Conservative versus Interventional Treatment for Spontaneous Pneumothorax.

BACKGROUND: Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown. METHODS: In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks. RESULTS: A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management. CONCLUSIONS: Although the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.).

Randomized controlled trial of the effect of regular paracetamol on influenza infection.

BACKGROUND AND OBJECTIVE: Anti-pyretic treatment is recommended in the management of influenza infection. In animal models anti-pyretic treatment increases mortality from influenza. We investigated the effects of paracetamol on viral and clinical outcomes in adults with influenza infection. METHODS: This is a randomized, double-blind, placebo-controlled trial of adults aged 18-65 years with influenza-like illness and positive influenza rapid antigen test. Treatments were 1 g paracetamol four times a day, or matching placebo, for 5 days. Pernasal swabs were taken for influenza quantitative RT-PCR at Baseline and Days 1, 2 and 5. Temperature and symptom scores were recorded for 5-14 days or time of resolution respectively. The primary outcome variable was area under the curve (AUC) for quantitative PCR log10 viral load from Baseline to Day 5. RESULTS: A total of 80 participants were randomized: no one was lost to follow up, and one withdrew after 4 days. There were 22 and 24 participants who were influenza PCR-positive in placebo and in paracetamol groups respectively. Mean (SD) AUC PCR log10 viral load was 4.40 (0.91) in placebo and 4.64 (0.88) in paracetamol; difference was -0.24, 95% CI: -0.78 to 0.29, P = 0.36. In all participants there were no differences in symptom scores, temperature, time to resolution of illness and health status, with no interaction between randomized treatment and whether influenza was detected by PCR. CONCLUSION: Regular paracetamol had no effect on viral shedding, temperature or clinical symptoms in patients with PCR-confirmed influenza. There remains an insufficient evidence base for paracetamol use in influenza infection. CLINICAL TRIAL REGISTRATION: ACTRN12611000497909 at the Australian New Zealand Clinical Trials Registry.

Comparative audit of oxygen use in the prehospital setting in acute COPD exacerbation over 5†years.

BACKGROUND: In 2009 the Wellington Free Ambulance implemented an education programme to reduce high concentration oxygen delivery to patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The aim of this audit was to compare pre-hospital oxygen delivery to patients with AECOPD before and after the programme. METHODS: An audit of patients who presented to Wellington Regional Hospital by ambulance with an AECOPD in 2005 and then in 2010, after implementation of the education programme. Oxygen therapy was categorised as: HIGH, supplemental high concentration oxygen therapy ≥3 L/min and/or delivery via high concentration mask; NEB, high concentration oxygen only during nebuliser use; or LOW, neither of these. RESULTS: In 2005 those in the HIGH, NEB and LOW categories were 81 (75.0%), 18 (16.7%) and 9 (8.3%) of 108 identified patients. In 2010 those in the HIGH, NEB and LOW categories were 80 (44.0%), 61 (33.5%) and 41 (22.5%) of 182 identified patients. The proportions of patients in the three oxygen groups were significantly different between 2005 and 2010 (p<0.001). CONCLUSIONS: The proportion of patients administered supplemental high concentration oxygen therapy markedly decreased between 2005 and 2010 following implementation of the education programme. However, in 2010 more than half of the patients not managed with high concentration oxygen therapy were still exposed to high concentration oxygen through the use of oxygen-driven nebulisers. To reduce exposure to high concentration oxygen in AECOPD the use of air-driven nebulisers or metered dose inhalers with spacers is required.

Accuracy of patient self-report as a measure of inhaled asthma medication use.

BACKGROUND AND OBJECTIVE: Measuring adherence to inhaled asthma treatment is a key priority for asthma care. The aim of this study was to determine the relationship between self-report and actual medication use as measured by electronic monitoring for single and combination inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) metered-dose inhaler therapy. METHODS: In this retrospective analysis from a previously completed prospective 24-week randomized, controlled trial of single or combination ICS/LABA therapy, medication use in the week prior to study visits determined by self-report questionnaire and electronic monitoring was compared. One hundred eleven participants received 125 µg fluticasone dipropionate and 25 µg salmeterol, two actuations twice daily, by either separate or combination ICS/LABA inhalers. Paired data for self-report and electronic monitoring were analysed. Measurement of agreement was by Bland-Altman-like plots by visit with calculation of limits of agreement. RESULTS: For single and combination ICS/LABA therapy, self-report consistently overestimated actual inhaler use assessed by electronic monitoring by a mean of 2.2-8.4 inhalations over a 1-week period, with limits of agreement ranging from ±15.8 to 25.6 inhalations. Participants who underused their inhalers tended to overreport their use, while those who overused tended to underreport their medication use. The greater the degree of underuse, the greater the magnitude of overreport, and likewise, the greater the degree of overuse, the greater the magnitude of underreport. CONCLUSIONS: Self-report is inaccurate in measuring actual use of inhaled asthma treatment with patients who underuse their maintenance therapy overreporting their use and those who overuse their therapy underreporting their use.

