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Interrupting the transmission of airborne (<≈5 µm) respiratory pathogens indoors is not a new challenge, but it has attracted unprecedented interest due to the COVID-19 pandemic during 2020-2021. However, bacterial respiratory pathogens with known or potential airborne transmission account for an appreciable proportion of the communicable disease burden globally. We aimed to systematically review quantitative, laboratory-based studies of air disinfection techniques for airborne respiratory bacteria. Three databases (PubMed, Web of Science, Scopus) were searched, following PRISMA guidelines. A total of 9596 articles were identified, of which 517 were assessed in detail and of which 26 met the inclusion and quality assessment criteria. Seven air disinfection techniques, including UV-C light, filtration, and face masks, among others, were applied to 13 different bacterial pathogens. More than 80% of studies suggested that air disinfection techniques were more effective at inactivating or killing bacteria than the comparator or baseline condition. However, it was not possible to compare these techniques because of methodological heterogeneity and the relatively small number of the studies. Laboratory studies are useful for demonstrating proof-of-concept and performance under controlled conditions. However, the generalisability of their findings to person-to-person transmission in real-world settings is unclear for most of the pathogens and techniques we assessed.

Background: Antimicrobial resistance in cystic fibrosis (CF) Pseudomonas aeruginosa airway infection is complex and often attributed to chromosomal mutations. How these mutations emerge in specific strains or whether particular gene mutations are clinically informative is unclear. This study focused on oprD, which encodes an outer membrane porin associated with carbapenem resistance when it is downregulated or inactivated., Aim: Determine how mutations in oprD emerge in two prevalent Australian shared CF strains of P. aeruginosa and their clinical relevance., Methods: The two most common shared CF strains in Queensland were investigated using whole genome sequencing and their oprD sequences and antimicrobial resistance phenotypes were established. P. aeruginosa mutants with the most common oprD variants were constructed and characterised. Clinical variables were compared between people with or without evidence of infection with strains harbouring these variants., Results: Frequently found nonsense mutations arising from a 1-base pair substitution in oprD evolved independently in three sub-lineages, and are likely major contributors to the reduced carbapenem susceptibility observed in the clinical isolates. Lower baseline FEV 1 %predicted was identified as a risk factor for infection with a sub-lineage (odds ratio=0.97; 95% confidence interval 0.96-0.99; p<0.001). However, acquiring these sub-lineage strains did not confer an accelerated decline in FEV 1 nor increase the risk of death/lung transplantation., Conclusions: Sub-lineages harbouring specific mutations in oprD have emerged and persisted in the shared strain populations. Infection with the sub-lineages was more likely in people with lower lung function, but this was not predictive of a worse clinical trajectory., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Pseudomonas aeruginosa is one of the principal pathogens implicated in respiratory infections of patients with cystic fibrosis (CF) and non-CF bronchiectasis. Previously, we demonstrated that impaired serum-mediated killing of P. aeruginosa was associated with increased severity of respiratory infections in patients with non-CF bronchiectasis. This inhibition was mediated by high titers of O-antigen-specific IgG2 antibodies that cloak the surface of the bacteria, blocking access to the membrane. Infection-related symptomatology was ameliorated in patients by using plasmapheresis to remove the offending antibodies. To determine if these inhibitory "cloaking antibodies" were prevalent in patients with CF, we investigated 70 serum samples from patients with P. aeruginosa infection and 5 from those without P. aeruginosa infection. Of these patients, 32% had serum that inhibited the ability of healthy control serum to kill P. aeruginosa. Here, we demonstrate that this inhibition of killing requires O-antigen expression. Furthermore, we reveal that while IgG alone can inhibit the activity of healthy control serum, O-antigen-specific IgA in patient sera can also inhibit serum-killing. We found that antibody affinity, not just titer, was also important in the inhibition of serum-mediated killing. These studies provide novel insight into cloaking antibodies in human infection and may provide further options in CF and other diseases for treatment of recalcitrant P. aeruginosa infections.

Mycobacterium abscessus, a multidrug-resistant nontuberculous mycobacterium, has emerged as a major pathogen affecting people with cystic fibrosis (CF). Although originally thought to be acquired independently from the environment, most individuals are infected with one of several dominant circulating clones (DCCs), indicating the presence of global transmission networks of M. abscessus. How and when these clones emerged and spread globally is unclear. Here, we use evolutionary analyses of isolates from individuals both with and without CF to reconstruct the population history, spatiotemporal spread and recent transmission networks of the DCCs. We demonstrate synchronous expansion of six unrelated DCCs in the 1960s, a period associated with major changes in CF care and survival. Each of these clones has spread globally as a result of rare intercontinental transmission events. We show that the DCCs, but not environmentally acquired isolates, exhibit a specific smoking-associated mutational signature and that current transmission networks include individuals both with and without CF. We therefore propose that the DCCs initially emerged in non-CF populations but were then amplified and spread through the CF community. While individuals with CF are probably the most permissive host, non-CF individuals continue to play a key role in transmission networks and may facilitate long-distance transmission., (© 2021. The Author(s).)

Background: SARS-CoV-2 poses a considerable threat to those living in residential aged care facilities (RACF). RACF COVID-19 outbreaks have been characterised by the rapid spread of infection and high rates of severe disease and associated mortality. Despite a growing body of evidence supporting airborne transmission of SARS-CoV-2, current infection control measures in RACF including hand hygiene, social distancing, and sterilisation of surfaces, focus on contact and droplet transmission. Germicidal ultraviolet (GUV) light has been used widely to prevent airborne pathogen transmission. Our aim is to investigate the efficacy of GUV technology in reducing the risk of SARS-CoV-2 infection in RACF., Methods: A multicentre, two-arm double-crossover, randomised controlled trial will be conducted to determine the efficacy of GUV devices to reduce respiratory viral transmission in RACF, as an adjunct to existing infection control measures. The study will be conducted in partnership with three aged care providers in metropolitan and regional South Australia. RACF will be separated into paired within-site zones, then randomised to intervention order (GUV or control). The initial 6-week period will be followed by a 2-week washout before crossover to the second 6-week period. After accounting for estimated within-zone and within-facility correlations of infection, and baseline infection rates (10 per 100 person-days), a sample size of n = 8 zones (n = 40 residents/zone) will provide 89% power to detect a 50% reduction in symptomatic infection rate. The primary outcome will be the incidence rate ratio of combined symptomatic respiratory infections for intervention versus control. Secondary outcomes include incidence rates of hospitalisation for complications associated with respiratory infection; respiratory virus detection in facility air and fomite samples; rates of laboratory confirmed respiratory illnesses and genomic characteristics., Discussion: Measures that can be deployed rapidly into RACF, that avoid the requirement for changes in resident and staff behaviour, and that are effective in reducing the risk of airborne SARS-CoV-2 transmission, would provide considerable benefit in safeguarding a highly vulnerable population. In addition, such measures might substantially reduce rates of other respiratory viruses, which contribute considerably to resident morbidity and mortality. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12621000567820 (registered on 14th May, 2021)., (© 2021. The Author(s).)

