Twenty-four Month Outcomes of Extended- Versus Standard-course Antibiotic Therapy in Children Hospitalized With Pneumonia in High-Risk Settings: A Randomized Controlled Trial.

BACKGROUND: Pediatric community-acquired pneumonia (CAP) can lead to long-term respiratory sequelae, including bronchiectasis. We determined if an extended (13-14 days) versus standard (5-6 days) antibiotic course improves long-term outcomes in children hospitalized with CAP from populations at high risk of chronic respiratory disease. METHODS: We undertook a multicenter, double-blind, superiority, randomized controlled trial involving 7 Australian, New Zealand, and Malaysian hospitals. Children aged 3 months to ≤5 years hospitalized with radiographic-confirmed CAP who received 1-3 days of intravenous antibiotics, then 3 days of oral amoxicillin-clavulanate, were randomized to either extended-course (8-day oral amoxicillin-clavulanate) or standard-course (8-day oral placebo) arms. Children were reviewed at 12 and 24 months. The primary outcome was children with the composite endpoint of chronic respiratory symptoms/signs (chronic cough at 12 and 24 months; ≥1 subsequent hospitalized acute lower respiratory infection by 24 months; or persistent and/or new chest radiographic signs at 12-months) at 24-months postdischarge, analyzed by intention-to-treat, where children with incomplete follow-up were assumed to have chronic respiratory symptoms/signs ("worst-case" scenario). RESULTS: A total of 324 children were randomized [extended-course (n = 163), standard-course (n = 161)]. For our primary outcome, chronic respiratory symptoms/signs occurred in 97/163 (60%) and 94/161 (58%) children in the extended-courses and standard-courses, respectively [relative risk (RR) = 1.02, 95% confidence interval (CI): 0.85-1.22]. Among children where all sub-composite outcomes were known, chronic respiratory symptoms/signs between groups, RR = 1.10, 95% CI: 0.69-1.76 [extended-course = 27/93 (29%) and standard-course = 24/91 (26%)]. Additional sensitivity analyses also revealed no between-group differences. CONCLUSION: Among children from high-risk populations hospitalized with CAP, 13-14 days of antibiotics (versus 5-6 days), did not improve long-term respiratory outcomes.

Erdosteine in children and adults with bronchiectasis (BETTER trial): study protocol for a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Bronchiectasis is a worldwide chronic lung disorder where exacerbations are common. It affects people of all ages, but especially Indigenous populations in high-income nations. Despite being a major contributor to chronic lung disease, there are no licensed therapies for bronchiectasis and there remain relatively few randomised controlled trials (RCTs) conducted in children and adults. Our RCT will address some of these unmet needs by evaluating whether the novel mucoactive agent, erdosteine, has a therapeutic role in children and adults with bronchiectasis.Our primary aim is to determine in children and adults aged 2-49 years with bronchiectasis whether regular erdosteine over a 12-month period reduces acute respiratory exacerbations compared with placebo. Our primary hypothesis is that people with bronchiectasis who regularly use erdosteine will have fewer exacerbations than those receiving placebo.Our secondary aims are to determine the effect of the trial medications on quality of life (QoL) and other clinical outcomes (exacerbation duration, time-to-next exacerbation, hospitalisations, lung function, adverse events). We will also assess the cost-effectiveness of the intervention. METHODS AND ANALYSIS: We are undertaking an international multicentre, double-blind, placebo-RCT to evaluate whether 12 months of erdosteine is beneficial for children and adults with bronchiectasis. We will recruit 194 children and adults with bronchiectasis to a parallel, superiority RCT at eight sites across Australia, Malaysia and Philippines. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, exacerbation duration, time-to-next exacerbation, hospitalisations and lung function. ETHICS AND DISSEMINATION: The Human Research Ethics Committees (HREC) of Children's Health Queensland (for all Australian sites), University of Malaya Medical Centre (Malaysia) and St. Luke's Medical Centre (Philippines) approved the study. We will publish the results and share the outcomes with the academic and medical community, funding and relevant patient organisations. TRIAL REGISTRATION NUMBER: ACTRN12621000315819.

Measuring the impact of pharmaceutical care bundle delivery on patient outcomes: an observational study.

