Publications by authors named "Scott Bell"

218 Publications

Dissemination of Mycobacterium abscessus via global transmission networks.

Nat Microbiol 2021 Oct 20;6(10):1279-1288. Epub 2021 Sep 20.

Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1038/s41564-021-00963-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478660PMC
October 2021

Outcomes of artery embolisation for cystic fibrosis patients with haemoptysis: a 20-year experience at a major Australian tertiary centre.

Intern Med J 2021 Sep;51(9):1526-1529

Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Brisbane, Queensland, Australia.

There are no published data on Australian adult cystic fibrosis (CF) patient outcomes post bronchial arterial embolisation (BAE). We report 20 years of experience of BAE at a major Australian tertiary adult CF centre, where 46 patients underwent 100 BAE during this period. Mortality rate was comparable to previous studies (4% per year) and most who died had repeat BAE requirements. A higher proportion (9 out of 45) of patients were transplanted compared to previous publications. Repeat BAE was common and significantly higher in patients already on tranexamic acid.
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http://dx.doi.org/10.1111/imj.15483DOI Listing
September 2021

Prevention of SARS-CoV-2 (COVID-19) transmission in residential aged care using ultraviolet light (PETRA): a two-arm crossover randomised controlled trial protocol.

BMC Infect Dis 2021 Sep 17;21(1):967. Epub 2021 Sep 17.

The South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.

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).
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http://dx.doi.org/10.1186/s12879-021-06659-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446719PMC
September 2021

Anti-LPS IgA and IgG can inhibit serum killing of in patients with cystic fibrosis.

Infect Immun 2021 Aug 30:IAI0041221. Epub 2021 Aug 30.

The University of Queensland Diamantina Institute, The University of Queensland, Brisbane 4102, QLD, Australia.

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 was associated with increased severity of respiratory infections in patients with non-CF bronchiectasis. This inhibition was mediated by high titres 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 infection, and five without infection. Thirty-two percent of patients had serum that inhibited the ability of healthy control serum to kill . 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 inhibited serum-killing. We found that antibody affinity, not just titre, 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 infections.
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http://dx.doi.org/10.1128/IAI.00412-21DOI Listing
August 2021

Wave 1 results of the INTerventions, Research, and Action in Cities Team (INTERACT) cohort study: Examining spatio-temporal measures for urban environments and health.

Health Place 2021 Aug 5:102646. Epub 2021 Aug 5.

Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada. Electronic address:

Built environment interventions have the potential to improve population health and reduce health inequities. The objective of this paper is to present the first wave of the INTErventions, Research, and Action in Cities Team (INTERACT) cohort studies in Victoria, Vancouver, Saskatoon, and Montreal, Canada. We examine how our cohorts compared to Canadian census data and present summary data for our outcomes of interest (physical activity, well-being, and social connectedness). We also compare location data and activity spaces from survey data, research-grade GPS and accelerometer devices, and a smartphone app, and compile measures of proximity to select built environment interventions.
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http://dx.doi.org/10.1016/j.healthplace.2021.102646DOI Listing
August 2021

Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.

Stem Cell Reports 2021 Jul 1;16(7):1749-1762. Epub 2021 Jul 1.

Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada. Electronic address:

Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells.
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http://dx.doi.org/10.1016/j.stemcr.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282463PMC
July 2021

Concussion Reporting and Safeguarding Policy Development in British American Football: An Essential Agenda.

Front Sports Act Living 2021 4;3:671876. Epub 2021 Jun 4.

Department of Sport, Exercise and Rehabilitation, Northumbria University, Newcastle upon Tyne, United Kingdom.

