Evaluation of Pediatric HIV Postexposure Prophylaxis Guideline Following Child Sexual Assault in Western Australia.

BACKGROUND: HIV postexposure prophylaxis (PEP) following child sexual assault (CSA) is recommended in select cases. High rates of poor adherence to PEP are reported. We evaluated adherence to the recommended management of children following CSA at the tertiary pediatric facility in Western Australia and compared our approach with international guidelines. METHODS: Medical records were reviewed for all children <16 years old assessed at Perth Children's Hospital between October 1, 2016 and November 30, 2020 following alleged CSA. Data, including exposure type, PEP adherence and follow-up, were collected. A review of contemporary national and international PEP guidelines was undertaken in parallel. RESULTS: There were 511 alleged CSA events over the study period; 62/511 (12%) were appropriately risk-assessed as requiring PEP by the treating clinician. PEP was not prescribed in 8/62 (13%) events, with a reason documented for 6/8 (75%). Overall, less than half of children who were eligible for PEP were adherent to the 28-day regimen (23/54, 43%). Gastrointestinal upset contributed to early cessation in 5/54 (9%). Final 3-month blood-borne virus serology results were available in less than one in 3 children. A review of international clinical practice revealed significant heterogeneity of criteria for the provision of PEP and a paucity of pediatric-specific data. CONCLUSIONS: We identified several areas of our PEP management that required strengthening, with limited direction available in current international guidelines. We have adopted a broader use of fixed drug combinations and implemented a multifaceted follow-up program. It will be essential to review the impact of these changes.

BEAT CF pulmonary exacerbations core protocol for evaluating the management of pulmonary exacerbations in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a rare, inherited, life-limiting condition predominantly affecting the lungs, for which there is no cure. The disease is characterized by recurrent pulmonary exacerbations (PEx), which are thought to drive progressive lung damage. Management of these episodes is complex and generally involves multiple interventions targeting different aspects of disease. The emergence of innovative trials and use of Bayesian statistical methods has created renewed opportunities for studying heterogeneous populations in rare diseases. Here, we present the protocol for the BEAT CF PEx cohort, a prospective, multi-site, perpetual, platform enrolling adults and children with CF. The BEAT CF PEx cohort will be used to evaluate the comparative effectiveness of interventions for the treatment of PEx requiring intensive therapy (PERITs), with a primary focus on short-term improvements in lung function. This will be achieved through the conduct of cohort-nested studies, including adaptive clinical trials, within the BEAT CF PEx cohort. This protocol will outline key features of the BEAT CF PEx cohort, including the design, implementation, data collection and management, governance and analysis, and dissemination of results. METHODS: This platform will be conducted across multiple sites, commencing with CF treatment centers in Australia. People of all ages with a clinical diagnosis of CF will be eligible to participate, except those who have previously received a lung transplant. Data including demographic and clinical information, treatment details, and outcomes (including safety, microbiology, and patient-reported outcome measures including quality of life scores) will be systematically collected and securely stored via a digital centralized trial management system (CTMS). The primary endpoint is the absolute change in the percentage predicted forced expiratory volume in 1 s (ppFEV1) from the commencement of intensive therapy to 7 to 10 days afterwards. DISCUSSION: The BEAT CF PEx cohort will report clinical, treatment, and outcome data for PEx among people with CF and is intended to serve as a core (master) protocol for future nested, interventional trials evaluating treatment(s) for these episodes. The protocols for nested sub-studies are beyond the scope of this document and will be reported separately. TRIAL REGISTRATION: ANZCTR BEAT CF Platform - ACTRN12621000638831. Registration date: Sept. 26, 2022.

Patient-reported outcome measures for paediatric acute lower respiratory infection studies.

