A non-randomised single centre cohort study, comparing standard and modified bowel preparations, in adults with cystic fibrosis requiring colonoscopy.

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.

Sources and dynamics of fluorescent particles in hospitals.

Fluorescent particles can be markers of bioaerosols and are therefore relevant to nosocomial infections. To date, little research has focused on fluorescent particles in occupied indoor environments, particularly hospitals. In this study, we aimed to determine the spatial and temporal variation of fluorescent particles in two large hospitals in Brisbane, Australia (one for adults and one for children). We used an Ultraviolet Aerodynamic Particle Sizer (UVAPS) to identify fluorescent particle sources, as well as their contribution to total particle concentrations. We found that the average concentrations of both fluorescent and non-fluorescent particles were higher in the adults' hospital (0.06×106 and 1.20×106  particles/m3 , respectively) than in the children's hospital (0.03×106 and 0.33×106  particles/m3 , respectively) (P<.01). However, the proportion of fluorescent particles was higher in the children's hospital. Based on the concentration results and using activity diaries, we were able to identify sources of particle production within the two hospitals. We demonstrated that particles can be easily generated by a variety of everyday activities, which are potential sources of exposure to pathogens. Future studies to further investigate their role in nosocomial infection are warranted.

Idiosyncratic reactions are the most common cause of abnormal liver function tests in patients with cystic fibrosis.

BACKGROUND: Beta-lactam antibiotic-related liver enzyme derangement can limit treatment options for infective exacerbations in cystic fibrosis (CF) bronchiectasis. AIM: To identify risk factors for elevated liver function tests (LFT) in CF patients receiving parenteral antibiotics. METHODS: All patients attending The Prince Charles Hospital (TPCH) Adult CF Centre in 2012 were identified using the CF Research Database and CF Data Registry. Biochemistry and haematology panels between 1 January 2012 and 31 December 2012 for each patient were retrieved from Queensland Health Pathology and private pathology providers. Patients with LFT more than three times the upper limit of normal were identified. For each laboratory test, concurrently administered antibiotic(s) were analysed from TPCH pharmacy dispensing system for patients who received intravenous (IV) antibiotic treatment. RESULTS: Abnormal liver enzymes were evident in significantly more patients receiving IV antibiotics than patients who did not (43% vs 18%, P < 0.001). Pre-existing CF-related liver disease and total IV antibiotic treatment days were not associated with abnormal LFT. Higher C-reactive protein and peripheral eosinophil counts were not more common in patients with abnormal LFT. Male sex, poorer lung function and lower leucocyte counts were associated with abnormal LFT; however, these variables only explained 4.2% of the variance in the multivariable logistic model. CONCLUSION: Elevated LFT are common during IV antibiotic treatment in CF. Although specific antibiotic exposure may contribute to abnormal LFT in a minority of cases, our study demonstrates that antibiotic-induced liver injury is largely idiosyncratic and unpredictable.

Quantifying the effectiveness of ultraviolet-C light at inactivating airborne Mycobacterium abscessus.

BACKGROUND: Mycobacterium abscessus (MABS) group are environmental organisms that can cause infection in people with cystic fibrosis (CF) and other suppurative lung diseases. There is potential for person-to-person airborne transmission of MABS among people with CF attending the same care centre. Ultraviolet light (band C, UV-C) is used for Mycobacterium tuberculosis control indoors; however, no studies have assessed UV-C for airborne MABS. AIM: To determine whether a range of UV-C doses increased the inactivation of airborne MABS, compared with no-UVC conditions. METHODS: MABS was generated by a vibrating mesh nebulizer located within a 400 L rotating drum sampler, and then exposed to an array of 265 nm UV-C light-emitting diodes (LED). A six-stage Andersen Cascade Impactor was used to collect aerosols. Standard microbiological protocols were used for enumerating MABS, and these quantified the effectiveness of UV-C doses (in triplicate). UV-C effectiveness was estimated using the difference between inactivation with and without UV-C. FINDINGS: Sixteen tests were performed, with UV-C doses ranging from 276 to 1104 µW s/cm2. Mean (±SD) UV-C effectiveness ranged from 47.1% (±13.4) to 83.6% (±3.3). UV-C led to significantly greater inactivation of MABS (all P-values ≤0.045) than natural decay at all doses assessed. Using an indoor model of the hospital environment, it was estimated that UV-C doses in the range studied here could be safely delivered in clinical settings where patients and staff are present. CONCLUSION: This study provides empirical in-vitro evidence that nebulized MABS are susceptible to UV-C inactivation.

