Fibroblast-derived Hgf controls recruitment and expansion of muscle during morphogenesis of the mammalian diaphragm.

The diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, congenital diaphragmatic hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors and effects on phrenic nerve have not been explicitly tested. Using conditional mutagenesis in mice and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue in the diaphragm, are the source of HGF critical for diaphragm muscularization. PPF-derived HGF is directly required for recruitment of MET+ muscle progenitors to the diaphragm and indirectly (via its effect on muscle development) required for phrenic nerve primary branching. In addition, HGF is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Localization of HGF at the diaphragm's leading edges directs dorsal and ventral expansion of muscle and regulates its overall size and shape. Surprisingly, large muscleless regions in HGF and Met mutants do not lead to hernias. While these regions are likely more susceptible to CDH, muscle loss is not sufficient to cause CDH.

Aggressive versus symptom-guided drainage of malignant pleural effusion via indwelling pleural catheters (AMPLE-2): an open-label randomised trial.

BACKGROUND: Indwelling pleural catheters are an established management option for malignant pleural effusion and have advantages over talc slurry pleurodesis. The optimal regimen of drainage after indwelling pleural catheter insertion is debated and ranges from aggressive (daily) drainage to drainage only when symptomatic. METHODS: AMPLE-2 was an open-label randomised trial involving 11 centres in Australia, New Zealand, Hong Kong, and Malaysia. Patients with symptomatic malignant pleural effusions were randomly assigned (1:1) to the aggressive (daily) or symptom-guided drainage groups for 60 days and minimised by cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group [ECOG] score 0-1 vs ≥2), presence of trapped lung, and prior pleurodesis. Patients were followed up for 6 months. The primary outcome was mean daily breathlessness score, measured by use of a 100 mm visual analogue scale during the first 60 days. Secondary outcomes included rates of spontaneous pleurodesis and self-reported quality-of-life measures. Results were analysed by an intention-to-treat approach. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000963527. FINDINGS: Between July 20, 2015, and Jan 26, 2017, 87 patients were recruited and randomly assigned to the aggressive (n=43) or symptom-guided (n=44) drainage groups. The mean daily breathlessness scores did not differ significantly between the aggressive and symptom-guided drainage groups (geometric means 13·1 mm [95% CI 9·8-17·4] vs 17·3 mm [13·0-22·0]; ratio of geometric means 1·32 [95% CI 0·88-1·97]; p=0·18). More patients in the aggressive group developed spontaneous pleurodesis than in the symptom-guided group in the first 60 days (16 [37·2%] of 43 vs five [11·4%] of 44, p=0·0049) and at 6 months (19 [44·2%] vs seven [15·9%], p=0·004; hazard ratio 3·287 [95% CI 1·396-7·740]; p=0·0065). Patient-reported quality-of-life measures, assessed with EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L), were better in the aggressive group than in the symptom-guided group (estimated means 0·713 [95% CI 0·647-0·779] vs 0·601 [0·536-0·667]). The estimated difference in means was 0·112 (95% CI 0·0198-0·204; p=0·0174). Pain scores, total days spent in hospital, and mortality did not differ significantly between groups. Serious adverse events occurred in 11 (25·6%) of 43 patients in the aggressive drainage group and in 12 (27·3%) of 44 patients in the symptom-guided drainage group, including 11 episodes of pleural infection in nine patients (five in the aggressive group and six in the symptom-guided drainage group). INTERPRETATION: We found no differences between the aggressive (daily) and the symptom-guided drainage regimens for indwelling pleural catheters in providing breathlessness control. These data indicate that daily indwelling pleural catheter drainage is more effective in promoting spontaneous pleurodesis and might improve quality of life. FUNDING: Cancer Council of Western Australia and the Sir Charles Gairdner Research Advisory Group.

Air in the Pleural Cavity Enhances Detection of Pleural Abnormalities by CT Scan.

