Pregnancy in women with cystic fibrosis and diabetes: An audit of outcomes at two tertiary obstetric hospitals in Australia in the pre-cystic fibrosis transmembrane conductance regulator modulator era.

Background: Pregnancy in women with cystic fibrosis (CF) is becoming more common. Long-term metabolic issues such as diabetes are also becoming more common and have potentially important impacts on pregnancy outcomes. This study aimed to assess the impact of diabetes on pregnancy outcomes for women with CF. Methods: We undertook a retrospective chart audit of pregnancies to women with CF at the two tertiary obstetric hospitals in Southeast Queensland associated with CF and transplant management clinics between 2006 and 2016. Results: A total of 38 pregnancies among 26 women were identified. Four women (five pregnancies) had cystic fibrosis-related diabetes (CFRD) diagnosed prior to pregnancy, and 12 women (15 pregnancies) developed gestational diabetes (GDM) complicating pregnancy. CFRD and GDM were associated with higher rates of delivery complications, prematurity, and the need for neonatal intensive care unit admission. Conclusion: Diabetes is common during pregnancy in women with CF and impacts pregnancy outcomes.

Paraquat ingestion in an adult with cystic fibrosis (CF): Diagnostic and management dilemmas.

N,N'-dimethyl-4,4'bipyridinium dichloride (Paraquat) is a potent herbicide used widely in agriculture. We report the effects of an ingestion of paraquat by a 28 year old male with cystic fibrosis and the diagnostic and management challenges this posed in both the acute and longer term setting. We describe the effects of direct paraquat toxicity on the lung tissue secondary to aspiration and review the long-term sequelae of paraquat, namely osteonecrosis. Our case is the first to describe osteonecrosis of the knee in the context of paraquat toxicity. Survival following ingestion remains poor with a high associated mortality. However, timely treatment with NAC and immunosuppression may impact on survival. In those patients who do survive the acute phase post ingestion, follow-up over years may be required to detect the long-term effects of paraquat on bone health.

COVID-19 (Omicron strain) hospital admissions from a virtual ward - who required further care?

BACKGROUND: The COVID-19 virtual ward was created to provide care for people at home with COVID-19. Given this was a new model of care, little was known about the clinical characteristics and outcomes of patients requiring admission to hospital from the virtual ward platform. The aims were to characterise hospital admission volume, patient epidemiology, clinical characteristics, and outcome from a virtual ward in the setting of an Omicron (BA.1, BA.2) outbreak. METHODS: A retrospective observational study was performed for all virtual ward patients admitted from 1st January 2022 to 25th March 2022 (over 16 years old). Epidemiological, clinical and laboratory data was reviewed on all patients who required hospital admission. RESULTS: A total of 7021 patients were cared for on the virtual ward over the study period with 473 referred to hospital for assessment. Twenty-six (0.4%) patients were admitted to hospital during their care on the ward. Twenty-two (84.6%) admissions were COVID-19 related. Fifty three percent of the hospitalised patients were fully vaccinated and 11 had received prior therapeutics for COVID-19. Shortness of breath was the most common reason for escalation to hospital. Chest pain was the second most common reason and the most common diagnosis after investigation was non-cardiac chest pain. CONCLUSIONS: Few patients required admission from the virtual ward in the setting of the Omicron variant (BA.1, BA.2) as a direct result of COVID-19 disease and virtual ward care. Shortness of breath and chest pain were the most common symptoms driving further clinical care.

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

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.

Lumacaftor/ivacaftor reduces exacerbations in adults homozygous for Phe508del mutation with severe lung disease.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pulmonary exacerbations. METHODS: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events. RESULTS: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 - 0.676), p <  0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%. CONCLUSIONS: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent, and resulted in a very high discontinuation rate.

Time of day effects on railroad roadway worker injury risk.