The risk of airborne influenza transmission in passenger cars.

Travel in passenger cars is a ubiquitous aspect of the daily activities of many people. During the 2009 influenza A(H1N1) pandemic a case of probable transmission during car travel was reported in Australia, to which spread via the airborne route may have contributed. However, there are no data to indicate the likely risks of such events, and how they may vary and be mitigated. To address this knowledge gap, we estimated the risk of airborne influenza transmission in two cars (1989 model and 2005 model) by employing ventilation measurements and a variation of the Wells-Riley model. Results suggested that infection risk can be reduced by not recirculating air; however, estimated risk ranged from 59% to 99·9% for a 90-min trip when air was recirculated in the newer vehicle. These results have implications for interrupting in-car transmission of other illnesses spread by the airborne route.

Transvenous correction of patent ductus arteriosus in two toy-breed dogs with the Amplatzer™ Vascular Plug 4.

Two Pomeranian dogs referred for interventional correction of a left-to-right shunting patent ductus arteriosus (PDA) had inadequate femoral arterial access for any occlusion device other than micro coils. The decision was made to attempt correction of the PDA using the Amplatzer™ Vascular Plug 4 (AVP4) from a femoral venous approach. An AVP4 was successfully deployed in each dog with complete occlusion noted within 5 min. Complete occlusion was persistent at 24 h after the procedure, while both dogs were subclinical, had no residual ductal flow, and complete or near complete reverse cardiac remodeling at subsequent visits. This report demonstrates the feasibility of PDA occlusion with the AVP4 from the femoral venous approach in small dogs where femoral arterial access is inadequate for other occlusion devices.

Neonatal administration of tamoxifen causes disruption of myometrial development but not adenomyosis in the C57/BL6J mouse.

We previously demonstrated that in the CD-1 mouse, which exhibits a high incidence of age-related adenomyosis, neonatal exposure to tamoxifen induced premature uterine adenomyosis and was associated with abnormal development particularly of the inner myometrium. In the present study, we examined the effect of neonatal tamoxifen administration upon uterine development in the C57/BL6J mouse strain that is not known to develop uterine adenomyosis. Female C57/BL6J pups (n=20) were treated with oral tamoxifen (1 mg/kg) from age 1 to 5 days. Uteri from control and treated mice were obtained on days 5, 10, 15 and 42 of age. We examined sections histologically using image analysis and immunohistochemistry for alpha-smooth muscle actin (ACTA2, alpha-SMA), desmin, vimentin, laminin, fibronectin and oestrogen receptor-alpha (ESR1). Following tamoxifen exposure, all uteri showed inner myometrium thinning, lack of continuity, disorganisation and bundling. However, adenomyosis was not seen in any uterus. ACTA2 immunostaining was less in the circular muscle layer of treated mice. The temporal pattern of desmin immunostaining found in control mice was absent in tamoxifen-treated mice. There was no difference in the localisation of laminin or fibronectin between control and tamoxifen-treated groups. However, laminin immunostaining was reduced in the circular muscle layer of treated mice. Vimentin could not be detected in either group. In conclusion, our results demonstrate that the development of the inner myometrium is particularly sensitive to oestrogen antagonism, and is affected by steroid receptor modulation. Although tamoxifen induces inner myometrial changes including that of ACTA2, desmin, ESR1 and laminin expression in C57/BL6J neonatal mice similar to those induced in CD-1 mice, C57/BL6J mice did not develop premature adenomyosis. Thus, disruption of the development and differentiation of the inner myometrium cannot alone explain the development of tamoxifen-associated adenomyosis, and this must be dependent upon its interaction with strain-dependent factors.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

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.