BACKGROUND: Clinical pharmacists perform activities to optimise medicines use and prevent patient harm. Historically, clinical pharmacy quality indicators have measured individual activities not linked to patient outcomes. AIM: To determine the proportion of patients who receive a pharmaceutical care bundle (PCB) (consisting of a medication history, medication review, discharge medication list and medicines information on the discharge summary) as well as investigate the relationship between delivery of this PCB and patient outcomes. METHOD: Pharmaceutical care bundle activities were defined within state-wide (Queensland, Australia) clinical information systems and datasets were linked. An observational study using routinely recorded data was performed at ten participating sites for adult patients who had a non-same day hospital stay. The association between extent of PCB delivery and three patient outcomes were investigated: length of stay (LOS), unplanned readmission, and mortality. RESULTS: In total 283,813 patient hospital stays were evaluated. The delivery of the PCB occurred in 26.9% of patients at the ten participating hospital sites, ranging from 0.6 to 61.2% across sites. Patients with a longer LOS were more likely to receive delivery of the complete PCB (P < 0.001). There was no correlation between PCB and hospital standardised mortality ratio (r = 0.03, p = 0.93). Higher rates of delivery of the PCB were associated with lower rates of unplanned readmission within 30 days (r = - 0.993, p < 0.001). CONCLUSION: A complete PCB was delivered to 26.9% of patients and was associated with a significantly lower rate of unplanned readmission within 30 days.

The introduction of a sound reduction bundle in the intensive care unit and its impact on sound levels and patients.

BACKGROUND: ICU outcomes are continuing to improve. However, this has not been matched by similar improvements of the ICU bedspace environment, which can detrimentally impact on patient outcomes. Excessive sound and noise, especially, has been linked with adverse and potentially preventable patient outcomes and staff errors. There are many sources of sound in the ICU, with alarms from bedside equipment frequently listed as a main source. The number of alarms is increasing in parallel with the introduction of new and more sophisticated technologies to monitor and support patients. However, most alarms are not accurate or critical and are commonly ignored by staff. OBJECTIVE: The objective of this study was to evaluate the impact of a sound reduction bundle on sound levels, number of alarms, and patients' experience and perceived quality of sleep in the ICU. METHODS: This was a pre-post, quasi-experimental study investigating the impact of three study interventions implemented sequentially (staff education, visual warnings when sound levels exceeded the preset levels, and monitor alarm reconfigurations). Effects of staff education were evaluated using pre-education and post-education questionnaires, and the impact on patients was evaluated via self-report questionnaires. A sound-level monitor was used to evaluate changes in sound levels between interventions. Alarm audits were completed before and after alarm reconfiguration. RESULTS: Staff knowledge improved; however, sound levels did not change across interventions. The number of monthly monitor alarms reduced from 600,452 to 115,927. No significant differences were found in patients' subjective rating of their experience and sleep. CONCLUSION: The interventions did not lead to a sound-level reduction; however, there was a large reduction in ICU monitor alarms without any alarm-related adverse events. As the sources of sound are diverse, multidimensional interventions, including staff education, alarm management solutions, and environmental redesign, are likely to be required to achieve a relevant, lasting, and significant sound reduction.

Radiographic Outcomes in Paediatric Bronchiectasis and Factors Associated with Reversibility.