Non-tuberculous mycobacteria (NTM) are an emerging group of pulmonary infectious pathogens of increasing importance to the management of patients with cystic fibrosis (CF). NTM include slow-growing mycobacteria such as Mycobacterium avium complex (MAC) and rapidly growing mycobacteria such as Mycobacterium abscessus. The incidence of NTM in the CF population is increasing and infection contributes to significant morbidity to the patient and costs to the health system. Treating M. abscessus requires the combination of multiple costly antibiotics for months, with potentially significant toxicity associated with treatment. Although international guidelines for the treatment of NTM infection in CF are available, there are a lack of robust pharmacokinetic studies in CF patients to inform dosing and drug choice. This paper aims to outline the pharmacokinetic and pharmacodynamic factors informing the optimal treatment of NTM infections in CF., (© 2021. Crown.)

Background: Chronic lung infections and their treatment pose risks for the development of antimicrobial resistance (AMR) in people with cystic fibrosis (PWCF). In this study, we evaluated the attitudes of healthcare providers' (HCP) and PWCF or their parents' toward AMR within the international CF community., Methods: HCP and PWCF identified through listservs and CF-related organizations were asked to complete an AMR centered survey, with additional questions on antimicrobial stewardship (AMS) for HCP. Descriptive analyses are reported., Results: The responding 443 HCP and 464 PWCF/Parents were from 30 and 25 countries, respectively. Sixty-two percent of HCP and 56% of PWCF stated they were "very concerned" about AMR, with Pseudomonas spp. and Burkholderia spp. considered the most concerning organisms for both HCP and PWCF/Parents. Non-tuberculous mycobacteria were of greater concern to HCP compared to PWCF/Parents. There was a discrepancy regarding AMR education to PWCF, with 80% of HCP stating having discussed this with PWCF/Parents, but only 50% of PWCF recalling such discussions., Conclusion: These results highlight that AMR is relevant to CF HCP and PWCF internationally, indicating that educational tools and research are warranted., (Copyright © 2020. Published by Elsevier B.V.)

Introduction. Mycobacterium abscessus complex (MABSC) is an environmental organism and opportunistic pathogen. MABSC pulmonary infections in people with cystic fibrosis are of growing clinical concern. Resistance data guide the use of macrolides and amikacin in MABSC pulmonary disease treatment. MABSC can acquire resistance against macrolides or amikacin via 23S or 16S rRNA gene mutations, respectively. Gap Statement. Current culture-based methods for MABSC detection and antibiotic resistance characterization are typically prolonged, limiting their utility to directly inform treatment or clinical trials. Culture-independent molecular methods may help address this limitation. Aim. To develop real-time PCR assays for characterization of key 23S or 16S rRNA gene mutations associated with constitutive resistance in MABSC. Methodology. We designed two real-time PCR assays to detect the key 23S and 16S rRNA gene mutations. The highly conserved nature of rRNA genes was a major design challenge. To reduce potential cross-reactivity, primers included non-template bases and targeted single-nucleotide polymorphisms unique to MABSC. We applied these assays, as well as a previously developed real-time PCR assay for MABSC detection, to 968 respiratory samples from people with cystic fibrosis. The results from the molecular methods were compared to those for gold standard culture methods and 23S and 16S rRNA gene sequencing. Results. The real-time PCR MABSC detection assay provided a sensitivity of 83.8 % and a specificity of 97.8 % compared to culture. The results from the real-time PCR resistance detection assays were mostly concordant (>77.4 %) with cultured isolate sequencing. The real-time PCR resistance detection assays identified several samples harbouring both resistant and susceptible MABSC, while culture-dependent methods only identified susceptible MABSC in these samples. Conclusion. Using the molecular methods described here, results for health care providers or researchers could be available days or weeks earlier than is currently possible via culture-based antibiotic susceptibility testing.

What is the impact of including an allied health assistant (AHA) role on physiotherapy service delivery in an acute respiratory service? A pragmatic pre-post design study examined physiotherapy services across two 3-month periods: current service delivery [P1] and current service delivery plus AHA [P2]. Clinical and non-clinical activity quantified as number, type and duration (per day) of all staff activity categorised for skill level (AHA, junior, senior). Physiotherapy service delivery increased in P2 compared to P1 (n = 4730 vs n = 3048). Physiotherapists undertook fewer respiratory (p < 0.001) and exercise treatments (p < 0.001) but increased reviews for inpatients (p < 0.001) and at multidisciplinary clinics in P2 (56% vs 76%, p < 0.01). The AHA accounted for 20% of all service provision. AHA activity comprised mainly non-direct clinical care including oversight of respiratory equipment use (e.g. supply, set-up, cleaning, loan audits) and other patient-related administrative tasks associated with delegation handovers, supervision and clinical documentation (72%), delegated supervision of established respiratory (5%) and exercise treatments (10%) and delegated exercise tests (3%). The AHA completed most of the exercise tests (n = 25). AHA non-direct clinical tasks included departmental management activities (11%). No adverse events were reported. AHA inclusion in an acute respiratory care service changed physiotherapy service provision. The AHA completed delegated routine clinical and non-clinical tasks. Physiotherapists increased clinic activity and annual reviews. Including an AHA role offers sustainable options for enhancing physiotherapy service provision in acute respiratory care.

Genetic signatures caused by demographic and adaptive processes during past climatic shifts can inform predictions of species' responses to anthropogenic climate change. To identify these signatures in Acropora tenuis , a reef-building coral threatened by global warming, we first assembled the genome from long reads and then used shallow whole-genome resequencing of 150 colonies from the central inshore Great Barrier Reef to inform population genomic analyses. We identify population structure in the host that reflects a Pleistocene split, whereas photosymbiont differences between reefs most likely reflect contemporary (Holocene) conditions. Signatures of selection in the host were associated with genes linked to diverse processes including osmotic regulation, skeletal development, and the establishment and maintenance of symbiosis. Our results suggest that adaptation to post-glacial climate change in A. tenuis has involved selection on many genes, while differences in symbiont specificity between reefs appear to be unrelated to host population structure., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Purpose of Review: With improving life expectancy and quality of life, sexual and reproductive health (SRH) has become an increasingly important aspect of patient-centered cystic fibrosis care. This review aims to describe advances in cystic fibrosis-related SRH and highlight optimal practices., Recent Findings: Recent publications suggest that people with cystic fibrosis follow a similar trajectory of sexual development and activity as their noncystic fibrosis peers, although contraception use is lower. Although fertility is reduced in patients with cystic fibrosis, improved survival and assisted reproductive technologies have led to an increasing pursuit and incidence of pregnancy. Cystic fibrosis transmembrane regulator modulators that correct the underlying cystic fibrosis defect might improve fertility and thus far appear safe in pregnancy, though data are limited.Despite medical knowledge of SRH in cystic fibrosis, patients continue to report they lack sufficient education about these aspects of their healthcare, and cystic fibrosis multidisciplinary teams are ill prepared to counsel their patients., Summary: Understanding of the effects of cystic fibrosis on SRH continues to improve, although many questions remain regarding optimal care from the choice of contraception to the safety of cystic fibrosis-specific medications in pregnancy. Further development of cystic fibrosis-informed interdisciplinary specialist networks and a wider framework of practice would both enhance health outcomes and better support patients.