BACKGROUND: Patient-reported outcome measures (PROMs) are recommended for capturing meaningful outcomes in clinical trials. The use of PROMs for children with acute lower respiratory infections (ALRIs) has not been systematically reported. We aimed to identify and characterise patient-reported outcomes and PROMs used in paediatric ALRI studies and summarise their measurement properties. METHODS: Medline, Embase and Cochrane were searched (until April 2022). Studies that reported on patient-reported outcome (or measure) use or development and included subjects aged <18 years with ALRIs were included. Study, population and patient-reported outcome (or measure) characteristics were extracted. RESULTS: Of 2793 articles identified, 18 met inclusion criteria, including 12 PROMs. Two disease-specific PROMs were used in settings in which they had been validated. The Canadian Acute Respiratory Illness and Flu Scale was the most frequently used disease-specific PROM (five studies). The EuroQol-Five Dimensions-Youth system was the most frequently used generic PROM (two studies). There was considerable heterogeneity in validation methods. The outcome measures identified in this review lack validation for young children and none involve sufficient content validity for use with First Nations children. CONCLUSIONS: There is an urgent need for PROM development that considers the populations in which the burden of ALRI predominates.

Predicting the causative pathogen among children with pneumonia using a causal Bayesian network.

BACKGROUND: Pneumonia remains a leading cause of hospitalization and death among young children worldwide, and the diagnostic challenge of differentiating bacterial from non-bacterial pneumonia is the main driver of antibiotic use for treating pneumonia in children. Causal Bayesian networks (BNs) serve as powerful tools for this problem as they provide clear maps of probabilistic relationships between variables and produce results in an explainable way by incorporating both domain expert knowledge and numerical data. METHODS: We used domain expert knowledge and data in combination and iteratively, to construct, parameterise and validate a causal BN to predict causative pathogens for childhood pneumonia. Expert knowledge elicitation occurred through a series of group workshops, surveys and one-on-one meetings involving 6-8 experts from diverse domain areas. The model performance was evaluated based on both quantitative metrics and qualitative expert validation. Sensitivity analyses were conducted to investigate how the target output is influenced by varying key assumptions of a particularly high degree of uncertainty around data or domain expert knowledge. RESULTS: Designed to apply to a cohort of children with X-ray confirmed pneumonia who presented to a tertiary paediatric hospital in Australia, the resulting BN offers explainable and quantitative predictions on a range of variables of interest, including the diagnosis of bacterial pneumonia, detection of respiratory pathogens in the nasopharynx, and the clinical phenotype of a pneumonia episode. Satisfactory numeric performance has been achieved including an area under the receiver operating characteristic curve of 0.8 in predicting clinically-confirmed bacterial pneumonia with sensitivity 88% and specificity 66% given certain input scenarios (i.e., information that is available and entered into the model) and trade-off preferences (i.e., relative weightings of the consequences of false positive versus false negative predictions). We specifically highlight that a desirable model output threshold for practical use is very dependent upon different input scenarios and trade-off preferences. Three commonly encountered scenarios were presented to demonstrate the potential usefulness of the BN outputs in various clinical pictures. CONCLUSIONS: To our knowledge, this is the first causal model developed to help determine the causative pathogen for paediatric pneumonia. We have shown how the method works and how it would help decision making on the use of antibiotics, providing insight into how computational model predictions may be translated to actionable decisions in practice. We discussed key next steps including external validation, adaptation and implementation. Our model framework and the methodological approach can be adapted beyond our context to broad respiratory infections and geographical and healthcare settings.

The Impact of a Multifaceted Tertiary Pediatric Hospital's Antimicrobial Stewardship Service.

BACKGROUND: Antimicrobials are the most commonly prescribed drug class in children. Overuse through inappropriate prescribing is a key driver of antimicrobial resistance and is recognized as one of the top 10 threats to global health by the World Health Organization. METHODS: A prospective observational cohort study was performed following implementation of a multifaceted Antimicrobial Stewardship (AMS) program (January 2014 to December 2020). Data were collected on AMS and "handshake" ward rounds from patient information sources and directly from clinicians responsible for patient care. Primary outcomes include appropriateness of therapy (drug, dose, antimicrobial spectrum, duration and route), compliance with prescribing guidelines, antimicrobial expenditure, use of high-priority antimicrobials and duration of hospitalization. We compared outcomes across 3 time periods; January 2014-December 2015, January 2016-December 2017 and January 2018-December 2020. RESULTS: The appropriateness of individual antimicrobial orders improved across the study periods from 6111/7040 (79.4%) in the first 2 years following implementation of the AMS program to 17,819/19,229 (92.3%) in the latter period. Guideline compliance increased from 5426/7700 (70.5%) to 17,822/19,316 (92.3%). A reduction in overall antimicrobial expenditure (34% reduction, equivalent to $12.52 per bed day) and a decrease in antifungal expenditure (37% reduction, equivalent to $5.56 per bed day) was observed across the time periods. CONCLUSIONS: This study quantifies a comprehensive pediatric AMS program's sustained impact on reducing inappropriate antimicrobial use and expenditure and improving compliance with guidelines. The effectiveness of these interventions has been demonstrated and should be considered by institutions seeking to improve rational antimicrobial use in children.