Detection of pleural abnormalities on CT scan is critical in diagnosis of pleural disease. CT scan detects minute parenchymal lung nodules, but often fails to detect similar-sized pleural nodularity. This is likely because the density of the visceral/parietal pleura and pleural fluid is similar. We hypothesize that an air-pleural interface enhances detection of pleural abnormalities. We describe six patients with pleural abnormalities that were not (or barely) detected on initial CT scan. However, pneumothorax (either ex vacuo or from a genuine air leak) after pleural fluid drainage permitted the visualization of small pleural abnormalities on CT scan, which would be amenable to imaging-guided biopsies. This case series provides proof-of-principle evidence that the sensitivity of CT scan detection of pleural abnormalities is dependent on adjacent tissue density and can be enhanced by intrapleural air. Future studies of the potential for artificial pneumothorax to improve the diagnosis of pleural disease are warranted.

Shifts in nursing and medical students' attitudes, beliefs and behaviours about interprofessional work: An interprofessional placement in ambulatory care.

AIM AND OBJECTIVES: To examine students' beliefs, behaviours and attitudes in relation to interprofessional socialisation, and their expectations and experience, before and after a 2-week clinical placement in ambulatory care. BACKGROUND: Interprofessional clinical placements for students are important for developing an understanding of interprofessional collaboration and identity, for the benefit of patient care. Ambulatory care environment involves collaborative management of complex chronic problems. This educator supported placement that enabled final-year nursing and medical students to work together. DESIGN: A descriptive matched before-after study was conducted. METHODS: Students' completed an online questionnaire before and after their clinical placement. The questionnaire comprised of three sections: demographic information, the Interprofessional Socialisation and Valuing Scale and open-ended questions. Descriptive analysis and paired t-tests were conducted for the three subscales, and thematic analysis of qualitative responses was conducted. RESULTS: Sixty-two of the 151 students between 2011-2014 completed both surveys. There was a significant increase after placement in the overall Interprofessional Socialisation and Valuing Scale scores. The change was greater for nursing students compared with medical students, although for both groups the change was small. The majority had a good-to-very good experience learning each other's and their own professions and identified the nurse educator and teaching registrar as key to success. CONCLUSION: A clinical placement in an ambulatory setting for nursing and medical students resulted in an increase in self-perceived ability to work with others and in valuing working with others. RELEVANCE TO CLINICAL PRACTICE: Interprofessional clinical placements are essential for students to understand interprofessional practice for better patient outcomes and developing their own perspective of future work within an interprofessional team. Ambulatory care is an ideal environment for nursing and other health professional students to engage in interprofessional clinical placements.

Acute oxygen therapy: an audit of prescribing and delivery practices in a tertiary hospital in Perth, Western Australia.

BACKGROUND: Oxygen is a widely used drug in the hospital setting. However, international audits suggest that oxygen administration practices are often not compliant with prescribed standards. This can place patients at risk and cause serious adverse events. AIM: To analyse data related to recent practices of oxygen prescription and administration at Royal Perth Hospital (RPH), Western Australia. The results of this audit aim to guide further research on possible interventional studies implementing key solutions. METHODS: All patients who received care in the Acute Medical Unit at RPH between 1 September and 14 September 2015 were included in this audit. Patients who were given supplemental oxygen during their admission were selected for further review of records. Appropriate medically indicated target oxygen saturations for each patient were judged under consultation with a respiratory specialist. RESULTS: A total of 65 patients received oxygen supplementation within the study period; 36 of these patients (55.4%) had target oxygen saturations prescribed by doctors, and 25% of the prescribed targets were judged to be inappropriate. In total, 49 patients (75.4%) were exposed to a potential risk from oxygen therapy due to prescription error and/or delivery error. A real risk was identified in 19 patients (29.2%) as they received oxygen at levels outside their appropriate medically indicated target range. CONCLUSION: The current practices of oxygen prescription and administration within RPH are suboptimal. Patients are placed at risk of oxygen toxicity due to deviation from oxygen prescription guidelines.

Protocol of the Australasian Malignant Pleural Effusion-2 (AMPLE-2) trial: a multicentre randomised study of aggressive versus symptom-guided drainage via indwelling pleural catheters.