International reports indicate a rising incidence of nontuberculous mycobacterial (NTM) disease. Many infectious diseases have seasonal variation in incidence, and major weather events and climate change have been implicated. The aim of this study was to explore the relationship between climate variables and NTM incident cases in Queensland, Australia., Methods: NTM data were obtained from the Queensland notifiable conditions database for the period 2001-2016. Rainfall and temperature data were obtained from the Australian Bureau of Meteorology. Poisson regression models were used to assess notification rates (incidence cases per 100,000 population) over time and to estimate incidence rate ratios (IRR). Cross correlation coefficients were used to examine the relationship between rainfall and temperature data and NTM incidence over time in each Hospital and Health Service (HHS)., Results: 12,219 NTM cases were reported. The most common species was M. intracellulare (39.1%), followed by M. avium (9.8%), M abscessus (8.5%), M. fortuitum (8.3%), M. chelonae (3.3%), and M. kansasii (2.4%). The estimated incidence rate increased from 11.10 (95% CI 8.10-15.22) in 2001 to 25.88 (95%CI 21.78-30.73) per 100,000 in 2016. The estimated IRR increased for all common species, except M. kansasii. Although increased IRRs were observed for most NTM species, geospatial heterogeneity was observed. The effect of rainfall and temperature on NTM incidence differed between species and geographic regions., Conclusions: The incidence of NTM infections increased between 2001 and 2016. Variations in temperature and rainfall may play a role in environmental exposure to some species of NTM. Spatial variation in IRR suggests that there may also be other environmental factors that influence transmission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A key measure of lung function in people with Cystic Fibrosis (CF) is Forced Expiratory Volume in the first second FEV 1 percent predicted (FEV 1 pp). This study aimed to address challenges in identifying predictors of FEV 1 pp, specifically dealing with non-linearity and the censoring effect of death. Data was obtained from a large multi-centre Australian Cystic Fibrosis Data Registry (ACFDR). A linear mixed model was used to study FEV 1 pp as the endpoint. There were 3655 patients (52.4% male) included in our study. Restricted cubic splines were used to fit the non-linear relationship between age of visit and FEV 1 pp. The following predictors were found to be significant in the multivariate model: age of patient at visit, BMI z-score, age interaction with lung transplantation, insulin dependent diabetes, cirrhosis/portal hypertension, pancreatic insufficiency, Pseudomonas aeruginosa infection and baseline variability in FEV 1 pp. Those with P. aeruginosa infection had a lower mean difference in FEV 1 pp of 4.7 units, p < 0.001 compared to those who did not have the infection. Joint modelling with mortality outcome did not materially affect our findings. These models will prove useful for to study the impact of CFTR modulator therapies on rate of change of lung function among patients with CF.

Chytridiomycosis has been a key driver of global frog declines and extinctions, particularly for high-altitude populations across Australia and the Americas. While recent evidence shows some species are recovering, the extent of such recoveries and the mechanisms underpinning them remain poorly resolved. We surveyed the historical latitudinal and elevational range of four Australian rainforest frogs that disappeared from upland sites between 1989 and 1994 to establish their contemporary distribution and elevational limits, and investigate factors affecting population recovery. Five rainforest streams were surveyed from mountain-base to summit (30 sites in total), with swabs collected from the target species (Litoria dayi, L. nannotis, L. rheocola, and L. serrata) to determine their infection status, and data loggers deployed to measure microclimatic variation across the elevational gradient. Infection probability increased with elevation and canopy cover as it was tightly and inversely correlated with stream-side air temperature. Occupancy patterns suggest varying responses to this disease threat gradient. Two species, L. rheocola and L. serrata, were found over their full historical elevational range (≥1,000 m above sea level [asl]), while L. dayi was not detected above 400 m (formerly known up to 900 m asl) and L. nannotis was not detected above 800 m (formerly known up to 1,200 m asl). Site occupancy probability was negatively related to predicted infection prevalence for L. dayi, L. nannotis, and L. rheocola, but not L. serrata, which appears to now tolerate high fungal burdens. This study highlights the importance of environmental refuges and connectivity across disease risk gradients for the persistence and natural recovery of frogs susceptible to chytridiomycosis. Likewise, in documenting both interspecific variation in recovery rates and intraspecific differences between sites, this study suggests interactions between disease threats and host selection exist that could be manipulated. For example, translocations may be warranted where connectivity is poor or the increase in disease risk is too steep to allow recolonization, combined with assisted selection or use of founders from populations that have already undergone natural selection., (© 2020 by the Ecological Society of America.)