The objective of this study was to examine concussion reporting and safeguarding policy in British American Football (BAF). Data were collected an online survey tool. The data presented are part of a broader study that examined injury profiles, concussion reporting behaviors, and medical provision in BAF. Concussion-like symptoms were found in over half (58.8%) of the participants. Of those, 36.4% reported they had previously been formally diagnosed with a concussion while playing BAF. Just under half of the participants (44.7%) had suspected they had had a concussion, although it was not formally diagnosed, and 23.5% of the participants had previously hidden concussion symptoms. Fifty-eight percent of the teams reported they did not have a regular game-day medic, with a range of hired medical personnel who attended the games. Prominent barriers to hiring a medic included budget, institutional support shortfall, and lack of medic reliability and game knowledge. BAF is a developing sport with a clear vision for growth of participation. Yet, the current concussion and medical provision policies do not address the sport's welfare needs. Through discussion of these policies in the context of this study's findings, we highlight vital areas of concern in policy and practice that the British American Football Association needs to address in their medical and concussion policies.
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http://dx.doi.org/10.3389/fspor.2021.671876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211898PMC
June 2021

Physiotherapy service provision in a specialist adult cystic fibrosis service: A pre-post design study with the inclusion of an allied health assistant.

Chron Respir Dis 2021 Jan-Dec;18:14799731211017895

School of Allied Health, Faculty of Health Sciences, Australian Catholic University, Banyo, Queensland, Australia.

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.
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http://dx.doi.org/10.1177/14799731211017895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216416PMC
June 2021

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Drug Treatment of Non-Tuberculous Mycobacteria in Cystic Fibrosis.

Clin Pharmacokinet 2021 Sep 13;60(9):1081-1102. Epub 2021 May 13.

Faculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.

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.
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http://dx.doi.org/10.1007/s40262-021-01010-4DOI Listing
September 2021

Rapid macrolide and amikacin resistance testing for in people with cystic fibrosis.

J Med Microbiol 2021 Apr;70(4)

The University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Queensland, Australia.

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. 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. To develop real-time PCR assays for characterization of key 23S or 16S rRNA gene mutations associated with constitutive resistance in MABSC. 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.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. 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.
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http://dx.doi.org/10.1099/jmm.0.001349DOI Listing
April 2021

A 65-Year-Old Man With Back Pain and Imaging Findings of Spinal Cord Compression.

Oncology (Williston Park) 2021 Mar;35(3):128-133

Midwest Imaging Interventional Radiology, Grand Island, Nebraska.

Spinal cord compression is a potentially devastating consequence of cancer. Early recognition of the signs and symptoms permit diagnosis prior to the development of irreversible neurological damage. This complication occurs in 5% to 10% of patients with malignancy, often at the end stages of the patient's illness; however, it can be the presenting manifestation of malignancy in up to 23% of patients. With the advances in surgical, radiation, and medical oncology approaches, the outcomes of patients with malignant spinal cord compression continue to improve. We discuss the case of a previously healthy man, aged 65 years, who presented with back pain and large T8 spinal mass, leading to a diagnosis of multiple myeloma with spinal cord compromise.
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http://dx.doi.org/10.46883/ONC.2021.3503.0128DOI Listing
March 2021

Emergence and impact of oprD mutations in Pseudomonas aeruginosa strains in cystic fibrosis.

J Cyst Fibros 2021 Mar 25. Epub 2021 Mar 25.

QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia; Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia. Electronic address:

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 %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 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.
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http://dx.doi.org/10.1016/j.jcf.2021.03.007DOI Listing
March 2021

Advanced Health Information Technologies to Engage Parents, Clinicians, and Community Nutritionists in Coordinating Responsive Parenting Care: Descriptive Case Series of the Women, Infants, and Children Enhancements to Early Healthy Lifestyles for Baby (WEE Baby) Care Randomized Controlled Trial.

JMIR Pediatr Parent 2020 Nov 24;3(2):e22121. Epub 2020 Nov 24.

Geisinger Obesity Institute, Geisinger, Danville, PA, United States.

Background: Socioeconomically disadvantaged newborns receive care from primary care providers (PCPs) and Women, Infants, and Children (WIC) nutritionists. However, care is not coordinated between these settings, which can result in conflicting messages. Stakeholders support an integrated approach that coordinates services between settings with care tailored to patient-centered needs.

Objective: This analysis describes the usability of advanced health information technologies aiming to engage parents in self-reporting parenting practices, integrate data into electronic health records to inform and facilitate documentation of provided responsive parenting (RP) care, and share data between settings to create opportunities to coordinate care between PCPs and WIC nutritionists.