INTRODUCTION: Malignant pleural effusions (MPEs) can complicate most cancers, causing dyspnoea and impairing quality of life (QoL). Indwelling pleural catheters (IPCs) are a novel management approach allowing ambulatory fluid drainage and are increasingly used as an alternative to pleurodesis. IPC drainage approaches vary greatly between centres. Some advocate aggressive (usually daily) removal of fluid to provide best symptom control and chance of spontaneous pleurodesis. Daily drainages however demand considerably more resources and may increase risks of complications. Others believe that MPE care is palliative and drainage should be performed only when patients become symptomatic (often weekly to monthly). Identifying the best drainage approach will optimise patient care and healthcare resource utilisation. METHODS AND ANALYSIS: A multicentre, open-label randomised trial. Patients with MPE will be randomised 1:1 to daily or symptom-guided drainage regimes after IPC insertion. Patient allocation to groups will be stratified for the cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group status 0-1 vs ≥2), presence of trapped lung (vs not) and prior pleurodesis (vs not). The primary outcome is the mean daily dyspnoea score, measured by a 100 mm visual analogue scale (VAS) over the first 60 days. Secondary outcomes include benefits on physical activity levels, rate of spontaneous pleurodesis, complications, hospital admission days, healthcare costs and QoL measures. Enrolment of 86 participants will detect a mean difference of VAS score of 14 mm between the treatment arms (5% significance, 90% power) assuming a common between-group SD of 18.9 mm and a 10% lost to follow-up rate. ETHICS AND DISSEMINATION: The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study (number 2015-043). Results will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: ACTRN12615000963527; Pre-results.

Histopathology of removed indwelling pleural catheters from patients with malignant pleural diseases.

BACKGROUND AND OBJECTIVE: Indwelling pleural catheters (IPC), used for management of malignant pleural effusions, are often left in situ for a long duration. This study reports for the first time the histological findings of IPCs removed from patients with underlying pleural malignancy. METHODS: Forty-one IPCs (in situ for median 126 days, interquartile range 43-226) that were removed over a 54-month period from a single centre were examined. RESULTS: Mesothelioma (n = 18) was the predominant underlying malignancy followed by breast, tubo-ovarian and lung carcinomas. The catheter tubing was fully intact macroscopically in all IPCs. There was no evidence of direct tumour invasion or cancer cell growth on the catheter surfaces in none of the 29 IPCs that were histologically examined. Malignant cells were seen within organizing fibrinous tissues in the lumen of 11 IPCs (27%). A foreign body giant cell reaction was present at the cuff site in all the 29 IPC in which the subcutaneous cuff was examined. Acute (n = 10) and/or chronic inflammatory changes were seen in the luminal contents in all 41 IPCs. CONCLUSION: Our study provides reassuring evidence that the IPC material does not support direct tumour growth or invasion even in the setting of high mesothelioma prevalence. See Editorial, page 787.

Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score.

BACKGROUND: Malignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in patients with MPE, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system. METHODS: Three large international cohorts of patients with MPE were used to calculate survival by cell type (univariable Cox model). The prognostic value of 14 predefined variables was evaluated in the most complete data set (multivariable Cox model). A clinical prognostic scoring system was then developed and validated. RESULTS: Based on the results of the international data and the multivariable survival analysis, the LENT prognostic score (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), neutrophil-to-lymphocyte ratio and tumour type) was developed and subsequently validated using an independent data set. Risk stratifying patients into low-risk, moderate-risk and high-risk groups gave median (IQR) survivals of 319 days (228-549; n=43), 130 days (47-467; n=129) and 44 days (22-77; n=31), respectively. Only 65% (20/31) of patients with a high-risk LENT score survived 1 month from diagnosis and just 3% (1/31) survived 6 months. Analysis of the area under the receiver operating curve revealed the LENT score to be superior at predicting survival compared with ECOG PS at 1 month (0.77 vs 0.66, p<0.01), 3 months (0.84 vs 0.75, p<0.01) and 6 months (0.85 vs 0.76, p<0.01). CONCLUSIONS: The LENT scoring system is the first validated prognostic score in MPE, which predicts survival with significantly better accuracy than ECOG PS alone. This may aid clinical decision making in this diverse patient population.

Regulatory responses to over-the-counter codeine analgesic misuse in Australia, New Zealand and the United Kingdom.