Protocol for establishing a core outcome set for evaluation in studies of pulmonary exacerbations in people with cystic fibrosis.

INTRODUCTION: Pulmonary exacerbations are associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no consensus about which outcomes should be evaluated in studies of pulmonary exacerbations or how these outcomes should be measured. Outcomes of importance to people with lived experience of the disease are frequently omitted or inconsistently reported in studies, which limits the value of such studies for informing practice and policy. To better standardise outcome reporting and measurement, we aim to develop a core outcome set for studies of pulmonary exacerbations in people with CF (COS-PEX) and consensus recommendations for measurement of core outcomes. METHODS AND ANALYSIS: Preliminary work for development of COS-PEX has been reported, including (1) systematic reviews of outcomes and methods for measurement reported in existing studies of pulmonary exacerbations; (2) workshops with people affected by CF within Australia; and (3) a Bayesian knowledge expert elicitation workshop with health professionals to ascertain outcomes of importance. Here we describe a protocol for the additional stages required for COS-PEX development and consensus methods for measurement of core outcomes. These include (1) an international two-round online Delphi survey and (2) consensus workshops to review and endorse the proposed COS-PEX and to agree with methods for measurement. ETHICS AND DISSEMINATION: National mutual ethics scheme approval has been provided by the Child and Adolescent Health Service Human Research Ethics Committee (RGS 4926). Results will be disseminated via consumer and research networks and peer-reviewed publications. This study is registered with the Core Outcome Measures in Effectiveness Trials database.

Infectious complications and optimising infection prevention for children with cochlear implants.

AIM: To describe the clinical epidemiology of children receiving cochlear implants, as well as the management and outcomes of cochlear implant infections and adherence to infection prevention measures. METHODS: A retrospective observational study was conducted in children ≤18 years who received cochlear implants in Western Australia's tertiary paediatric hospital. Information was obtained from medical and laboratory records regarding demographics, indication for implant, implant infection and preoperative Staphylococcus aureus screening/decolonisation. Immunisation history was examined using the Australian Immunisation Register. RESULTS: Overall, 118 children received cochlear implants, with 158 devices inserted (599 cochlear implant insertion-years). An implant infection rate of 3.8% (6/158) was identified during the study period (four pneumococcal and two community-acquired methicillin resistant S. aureus infections). All required surgical management, with an overall median duration of antibiotic therapy of 37 days (interquartile range (IQR) 29-48) and median length of stay of 8 days (IQR 8-9.5). All devices were retained and there were no relapses or deaths. Half of the children who developed cochlear implant infections (50%, 3/6) were up-to-date with additional pneumococcal vaccinations and no children (0%, 0/118) received S. aureus screening/decolonisation before implant insertion. CONCLUSIONS: Favourable outcomes were achieved with cochlear implant retention; however, the treatment was burdensome for families. We demonstrate significant scope to improve adherence to existing infection prevention strategies and provide direction for optimising preventative measures in the future. These include ensuring parental education, additional pneumococcal vaccinations and S. aureus decolonisation which are delivered as an infection prevention bundle to the growing population of infants receiving cochlear implants.

Preferred health outcome states following treatment for pulmonary exacerbations of cystic fibrosis.