Introduction: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems. Research and innovations in novel therapeutic agents and health care delivery have resulted in dramatic improvements in quality of life and survival for people with CF. Despite this, significant disease burden persists for many and this is compounded by disparities in treatment access and care which globally necessitates further work to improve outcomes. Because of the advent of numerous therapies which include gene-targeted modulators in parallel with specialized care delivery models, innovative efforts continue., Areas Covered: In this review, we discuss the available data on investigational agents in clinical development and currently available treatments for CF. We also evaluate approaches to care delivery, consider treatment gaps, and propose future directions for advancement., Expert Opinion: Since the discovery of the CF gene, CFTR modulators have provided a hallmark of success, even though it was thought not previously possible. This has led to reinvigorated efforts and innovations in treatment approaches and care delivery. Numerous challenges remain because of genetic and phenotypic heterogeneity, access issues, and therapeutic costs, but the collaborative approach between stakeholders for continued innovation fuels optimism. Abbreviations: CF cystic fibrosis; CFF Cystic Fibrosis Foundation (USA); CFTR cystic fibrosis transmembrane regulator; CRISPR clustered regularly interspaced short palindromic repeats; COX cyclo oxygenase; FDA US Food and Drug Administration; FEV1% forced expiratory volume in one second % predicted; F508del deletion of phenylalanine (F) in the 508th position (most common mutation); G551D substitution of the amino acid glycine by aspartate at position 551 in the nucleotide binding domain-1 of the CFTR gene; LMIC low- and middle-income country; LTB4 leukotriene B4; MDT multi-disciplinary care team; NO nitric oxide; NSAIDs non-steroidal anti-inflammatory drugs; SLPI secretory leukocyte protease inhibitor.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development., Competing Interests: Declaration of Competing Interest NMH serves as a consultant through her institution in her role as Executive Director of the CF Therapeutics Development Network Coordinating Center (CF TDNCC) and has received personal consulting fees from Kala Pharmaceuticals and Calithera. She has received grant funding from the Cystic Fibrosis Foundation (CFF) and National Institutes of Health (NIH). SvKR has received personal consulting fees from Antabio, Proteostasis Therapeutics (PTI), and Vertex Pharmaceuticals (VRTX). She has received grant support to her institution for her participation in the European Union HORIZON 2020 work. DPN serves as a consultant through his institution in his role as Medical Director of CF TDNCC. He has received grant support to his Institution from the CFF and Gilead Sciences. DRV has received personal consulting fees from AbbVie, Albumedix, AN2, Aradigm, Armata, Arrevus, Calithera, Chiesi USA, Cipla, Corbus, CFF, Eloxx, Enbiotix, Eveo, Galephar, Horizon, IBF, ICON clinical sciences, Ionis, Kala, Merck, Microbion, NDA, Protalix, PTC, Pulmocide, Recida, Savara, Vast, and VRTX. JCD has received other support from Aligipharma AS, Bayer AG, BI, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics, ProQR Therapeutics, PTI, Raptor Pharamceuticals, VRTX, Enterprise, Novartis, Pulmocide, Flately and Teva for advisory board and educational activities. She has received grant support from the CF Trust. TL has received personal fees from Alan Boyd Consultants, Ltd for his participation in DSMB activities. FAR has received personal consulting fees from Novartis, Bayer, Roche, and Genentech for participation in CF related consulting activities. He has received grant support to his institution from VRTX for his participation as site PI in multicenter trials which they have funded as well as personal consulting fees. MWK has received personal consulting fees for advisory board participation, grant support to his institution for clinical trial participation, and non-financial support from VRTX, Savara, Laurent, Corbus Pharmaceuticals, PTC, and AzurRx. He has received personal consulting fees and non-financial support from Chiesi, Celtaxsys, Merck, and Kala. Personal consulting fees were received from Albumedix, Paranta, Protalix, Santhera, pH Pharma, Novartis, Ionis, the Italian Cystic Fibrosis Foundation, and the Food and Drug Administration. Grant support was provided to his Institution by NIH. Grant support was provided to his Institution by Anthera as well as personal consulting fees. SCB has received support from VRTX, Galapagos, and AbbVie for his participation in advisory boards and as site PI in multicenter trials which they have funded. JLTC has received personal consulting fees from Gilead Sciences, Protalix, and Santhera for participation in advisory board activities. She has received grant support to her institution from PTI, Celtaxsys, and VRTX as well as personal consulting fees for advisory activities. Grant support to her institution for her participation as site PI in a multicenter trial which they have funded from Eloxx. KDB has received consulting fees from Boehringer-Ingelheim (BI), Protalix Biotherapeutics, Raptor Pharmaceuticals, Novabiotics, Eloxx Pharmaceutics, Galapagos, and Chiesi. She has received speaker fees from Teva Pharmaceutical Industries and serves on the Steering Committee and Advisory Board for VRTX. DGD has received consulting fees from VRTX and consulting fees as well as grant support from PTI and Chiesi. PAF has received personal consulting fees from the Food and Drug Administration, Polyphor, and Santhera. He has received personal consulting fees and grant support from CFF, PTI, Savara, and VRTX. He has received grant support from NIH, Novartis, Novoteris, and Sound Pharmaceuticals. PD has received personal consulting fees from VRTX, PTI, and Actelion Pharmaceuticals. He has also received support for his participation as site PI in multicenter trials funded by Corbus Pharmaceuticals and VRTX. CHG has received grant funding from CFF, NIH, the European Commission and the Food and Drug Administration. He has also received honoraria from Gilead Sciences for grant reviews, honoraria from VRTX and Mylan for invited talks, and BI for participation as a PI in a multicenter trial in CF that they have funded. IF has received consulting fees and support from PTI, VRTX and BI for her participation in advisory boards as well as site PI in multicenter trials which they have funded. She has received support from Corbus Pharmaceuticals for participation as site PI in multicenter trials which they have funded ASM has received grant support to her Institution from CFF. BSQ has received grant support to his institution from the Cystic Fibrosis Canada, CFF, Michael Smith Foundation for Health Research, BC Lung Association, and Gilead Sciences. GZRB's institution has received support from the CFF, NIH and VRTX. for his participation as site PI in multicenter trials which they have funded. AGD, KP, JPC, SHD, SMS, and JMVD have nothing to disclose., (Copyright © 2020. Published by Elsevier B.V.)

Several members of the Gram-negative environmental bacterial genus Achromobacter are associated with serious infections, with Achromobacter xylosoxidans being the most common. Despite their pathogenic potential, little is understood about these intrinsically drug-resistant bacteria and their role in disease, leading to suboptimal diagnosis and management. Here, we performed comparative genomics for 158 Achromobacter spp. genomes to robustly identify species boundaries, reassign several incorrectly speciated taxa and identify genetic sequences specific for the genus Achromobacter and for A. xylosoxidans . Next, we developed a Black Hole Quencher probe-based duplex real-time PCR assay, Ac-Ax, for the rapid and simultaneous detection of Achromobacter spp. and A. xylosoxidans from both purified colonies and polymicrobial clinical specimens. Ac-Ax was tested on 119 isolates identified as Achromobacter spp. using phenotypic or genotypic methods. In comparison to these routine diagnostic methods, the duplex assay showed superior identification of Achromobacter spp. and A. xylosoxidans , with five Achromobacter isolates failing to amplify with Ac-Ax confirmed to be different genera according to 16S rRNA gene sequencing. Ac-Ax quantified both Achromobacter spp. and A. xylosoxidans down to ~110 genome equivalents and detected down to ~12 and ~1 genome equivalent(s), respectively. Extensive in silico analysis, and laboratory testing of 34 non- Achromobacter isolates and 38 adult cystic fibrosis sputa, confirmed duplex assay specificity and sensitivity. We demonstrate that the Ac-Ax duplex assay provides a robust, sensitive and cost-effective method for the simultaneous detection of all Achromobacter spp. and A. xylosoxidans and will facilitate the rapid and accurate diagnosis of this important group of pathogens.

