Peter A. Wark

Background: Distal intestinal obstruction syndrome (DIOS) presents significant management challenges for people with cystic fibrosis (pwC). We evaluated the treatment outcomes and identified risk factors associated with the need for surgical intervention in patients admitted with DIOS. Methods: We conducted a retrospective case series of 96 encounters of DIOS over a 20-year period, observing outcomes between cases of medical management versus those requiring for operative intervention. To our knowledge, this is the largest Australian study to review intervention in DIOS. Results: Among the patients studied, 94.8% were successfully treated non-surgically. Using computed tomography (CT) confirmation of DIOS as the gold standard, only 9.1% of abdominal x-rays were accurate in finding DIOS. Gastrografin was used in half of cases and was associated with a shorter recovery time. One in 16 patients required operative management, with two cases experiencing surgery following prolonged medical treatment. A history of previous laparotomy increased the odds of requiring surgical intervention by 16 times (95% CI: 1.2-209.9, P = 0.035), while a history of meconium ileus increased the odds by 15.6 times (95% CI: 1.2-204.8, P = 0.036). All patients who underwent surgery also had pancreatic insufficiency. Conclusions: Medical management was successful in the majority of DIOS presentations. Our study emphasizes a low threshold for abdominal CT scans to identify complete DIOS in high-risk patients, particularly those with a history of laparotomy or meconium ileus, who may require surgical intervention. Furthermore, we advocate for the adjunctive use of Gastrografin alongside medical management. Future research should refine protocols for these high-risk groups to improve outcomes and reduce morbidity.

Treatment targets in severe asthma have evolved towards a remission-focused paradigm guided by precision medicine. This novel concept requires a shift from evaluating the efficacy of therapies based on a single outcome at a single time point to an outcome that captures the complexity of asthma remission involving several domains assessed over a sustained period. Since the concept is still emerging, multiple definitions have been proposed, ranging from symptom control and exacerbation-free to resolution of underlying pathobiology, with varying rigour in each parameter. Understanding the strengths and weaknesses of the current construct is needed to progress further. We conducted a roundtable discussion with 27 asthma experts to address this issue, and discussions were narratively synthesised and summarised. The participants observed that between one in three and one in five people treated with targeted biological therapies or macrolides experience low disease activity over a sustained period. They unanimously agreed that labelling the attained clinical state as clinical remission is useful as a clinical (e.g., facilitating a treat-to-target approach), policy (e.g., widening eligibility criteria for biologics), and scientific (e.g., a path to understanding cure) tool. Current remission rates vary significantly due to definition variability. When assessing remission, it is essential to consider confounding factors (e.g., steroid use for adrenal insufficiency). More research is required to reach an acceptable definition, and including the patient's voice in such research is essential. In conclusion, the concept of treatment-induced clinical remission is possible and valuable in asthma. However, further refinement of the definition is required.

Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is a term used to describe a patient with coexisting clinical features of asthma and COPD. We have previously reported that epithelial to mesenchymal transition (EMT) is active in the lungs of patients with COPD however, EMT in ACO remains an unexplored area. We hypothesize that EMT is an active process in ACO. In this cross-sectional study, large airway endobronchial biopsy (EBB) tissues from patients with asthma (14), COPD (22), current (CS) and ex-smokers (ES), and ACO (12) were immunohistochemically stained for EMT markers (E and N cadherin, vimentin, S100A4, and Collagen IV) and compared with 12 current smokers with normal lung function (NLFS) and 10 non-smoking healthy control (HC) subjects. In addition, air-liquid interface (ALI) cell cultures were performed and cells from patients with ACO and HC were treated with TGF-β, IL-13 and cigarette smoke extract (CSE). Later cells from ALI cultures were lysed for Immunoblotting. Immunostained tissues were enumerated for percent expression of E and N-Cadherin in the epithelium, vimentin and S100A4 positive cells both in the epithelium and reticular basement membrane (RBM). Additionally, the degree of RBM fragmentation was evaluated, a key tissue structural marker of EMT. Compared to healthy controls and asthmatics, ACO had the greatest fragmentation of RBM (P < 0.01). ACO also had substantially decreased percentage expression of E-cadherin (P <0.01), increase percentage of N-cadherin expression, and higher vimentin and S100A4 positive basal cells, in comparison to healthy controls. In the RBM of ACO, S100A4 positive cells (P <0.05) and Vimentin-positive cells were markedly higher in comparison to HC. Similar changes were observed with western blots in response to Th-2 cytokine IL-13, CSE and EMT activator TGF-β. These data are suggestive of active EMT in ACO. Additionally, 50% of the patients with ACO were on 800 mcg/day inhaled corticosteroid (ICS) treatment which may have abrogated some EMT activity; however, it suggests protective effects of ICS as we previously reported in COPD. Studies with larger cohorts are needed to further confirm ICS effects in ACO.