BACKGROUND: Treatment for pulmonary exacerbations of cystic fibrosis (CF) can produce a range of positive and negative outcomes. Understanding which of these outcomes are achievable and desirable to people affected by disease is critical to agreeing to goals of therapy and determining endpoints for trials. The relative importance of outcomes resulting from treatment of these episodes are not reported. We aimed to (i) quantify the relative importance of outcomes resulting from treatment for pulmonary exacerbations and (ii) develop patient and proxy carer-reported weighted outcome measures for use in adults and children, respectively. METHODS: A discrete choice experiment (DCE) survey was conducted. Participants were asked to make a series of hypothetical decisions about treatment for pulmonary exacerbations to assess how they make trade-offs between different attributes of health. Data were analysed using a conditional logistic regression model. The correlation coefficients from these data were rescaled to enable generation of a composite health outcome score between 0 and 100 (worst to best health state). RESULTS: 362 individuals participated (167 people with CF and 195 carers); of these, 206 completed the survey (56.9%). Most participants were female and resided in Australia. Difficult/painful breathing had the greatest impact on the preferred health state amongst people with CF and carers alike. Avoidance of gastrointestinal problems also heavily influenced decision-making. CONCLUSIONS: These data should be considered when making treatment decisions and determining endpoints for trials. Further research is recommended to quantify the preferences of children and to determine whether these align with those of their carer(s).

Re-examining Hepatitis B Postexposure Prophylaxis Following Pediatric Community-acquired Needle-stick Injury in an Era of a National Immunization Registry.

BACKGROUND: Long-term hepatitis B immunity has been demonstrated following the completion of the primary vaccination series in childhood. Some guidelines recommend a hepatitis B surface antibody (anti-HBs) directed approach following community-acquired needle-stick injury (CANSI) to inform hepatitis B postexposure prophylaxis (PEP) management. We assessed the utility of anti-HBs testing post-CANSI, as well as the costing of, and adherence to PEP at a pediatric hospital. METHODS: Children presenting to an Australian tertiary pediatric hospital post-CANSI (2014-2019) were identified retrospectively using medical and laboratory records. Immunization status was obtained from the Australian Immunisation Registry. RESULTS: Fifty-six children with CANSI were identified. Of those with immunization records, all had completed hepatitis B vaccinations (n = 52). At presentation, 44% (n = 23) had anti-HBs <10 IU/L, which was more likely in older (≥6 years, 68%) versus younger children (OR 4.59, P < 0.02). HBIG and hepatitis B vaccine adherence was 65% (15/23) and 78% (18/23), respectively. All children (n = 14) with anti-HBs ≥4 weeks postvaccination ±HBIG, demonstrated an anamnestic response. No hepatitis B infections were detected. Using completed immunizations versus anti-HBs levels as a marker of immunity to direct PEP resulted in a projected cost savings of AUD$ 4234. CONCLUSION: Anti-HBs levels <10 IU/L, despite previous vaccinations, were frequent in children post-CANSI, with many demonstrating an anamnestic response. Adherence to postexposure HBIG and hepatitis B vaccine was suboptimal using an anti-HBs directed approach. These data support re-evaluating PEP in an era of the national immunization registry; completion of hepatitis B vaccinations as a marker of immunity provides a practical approach, ensuring optimized care for pediatric CANSI.

Novel method to select meaningful outcomes for evaluation in clinical trials.

BACKGROUND: A standardised framework for selecting outcomes for evaluation in trials has been proposed by the Core Outcome Measures in Effectiveness Trials working group. However, this method does not specify how to ensure that the outcomes that are selected are causally related to the disease and the health intervention being studied. Causal network diagrams may help researchers identify outcomes that are both clinically meaningful and likely to be causally dependent on the intervention, and endpoints that are, in turn, causally dependent on those outcomes. We aimed to (1) develop a generalisable method for selecting outcomes and endpoints in trials and (2) apply this method to select outcomes for evaluation in a trial investigating treatment strategies for pulmonary exacerbations of cystic fibrosis (CF). METHODS: We conducted a series of online surveys and workshops among people affected by CF. We used a modified Delphi approach to develop a consensus list of important outcomes. A workshop involving domain experts elicited how these outcomes were causally related to the underlying pathophysiological processes. Meaningful outcomes were prioritised based on the extent to which each outcome captured separate rather than common aspects of the underlying pathophysiological process. RESULTS: The 10 prioritised outcomes were: breathing difficulty/pain, sputum production/clearance, fatigue, appetite, pain (not related to breathing), motivation/demoralisation, fevers/night sweats, treatment burden, inability to meet personal goals and avoidance of gastrointestinal symptoms. CONCLUSIONS: This proposed method for selecting meaningful outcomes for evaluation in clinical trials may improve the value of research as a basis for clinical decisions.