Antimicrobials have undoubtedly improved the lives of people with CF, but important antimicrobial-related toxicities and the emergence of antimicrobial-resistant bacteria associated with their use must be considered. Antimicrobial stewardship (AMS) is advocated across the spectrum of healthcare to promote the appropriate use of antimicrobials to preserve their current effectiveness and to optimise treatment, and it is clear that AMS strategies are applicable to and can benefit both non-CF and CF populations. This perspective explores the definition and components of an AMS program, the current evidence for AMS, and the reasons why AMS is a challenging concept in the provision of CF care. We also discuss the elements of CF care which align with AMS programs and principles and propose research priorities for AMS in CF., Competing Interests: Declaration of Competing Interest Drs. Kahl, Maples, Holmes and Muhlebach have nothing to disclose. Dr. Cogen reports grants from the Cystic Fibrosis Foundation outside of this work. Dr. McColley reports disclosures from Vertex Pharmaceuticals, Gilead Sciences, and grants from Northwestern University Clinical and Translational Sciences Institute outside of this work. Dr. Roberts reports grants and personal fees from MSD, grants from QPEX, personal fees from Discuva, personal fees from Accelerate Diagnostics, grants and personal fees from Biomerieux, grants and personal fees from Pfizer and grants from The Medicines Company outside of this work. Dr. Winthrop reports grants and personal fees from Pfizer, personal fees from AbbVie, personal fees from UCB, personal fees from Lilly, personal fees from Galapagos, personal fees from GSK, personal fees from Roche, personal fees from Gilead, grants from BMS, and grants from Insmed outside of this work. Dr. Morris reports and receives salary support from the Sinai Health and University Health Network in his role as Director of their Antimicrobial Stewardship Program. Dr. Flume reports grants outside of this submitted work from the European Cystic Fibrosis Society, the Cystic Fibrosis Foundation, Cystic Fibrosis Trust, Cystic Fibrosis Canada, Cystic Fibrosis Australia, and Novoteris. Dr. Flume also receives personal fees from Insmed outside this submitted work. Dr. VanDevanter reports personal fees from AbbVie, Albumedix, AN2, Aradigm, Armata, Arrevus, Calithera, Chiesi USA, Cipla, Corbus, Cystic Fibrosis Foundation, Eloxx, Enbiotix, Eveo, Galephar, Horizon, IBF, ICON clinical sciences, Ionis, Kala, Merck, Microbion, NDA, Protalix, PTC, Pulmocide, Recida, Savara, Vast, and Vertex outside of this work. Dr. Waters reports grants from Gilead and Astrazenca outside of this work. Dr. Elborn reports grants from Innovative Medicines Institute, Framework Seven, European Commission, Medical Research Council, and Bronch UK during the conduct of the study. Dr. Saiman reports grants from the CF Foundation, Merck, and AztraZeneca outside of this work. Dr. Bell reports grants and other support from Vertex, Galapagos and AbbVie outside of this work., (Copyright © 2020. Published by Elsevier B.V.)

Marine sponges often host diverse and species-specific communities of microorganisms that are critical for host health. Previous functional genomic investigations of the sponge microbiome have focused primarily on specific symbiont lineages, which frequently make up only a small fraction of the overall community. Here, we undertook genome-centric analysis of the symbiont community in the model species Ircinia ramosa and analyzed 259 unique, high-quality metagenome-assembled genomes (MAGs) that comprised 74% of the I. ramosa microbiome. Addition of these MAGs to genome trees containing all publicly available microbial sponge symbionts increased phylogenetic diversity by 32% within the archaea and 41% within the bacteria. Metabolic reconstruction of the MAGs showed extensive redundancy across taxa for pathways involved in carbon fixation, B-vitamin synthesis, taurine metabolism, sulfite oxidation, and most steps of nitrogen metabolism. Through the acquisition of all major taxa present within the I. ramosa microbiome, we were able to analyze the functional potential of a sponge-associated microbial community in unprecedented detail. Critical functions, such as carbon fixation, which had previously only been assigned to a restricted set of sponge-associated organisms, were actually spread across diverse symbiont taxa, whereas other essential pathways, such as ammonia oxidation, were confined to specific keystone taxa.

Information is lacking on the clinical impact of the novel coronavirus, SARS-CoV-2, on people with cystic fibrosis (CF). Our aim was to characterise SARS-CoV-2 infection in people with cystic fibrosis., Methods: Anonymised data submitted by each participating country to their National CF Registry was reported using a standardised template, then collated and summarised., Results: 40 cases have been reported across 8 countries. Of the 40 cases, 31 (78%) were symptomatic for SARS-CoV-2 at presentation, with 24 (60%) having a fever. 70% have recovered, 30% remain unresolved at time of reporting, and no deaths have been submitted., Conclusions: This early report shows good recovery from SARS-CoV-2 in this heterogeneous CF cohort. The disease course does not seem to differ from the general population, but the current numbers are too small to draw firm conclusions and people with CF should continue to strictly follow public health advice to protect themselves from infection., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare relating to this work., (Copyright © 2020. Published by Elsevier B.V.)

Background: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community., Methods: We engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing., Results: Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results., Conclusions: Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 European Cystic Fibrosis Society. All rights reserved.)

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.

Although acute melioidosis is the most common outcome of Burkholderia pseudomallei infection, we have documented a case, P314, where disease severity lessened with time, and the pathogen evolved towards a commensal relationship with the host. In the current study, we used whole-genome sequencing to monitor this long-term symbiotic relationship to better understand B. pseudomallei persistence in P314's sputum despite intensive initial therapeutic regimens. We collected and sequenced 118 B. pseudomallei isolates from P314's airways over a >16-year period, and also sampled the patient's home environment, recovering six closely related B. pseudomallei isolates from the household water system. Using comparative genomics, we identified 126 SNPs in the core genome of the 124 isolates or 162 SNPs/indels when the accessory genome was included. The core SNPs were used to construct a phylogenetic tree, which demonstrated a close relationship between environmental and clinical isolates and detailed within-host evolutionary patterns. The phylogeny had little homoplasy, consistent with a strictly clonal mode of genetic inheritance. Repeated sampling revealed evidence of genetic diversification, but frequent extinctions left only one successful lineage through the first four years and two lineages after that. Overall, the evolution of this population is nonadaptive and best explained by genetic drift. However, some genetic and phenotypic changes are consistent with in situ adaptation. Using a mouse model, P314 isolates caused greatly reduced morbidity and mortality compared to the environmental isolates. Additionally, potentially adaptive phenotypes emerged and included differences in the O-antigen, capsular polysaccharide, motility, and colony morphology. The >13-year co-existence of two long-lived lineages presents interesting hypotheses that can be tested in future studies to provide additional insights into selective pressures, niche differentiation, and microbial adaptation. This unusual melioidosis case presents a rare example of the evolutionary progression towards commensalism by a highly virulent pathogen within a single human host., Competing Interests: The authors have declared that no competing interests exist.

The incidence and number of deaths from non-tuberculous mycobacterial (NTM) disease have been steadily increasing globally. These lesser known "cousins" of Mycobacterium tuberculosis (TB) were once thought to be harmless environmental saprophytics and only dangerous to individuals with defective lung structure or the immunosuppressed. However, NTM are now commonly infecting seemingly immune competent children and adults at increasing rates through pulmonary infection. This is of concern as the pathology of NTM is difficult to treat. Indeed, NTM have become extremely antibiotic resistant, and now have been found to be internationally dispersed through person-to-person contact. The reasons behind this NTM increase are only beginning to be elucidated. Solutions to the problem are needed given NTM disease is more common in the tropics. Importantly, 40% of the world's population live in the tropics and due to climate change, the Tropics are expanding which will increase NTM infection regions. This review catalogs the global and economic disease burden, at risk populations, treatment options, host-bacterial interaction, immune dynamics, recent developments and research priorities for NTM disease., (Copyright © 2020 Ratnatunga, Lutzky, Kupz, Doolan, Reid, Field, Bell, Thomson and Miles.)

Cystic fibrosis (CF) is a common life-limiting genetic condition. As the disease progresses access to specialist tertiary multi-disciplinary care services may become necessary. For patients living in regional/remote Australia, accessing such services may be a challenge. Here, we describe long-term outcomes for CF patients according to their access to specialist CF centre care in childhood., (© 2020 Royal Australasian College of Physicians.)