OBJECTIVE: Analysis of the policy response by Australia's National Drugs and Poisons Schedule Committee (NDPSC) and comparison with recommendations by expert advisory committees in New Zealand and the United Kingdom. METHODS: Analysis of public policy documents of relevant regulatory authorities was conducted. Data were extracted regarding changes to over-the-counter (OTC) codeine analgesic scheduling, indications, maximum unit dose, maximum daily dose, maximum pack size, warning labels, consumer medicine information and advertising. Where available, public submissions and other issues considered by the committees and rationale for their recommendations were recorded and thematically analysed. RESULTS: Expert advisory committees in Australia, NZ and the UK defined the policy problem of OTC codeine misuse and harm as small relative to total use and responded by restricting availability. Pharmacist supervision was required at the point-of-sale and pack sizes were reduced to short-term use. CONCLUSIONS: Comparison with recommendations by expert advisory committees in NZ and the UK suggests the NDPSC's actions in response to OTC codeine misuse were appropriate given the available evidence of misuse and harm, but highlights opportunities to utilise additional regulatory levers. IMPLICATIONS: Framing policy problems as matters of public health in the context of limited evidence may support decision makers to implement cautionary incremental policy change.

Pleural infection: what we need to know but don't.

PURPOSE OF REVIEW: Pleural infection remains a common and difficult problem to manage in the 21st century. Despite advances in modern healthcare, the rising incidence and mortality of empyema highlights a need for better understanding of the disease and more effective strategies in its diagnosis and treatment. RECENT FINDINGS: Recent studies have progressed our knowledge and understanding of the bacteriology and pathophysiology of pleural infection. However, rather than providing firm conclusions, examination of current literature provokes several unanswered questions on most aspects of the disease. SUMMARY: This review aims to challenge traditional current concepts and approaches to clinical practice in pleural infection, to stimulate debate and research into potential novel future therapies.

Support for breaking the nexus between alcohol and community sports settings: findings from the VicHealth Community Attitudes Survey in Australia.

INTRODUCTION AND AIMS: This study describes levels and predictors of community attitudes towards alcohol, support for structural alterations to the drinking context, and intention to increase participation in community sports clubs. DESIGN AND METHODS: Cross-sectional data were obtained from the VicHealth Community Attitudes Survey on Healthy Sporting Environments, administered to a random sample of Victorian adults. Descriptive and multivariate logistic regression analysis was undertaken. RESULTS: Very high support for removing alcohol sponsorship of community sport and for a levy on alcohol advertising was found. The groups most supportive of breaking the nexus between alcohol and community sport were female, older-aged and non-English-speaking citizens and those not involved in sport clubs. If alcohol sales at community sports clubs were reduced, participation may increase among population groups currently identified as least engaged with community sport. DISCUSSION AND CONCLUSIONS: An optimal climate exists for policy reforms to make community sporting environments healthier by reducing the ties with alcohol. If implemented, these reforms may lead to an increase and diversification of participants in community sport.

Over-the-counter codeine analgesic misuse and harm: characteristics of cases in Australia and New Zealand.

AIM: To describe the characteristics of clients addicted to over-the-counter (OTC) codeine analgesics presenting to an Auckland open-access clinic, and to compare them to clients admitted to a New Zealand detoxification unit, and in the Australian community. METHOD: Cross-sectional study of clients presenting to a regional, open-access detoxification clinic covering the Greater Auckland area between 1 January and 31 March 2010. RESULTS: Fifteen clients were analysed, and compared to 77 similar clients identified in Victoria and five other Australian States, and 7 clients admitted to a New Zealand detoxification unit. Cases in each cohort were consistent with those in the published literature, and appear to be similar to each other both demographically and in terms of the high average tablets consumption (49-65 tablets per day), the serious non-steroidal anti-inflammatory drug (NSAID) adverse drug reactions identified, and the long duration of misuse. Many had a history of alcohol or other drug use and mental health disorder. CONCLUSIONS: This study has identified that controls on OTC codeine analgesics in both countries were not sufficient to limit non-medical use of these products. As a result, cases identified in these two countries escalated the number of self-administered tablets taken daily for misuse, resulting in codeine dependence and serious NSAID toxicity secondary to this dependence.

fMRI activation during response inhibition and error processing: the role of the DAT1 gene in typically developing adolescents and those diagnosed with ADHD.