RATIONALE: Conventionally considered irreversible, bronchiectasis reversibility in children has been demonstrated in small studies. However, the factors associated with radiographic reversibility in bronchiectasis have yet to be defined. OBJECTIVES: In a large cohort of children with bronchiectasis, we aimed to determine (a) if and to what extent bronchiectasis is reversible and (b) factors associated with radiographic chest high resolution computed tomography (cHRCT) resolution. METHODS: We identified children with bronchiectasis who had a repeat multidetector HRCT between 2010-2021. We excluded those with cystic fibrosis, surgical pulmonary resection, traction bronchiectasis only, or lobar opacification. MAIN RESULTS: cHRCT scans were scored using the modified Reiff-score (MRS) with a paediatric correction. Resolution was defined as absence of abnormal broncho-arterial ratio (>0.8) on the second cHRCT. We included 142 children (median age=5years: IQR 2.6-7.4), Inter- and intra-rater agreement in MRSs was excellent (weighted kappa=0.83-0.86 and 0.95 respectively). Radiographically resolution was documented in 57/142 (40.1%), improved in 56/142 (39.4%), unchanged/worse in 29/142 (20.4%). Pseudomonas aeruginosa (PsA) was absolutely associated with non-resolution. On multivariable regression, in those without PsA cultured, younger age-at-diagnosis (risk ratio (RR)=0.94, 95%CI 0.88-0.99) lower MRS (RR=0.89, 95% CI 0.82-0.97) and lower annual exacerbation rate requiring intravenous antibiotics (RR=0.60, 95%CI 0.37-0.98) increased the likelihood of radiographic resolution. CONCLUSIONS: This first large cohort confirms bronchiectasis in children is often reversible with appropriate management. Younger aged children and those with lesser radiographic severity at diagnosis were most likely to achieve radiographic reversibility whilst those with PsA infection were least likely.

Improving the Diagnosis and Treatment of Paediatric Bronchiectasis Through Research and Translation.

Bronchiectasis, particularly in children, is an increasingly recognised yet neglected chronic lung disorder affecting individuals in both low-to-middle and high-income countries. It has a high disease burden and there is substantial inequity within and between settings. Furthermore, compared with other chronic lung diseases, considerably fewer resources are available for children with bronchiectasis. The need to prevent bronchiectasis and to reduce its burden also synchronously aligns with its high prevalence and economic costs to health services and society. Like many chronic lung diseases, bronchiectasis often originates early in childhood, highlighting the importance of reducing the disease burden in children. Concerted efforts are therefore needed to improve disease detection, clinical management and equity of care. Modifiable factors in the causal pathways of bronchiectasis, such as preventing severe and recurrent lower respiratory infections should be addressed, whilst also acknowledging the role played by social determinants of health. Here, we highlight the importance of early recognition/detection and optimal management of bronchiectasis in children, and outline our research, which is attempting to address important clinical knowledge gaps discussed in a recent workshop. The research is grouped under three themes focussing upon primary prevention, improving diagnosis and disease characterisation, and providing better management. Our hope is that others in multiple settings will undertake additional studies in this neglected field to further improve the lives of people with bronchiectasis. We also provide a resource list with links to help inform consumers and healthcare professionals about bronchiectasis and its recognition and management.

Endotypes of Paediatric Cough-Do They Exist and Finding New Techniques to Improve Clinical Outcomes.

Chronic cough is a common symptom of many childhood lung conditions. Given the phenotypic heterogeneity of chronic cough, better characterization through endotyping is required to provide diagnostic certainty, precision therapies and to identify pathobiological mechanisms. This review summarizes recent endotype discoveries in airway diseases, particularly in relation to children, and describes the multi-omic approaches that are required to define endotypes. Potential biospecimens that may contribute to endotype and biomarker discoveries are also discussed. Identifying endotypes of chronic cough can likely provide personalized medicine and contribute to improved clinical outcomes for children.

Clinical utility of elective paediatric flexible bronchoscopy and impact on the quality of life: protocol for a single-centre, single-blind, randomised controlled trial.

INTRODUCTION: Elective flexible bronchoscopy (FB) is now widely available and standard practice for a variety of indications in children with respiratory conditions. However, there are no randomised controlled trials (RCTs) that have examined its benefits (or otherwise).Our primary aim is to determine the impact of FB on the parent-proxy quality-of-life (QoL) scores. Our secondary aims are to determine if undertaking FB leads to (a) change in management and (b) improvement of other relevant patient-reported outcome measures (PROMs). We also quantified the benefits of elective FB (using 10-point Likert scale). We hypothesised that undertaking elective FB will contribute to accurate diagnosis and therefore appropriate treatment, which will in turn improve QoL and will be deemed to be beneficial from patient and doctor perspectives. METHODS AND ANALYSIS: Our parallel single-centre, single-blind RCT (commenced in May 2020) has a planned sample size of 114 children (aged <18 years) recruited from respiratory clinics at Queensland Children's Hospital, Brisbane, Australia. Children are randomised (1:1 concealed allocation) within two strata: age (≤2 vs >2 years) and indication for FB (chronic cough vs other indications) to either (a) early arm (intervention where FB undertaken within 2 weeks) or (b) delayed (control, FB undertaken at usual wait time). Our primary outcome is the difference between groups in their change in QoL at the T2 timepoint when the intervention group has had the FB and the control group has not. Our secondary outcomes are change in management, change in PROMs, adverse events and the Likert scales. ETHICS AND DISSEMINATION: The human research ethics committee of the Queensland Children's Hospital granted ethical clearance (HREC/20/QCHQ/62394). Our RCT is conducted in accordance with Good Clinical Practice and the Australian legislation. Results will be disseminated through conference presentations, teaching avenues, workshops, websites and publications. REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12620000610932.