INTRODUCTION: The purpose of this study is to examine how time of day affects injury risk of railroad maintenance of way employees and signalmen (roadway workers). Railroads reported 15,654 serious roadway worker injuries between 1997 and 2014. Roadway workers primarily work outdoors on or near railroad tracks and frequently encounter hazardous conditions. To avoid closing an active rail line during peak hours, railroads sometimes require roadway workers to work at night. Previous studies of roadway worker injury have not adequately accounted for exposure to time of day effects, nor have they investigated the human factors issues contributing to roadway worker injury. METHOD: The Federal Railroad Administration (FRA) database of injury reports provided data for circadian rhythm models of the odds of fatal and nonfatal injuries. The FRA database and fatal injury investigation reports also permitted an analysis of the circumstances and the human factors issues associated with injuries that occur at different times of day. RESULTS: Odds of injury increased during nighttime work. The odds of nonfatal injury for both roadway worker crafts rose above 9:1 in the early morning hours. The relative odds of a fatal injury also increased significantly at night. A human factors analysis suggested that during all three shifts most nonfatal injuries involve workload, but workload was not identified as a factor in fatal injuries. CONCLUSIONS: Nighttime work is more hazardous for roadway workers than daytime work. Several factors related to fatigue and other conditions appear to increase the risk of injury during the outdoor, nighttime work required of roadway workers. PRACTICAL APPLICATION: For practical reasons, nighttime roadway work is sometimes unavoidable. Therefore, new practices for nighttime work must be developed to adequately address fatigue and protect roadway workers from harm.

Ivacaftor in severe cystic fibrosis lung disease and a G551D mutation.

Ivacaftor is gene-specific oral therapy for patients with cystic fibrosis who have a cystic fibrosis transmembrane conductance regulator mutation, G551D. To date, limited information is available about the benefit in patients with severe CF related lung disease, as such patients were excluded from the phase III trials. We report the early results on clinical outcomes, sweat electrolytes and C-reactive protein in three adults with a G551D mutation and advanced lung disease. A mean increase of 6% in FEV1 was observed at 2 weeks and a mean reduction in sweat chloride of -48.9 mmol/L. While improvements in spirometry, weight gain and reduction in sweat electrolytes are similar with those reported in the phase III trials, a formal comparison was not performed.

Intraventricular injection of myxoma virus results in transient expression of viral protein in mouse brain ependymal and subventricular cells.

Oncolytic viruses that selectively infect and lyse cancer cells have potential as therapeutic agents. Myxoma virus, a poxvirus that is known to be pathogenic only in rabbits, has not been reported to infect normal tissues in humans or mice. We observed that when recombinant virus was injected directly into the lateral ventricle of the mouse brain, virally encoded red fluorescent protein was expressed in ependymal and subventricular cells. Cells were positive for nestin, a marker of neural stem cells. Rapamycin increased the number of cells expressing the virally encoded protein. However, protein expression was transient. Cells expressing the virally encoded protein did not undergo apoptosis and the ependymal lining remained intact. Myxoma virus appears to be safe when injected into the brain despite the transient expression of virally derived protein in a small population of periventricular cells.

The month of July: an early experience with pandemic influenza A (H1N1) in adults with cystic fibrosis.

BACKGROUND: Pandemic Influenza A (H1N1) 2009 is a novel viral infection that emerged in March 2009. This is the first report addressing the clinical course of patients with cystic fibrosis (CF) and H1N1 infection. METHODS: All patients with an influenza-like illness (ILI) attending our adult centre during July 2009 were identified. Baseline respiratory function, nutritional status, approach to management and short-term clinical course were recorded. RESULTS: Most patients experienced a mild course and were able to be managed with antiviral agents as an outpatient. Robust infection control policies were implemented to limit transmission of H1N1 infection within our CF centre. Patients with severe lung disease, poor baseline nutritional reserve and presenting with more than 48 hours of ILI experienced a more severe course. Prompt antiviral therapy within the first 48 hours of illness may have been important in improving outcomes. CONCLUSIONS: This observational study demonstrates that most adults with CF with H1N1 infection had mild clinical courses and recovered rapidly.

Temocillin in cystic fibrosis: a retrospective pilot study.