Background: The 2013 update of the Infection Prevention and Control (IP&C) Guideline outlined recommendations to prevent the spread of CF respiratory pathogens. We aimed to investigate the current infection control practices used in Australian and New Zealand (NZ) CF centers., Methods: Two online surveys were distributed to Australian and NZ CF centers regarding the uptake of selected IP&C recommendations. One survey was distributed to all the Medical Directors and Lead CF Nurses and the second survey was distributed to all the Lead CF Physiotherapists., Results: The response rate was 60% (60/100) for medical/nursing and 58% (14/24) for physiotherapy. Over 90% (55/60) of CF centers followed CF-specific infection control guidelines and consistent infection control practices were seen in most CF centers; 76% (41/54) had implemented segregation strategies for ambulatory care and no CF centers housed people with CF in shared inpatient accommodation. However, the application of contact precautions (wearing gloves and apron/gown) by healthcare professionals when reviewing a CF person was variable between CF center respondents but was most often used when seeing CF persons with MRSA infection in both ambulatory care and hospital admission (20/50, 40% and 42/45, 93% of CF centers, respectively). Mask wearing by people with CF was implemented into 61% (36/59) of centers. Hospital rooms were cleaned daily in 79% (37/47) of CF centers and the ambulatory care consult rooms were always cleaned between consults (49/49, 100%) and at the end of the clinic session (51/51, 100%); however the staff member tasked with cleaning changed with 37% (18/49) of CF centers responding that CF multidisciplinary team (MDT) members cleaned between patients whereas at the end of the clinic session, only 12% (6/51) of the CF MDT cleaned the consult room., Conclusions: Overall, Australian and NZ CF centers have adopted many recommendations from the IP&C. Although, the application of contact precautions was inconsistent and had overall a low level of adoption in CF centers. In ~ 25% of centers, mixed waiting areas occurred in the ambulatory care. Given the variability of responses, additional work is required to achieve greater consistency between centers.

The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To investigate sex differences in associations between sexual violence victimization (SVV), sexual violence perpetration (SVP), and binge drinking and/or alcohol problems among high school students. While SVV has been linked to problem alcohol use among young women, little research has addressed the unique associations of SVV and SVP on alcohol use/problems within both sexes. A cross-sectional analysis of 16,992 high school students' self-reports of past-year SVP and SVV was used where SVV/SVP was defined by three tactics (sexual coercion, drug/alcohol-facilitated or incapacitated sex, and physically forced sex). Alcohol measures included past-month binge drinking and past-year alcohol problems. Rates of SVV were twice as high in females (21.2% vs. 13.3%), and SVP rates were twice as high in males (10.9% vs. 5.2%). SVV and SVP were each associated with an increased rate of current binge drinking and problem alcohol use for both sexes, across increasing numbers of SV tactics and within each of three tactics. After controlling for demographic and other risk factors including SVP, drug/alcohol-facilitated or incapacitated SVV was more strongly linked to binge drinking and alcohol problems among females. SVP was more strongly linked to binge drinking and alcohol problems among males (adjusting for SVV and other covariates). No sex differences emerged in associations between coerced or physically forced SVV/SVP and alcohol-related outcomes. Both SVV and SVP are associated with an increased likelihood of binge drinking and alcohol problems for males and females. Important sex differences emerged when SV tactics are considered., (© The Author(s) 2019.)

Corals and the reef ecosystems that they support are in global decline due to increasing anthropogenic pressures such as climate change 1 . However, effective reef conservation strategies are hampered by a limited mechanistic understanding of coral biology and the functional roles of the diverse microbial communities that underpin coral health 2,3 . Here, we present an integrated genomic characterization of the coral species Porites lutea and its microbial partners. High-quality genomes were recovered from P. lutea, as well as a metagenome-assembled Cladocopium C15 (the dinoflagellate symbiont) and 52 bacterial and archaeal populations. Comparative genomic analysis revealed that many of the bacterial and archaeal genomes encode motifs that may be involved in maintaining association with the coral host and in supplying fixed carbon, B-vitamins and amino acids to their eukaryotic partners. Furthermore, mechanisms for ammonia, urea, nitrate, dimethylsulfoniopropionate and taurine transformation were identified that interlink members of the holobiont and may be important for nutrient acquisition and retention in oligotrophic waters. Our findings demonstrate the critical and diverse roles that microorganisms play within the coral holobiont and underscore the need to consider all of the components of the holobiont if we are to effectively inform reef conservation strategies.

Background and Objective: No published studies have examined the long-term effects of non-invasive ventilation (NIV) in cystic fibrosis (CF). Our primary aim was to determine if adults with CF and sleep desaturation were less likely to develop hypercapnia with NIV ± O 2 compared to low-flow oxygen therapy (LFO 2 ) or meet the criteria for failure of therapy over 12 months. We studied event-free survival, hospitalizations, lung function, arterial blood gases (ABG), sleep quality and health-related quality of life., Methods: A prospective, randomized, parallel group study in adult patients with CF and sleep desaturation was conducted, comparing 12 months of NIV ± O 2 to LFO 2 . Event-free survival was defined as participants without events. Events included: failure of therapy with PaCO 2  > 60 mm Hg, or increase in PaCO 2  > 10 mm Hg from baseline, increases in TcCO 2  > 10 mm Hg, lung transplantation or death. Outcomes were measured at baseline, 3, 6 and 12 months, including lung function, ABG, Pittsburgh Sleep Quality Inventory (PSQI), SF36 and hospitalizations., Results: A total of 29 patients were randomized to NIV ± O 2 (n = 14) or LFO 2 (n = 15) therapy for 12 months. Of the 29 patients, 18 met the criteria for event-free survival over 12 months. NIV ± O 2 group had 33% (95% CI: 5-58%) and 46% (95% CI: 10-68%) more event-free survival at 3 and 12 months than LFO 2 group. No statistically significant differences were seen in spirometry, ABG, questionnaires or hospitalizations., Conclusion: NIV ± O 2 during sleep increases event-free survival over 12 months in adults with CF. Further studies are required to determine which subgroups benefit the most from NIV., (© 2019 Asian Pacific Society of Respirology.)

Patient-derived isolates of the opportunistic pathogen Pseudomonas aeruginosa are frequently resistant to antibiotics due to the presence of sequence variants in resistance-associated genes. However, the frequency of antibiotic resistance and of resistance-associated sequence variants in environmental isolates of P. aeruginosa has not been well studied. Antimicrobial susceptibility testing (ciprofloxacin, ceftazidime, meropenem, tobramycin) of environmental ( n =50) and cystic fibrosis ( n =42) P. aeruginosa isolates was carried out. Following whole genome sequencing of all isolates, 25 resistance-associated genes were analysed for the presence of likely function-altering sequence variants. Environmental isolates were susceptible to all antibiotics with one exception, whereas patient-derived isolates had significant frequencies of resistance to each antibiotic and a greater number of likely resistance-associated genetic variants. These findings indicate that the natural environment does not act as a reservoir of antibiotic-resistant P. aeruginosa, supporting a model in which antibiotic susceptible environmental bacteria infect patients and develop resistance during infection.