The utility of elective flexible bronchoscopy to improve quality of life and clinical outcomes for children: A systematic review.

INTRODUCTION: Elective flexible bronchoscopy (FB) is now widely available and standard practice for a variety of indications in children with respiratory conditions. However, there is limited evidence regarding the utility of elective FB in children. This systematic review (SRs) aimed to determine the utility of FB on its impact in clinical decision making and quality of life (QoL). METHODS: We searched Pubmed, Cochrane central register of controlled trials, Embase, World Health Organization Clinical Trials Registry Platform and Cochrane database of SRs from inception to April 20, 2023. We included SRs and randomized controlled trials (RCTs) that used parallel group design (comparing use of elective FB vs. no FB, or a wait-list approach [early FB vs. usual wait FB]) in children aged ≤ 18 years. Our protocol was prospectively registered and used Cochrane methodology for systemic reviews of interventions. RESULTS: Our search identified 859 articles; 102 duplicates were removed, and 753 articles were excluded by title and abstract. Four full text articles were reviewed and subsequently excluded, as none met the inclusion criteria outlined in our patient, intervention, comparator, outcome measures framework. CONCLUSIONS: There is a paucity of high-quality RCT evidence to support the routine use of elective FB in children with respiratory conditions. However, available retrospective and a single prospective study demonstrate the high utility of FB in the elective pediatric setting. REGISTRATION: PROSPERO CRD42021291305.

Defining quality indicators, pharmaceutical care bundles and outcomes of clinical pharmacy service delivery using a Delphi consensus approach.

BACKGROUND: Clinical pharmacy quality indicators are often non-uniform and measure individual activities not linked to outcomes. AIM: To define a consensus agreed pharmaceutical care bundle and patient outcome measures across an entire state health service. METHOD: A four-round modified-Delphi approach with state Directors of Pharmacy was performed (n = 25). They were asked to rate on a 5-point Likert scale the relevance and measurability of 32 inpatient clinical pharmacy quality indicators and outcome measures. They also ranked clinical pharmacy activities in order from perceived most to least beneficial. Based upon these results, pharmaceutical care bundles consisting of multiple clinical pharmacy activities were formed, and relevance and measurability assessed. RESULTS: Response rate ranged from 40 to 60%. Twenty-six individual clinical pharmacy quality indicators reached consensus. The top ranked clinical pharmacy quality indicator was 'proportion of patients where a pharmacist documents an accurate list of medicines during admission'. There were nine pharmaceutical care bundles formed consisting between 3 and 7 activities. Only one pharmaceutical care bundle reached consensus: medication history, adverse drug reaction/allergy documentation, admission and discharge medication reconciliation, medication review, provision of medicines education and provision of a medication list on discharge. Sixteen outcome measures reached consensus. The top ranked were hospital acquired complications, readmission due to medication misadventure and unplanned readmission within 10 days. CONCLUSION: Consensus has been reached on one pharmaceutical care bundle and sixteen outcomes to monitor clinical pharmacy service delivery. The next step is to measure the extent of pharmaceutical care bundle delivery and the link to patient outcomes.

Ventilation-perfusion scan for diagnosing pulmonary embolism: do chest x-rays matter?