Background: Cystic fibrosis (CF) registries capture important information in high-burden health domains to support improvement in health outcomes, although a number of unanswered questions persist, as follows. 1) Do CF registries utilise implementation science strategies to improve patient outcomes? 2) Which implementation strategies have been engaged? 3) Has the engagement of these strategies been effective in improving clinical outcomes? Methods: We undertook a systematic review to exploring the use of implementation science strategies by CF registries for healthcare improvement. We searched MEDLINE, Embase, Scopus, Emcare and Web of Science databases for use of Expert Recommendations for Implementing Change (ERIC) implementations and use of the Knowledge to Action framework for improvement. We used the Risk of Bias in Non-randomised Studies - of Interventions tool for risk-of-bias assessment. Results: 1974 citations were identified and 12 studies included. Included studies described 45 ERIC implementation strategies from nine categories. Strategies included "use evaluative and iterative strategies" (n=9) and "develop stakeholder interrelationships" (n=10). Least-used strategies were "utilise financial strategies" (n=1), "support clinicians" category (n=3) and "provide interactive assistance" (n=2). All 12 studies utilised monitoring of knowledge use, and assessing barriers and facilitators of knowledge use. Only seven studies utilised mechanisms to sustain knowledge use. Conclusions: Reported studies describe significant benefits in important CF outcomes for people with CF reported at site-specific and population levels. Studies highlighted the importance of governance, leadership, patient and family engagement, multidisciplinary engagement, quality improvement, data and analytics and research. The ready availability of clinical performance data feedback to clinicians and patients by CF registries is likely to strengthen the effectiveness of CF registries in driving healthcare improvement within a learning health system.

Influenza vaccine effectiveness and immunogenicity can be compromised with repeated vaccination. We assessed immunological markers in a cohort of healthcare workers (HCW) from six public hospitals around Australia during 2020-2021. Sera were collected pre-vaccination and ~14 and ~ 180 days post-vaccination and assessed in haemagglutination inhibition assay against egg-grown vaccine and equivalent cell-grown viruses. Responses to vaccination were compared by the number of prior vaccinations. Baseline sera were available for 595 HCW in 2020 and 1031 in 2021. 5% had not been vaccinated during five years prior to enrolment and 55% had been vaccinated every year. Post-vaccination titres for all vaccine antigens were lowest among HCW vaccinated in all 5-prior years and highest among HCW with 0 or 1 prior vaccinations, even after adjustment. This was observed for both influenza A subtypes and was dependent on pre-vaccination titre. Expanded cohorts are needed to better understand how this translates to vaccine effectiveness.

A Multi-center, Randomized, Double-blind, Parallel-group, Placebo-controlled Study of Mepolizumab 100 mg SC as add-on Treatment in Participants With COPD Experiencing Frequent Exacerbations and Characterized by Eosinophil Levels (Study 208657)

APPLAUD: A Double-Blind, Randomized, Placebo-Controlled, Phase II Study of the Efficacy and Safety of LAU-7b in the Treatment of Cystic Fibrosis in Adults

A Multi-center, Randomized, Double-blind, Placebo Controlled, Parallel Group Study to Compare Cessation Versus Continuation of Long-term Mepolizumab Treatment in Patients With Severe Eosinophilic Asthma (201810)