Methods: Parents and newborns (dyads) who were eligible for WIC care and received pediatric care in a single health system were recruited and randomized to a RP intervention or control group. For the 6-month intervention, electronic systems were created to facilitate documentation, data sharing, and coordination of provided RP care. Prior to PCP visits, parents were prompted to respond to the Early Healthy Lifestyles (EHL) self-assessment tool to capture current RP practices. Responses were integrated into the electronic health record and shared with WIC. Documentation of RP care and an 80-character, free-text comment were shared between WIC and PCPs. A care coordination opportunity existed when the dyad attended a WIC visit and these data were available from the PCP, and vice versa. Care coordination was demonstrated when WIC or PCPs interacted with data and documented RP care provided at the visit.

Results: Dyads (N=131) attended 459 PCP (3.5, SD 1.0 per dyad) and 296 WIC (2.3, SD 1.0 per dyad) visits. Parents completed the EHL tool prior to 53.2% (244/459) of PCP visits (1.9, SD 1.2 per dyad), PCPs documented provided RP care at 35.3% (162/459) of visits, and data were shared with WIC following 100% (459/459) of PCP visits. A WIC visit followed a PCP visit 50.3% (231/459) of the time; thus, there were 1.8 (SD 0.8 per dyad) PCP to WIC care coordination opportunities. WIC coordinated care by documenting RP care at 66.7% (154/231) of opportunities (1.2, SD 0.9 per dyad). WIC visits were followed by a PCP visit 58.9% (116/197) of the time; thus, there were 0.9 (SD 0.8 per dyad) WIC to PCP care coordination opportunities. PCPs coordinated care by documenting RP care at 44.0% (51/116) of opportunities (0.4, SD 0.6 per dyad).

Conclusions: Results support the usability of advanced health information technology strategies to collect patient-reported data and share these data between multiple providers. Although PCPs and WIC shared data, WIC nutritionists were more likely to use data and document RP care to coordinate care than PCPs. Variability in timing, sequence, and frequency of visits underscores the need for flexibility in pragmatic studies.

Trial Registration: ClinicalTrials.gov NCT03482908; https://clinicaltrials.gov/ct2/show/NCT03482908.

International Registered Report Identifier (irrid): RR2-10.1186/s12887-018-1263-z.
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http://dx.doi.org/10.2196/22121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723742PMC
November 2020

Lung function over the life course of paediatric and adult patients with cystic fibrosis from a large multi-centre registry.

Sci Rep 2020 10 15;10(1):17421. Epub 2020 Oct 15.

School of Public Health and Preventive Medicine, Monash University, Room 415, Level 4, 553 St. Kilda Road, Melbourne, VIC, 3004, Australia.

A key measure of lung function in people with Cystic Fibrosis (CF) is Forced Expiratory Volume in the first second FEV percent predicted (FEVpp). This study aimed to address challenges in identifying predictors of FEVpp, 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 FEVpp 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 FEVpp. 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 FEVpp. Those with P. aeruginosa infection had a lower mean difference in FEVpp 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.
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http://dx.doi.org/10.1038/s41598-020-74502-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567842PMC
October 2020

Sexual and reproductive health in cystic fibrosis.

Curr Opin Pulm Med 2020 11;26(6):685-695

The Prince Charles Hospital, Brisbane.

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.
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http://dx.doi.org/10.1097/MCP.0000000000000731DOI Listing
November 2020

Cystic fibrosis - Ten promising therapeutic approaches in the current era of care.

Expert Opin Investig Drugs 2020 Oct 10;29(10):1107-1124. Epub 2020 Oct 10.

Department of Thoracic Medicine, The Prince Charles Hospital , Brisbane, QLD, Australia.

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. 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.
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http://dx.doi.org/10.1080/13543784.2020.1805733DOI Listing
October 2020

Duplex real-time PCR assay for the simultaneous detection of and spp.

Microb Genom 2020 07 15;6(7). Epub 2020 Jul 15.

Sunshine Coast Health Institute, Birtinya, Queensland, Australia.

