1·12], p=0·81; I2 0%; n=6218, 58 studies; moderate certainty). Subgroup analysis was hindered by the large amount of data that could not be allocated and analysed, making the results hypothesis generating only. INTERPRETATION: Implementation of mobilisation in the ICU was associated with a less than 3% chance of an adverse event occurring and was not found to increase adverse events or mortality overall, providing reassurance for clinicians about the safety of performing this intervention. Subgroup analyses did not clearly identify any specific variable of mobilisation implementation that increased harm. FUNDING: None.

How do Australian osteopaths manage migraines? Outcomes from a national practice-based research network.

BACKGROUND: Individuals who experience migraines often seek out a variety of treatment options including manual or physical therapy. Evidence suggests that manual therapy, including osteopathy, can play a role in the management of migraines. Whilst there is some literature on the role osteopathy therapy plays in migraine management, none describes the treatment approaches used by practitioners. OBJECTIVES: To explore the demographic, practice and clinical management characteristics of Australian osteopaths who report treating migraine 'often' in clinical practice. METHODS: Secondary analysis of a cross-sectional survey of 988 osteopaths from the Osteopathy Research and Innovation Network (ORION), an Australian practice-based research network. Regression analysis was used to identify demographic, practice and clinical management characteristics of Australian osteopaths who reported 'often' treating migraine patients. RESULTS: Over 40% of respondents (n = 400) indicated treating patients with migraines 'often'. These osteopaths were less likely to be involved in research and be co-located with a dietician compared to osteopaths who do 'not often' treat migraine. Osteopaths who reported 'often' treating migraine were: five times as likely to treat non-English speaking ethnic groups; 2.5 times as likely to treat chronic pain, temporomandibular joint disorders and hand musculoskeletal complaints; compared to those that do not treat migraines 'often'. CONCLUSION: Australian osteopaths who treat migraine are five times more likely to treat non-English speaking ethnic groups; twice as likely to treat chronic pain; temporomandibular joint disorders, and hand musculoskeletal complaints. More research is needed to identify the practices and patient outcomes associated with osteopathy care for those experiencing migraines.

Physical activity and depression symptoms in people with osteoarthritis-related pain: A cross-sectional study.

Osteoarthritis is a leading cause of chronic pain and is associated with high rates of depression. Physical activity reduces depression symptoms and pain levels. It remains unknown if physical activity is associated with lower symptoms of depression irrespective of pain levels in individuals with osteoarthritis. We explored whether pain mediated or moderated the relationship between levels of physical activity engagement and depression symptoms. Individuals with osteoarthritis who were waiting for an orthopaedic consultation at a public hospital in Melbourne, Australia, were recruited. Data collected on pain levels, physical activity engagement and depression symptoms. Descriptive statistics were used to summarise participant characteristics. Moderation and mediation analyses were used to establish the impact of pain on the relationship between physical activity and depression, after adjusting for demographic and joint specific characteristics. The results indicated that the inverse association between physical activity and depression depended on the level of pain, such that the association was stronger in people with greater pain. The mediation results confirm that participating in physical activity is indirectly, inversely associated with symptoms of depression through lower levels of pain. The highest levels of pain were associated with the most potential benefit in terms of reduction in symptoms of depression from engaging in physical activity. Physical activity may be particularly important to manage depression symptoms in people with greater osteoarthritis-related pain as patients with the highest pain may have the greatest benefits.

Predictors of the efficacy of His bundle pacing in patients with a prolonged PR interval: A stratified analysis of the HOPE-HF randomized controlled trial.

AIMS: The randomized, double-blind, placebo-controlled HOPE-HF trial assessed the benefit of atrio-ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO2max) but there was significant improvement in heart failure specific quality of life. In this pre-specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E-A fusion, and the magnitude of acute high-precision haemodynamic response to pacing, on outcomes. METHODS AND RESULTS: All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E-A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO2max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ-5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E-A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints. CONCLUSIONS: In the HOPE-HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV-optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high-precision AV-optimized haemodynamic assessment to be performed.

The Effect of Mobilization at 6 Months after Critical Illness - Meta-Analysis.

BACKGROUND: The comparative efficacy and safety of early active mobilization compared with usual care regarding long-term outcomes for adult critically ill survivors remain uncertain. METHODS: We systematically reviewed randomized clinical trials comparing early active mobilization versus usual care in critically ill adults. The primary outcome was days alive and out of hospital to day 180 after pooling data using random effects modeling. We also performed a Bayesian meta-analysis to describe the treatment effect in probability terms. Secondary outcomes were mortality, physical function, strength, health-related quality of life at 6 months, and adverse events. RESULTS: Fifteen trials from 11 countries were included with data from 2703 participants. From six trials (1121 participants) reporting the primary outcome, the pooled mean difference was an increase of 4.28 days alive and out of hospital to day 180 in those patients who received early active mobilization (95% confidence interval, −4.46 to 13.03; I2=41%). Using Bayesian analyses with vague priors, the probability that the intervention increased days alive and out of hospital was 75.1%. In survivors, there was a 95.1% probability that the intervention improved physical function measured through a patient-reported outcome measure at 6 months (standardized mean difference, 0.2; 95% confidence interval, 0.09 to 0.32; I2=0%). Although no treatment effect was identified on any other secondary outcome, there was a 66.4% possibility of increased adverse events with the implementation of early active mobilization and a 72.2% chance it increased 6-month mortality. CONCLUSIONS: Use of early active mobilization for critically ill adults did not significantly affect days alive and out of hospital to day 180. Early active mobilization was associated with improved physical function in survivors at 6 months; however, the possibility that it might increase mortality and adverse events needs to be considered when interpreting this finding. (PROSPERO number, CRD42022309650.)