The measurement properties of tests and tools used in cystic fibrosis studies: a systematic review.

There is no consensus on how best to measure responses to interventions among children and adults with cystic fibrosis (CF). We have systematically reviewed and summarised the characteristics and measurement properties of tests and tools that have been used to capture outcomes in studies among people with CF, including their reliability, validity and responsiveness. This review is intended to guide researchers when selecting tests or tools for measuring treatment effects in CF trials. A consensus set of these tests and tools could improve consistency in how outcomes are captured and thereby facilitate comparisons and synthesis of evidence across studies.

Outcomes and endpoints reported in studies of pulmonary exacerbations in people with cystic fibrosis: A systematic review.

BACKGROUND: There is no consensus about which outcomes should be evaluated in studies of pulmonary exacerbations in people with cystic fibrosis (CF). Outcomes used for evaluation should be meaningful; that is, they should capture how people feel, function or survive and be acknowledged as important to people with CF, or should be reliable surrogates of those outcomes. We aimed to summarise the outcomes and corresponding endpoints which have been reported in studies of pulmonary exacerbations, and to identify those which are most likely to be meaningful. METHODS: A PROSPERO registered systematic review (CRD42020151785) was conducted in Medline, Embase and Cochrane from inception until July 2020. Registered trials were also included. RESULTS: 144 studies met the inclusion criteria. A wide range of outcomes and corresponding endpoints were reported. Death, QoL and many patient-reported outcomes are likely to be meaningful as they directly capture how people feel, function or survive. Forced expiratory volume in 1-second [FEV1] is a validated surrogate of risk of death and reduced QoL. The extent of structural lung disease has also been correlated with lung function, pulmonary exacerbations and risk of death. Since no evidence of a correlation between airway microbiology or biomarkers with clinically meaningful outcomes was found, the value of these as surrogates was unclear. CONCLUSIONS: Death, QoL, patient-reported outcomes, FEV1, and structural lung changes were identified as outcomes that are most likely to be meaningful. Development of a core outcome set in collaboration with stakeholders including people with CF is recommended.

International Survey to Establish Prioritized Outcomes for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: There are over 4,000 trials conducted in people with coronavirus disease 2019. However, the variability of outcomes and the omission of patient-centered outcomes may diminish the impact of these trials on decision-making. The aim of this study was to generate a consensus-based, prioritized list of outcomes for coronavirus disease 2019 trials. DESIGN: In an online survey conducted in English, Chinese, Italian, Portuguese, and Spanish languages, adults with coronavirus disease 2019, their family members, health professionals, and the general public rated the importance of outcomes using a 9-point Likert scale (7-9, critical importance) and completed a Best-Worst Scale to estimate relative importance. Participant comments were analyzed thematically. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public, and health professionals (including clinicians, policy makers, regulators, funders, and researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: In total, 9,289 participants from 111 countries (776 people with coronavirus disease 2019 or family members, 4,882 health professionals, and 3,631 members of the public) completed the survey. The four outcomes of highest priority for all three groups were: mortality, respiratory failure, pneumonia, and organ failure. Lung function, lung scarring, sepsis, shortness of breath, and oxygen level in the blood were common to the top 10 outcomes across all three groups (mean > 7.5, median ≥ 8, and > 70% of respondents rated the outcome as critically important). Patients/family members rated fatigue, anxiety, chest pain, muscle pain, gastrointestinal problems, and cardiovascular disease higher than health professionals. Four themes underpinned prioritization: fear of life-threatening, debilitating, and permanent consequences; addressing knowledge gaps; enabling preparedness and planning; and tolerable or infrequent outcomes. CONCLUSIONS: Life-threatening respiratory and other organ outcomes were consistently highly prioritized by all stakeholder groups. Patients/family members gave higher priority to many patient-reported outcomes compared with health professionals.