BACKGROUND: Ventilation-perfusion (V/Q) scan coupled with single photon emission computed tomography (SPECT) is commonly used for the diagnosis of pulmonary embolism (PE). An abnormal chest x-ray (CXR) is deemed to hinder the interpretation of V/Q scan and therefore a normal CXR is recommended prior to V/Q scan. AIMS: To determine if an abnormal CXR impacted on V/Q scan interpretation and subsequent management. METHODS: A retrospective cohort analysis of all patients who underwent a V/Q scan for diagnosis of suspected acute PE between March 2016 and 2022 was performed. CXR reports were reviewed and classified as normal or abnormal. Low-dose computerised tomography was routinely performed in patients above the age of 70. Data regarding V/Q scan results and subsequent management including initiation of anticoagulation for PE or further diagnostic investigations were collected. RESULTS: A total of 340 cases were evaluated. Of the positive V/Q scans (92/340), 98.3% of the normal CXR were anticoagulated compared to 100% of the abnormal CXR group. Of the negative V/Q scans (239/340), no cases were started on anticoagulation and no further investigations were performed across both normal and abnormal CXR groups. Indeterminate results occurred in only 9 cases with no significant difference in management between normal and abnormal CXR groups. CONCLUSION: An abnormal CXR does not affect the reliability of V/Q scan interpretation in the diagnosis of PE when coupled with SPECT. Unless clinically indicated, the mandate by clinical society guidelines for a normal CXR prior to V/Q should be revisited.

A core outcome set for bronchiectasis in children and adolescents for use in clinical research: an international consensus study.

Improving the treatment of non-cystic fibrosis bronchiectasis in children and adolescents requires high-quality research with outcomes that meet study objectives and are meaningful for patients and their parents and caregivers. In the absence of systematic reviews or agreement on the health outcomes that should be measured in paediatric bronchiectasis, we established an international, multidisciplinary panel of experts to develop a core outcome set (COS) that incorporates patient and parent perspectives. We undertook a systematic review from which a list of 21 outcomes was constructed; these outcomes were used to inform the development of separate surveys for ranking by parents and patients and by health-care professionals. 562 participants (201 parents and patients from 17 countries, 361 health-care professionals from 58 countries) completed the surveys. Following two consensus meetings, agreement was reached on a ten-item COS with five outcomes that were deemed to be essential: quality of life, symptoms, exacerbation frequency, non-scheduled health-care visits, and hospitalisations. Use of this international consensus-based COS will ensure that studies have consistent, patient-focused outcomes, facilitating research worldwide and, in turn, the development of evidence-based guidelines for improved clinical care and outcomes. Further research is needed to develop validated, accessible measurement instruments for several of the outcomes in this COS.

Pulmonary function outcomes after tuberculosis treatment in children: a systematic review and meta-analysis.

BACKGROUND: Despite tuberculosis (TB) being a curable disease, current guidelines fail to account for the long-term outcomes of post-tuberculosis lung disease-a cause of global morbidity despite successful completion of effective treatment. Our systematic review aimed to synthesise the available evidence on the lung function outcomes of childhood pulmonary tuberculosis (PTB). METHODS: PubMed, ISI Web of Science, Cochrane Library and ProQuest databases were searched for English-only studies without time restriction (latest search date 22 March 2023). Inclusion criteria were (1) patients who had TB with pulmonary involvement at age ≤18 years; (2) pulmonary function tests (PFTs) performed on patients after treatment completion; and (3) observational studies, including cohort and cross-sectional studies. We adhered to the recommendations of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: From 8040 records, 5 studies were included (involving n=567 children), with spirometry measures from 4 studies included in the meta-analyses. The effect sizes of childhood TB on forced expiratory volume in the first second and forced vital capacity z-scores were estimated to be -1.53 (95% CI -2.65, -0.41; p=0.007) and -1.93 (95% CI -3.35, -0.50; p=0.008), respectively. DISCUSSION: The small number of included studies reflects this under-researched area, relative to the global burden of TB. Nevertheless, as childhood PTB impacts future lung function, PFTs (such as spirometry) should be considered a routine test when evaluating the long-term lung health of children beyond their completion of TB treatment. PROSPERO registration number CRD42021250172.

Clinical determinants for State-Trait Anxiety Inventory of the parents of children with respiratory problems.