The DAT1 gene codes for the dopamine transporter, which clears dopamine from the synaptic cleft, and a variant of this gene has previously been associated with compromised response inhibition in both healthy and clinical populations. This variant has also been associated with ADHD, a disorder that is characterised by disturbed dopamine function as well as problems with response inhibition. In the present study we used fMRI to investigate the role of dopaminergic genetic variation on executive functioning by comparing how activation associated with successful and unsuccessful inhibitions differs based on DAT1-genotype and ADHD-diagnosis in adolescents performing a go/nogo task. The results identify regional specificity concerning which functional differences can be attributed to the possession of the high risk DAT1 genotype, the clinical condition or an interaction between the two. During response inhibition, individuals with two copies of the 10-repeat allele showed increased activation in frontal, medial, and parietal regions, which may indicate that inhibition is more effortful for this group. Conversely, this group displayed a reduced error response in the parahippocampal gyrus, suggestive of reduced learning from errors. There were also a number of frontal, parietal, medial and occipital regions, where the relationship between genotype and fMRI-activation differed between the ADHD group and the typically developing adolescents. Finally, the ADHD group displayed decreased activation in parietal and (pre)frontal regions during response inhibition, and in frontal and medial brain regions on error trials.

A review of public opinion towards alcohol controls in Australia.

BACKGROUND: Increasing concern about the negative impact of alcohol on the Australian community has renewed calls for tighter regulatory controls. This paper reviews levels of and trends in public support for liquor control regulations, regulation of alcohol promotions, and alcohol pricing and taxation reforms in Australia between 1998 and 2009. METHODS: Six electronic databases and twenty public health and alcohol organisation websites were searched for research literature, reports and media releases describing levels of public support for alcohol controls. Only studies which randomly selected participants were included. RESULTS: Twenty-one studies were included in the review. The majority of the Australian public support most proposed alcohol controls. Levels of support are divided between targeted and universal controls. CONCLUSIONS: Implementation of targeted alcohol policies is likely to be strongly supported by the Australian public, but universal controls are liable to be unpopular. Policy makers are provided with insights into factors likely to be associated with higher public support.

Serious morbidity associated with misuse of over-the-counter codeine-ibuprofen analgesics: a series of 27 cases.

OBJECTIVE: To investigate morbidity related to misuse of over-the-counter (OTC) codeine-ibuprofen analgesics. DESIGN AND SETTING: Prospective case series collected from Victorian hospital-based addiction medicine specialists between May 2005 and December 2008. MAIN OUTCOME MEASURES: Morbidity associated with codeine-ibuprofen misuse. RESULTS: Twenty-seven patients with serious morbidity were included, mainly with gastrointestinal haemorrhage and opioid dependence. The patients were taking mean daily doses of 435-602 mg of codeine phosphate and 6800-9400 mg ibuprofen. Most patients had no previous history of substance use disorder. The main treatment was opioid substitution treatment with buprenorphine-naloxone or methadone. CONCLUSIONS: Although codeine can be considered a relatively weak opioid analgesic, it is nevertheless addictive, and the significant morbidity and specific patient characteristics associated with overuse of codeine-ibuprofen analgesics support further awareness, investigation and monitoring of OTC codeine-ibuprofen analgesic use.

Functional developmental changes underlying response inhibition and error-detection processes.

This study examined the developmental trajectories associated with response inhibition and error processing as exemplar executive processes. We present fMRI data showing developmental changes to the functional networks underlying response inhibition and error-monitoring, comparing activation between adults and young adolescents performing the sustained attention to response task (SART). During successful inhibitions, we observed greater activation for the young adolescents than for the adults, in a widely distributed network including frontal, parietal and medial regions. When inhibition failed, however, adults showed increased activation compared to young adolescents in a number of regions, including bilateral parahippocampal gyrus, left and right lingual gyri, the right insula, and cerebellar regions. These differences largely remained even when the two groups were matched for performance, suggesting that performance differences are unlikely to be the driving factor behind these developmental differences. Instead, the neurodevelopmental trajectory of these important executive functions may reveal the basis for the immature executive functioning of the young adolescent.