Purpose of Review: This review provides an update on definitions of chronicity of infection, approaches to airway sampling to detect infection, strategies for Pseudomonas aeruginosa eradication, impact of cystic fibrosis transmembrane regulator protein (CFTR) modulators and future challenges for clinical trials., Recent Findings: Rates of P. aeruginosa have decreased over the past two decades with establishment of effective eradication protocols. Definitions of chronic P. aeruginosa infection have required adaptation for healthier populations. Although molecular (PCR) approaches to early P. aeruginosa detection are sensitive, to date, earlier diagnosis has not impacted on clinical outcomes. Despite eradication regimens, some people with early P. aeruginosa fail to clear their infection. Most people also experience a recurrence and eventual transition to chronic infection. Several recent studies sought to address this gap. CFTR modulators (predominantly ivacaftor) demonstrated reduced P. aeruginosa density, although infection may persist or recur demonstrating the need for continued antiinfective therapies in the modulator era., Summary: Future studies of approaches to P. aeruginosa eradication will be complex due to expanded availability and ongoing competitive clinical trials of CFTR modulators. Studies to address optimal eradication therapy, particularly in adults, will be required, though adequate recruitment to power these studies may prove challenging.

Median cystic fibrosis (CF) survival has increased dramatically over time due to several factors, including greater availability and use of antimicrobial therapies. During the progression of CF lung disease, however, the emergence of multidrug antimicrobial resistance can limit treatment effectiveness, threatening patient longevity. Current planktonic-based antimicrobial susceptibility testing lacks the ability to predict clinical response to antimicrobial treatment of chronic CF lung infections. There are numerous reasons for these limitations including bacterial phenotypic and genotypic diversity, polymicrobial interactions, and impaired antibiotic efficacy within the CF lung environment. The parallels to other chronic diseases such as non-CF bronchiectasis are discussed as well as research priorities for moving forward., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Healthcare-acquired infections (HAIs) continue to persist in hospitals, despite the use of increasingly strict infection-control precautions. Opportunistic airborne transmission of potentially pathogenic bioaerosols may be one possible reason for this persistence. Therefore, this study aimed to systematically review the concentrations and compositions of indoor bioaerosols in different areas within hospitals and the effects of different ventilation systems. Electronic databases (Medline and Web of Science) were searched to identify articles of interest. The search was restricted to articles published from 2000 to 2017 in English. Aggregate data was used to examine the differences in mean colony forming units per cubic metre (cfu/m 3 ) between different hospital areas and ventilation types. A total of 36 journal articles met the eligibility criteria. The mean total bioaerosol concentrations in the different areas of the hospitals were highest in the inpatient facilities (77 cfu/m 3 , 95% confidence interval (CI): 55-108) compared with the restricted (13cfu/m 3 , 95% CI: 10-15) and public areas (14 cfu/m 3 , 95% CI: 10-19). Hospital areas with natural ventilation had the highest total bioaerosol concentrations (201 cfu/m 3 , 95% CI: 135-300) compared with areas using conventional mechanical ventilation systems (20 cfu/m 3 , 95% CI: 16-24). Hospital areas using sophisticated mechanical ventilation systems (such as increased air changes per hour, directional flow and filtration systems) had the lowest total bioaerosol concentrations (9 cfu/m 3 , 95% CI: 7-13). Operating sophisticated mechanical ventilation systems in hospitals contributes to improved indoor air quality within hospitals, which assists in reducing the risk of airborne transmission of HAIs., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Stenotrophomonas maltophilia is emerging as an important cause of disease in nosocomial and community-acquired settings, including bloodstream, wound and catheter-associated infections. Cystic fibrosis (CF) airways also provide optimal growth conditions for various opportunistic pathogens with high antibiotic tolerance, including S. maltophilia . Currently, there is no rapid, cost-effective and accurate molecular method for detecting this potentially life-threatening pathogen, particularly in polymicrobial specimens, suggesting that its true prevalence is underestimated. Here, we used large-scale comparative genomics to identify a specific genetic target for S. maltophilia , with subsequent development and validation of a real-time PCR assay for its detection. Analysis of 167 Stenotrophomonas spp. genomes identified a conserved 4 kb region in S. maltophilia , which was targeted for Black Hole Quencher assay design. Our assay yielded the positive detection of 89 of 89 (100%) clinical S. maltophilia strains, and no amplification of 23 non- S. maltophilia clinical isolates. S. maltophilia was detected in 10 of 16 CF sputa, demonstrating the assay's utility for direct detection in respiratory specimens. The assay demonstrated good sensitivity, with limits of detection and quantitation on pure culture of ~10 and ~100 genome equivalents, respectively. Our assay provides a highly specific, sensitive and cost-effective method for the accurate identification of S. maltophilia , and will improve the diagnosis and treatment of this under-recognized pathogen by enabling its accurate and rapid detection from polymicrobial clinical and environmental samples.

Background and Objective: Aerosol transmission of Pseudomonas aeruginosa has been suggested as a possible mode of respiratory infection spread in patients with cystic fibrosis (CF); however, whether this occurs in other suppurative lung diseases is unknown. Therefore, we aimed to determine if (i) patients with bronchiectasis (unrelated to CF) or chronic obstructive pulmonary disease (COPD) can aerosolize P. aeruginosa during coughing and (ii) if genetically indistinguishable (shared) P. aeruginosa strains are present in these disease cohorts., Methods: People with bronchiectasis or COPD and P. aeruginosa respiratory infection were recruited for two studies. Aerosol study: Participants (n = 20) underwent cough testing using validated cough rigs to determine the survival of P. aeruginosa aerosols in the air over distance and duration. Genotyping study: P. aeruginosa sputum isolates (n = 95) were genotyped using the iPLEX20SNP platform, with a subset subjected to the enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) assay to ascertain their genetic relatedness., Results: Aerosol study: Overall, 7 of 20 (35%) participants released P. aeruginosa cough aerosols during at least one of the cough aerosol tests. These cough aerosols remained viable for 4 m from the source and for 15 min after coughing. The mean total aerosol count of P. aeruginosa at 2 m was two colony-forming units. Typing study: No shared P. aeruginosa strains were identified., Conclusion: Low viable count of P. aeruginosa cough aerosols and a lack of shared P. aeruginosa strains observed suggest that aerosol transmission of P. aeruginosa is an unlikely mode of respiratory infection spread in patients with bronchiectasis and COPD., (© 2019 Asian Pacific Society of Respirology.)