Neutrophils in cystic fibrosis.

Lung injury in cystic fibrosis is caused by recurrent airway infection and inflammation. Neutrophils are important in combating these infections but are also the predominate cells involved in the inflammatory process. This review of neutrophils in cystic fibrosis describes the cellular mechanisms involved in their migration into the airways and their role in bacterial phagocytosis. We discuss the inflammatory process and its resolution and ultimately how neutrophil function can be modulated.

Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis.

BACKGROUND: Pseudomonas aeruginosa is the most common bacterial pathogen in patients with cystic fibrosis (CF). Current infection control guidelines aim to prevent transmission via contact and respiratory droplet routes and do not consider the possibility of airborne transmission. It was hypothesised that subjects with CF produce viable respirable bacterial aerosols with coughing. METHODS: A cross-sectional study was undertaken of 15 children and 13 adults with CF, 26 chronically infected with P aeruginosa. A cough aerosol sampling system enabled fractioning of respiratory particles of different sizes and culture of viable Gram-negative non-fermentative bacteria. Cough aerosols were collected during 5 min of voluntary coughing and during a sputum induction procedure when tolerated. Standardised quantitative culture and genotyping techniques were used. RESULTS: P aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles

The effects of tamoxifen and estradiol on myometrial differentiation and organization during early uterine development in the CD1 mouse.

We used a neonatal mouse model to examine the histogenesis of uterine adenomyosis, and to test whether adenomyosis is due to an abnormality in myometrial differentiation, or in extracellular matrix proteins expression. We also studied the effects of tamoxifen and estradiol on uterine development, myometrial differentiation, and organization. Female CD1 pups were treated with oral tamoxifen (1 mg/kg) (n=27) or estradiol (0.1 mg/kg) (n=24) from age 1 to 5 days. Uteri from control (n=27) and treated mice were obtained on days 2, 5, 10, 15, and 42 of age. We examined the sections histologically, using image analysis and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, laminin, fibronectin, and estrogen receptor-alpha. Following tamoxifen exposure, all uteri showed adenomyosis by 6 weeks of age (seen as early as day 10). The inner myometrium showed thinning, lack of continuity, disorganization, and bundling. alpha-SMA expression was normal. Desmin expression normally showed a wave of maturation that was absent in tamoxifen-treated mice. In the estradiol group, adenomyosis was not observed. All uterine layers were normally developed, but hypertrophied. The inner myometrium retained its circular arrangement. There was no difference in the localization of laminin or fibronectin between groups (laminin expression was reduced in the tamoxifen treated uteri). Vimentin could not be detected in all groups. Our results suggest that the development of the inner myometrium is particularly sensitive to estrogen antagonism, and can be affected by steroid receptors modulation. Disruption of the inner myometrium may play a role in the development of uterine adenomyosis.

Indoor hospital air and the impact of ventilation on bioaerosols: a systematic review.

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/m3) 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/m3, 95% confidence interval (CI): 55-108) compared with the restricted (13cfu/m3, 95% CI: 10-15) and public areas (14 cfu/m3, 95% CI: 10-19). Hospital areas with natural ventilation had the highest total bioaerosol concentrations (201 cfu/m3, 95% CI: 135-300) compared with areas using conventional mechanical ventilation systems (20 cfu/m3, 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/m3, 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.

Epidemiological analysis of methicillin-resistant Staphylococcus aureus isolates from adult patients with cystic fibrosis.