BACKGROUND: Temocillin is currently used in the treatment of acute pulmonary exacerbations caused by Burkholderia cepacia complex and multi-resistant Pseudomonas aeruginosa in cystic fibrosis (CF) patients despite little published clinical data. This study assessed if intravenous (IV) antibiotic therapy including temocillin was equivalent to standard combination therapy for an acute exacerbation. METHODS: A retrospective, pilot cross-over study. Adult patients attending two CF centres between 1997 and 2006 who had received a course of IV antibiotics including temocillin (TIV) and a further IV course (within +/-1 year) which did not include temocillin (NTIV) were included. Outcome measures at the start and end of each IV course were recorded (FEV(1)%, FVC%). RESULTS: Twenty six patients had received temocillin. Baseline values of FEV(1)% predicted were comparable for both groups (TIV: 37(18%), NTIV: 39(20%)). FEV(1)% increased by 7.12(11.67)% after TIV (p<0.01) and 6.65(7.62)% after NTIV (p<0.01). There was no significant difference between the IV courses in mean %change in lung function TIV versus NTIV (FEV(1) 0.46% [95%CI: -4.55 to 5.48%]). CONCLUSION: These data suggest equivalence in the lung function outcome of IV antibiotic therapy includingtemocillin versus standard IV antibiotic therapy.

The changing epidemiology of Burkholderia species infection at an adult cystic fibrosis centre.

BACKGROUND: This study reviews the impact of changing infection control practices at the Manchester Adult Cystic Fibrosis Centre (MACFC) upon the epidemiology of Burkholderia species infections. METHODS: We reviewed strain and genomovar typing of all available Burkholderia isolates at our centre between 1983-2006. RESULTS: The incidence/prevalence of infection with Burkholderia species between 1983-1990 was below 5%/9% each year. There was a rise in incidence/prevalence of Burkholderia species between 1991 and 1994 with a peak of 16.3%/31.2% in 1992. Following complete cohort segregation, the incidence has fallen to below 3% for all but one year and the prevalence has gradually reduced to 9.3% in 2005. Currently, there is an increase in the prevalence to 10.6% for the first time since 1994, predominantly due to patients with unique infections transferring into the unit from referring centres. The presence of unique strains now exceeds transmissible strains for the first time since 1991. CONCLUSIONS: Infection control measures including patient segregation have controlled spread of transmissible B. cenocepacia strains, but not the acquisition of unique strains. Unique strains of Burkholderia species now account for the majority of new infections at the Manchester Adult Cystic Fibrosis Centre.

A d-optimal designed population pharmacokinetic study of oral itraconazole in adult cystic fibrosis patients.

AIM: The primary objective of the study was to estimate the population pharmacokinetic parameters for itraconazole and hydroxy-itraconazole, in particular, the relative oral bioavailability of the capsule compared with solution in adult cystic fibrosis patients, in order to develop new dosing guidelines. A secondary objective was to evaluate the performance of a population optimal design. METHODS: The blood sampling times for the population study were optimized previously using POPT v.2.0. The design was based on the administration of solution and capsules to 30 patients in a cross-over study. Prior information suggested that itraconazole is generally well described by a two-compartment disposition model with either linear or saturable elimination. The pharmacokinetics of itraconazole and the metabolite were modelled simultaneously using NONMEM. Dosing schedules were simulated to assess their ability to achieve a trough target concentration of 0.5 mg ml(-1). RESULTS: Out of 241 blood samples, 94% were taken within the defined optimal sampling windows. A two-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order metabolism to the hydroxy-metabolite. For itraconazole the absorption rate constants (between-subject variability) for capsule and solution were 0.0315 h(-1) (91.9%) and 0.125 h(-1) (106.3%), respectively, and the relative bioavailability of the capsule was 0.82 (62.3%) (confidence interval 0.36, 1.97), compared with the solution. There was no evidence of nonlinearity. Simulations from the final model showed that a dosing schedule of 500 mg twice daily for both formulations provided the highest chance of target success. CONCLUSION: The optimal design performed well and the pharmacokinetics of itraconazole and hydroxy-itraconazole were described adequately by the model. The relative bioavailability for itraconazole capsules was 82% compared with the solution.