Several members of the Gram-negative environmental bacterial genus are associated with serious infections, with 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 spp. genomes to robustly identify species boundaries, reassign several incorrectly speciated taxa and identify genetic sequences specific for the genus and for . Next, we developed a Black Hole Quencher probe-based duplex real-time PCR assay, Ac-Ax, for the rapid and simultaneous detection of spp. and from both purified colonies and polymicrobial clinical specimens. Ac-Ax was tested on 119 isolates identified as spp. using phenotypic or genotypic methods. In comparison to these routine diagnostic methods, the duplex assay showed superior identification of spp. and , with five isolates failing to amplify with Ac-Ax confirmed to be different genera according to 16S rRNA gene sequencing. Ac-Ax quantified both spp. and down to ~110 genome equivalents and detected down to ~12 and ~1 genome equivalent(s), respectively. Extensive analysis, and laboratory testing of 34 non- 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 spp. and and will facilitate the rapid and accurate diagnosis of this important group of pathogens.
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http://dx.doi.org/10.1099/mgen.0.000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478622PMC
July 2020

Influence of climate variables on the rising incidence of nontuberculous mycobacterial (NTM) infections in Queensland, Australia 2001-2016.

Sci Total Environ 2020 Oct 13;740:139796. Epub 2020 Jun 13.

Research School of Population Health, Australian National University, Canberra, Australia.

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.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139796DOI Listing
October 2020

Antimicrobial resistance: Concerns of healthcare providers and people with CF.

J Cyst Fibros 2021 05 17;20(3):407-412. Epub 2020 Jun 17.

Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jcf.2020.05.009DOI Listing
May 2021

Pursuit of Equity.

J Cyst Fibros 2020 03;19(2):171

Departments of Medicine and Pediatrics, Medical University of South Carolina, Charleston, SC, USA; Department of Thoracic Medicine, The Prince Charles Hospital and QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genova, Italy.

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http://dx.doi.org/10.1016/j.jcf.2020.02.019DOI Listing
March 2020

Benchmarking service provision, scope of practice, and skill mix for physiotherapists in adult cystic fibrosis care delivery.

Physiother Theory Pract 2020 Jun 11:1-7. Epub 2020 Jun 11.

Physiotherapy, School of Allied Health, Faculty of Health Sciences, Australian Catholic University, Banyo, Australia.

Background: Increasing age, numbers, and complexity of care are potentially impacting physiotherapy service delivery for adults with cystic fibrosis (CF).

Purpose: This study aimed to describe physiotherapy service provision, scope of practice, and skill mix in a large tertiary adult CF center, and determine if services were meeting clinical practice recommendations.

Methods: A prospective cross-sectional study examined inpatient and outpatient physiotherapy care across a three-month period in a tertiary adult CF center. Physiotherapy services were described by number and skill level of physiotherapists, total hours of activity, and number, type, and duration of each physiotherapy activity.

Results: Twenty-two physiotherapists provided care. Respiratory (n = 1058, 38%), and exercise treatments (n = 338, 12%) were the most frequent. Exercise testing (n = 20, 1%), and detailed treatment reviews (n = 79, 3%) occurred infrequently. Time for research was limited. Junior physiotherapists undertook more exercise treatments per day (p < .01), with senior physiotherapists attending outpatient clinics (p.01).

Conclusion: A large number of physiotherapists were involved in the delivery of services. Recommended respiratory and exercise treatments were frequently provided; however, other recommended activities occurred infrequently. The impact of increasing age, numbers of patients, and complexity of care may be contributing to demand exceeding supply for physiotherapy services. Future studies are required to determine innovative approaches to address the gaps in clinical practice recommendations.
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http://dx.doi.org/10.1080/09593985.2020.1777606DOI Listing
June 2020

A multinational report to characterise SARS-CoV-2 infection in people with cystic fibrosis.

J Cyst Fibros 2020 05 25;19(3):355-358. Epub 2020 Apr 25.

Royal Brompton Hospital and Imperial College London, UK.

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.
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http://dx.doi.org/10.1016/j.jcf.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183287PMC
May 2020

Redesign of the Australian Cystic Fibrosis Data Registry: A multidisciplinary collaboration.

Paediatr Respir Rev 2021 Mar 26;37:37-43. Epub 2020 Mar 26.