BACKGROUNDS: Understanding factors associated with anxiety of parents/carers of children with respiratory problems is clinically important yet there is relative paucity of data. In 106 children seen in the respiratory clinic of a pediatric hospital, we evaluated (a) the determinants for parental anxiety and (b) whether the anxiety scores correlate with quality-of-life (QoL) scores in the subset with chronic cough. METHODS: We opportunistically re-analyzed data of our main study that examined the benefits of using spirometry for pediatric respiratory consultation where parents completed an anxiety questionnaire (State-Trait Anxiety Inventory, STAI) pre- and postconsultation. A subset (children with chronic cough) also completed the parent-proxy quality-of-life (PC-QoL) tool. We computed the association between clinical characteristics and anxiety scores using multivariable regression and between the two patient-reported outcome measures using Spearman's correlation. RESULTS: The majority of parents/carers were women (n = 89, 84%). Most children (mean age = 10.9 years, SD = 3.7 years) were previously seen at the clinic (n = 67, 63.2%). In multivariate regression, parental anxiety score was significantly associated with reported presence of cough [coefficient ß = 17.31 (95% confidence interval 9.62, 25.1)] and lower forced expiratory volume in first second (FEV1 )/forced vital capacity (FVC) [-3.88 (-7.05, -0.71)] at preconsultation, but associated with cough only [coefficient ß = 12.04 (5.24, 18.84)] at postconsultation, all p < .05. STAI strongly correlated with PC-QoL scores at pre- but only modestly at postconsultation (rs = -.63 and -.39, respectively, p < .05). CONCLUSION: Parental anxiety levels of children attending respiratory clinics are influenced by the presence of cough and low FEV1 /FVC of their child and are associated with poorer QoL. These highlight the need for on-going research to reduce parental anxiety focusing on cough and lung function indices.

Evaluation of the sensory environment in a large tertiary ICU.

BACKGROUND: ICU survival is improving. However, many patients leave ICU with ongoing cognitive, physical, and/or psychological impairments and reduced quality of life. Many of the reasons for these ongoing problems are unmodifiable; however, some are linked with the ICU environment. Suboptimal lighting and excessive noise contribute to a loss of circadian rhythms and sleep disruptions, leading to increased mortality and morbidity. Despite long-standing awareness of these problems, meaningful ICU redesign is yet to be realised, and the 'ideal' ICU design is likely to be unique to local context and patient cohorts. To inform the co-design of an improved ICU environment, this study completed a detailed evaluation of the ICU environment, focussing on acoustics, sound, and light. METHODS: This was an observational study of the lighting and acoustic environment using sensors and formal evaluations. Selected bedspaces, chosen to represent different types of bedspaces in the ICU, were monitored during prolonged study periods. Data were analysed descriptively using Microsoft Excel. RESULTS: Two of the three monitored bedspaces showed a limited difference in lighting levels across the day, with average daytime light intensity not exceeding 300 Lux. In bedspaces with a window, the spectral power distribution (but not intensity) of the light was similar to natural light when all ceiling lights were off. However, when the ceiling lights were on, the spectral power distribution was similar between bedspaces with and without windows. Average sound levels in the study bedspaces were 63.75, 56.80, and 59.71 dBA, with the single room being noisier than the two open-plan bedspaces. There were multiple occasions of peak sound levels > 80 dBA recorded, with the maximum sound level recorded being > 105 dBA. We recorded one new monitor or ventilator alarm commencing every 69 s in each bedspace, with only 5% of alarms actioned. Acoustic testing showed poor sound absorption and blocking. CONCLUSIONS: This study corroborates other studies confirming that the lighting and acoustic environments in the study ICU were suboptimal, potentially contributing to adverse patient outcomes. This manuscript discusses potential solutions to identified problems. Future studies are required to evaluate whether an optimised ICU environment positively impacts patient outcomes.

A Methodological Approach to Identify Natural Compounds with Antifibrotic Activity and the Potential to Treat Pulmonary Fibrosis Using Single-Cell Sequencing and Primary Human Lung Macrophages.