High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.

BACKGROUND: The optimal approach to oxygen therapy in ST-elevation myocardial infarction (STEMI) is uncertain. METHODS: A randomized controlled trial was undertaken in which 136 patients presenting with their first STEMI uncomplicated by cardiogenic shock or marked hypoxia were randomized to receive high-concentration (6 L/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturation 93%-96%) for 6 hours after presentation. The main outcome variables were 30-day mortality and infarct size assessed by troponin T level at 72 hours. Secondary outcomes included a meta-analysis of mortality data from this study and previous randomized controlled trials, and infarct size was assessed by magnetic resonance imaging at 4 to 6 weeks. RESULTS: There were 1 of 68 and 2 of 68 deaths in the high-concentration and titrated oxygen groups, respectively; a meta-analysis including these data with those from the 2 previous studies showed an odds ratio for mortality of high-concentration oxygen compared with room air or titrated oxygen of 2.2 (95% CI 0.8-6.0). There was no significant difference between high-concentration versus titrated oxygen in troponin T (ratio of mean levels 0.74, 95% CI 0.50-1.1, P = .14), infarct mass (mean difference -0.8 g, 95% CI -7.6 to 6.1, P = .82), or percent infarct mass (mean difference -0.6%, 95% CI -5.6 to 4.5, P = .83). CONCLUSION: This study found no evidence of benefit or harm from high-concentration compared with titrated oxygen in initially uncomplicated STEMI. However, our estimates have wide CIs, and as a result, large randomized controlled trials are required to resolve the clinical uncertainty.

The risk of serious adverse outcomes associated with hypoxaemia and hyperoxaemia in acute exacerbations of COPD.

BACKGROUND: Prehospital high concentration oxygen therapy leads to worse clinical outcomes in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Less is known about the risks of hypoxaemia despite oxygen treatment. Current respiratory and ambulance guidelines recommend titration of supplemental oxygen to a target oxygen saturation range of 88%-92%. AIM: To explore the association between PaO(2) and risk of serious adverse clinical outcomes in AECOPD. METHODS: A retrospective review of consecutive patients presenting via ambulance to the Wellington Regional Hospital Emergency Department with AECOPD between June 2005 and January 2008. Patients with an arterial blood gas taken within 4 h of triage were included in the study and were categorised as hypoxaemic (PaO(2)<60 mm Hg), normoxaemic (PaO(2) 60-100 mm Hg) or hyperoxaemic (PaO(2)>100 mm Hg). Serious adverse outcome was defined as a composite of hypercapnic respiratory failure, assisted ventilation or inpatient death. Multivariate logistic regression analysis examined the association between PaO(2) category and the composite outcome. RESULTS: Of the 680 patients presenting with AECOPD in the review period, 254 presentations in 180 patients had data suitable for analysis. Hyperoxaemia occurred in 61/254 (24%) presentations and was strongly associated with serious adverse outcome compared with normoxaemia (OR 9.17, 95% CI 4.08 to 20.6). Hypoxaemia was also associated with an increased risk of serious adverse outcome compared with normoxaemia (OR 2.16, 95% CI 1.11 to 4.20). Compared with the recommended target oxygen saturation range of 88%-92%, the risk of a serious adverse outcome was increased in both the <88% group (OR 2.0, 95% CI 1.03 to 3.80) and the >96% group (OR 2.37, 95% CI 1.34 to 4.20). CONCLUSIONS: In patients presenting via ambulance to the Emergency Department with AECOPD, serious adverse clinical outcomes are associated with both hypoxaemia and hyperoxaemia. These data provide further support for the principle of titrating supplemental oxygen therapy to target oxygen saturations.

Randomised controlled crossover trial of the effect on PtCO2 of oxygen-driven versus air-driven nebulisers in severe chronic obstructive pulmonary disease.