Background: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation., Methods: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms., Results: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects., Conclusions: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators., Funding: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Clinical studies demonstrate that ivacaftor (IVA) improves health-related quality of life (HRQoL) in patients aged ≥6 years with cystic fibrosis (CF). The real-world impact of IVA and standard of care (SOC) in groups of patients with G551D and F508del mutations, respectively, was assessed using a survey comprising disease-specific and generic HRQoL measures., Methods: Patients with CF aged ≥12 years, or aged 6-11 years with caregiver support, with either (1) a G551D mutation and receiving IVA (G551D/IVA) for ≥3 months, or (2) homozygous for F508del and receiving SOC before lumacaftor/IVA availability (F508del/SOC), were eligible to participate in a cross-sectional survey. Demographic and clinical characteristics, and HRQoL measures were compared between patient groups, and multiple regression analyses were conducted., Results: After differences in patient demographic and clinical characteristics were controlled for, significantly better scores were observed in the G551D/IVA group than in the F508del/SOC group on multiple domains of the validated Cystic Fibrosis Questionnaire-Revised and the EuroQol 5-dimensions 5-level questionnaire., Conclusions: G551D/IVA patients reported better HRQoL than F508del/SOC patients on generic and disease-specific measures in a real-world setting.

Background: Adults with cystic fibrosis (CF) have been reported to be at five to ten-fold risk (25 to 30 fold risk after solid organ transplant) of colorectal cancer (CRC) than the general population. Limited publications to date have reported on practical aspects of achieving adequate colonic cleanse producing good visualisation. In this study, we compared two bowel preparation regimens, standard bowel preparation and a modified CF bowel preparation., Methods: A non-randomised study of adults with CF attending a single centre, requiring colonoscopy investigation were selected. Between 2001 and 2015, 485 adults with CF attended the clinic; 70 adults with CF had an initial colonoscopy procedure. After five exclusions, standard bowel preparation was prescribed for 27 patients, and modified CF bowel preparation for 38 patients. Demographic and clinical data were collected for all consenting patients., Results: There was a significant difference between modified CF bowel preparation group and standard bowel preparation group in bowel visualisation outcomes, with the modified CF bowel preparation group having a higher proportion of "excellent/good" GI visualisation cleanse (50.0% versus 25.9%) and lower rates of "poor" visualisation cleanse (10.5% versus 44.5%) than standard bowel preparation (p = 0.006). Rates of "fair" GI cleanse visualisation were similar between the two groups (39.4% versus 29.6%) (Additional file 1: Table S1). Detection rates of adenomatous polyps at initial colonoscopy was higher in modified CF bowel preparation cohort than with standard preparation group (50.0% versus 18.5%, p < 0.01). Positive adenomatous polyp detection rate in patient's age > 40 years of age was higher (62.5%) than those < 40 years of age (24.3%) (p = 0.003). Colonic adenocarcinoma diagnosis was similar in both groups., Conclusion: This study primarily highlights that standard colonoscopy bowel preparation is often inadequate in patients with CF, and that colonic lavage using modified CF bowel preparation is required to obtain good colonic visualisation. A higher rate of polyps in patients over 40 years of age (versus less than 40 years) was evident. These results support adults with CF considered for colonoscopy screening at 40 years of age, or prior to this if symptomatic; which is earlier than CRC screening in the non-CF Australian population.

Background: The inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, while continuing separate governance review for each centre covering financial and operational aspects of the research project., Aim: To compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015 to approval times for an earlier pre-NMA study utilising a similar study design and study sites and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects., Methods: We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low-risk non-interventional study looking at the prevalence and aetiology of non-tuberculous mycobacterial infection in people with cystic fibrosis in Australia., Results: Applications were submitted to three hospitals and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 to 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23-225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of AU$56000 (US$ 42 000)., Conclusion: Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA., (© 2018 Royal Australasian College of Physicians.)

Introduction: We previously reported defective alternative polarization (M2) of macrophages and early expression of classically polarized (M1) macrophage markers in unpolarized monocyte-derived macrophages (MDMs) in patients with cystic fibrosis (CF). The present study assessed whether the mechanism(s) underlying defective macrophage polarization resided in circulating monocytes., Methods: Monocyte subsets (classical, intermediate and non-classical), markers for monocyte activation (CD163) and recruitment (CD195), receptors/genes associated with macrophage differentiation and polarization were analyzed in CF and compared with healthy individuals., Results: No differences were observed in the monocyte subsets or in the expression of CD163 or CD195. Expression of the M-CSF receptor, TLR4, γC, IL-4Rα, IL-13Rα1, TIMP-1 and Cox-2 were higher in CF monocytes, albeit at low levels, whereas, LRP1, MMP9, MMP28 were downregulated compared to mooncytes from healthy individuals., Conclusions: Our data suggest that differences in CF monocytes may contribute to the reported CFTR-dependent defect in macrophage differentiation, polarization and function., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Background: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management. Cystic fibrosis (CF) treatment guidelines recommend AST to select antimicrobial treatments for CF airway infection but its utility in this setting has never been objectively demonstrated., Methods: We conducted a systematic review of primary published articles designed to address two PICO (patient, intervention, comparator, outcome) questions: 1) "For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection predictable from AST results available at treatment initiation?" and 2) "For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection affected by the method used to guide antimicrobial selection?" Relationships between AST results and clinical response (changes in pulmonary function, weight, signs and symptoms of respiratory tract infection, and time to next event) were assessed for each article and results were compared across articles when possible., Results: Twenty-five articles describing the results of 20 separate studies, most of which described Pseudomonas aeruginosa treatment, were identified. Thirteen studies described pulmonary exacerbation (PEx) treatment and seven described 'maintenance' of chronic bacterial airways infection. In only three of 16 studies addressing PICO question #1 was there a suggestion that baseline bacterial isolate antimicrobial susceptibility was associated with clinical response to treatment. None of the four studies addressing PICO question #2 suggested that antimicrobial selection methods influenced clinical outcomes., Conclusions: There is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment, suggesting a need for careful consideration of current AST use by the CF community., (Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy., Methods: In this retrospective clinical study, 3 independent CF patient cohorts (US-American: 29, Australian: 12 and Irish: 19 cases) were enrolled carrying at least one Class III CFTR CF-causing mutation (p.Gly551Asp) and being treated with CFTR potentiator ivacaftor. Plasma HE4 was measured by immunoassay before treatment (baseline) and 1-6 months after commencement of ivacaftor, and were correlated with FEV 1 (% predicted), sweat chloride, C-reactive protein (CRP) and body mass index (BMI)., Results: After 1 month of therapy, HE4 levels were significantly lower than at baseline and remained decreased up to 6 months. A significant inverse correlation between absolute and delta values of HE4 and FEV 1 (r = -0.5376; P < .001 and r = -0.3285; P < .001), was retrospectively observed in pooled groups, including an independent association of HE4 with FEV 1 by multiple regression analysis (β = -0.57, P = .019). Substantial area under the receiver operating characteristic curve (ROC-AUC) value was determined for HE4 when 7% mean change of FEV 1 (0.722 [95% CI 0.581-0.863]; P = .029) were used as classifier, especially in the first 2 months of treatment (0.806 [95% CI 0.665-0.947]; P < .001)., Conclusions: This study shows that plasma HE4 levels inversely correlate with lung function improvement in CF patients receiving ivacaftor. Overall, this potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)