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of the interstitial pneumonias. The cause of the disease is unknown, and new therapies that stop or reverse disease progression are desperately needed. Recent advances in next-generation sequencing have led to an abundance of freely available, clinically relevant, organ-and-disease-specific, single-cell transcriptomic data, including studies from patients with IPF. We mined data from published IPF data sets and identified gene signatures delineating pro-fibrotic or antifibrotic macrophages and then used the Enrichr platform to identify compounds with the potential to drive the macrophages toward the antifibrotic transcriptotype. We then began testing these compounds in a novel in vitro phenotypic drug screening assay utilising human lung macrophages recovered from whole-lung lavage of patients with silicosis. As predicted by the Enrichr tool, glitazones potently modulated macrophage gene expression towards the antifibrotic phenotype. Next, we assayed a subset of the NatureBank pure compound library and identified the cyclobutane lignan, endiandrin A, which was isolated from the roots of the endemic Australian rainforest plant, Endiandra anthropophagorum, with a similar antifibrotic potential to the glitazones. These methods open new avenues of exploration to find treatments for lung fibrosis.

Hemostatic Profiles of Patients Who Underwent Transcatheter Versus Surgical Aortic Valve Replacement Versus Percutaneous Coronary Intervention.

Guidelines for transcatheter aortic valve replacement (TAVR) antithrombotic prophylaxis are extrapolated predominantly from percutaneous coronary intervention (PCI) data. Here, we examined temporal coagulation changes occurring in the early perioperative period to determine the pathobiologic validity of this supposition. This was a prospective observational study of consecutive patients who underwent transfemoral TAVR (n = 27), PCI (n = 12), or surgical aortic valve replacement (SAVR) requiring cardiopulmonary bypass and cross-clamping (n = 12). Blood samples were taken at 4 time points: T1 (baseline), after general anesthesia or sedation; T2, after heparin administration; T3, at the end of the procedure; and T4, 6 hours after the procedure. The samples were assessed concurrently using standard laboratory coagulation tests and viscoelastic tests of whole blood clotting, including the latest generation thromboelastometry (ROTEM sigma) and thromboelastometry (TEG 6s). Patients in the TAVR cohort were older and a had lower baseline hemoglobin level than patients in the PCI and SAVR cohorts. The baseline platelet function was similar between the TAVR and PCI cohorts and impaired in the SAVR cohort Figure S1. The baseline hemostatic measures were comparable among cohorts. Regarding the per-patient change from baseline, the TAVR cohort showed an overall more prothrombotic state than the other cohorts, with the most marked differences from the SAVR cohort after intraoperative heparin administration and from the PCI cohorts 6 hours after the procedure. In addition, the ROTEM and TEG parameters were well correlated but not interchangeable. In conclusion, patients who underwent TAVR have a more prothrombotic hemostatic profile than PCI and SAVR patients. These findings question the current guidelines that extrapolate antithrombotic regimens from PCI to TAVR settings.

Phenotypic Features of Pediatric Bronchiectasis Exacerbations Associated With Symptom Resolution After 14 Days of Oral Antibiotic Treatment.

BACKGROUND: Respiratory exacerbations in children and adolescents with bronchiectasis are treated with antibiotics. However, antibiotics can have variable interindividual effects when treating exacerbations. RESEARCH QUESTION: Can phenotypic features associated with symptom resolution after a 14-day course of oral antibiotics for a nonsevere exacerbation of bronchiectasis be identified? STUDY DESIGN AND METHODS: Combining data from two multicenter randomized controlled trials, we identified 217 children with bronchiectasis assigned to at least 14 days of oral antibiotics to treat nonsevere (nonhospitalized) exacerbations. Univariable and then multivariable logistic regression were used to identify factors associated with symptom resolution within 14 days of commencing antibiotics. Identified associations were re-evaluated by mediation analysis. RESULTS: Of the 217 study participants (52% male patients), 41% were Indigenous (Australian First Nations, New Zealand Maori, or Pacific Islander). The median age was 6.6 years (interquartile range, 4.0-10.1 years). By day 14, symptoms had resolved in 130 children (responders), but persisted in the remaining 87 children (nonresponders). Multivariable analysis found those who were Indigenous (adjusted OR [AOR], 3.59; 95% CI, 1.35-9.54) or showed new abnormal auscultatory findings (AOR, 3.85; 95% CI, 1.56-9.52) were more likely to be responders, whereas those with multiple bronchiectatic lobes at diagnosis (AOR, 0.66; 95% CI, 0.46-0.95) or higher cough scores when starting exacerbation treatment (AOR, 0.55; 95% CI, 0.34-0.90) were more likely to be nonresponders. Detecting a respiratory virus at the beginning of an exacerbation was not associated with antibiotic failure at 14 days. INTERPRETATION: Children with Indigenous ethnicity, milder bronchiectasis, mild exacerbations (low reported cough scores), or new abnormal auscultatory signs are more likely to respond to appropriate oral antibiotics than those without these features. These patient and exacerbation phenotypes may assist clinical management and development of biomarkers to identify those whose symptoms are more likely to resolve after 14 days of oral antibiotics. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; Nos.: ACTRN12612000011886 and ACTRN12612000010897; URL: https://www.anzctr.org.au.