BACKGROUND: The comparative safety of oxygen versus air-driven nebulised bronchodilators in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) is uncertain. A randomised controlled trial was performed to assess the effect on the arterial partial pressure of carbon dioxide of nebulised bronchodilator driven with oxygen versus air in stable severe COPD. METHODS: In an open label randomised study, 18 subjects with stable severe COPD attended on 2 days to receive nebulised bronchodilator therapy driven by air or oxygen. Subjects received 5 mg salbutamol and 0.5 mg ipratropium bromide by nebulisation over 15 min, then, after 5 min, 5 mg salbutamol nebulised over 15 min, followed by 15 min of observation. Transcutaneous carbon dioxide tension (PtCO(2)) and oxygen saturations were recorded at 5 min intervals during the study. The primary outcome was the PtCO(2) after the completion of the second bronchodilator treatment. RESULTS: PtCO(2) was higher with nebulised bronchodilator therapy delivered by oxygen, but decreased back to the level associated with air nebulisation 15 min after completion of the second nebulised dose. One subject experienced an increase in PtCO(2) of 11 mm Hg after the first bronchodilator nebulisation driven by oxygen. The mean PtCO(2) difference between the oxygen and air groups after the second nebulisation was 3.1 mm Hg (95% CI 1.6 to 4.5, p<0.001). CONCLUSION: Nebulisers driven with oxygen result in significantly higher levels of PtCO(2) than those driven with air in patients with severe COPD. CLINICAL TRIAL REGISTRATION NUMBER: The study was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12610000080022).

Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma.

BACKGROUND: The effect on Paco2 of high concentration oxygen therapy when administered to patients with severe exacerbations of asthma is uncertain. METHODS: 106 patients with severe exacerbations of asthma presenting to the Emergency Department were randomised to high concentration oxygen (8 l/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93% and 95%) for 60 min. Patients with chronic obstructive pulmonary disease or disorders associated with hypercapnic respiratory failure were excluded. The transcutaneous partial pressure of carbon dioxide (Ptco2) was measured at 0, 20, 40 and 60 min. The primary outcome variable was the proportion of patients with a rise in Ptco2 ≥4 mm Hg at 60 min. RESULTS: The proportion of patients with a rise in Ptco2 ≥4 mm Hg at 60 min was significantly higher in the high concentration oxygen group, 22/50 (44%) vs. 10/53 (19%), RR 2.3 (95% CI 1.2 to 4.4, p<0.006). The high concentration group had a higher proportion of patients with a rise in Ptco2 ≥8 mm Hg, 11/50 (22%) vs. 3/53 (6%), RR 3.9 (95% CI 1.2 to 13.1, p=0.016). All 10 patients with a final Ptco2 ≥45 mm Hg received high concentration oxygen therapy, and in five there was an increase in Ptco2 ≥10 mm Hg. CONCLUSION: High concentration oxygen therapy causes a clinically significant increase in Ptco2 in patients presenting with severe exacerbations of asthma. A titrated oxygen regime is recommended in the treatment of severe asthma, in which oxygen is administered only to patients with hypoxaemia, in a dose that relieves hypoxaemia without causing hyperoxaemia. Clinical trial number ACTRN12607000131459.

The value of the CRB65 score to predict mortality in exacerbations of COPD requiring hospital admission.

BACKGROUND AND OBJECTIVE: The CRB65 score, a risk stratification method validated for use in community-acquired pneumonia, has recently been shown to have utility in acute exacerbations of COPD (AECOPD). The objective of this study was to independently validate the CRB65 score as a predictor of mortality in patients who required hospital admission with AECOPD. METHODS: The medical records of patients admitted to Wellington Hospital with AECOPD during a 12-month period from June 2006 were reviewed. Logistic regression was used to determine the strength of the association between the CRB65 score and death at three measurement times: in-hospital, 30days and 12months. RESULTS: Complete data were available in 133/174 patient admissions. In-hospital and 30-day mortality increased progressively with increasing CRB65 score and was markedly higher in the CRB 3-4 group (3%, 5%, 29%, and 4%, 9%, 43% for CRB65 scores 0-1, 2, 3-4 for in-hospital and 30-day mortality, respectively). Differences in 1-year mortality were less apparent (24%, 25%, 57% for CRB65 scores 0-1, 2, 3-4, respectively). The CRB65 score demonstrated a modest value for predicting in-hospital and 30-day mortality with a c statistic of 0.68 at both time points. CONCLUSIONS: The CRB65 score shows similar characteristics for predicting short-term mortality in AECOPD as its use in community-acquired pneumonia. We recommend its use in clinical practice, particularly in patients with a score ≥3, which is associated with a high risk of early mortality, and need for intensive hospital management.

Randomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting beta-agonist inhaler therapy in asthma.