Translational Research Institute 37 Kent Street Woolloongabba, Queensland 4102, Australia. Electronic address:

Clinical registries that monitor and review outcomes for patients with cystic fibrosis have existed internationally for many decades. However, their purpose continues to evolve and now includes the capability to support clinical effectiveness research, clinical trials and Phase IV studies, and international data comparisons and projects. To achieve this, registries must regularly update the information that they collect and ensure design that is adaptable and flexible to changing needs. The Australian Cystic Fibrosis Data Registry commenced in 1998, and in 2018-19 undertook a transformation to enable it to meet the needs of multiple stakeholders into the future. This included a comprehensive, multidisciplinary review of the registry's data elements, and a redesign and rebuild of the registry's database. The data element review comprised the processes of alignment, comparison, selection, consolidation, revision and definition of finalised data elements. The database redesign included attention to each of the registry functions of data collection, storage and management, and reporting. The revision of a national data collection system is a time-intensive process, and requires significant clinical and other expert engagement. The resulting database, while being continually refined, is now fit for purpose to support Australian clinicians and patients with CF to receive best practice care.
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http://dx.doi.org/10.1016/j.prrv.2020.03.001DOI Listing
March 2021

Seven P's of publication practices.

J Cyst Fibros 2020 05 31;19(3):333-335. Epub 2020 Mar 31.

Cystic Fibrosis Centre, IRCCS Giannina, Gaslini Institute, Genoa, Italy.

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http://dx.doi.org/10.1016/j.jcf.2020.02.007DOI Listing
May 2020

The Rise of Non-Tuberculosis Mycobacterial Lung Disease.

Front Immunol 2020 3;11:303. Epub 2020 Mar 3.

The Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.

The incidence and number of deaths from non-tuberculous mycobacterial (NTM) disease have been steadily increasing globally. These lesser known "cousins" of (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.
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http://dx.doi.org/10.3389/fimmu.2020.00303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062685PMC
March 2021

Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells.

Stem Cells Transl Med 2020 Jun 10;9(6):697-712. Epub 2020 Mar 10.

Psychiatric Genetics Group, McGill University, Montreal, Quebec, Canada.

Making high-quality dopamine (DA)-producing cells for basic biological or small molecule screening studies is critical for the development of novel therapeutics for disorders of the ventral midbrain. Currently, many ventral midbrain assays have low signal-to-noise ratio due to low levels of cellular DA and the rate-limiting enzyme of DA synthesis, tyrosine hydroxylase (TH), hampering discovery efforts. Using intensively characterized ventral midbrain cells derived from human skin, which demonstrate calcium pacemaking activity and classical electrophysiological properties, we show that an L-type calcium agonist can significantly increase TH protein levels and DA content and release. Live calcium imaging suggests that it is the immediate influx of calcium occurring simultaneously in all cells that drives this effect. Genome-wide expression profiling suggests that L-type calcium channel stimulation has a significant effect on specific genes related to DA synthesis and affects expression of L-type calcium receptor subunits from the CACNA1 and CACNA2D families. Together, our findings provide an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.
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http://dx.doi.org/10.1002/sctm.18-0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214648PMC
June 2020

Development and Reporting of Prediction Models: Guidance for Authors From Editors of Respiratory, Sleep, and Critical Care Journals.

Crit Care Med 2020 05;48(5):623-633

Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, United Kingdom.

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.
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http://dx.doi.org/10.1097/CCM.0000000000004246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161722PMC
May 2020

Pathogen to commensal? Longitudinal within-host population dynamics, evolution, and adaptation during a chronic >16-year Burkholderia pseudomallei infection.

PLoS Pathog 2020 03 5;16(3):e1008298. Epub 2020 Mar 5.

Pathogen & Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, United States of America.

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.
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http://dx.doi.org/10.1371/journal.ppat.1008298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077878PMC
March 2020

Finding the relevance of antimicrobial stewardship for cystic fibrosis.

J Cyst Fibros 2020 07 29;19(4):511-520. Epub 2020 Feb 29.

Department of Thoracic Medicine, The Prince Charles Hospital, and QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

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.
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http://dx.doi.org/10.1016/j.jcf.2020.02.012DOI Listing
July 2020
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