Perioperative Blood Transfusions and Anastomotic Leak After Colorectal Surgery for Cancer in an Australian Hospital.

PURPOSE: Peri-operative blood transfusion has been identified as a risk factor for anastomotic leak in recent studies, but little is known about which patients are at risk for blood transfusion. This study aims to assess the relationship between blood transfusion and anastomotic leak and factors predisposing to leak in patients undergoing colorectal cancer surgery. METHODS: This retrospective cohort study was conducted in a tertiary hospital in Brisbane, Australia, between 2010 and 2019. A total of 522 patients underwent resection of colorectal cancer with primary anastomosis with no covering stoma and the prevalence of anastomotic leak was compared between those who had had perioperative blood transfusion(s) and those who had not. RESULTS: A total of 19 of 522 patients undergoing surgery for colorectal cancer had developed an anastomotic leak (3.64%). 11.3% of patients who had had a perioperative blood transfusion developed an anastomotic leak whereas 2.2% of patients who had not had a blood transfusion developed an anastomotic leak (p = 0.0002). Patients undergoing procedure on their right colon had proportionally more blood transfusions and this approached statistical significance (p = 0.06). Patients who received a greater quantity of units of blood transfusion prior to their diagnosis of anastomotic leak were more likely to develop an anastomotic leak (p = 0.001). CONCLUSION: Perioperative blood transfusions are associated with a significantly increased risk of an anastomotic leak following bowel resection with primary anastomosis for colorectal cancer.

Does routine spirometry impact on clinical decisions and patient-related outcome measures of children seen in respiratory clinics: an open-label randomised controlled trial.

INTRODUCTION: There is limited evidence on the efficacy of using spirometry routinely in paediatric practice for improving outcomes. OBJECTIVE: To determine whether the routine use of spirometry alters clinical decisions and patient-related outcome measures for children managed by respiratory paediatricians. METHODS: We undertook a parallel open-label randomised controlled trial involving children (aged 4-18 years) able to perform spirometry in a specialist children's hospital in Australia. Children were randomised to either routine use of spirometry (intervention) or clinical review without use of spirometry (control) for one clinic visit. The primary outcomes were the (a) proportion of children with 'any change in clinical decisions' and (b) 'change score' in clinical decisions. Secondary outcomes were change in patient-related outcome measures assessed by State-Trait Anxiety Inventory (STAI) and Parent-Proxy QoL questionnaire for paediatric chronic cough (PC-QoL). RESULTS: Of 136 eligible children, 106 were randomised. Compared with controls, the intervention group had significantly higher proportion of children with 'any change in clinical decisions' (n=54/54 (100%) vs n=34/52 (65.4%), p<0.001) and higher clinical decision 'change score' (median=2 (IQR 1-4) vs 1 (0-2), p<0.001). Also, improvement was significantly greater in the intervention group for overall STAI score (median=-5 (IQR -10 to -2) vs -2.5 (-8.5, 0), p=0.021) and PC-QoL social domain (median=3 (IQR 0 to 5) vs 0 (-1, 1), p=0.017). CONCLUSION: The routine use of spirometry in children evaluated for respiratory issues at clinical outpatient review is beneficial for optimising clinical management and improving parent psychosocial well-being. REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12619001686190.