BACKGROUND: The inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) combination inhaler has the potential to improve adherence with ICS therapy in asthma. OBJECTIVE: To determine whether ICS/LABA combination inhaler therapy improves adherence compared with separate inhaler use. METHODS: In a 24-week randomized controlled parallel group study, 111 subjects were prescribed 125 microg fluticasone dipropionate (FP) and 25 microg salmeterol, 2 actuations twice daily through either a combination inhaler or separate inhalers concurrently. Medication use was recorded by covert electronic monitors. The primary outcome variable was adherence during the final 6-week period, defined as the number of doses taken as a percentage of those prescribed. RESULTS: Complete adherence data from the final 6-week period were available for 49 and 54 subjects in the separate and combination groups, respectively. The mean (SD) adherence was 73.7% (36.0) for FP, 76.7% (30.5) for salmeterol, and 82.4% (24.5) for FP/salmeterol. There were no significant differences in adherence between FP/salmeterol and FP (-8.7%; 95% CI, -10.6 to 3.3) and salmeterol (-5.6%; 95% CI, -16.4 to 5.1). There was no significant difference in overuse among the FP, salmeterol, or FP/salmeterol groups. In 2 (4%) of 49 subjects, salmeterol was effectively taken as monotherapy during a 6-week period. CONCLUSION: In the setting of a randomized controlled trial, use of a combination ICS/LABA inhaler does not markedly increase adherence above that observed with separate inhaler use. LABA monotherapy was observed in a small proportion of patients prescribed ICS and LABA therapy via separate inhalers.

Long-acting beta-agonists and asthma death: how useful are different study designs to evaluate the potential association?

BACKGROUND AND OBJECTIVE: There is uncertainty whether long-acting beta-agonist (LABA) drugs may increase the risk of asthma mortality. This uncertainty is partly due to the difficulty in estimating the risk of rare adverse outcomes. The aim of this paper is to consider the utility of three approaches to determine the magnitude and statistical significance of this potential association. METHODS: Using a death rate of 9 per 10,000 subjects with asthma, derived from a meta-analysis of randomized controlled trials (RCTs) of formoterol, power calculations for a single RCT, a case-control study, and a meta-analysis of RCTs were determined. RESULTS: For each study design, the number of subjects and events required to have adequate statistical power to detect a 1.5- and 2.0-fold increased risk of death were calculated. For a single RCT, or meta-analyses of RCTs, very large sample sizes are required. In contrast, case-control methodology represents a realistic method of estimating the risk of rare serious adverse events. CONCLUSIONS: Major practical limitations exist in the use of RCTs to determine the potential risk of death with LABAs in the treatment of asthma. Case-control methodology may be more effective in establishing causation; however, if selection bias occurs, estimates of risk may be inaccurate.

An audit of the effect of oxygen prescription charts on clinical practice.

PROBLEM: The need to improve the prescription, administration and monitoring of oxygen therapy. DESIGN: An interventional, prospective audit. BACKGROUND AND SETTING: Wellington Hospital, a teaching and tertiary referral hospital in New Zealand in 2007 and 2008. KEY MEASURES FOR IMPROVEMENT: Demonstration of adequate oxygen prescribing, administration and monitoring of oxygen therapy. STRATEGIES FOR IMPROVEMENT: The introduction of a new drug chart with a specific oxygen prescription section. Targeted educational lectures primarily to medical staff. EFFECTS OF CHANGE: 610 and 566 patients were reviewed in the first and second audits. After introduction of the new oxygen prescription section on the drug chart the proportion of patients whose oxygen therapy was prescribed increased from 15/85 (17.6%) to 39/98 (39.8%), relative risk 2.3 (95% CI 1.3 to 3.9). The proportion with adequate oxygen prescription, with documentation of device, flow rate or inspired oxygen concentration, and the target oxygen saturation increased from 5/85 (5.9%) to 36/98 (36.7%), relative risk 6.2 (95% CI 2.5 to 15.0). Introduction of the new charts was not associated with changes in clinical practice in terms of assessment of oxygen saturations on room air and commencement if < or = 92%, or the titration of oxygen therapy in response to oxygen saturations < or = 92%. LESSONS LEARNT: An oxygen prescription section on hospital drug charts improved the prescription of oxygen but did not improve clinical practice. Additional strategies are required to improve the administration of oxygen therapy in hospitals.

Systematic review of studies of the effect of hyperoxia on coronary blood flow.