Core Outcomes Set for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: The outcomes reported in trials in coronavirus disease 2019 are extremely heterogeneous and of uncertain patient relevance, limiting their applicability for clinical decision-making. The aim of this workshop was to establish a core outcomes set for trials in people with suspected or confirmed coronavirus disease 2019. DESIGN: Four international online multistakeholder consensus workshops were convened to discuss proposed core outcomes for trials in people with suspected or confirmed coronavirus disease 2019, informed by a survey involving 9,289 respondents from 111 countries. The transcripts were analyzed thematically. The workshop recommendations were used to finalize the core outcomes set. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public and health professionals (including clinicians, policy makers, regulators, funders, researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: Six themes were identified. "Responding to the critical and acute health crisis" reflected the immediate focus on saving lives and preventing life-threatening complications that underpinned the high prioritization of mortality, respiratory failure, and multiple organ failure. "Capturing different settings of care" highlighted the need to minimize the burden on hospitals and to acknowledge outcomes in community settings. "Encompassing the full trajectory and severity of disease" was addressing longer term impacts and the full spectrum of illness (e.g. shortness of breath and recovery). "Distinguishing overlap, correlation and collinearity" meant recognizing that symptoms such as shortness of breath had distinct value and minimizing overlap (e.g. lung function and pneumonia were on the continuum toward respiratory failure). "Recognizing adverse events" refers to the potential harms of new and evolving interventions. "Being cognizant of family and psychosocial wellbeing" reflected the pervasive impacts of coronavirus disease 2019. CONCLUSIONS: Mortality, respiratory failure, multiple organ failure, shortness of breath, and recovery are critically important outcomes to be consistently reported in coronavirus disease 2019 trials.

Predicting the causative pathogen among children with osteomyelitis using Bayesian networks - improving antibiotic selection in clinical practice.

Infection of bone, osteomyelitis (OM), is a serious bacterial infection in children requiring urgent antibiotic therapy. While biological specimens are often obtained and cultured to guide antibiotic selection, culture results may take several days, are often falsely negative, and may be falsely positive because of contamination by non-causative bacteria. This poses a dilemma for clinicians when choosing the most suitable antibiotic. Selecting an antibiotic which is too narrow in spectrum risks treatment failure; selecting an antibiotic which is too broad risks toxicity and promotes antibiotic resistance. We have developed a Bayesian Network (BN) model that can be used to guide individually targeted antibiotic therapy at point-of-care, by predicting the most likely causative pathogen in children with OM and the antibiotic with optimal expected utility. The BN explicitly models the complex relationship between the unobserved infecting pathogen, observed culture results, and clinical and demographic variables, and integrates data with critical expert knowledge under a causal inference framework. Development of this tool resulted from a multidisciplinary approach, involving experts in infectious diseases, modelling, paediatrics, microbiology, computer science and statistics. The model-predicted prevalence of causative pathogens among children with osteomyelitis were 56 % for Staphylococcus aureus, 17 % for 'other' culturable bacteria (like Streptococcus pyogenes), and 27 % for bacterial pathogens that are not culturable using routine methods (like Kingella kingae). Log loss cross-validation suggests that the model performance is robust, with the best fit to culture results achieved when data and expert knowledge were combined during parameterisation. AUC values of 0.68 - 0.77 were achieved for predicting culture results of different types of specimens. BN-recommended antibiotics were rated optimal or adequate by experts in 82-98% of 81 cases sampled from the cohort. We have demonstrated the potential use of BNs in improving antibiotic selection for children with OM, which we believe to be generalisable in the development of a broader range of decision support tools. With appropriate validation, such tools might be effectively deployed for real-time clinical decision support, to promote a shift in clinical practice from generic to individually-targeted antibiotic therapy, and ultimately improve the management and outcomes for a range of serious bacterial infections.

Choosing primary endpoints for clinical trials of health care interventions.

The purpose of late phase clinical trials is to generate evidence of sufficient validity and generalisability to be translated into practice and policy to improve health outcomes. It is therefore crucial that the chosen endpoints are meaningful to the clinicians, patients and policymakers that are the end-users of evidence generated by these trials. The choice of endpoints may be improved by understanding their characteristics and properties. This narrative review describes the evolution, range and relative strengths and weaknesses of endpoints used in late phase trials. It is intended to serve as a reference to assist those designing trials when choosing primary endpoint(s), and for the end-users charged with interpreting these trials to inform practice and policy.