BACKGROUND: International guidelines recommend the routine use of oxygen in the initial treatment of myocardial infarction, yet it is uncertain what effect this might have on physiologic and clinical outcomes. METHODS: We undertook a systematic search of Medline, Cochrane Database of Systematic Reviews, EMBASE, and CINHAL using the key words "oxygen," "coronary blood flow," "hyperoxia," and "coronary circulation" to identify human studies involving a measure of coronary blood flow while breathing oxygen and room air. The primary outcome measure was coronary blood flow; secondary outcomes included coronary vascular resistance and myocardial oxygen consumption. RESULTS: From 2,072 potential publications, there were 6 studies from 4 publications that met the inclusion criteria, with 6 healthy subjects and 61 subjects with cardiac disease. It was not possible to undertake a meta-analysis due to methodological limitations. In the 6 studies, high-concentration oxygen therapy resulted in hyperoxia, with a range in mean Pao(2) of 273 to 425 mm Hg. Hyperoxia caused a significant reduction in coronary blood flow (mean change -7.9% to -28.9%, n = 6 studies). Hyperoxia caused a significant increase in coronary vascular resistance (mean change 21.5% to 40.9%, n = 4 studies) and a significant reduction in myocardial oxygen consumption (mean change -15.3% to -26.9%, n = 3 studies). CONCLUSIONS: Hyperoxia from high-concentration oxygen therapy causes a marked reduction in coronary blood flow and myocardial oxygen consumption. These physiologic effects may have the potential to cause harm and are relevant to the use of high-concentration oxygen therapy in the treatment of cardiac and other disorders.

Dose-response relationship of inhaled corticosteroids and cataracts: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The risk of cataracts associated with the long-term use of inhaled corticosteroids (ICS) is poorly recognized, yet may be of major public health importance. The aim of this study was to determine the dose-response relationship of ICS use and risk of cataracts in adults. METHODS: A systematic review and meta-analysis was performed of case-control studies of cataracts and ICS use, which included at least two doses of ICS and in which the number of cases and controls using each dose of ICS was reported. The primary outcome variable was risk of cataracts. RESULTS: Four case-control studies were identified, with a total of 46 638 cases and 146 378 controls. There was a significant relationship between the risk of cataracts and ICS dose, with a random effects pooled odds ratio for risk of cataracts per 1000 microg increase in daily beclomethasone dipropionate dose of 1.25 (95% CI: 1.14-1.37). CONCLUSIONS: The risk of cataracts was increased by approximately 25% for each 1000 microg per day increase in the dose of beclomethasone dipropionate or equivalent. These findings reinforce the importance of prescribing within the therapeutic dose-response range for ICS in asthma and the need to determine the dose-response relationship for the efficacy of ICS in COPD. Screening for the presence of cataracts could usefully be undertaken in older subjects with asthma and COPD, particularly current or ex-smokers.

A case-control study of seated immobility at work as a risk factor for venous thromboembolism.

OBJECTIVE: To determine the relative risk of prolonged seated immobility at work in patients with a deep vein thrombosis (DVT) or pulmonary embolism (PE). DESIGN: A case-control study: cases and controls completed an interviewer-administered questionnaire to obtain information on risk factors for venous thromboembolism (VTE), including prolonged seated immobility at work. Univariate and multivariate logistic regression was used to determine the association between predicted variables and the probability of being a case or control. PARTICIPANTS: Cases were patients<65 years old attending the Wellington Hospital Outpatient VTE Clinic following hospital discharge for DVT and/or PE. Controls were patients<65 years old admitted to the Coronary Care Unit at Wellington Hospital. SETTING: The Wellington Hospital Outpatient VTE Clinic and Coronary Care Unit. MAIN OUTCOME MEASURES: Odds ratio of VTE for prolonged seated immobility. RESULTS: There were 97 cases (53 DVT, 29 PE, 15 DVT and PE), and 106 controls. In the multivariate analysis the odds ratio of VTE for prolonged seated immobility at work was 1.8 (95% CI 0.71-4.8). The maximum number of hours seated at work was associated with VTE, with the risk increasing by 10% per hour longer seated (odds ratio 1.1, 95% CI 1.0-1.2). The maximum number of hours seated at work without getting up was associated with VTE, with the risk increasing by 20% per hour longer seated (odds ratio 1.2, 95% CI 0.96-1.6). CONCLUSIONS: This study provides preliminary evidence that prolonged seated immobility at work may represent a risk factor for VTE.

Asthma and Respiratory Foundation NZ adult asthma guidelines: a quick reference guide.

The purpose of the Asthma and Respiratory Foundation NZ Adult Asthma Guidelines is to provide simple, practical and evidence-based recommendations for the diagnosis, assessment and management of asthma in adults (aged 16 and over) in a quick reference format. The intended users are health professionals responsible for delivering asthma care in the community and hospital Emergency Department settings, and those responsible for the training of such health professionals.