Using pulsed-field gel electrophoresis, we genotyped 21 methicillin-resistant Staphylococcus aureus isolates from patients attending an adult cystic fibrosis unit. Eleven patients exhibited pulsotypes related to 2 locally endemic strains. Eleven chronically colonized patients were assessed over a period of up to 2 years, and all demonstrated a retention of strain type.

Use of biochemical markers of osteoarthritis to investigate the potential disease-modifying effect of tibial plateau levelling osteotomy.

OBJECTIVES: To evaluate the hypothesis that the concentration of the 1/20/5D4 epitope of keratan sulphate, cartilage oligomeric matrix protein and total sulphated glycosaminoglycans in synovial fluids from dogs with cranial cruciate ligament disease would be affected by tibial plateau levelling osteotomy. In addition, to evaluate the hypothesis that medial meniscal release or meniscal injury would alter the expression of these candidate biomarkers. METHODS: Forty-one dogs with naturally occurring cranial cruciate ligament disease were recruited prospectively. Synovial fluids were collected from the index joint before surgery and six weeks and six months postsurgery. Following tibial plateau levelling osteotomy, synovial fluids were assayed for 1/20/5D4 epitope of keratan sulphate and cartilage oligomeric matrix protein concentration using an inhibition ELISA and for sulphated glycosaminoglycans using a direct dye-binding assay. RESULTS: The sulphated glycosaminoglycans ratio did not change significantly during the study. Medial meniscal injury at entry was associated with lower concentrations of synovial fluid cartilage oligomeric matrix protein (P<0.05, unpaired t test). There was no association between medial meniscal release and the changes in marker concentrations, either from 0 to six weeks or 0 to six months. CLINICAL SIGNIFICANCE: Tibial plateau levelling osteotomy did not significantly alter the expression of the named candidate biomarkers. These findings reflect the limited nature of the arthrotomy or indicate that tibial plateau levelling osteotomy does not influence the progression of osteoarthritis (OA). From these studies, there is no evidence that tibial plateau levelling osteotomy affects cartilage metabolism.

Production of insulin-like growth factor-binding proteins by human central nervous system tumors.

Central nervous system (CNS) tumor cells possess specific receptors for insulin-like growth factors (IGFs) and respond to the growth-promoting effects of IGFs in cell culture. In the present study, we asked whether CNS tumors also produce IGF-binding proteins (BPs) which may modulate the effects of IGFs on CNS tumor cells. Primary cell cultures were established from 20 CNS tumors. Dot blot analysis with 125I-labeled recombinant human IGF-I revealed IGF-binding activity in serum-free conditioned medium from 5 of 7 meningiomas, 7 of 8 malignant gliomas, and 3 of 5 other CNS tumors. Specific IGF BPs in conditioned medium were characterized further by Western ligand and immunoblotting, affinity labeling, and precipitation with specific antibodies against human IGFBP-1, -2, and -3. All conditioned media tested contained an Mr 35,000 BP which was recognized by antiserum against IGFBP-2 and an Mr 24,000 BP that was not recognized by available antisera. Medium conditioned by meningiomas (and one glioma) also contained Mr 45,000 and 50,000 IGF BPs, similar in size and/or immunological properties to growth hormone-dependent BPs present in normal human serum (IGFBP-3). Ligand blotting also showed that meningiomas produce an Mr 29,000 BP; immunoblotting and immunoprecipitation of affinity-labeled IGF-BP complexes confirmed that this BP is recognized by antiserum against IGFBP-1. Immunohistochemistry with specific monoclonal antibodies demonstrated that IGFBP-1 is abundant in pathological specimens of meningiomas and that lower amounts also are detected in malignant gliomas. We conclude that human CNS tumor cells produce a variety of IGF BPs in cell culture, including several that are similar in size and immunological properties to previously characterized human IGF BPs. Immunohistochemistry with specific monoclonal antibodies against IGFBP-1 confirms that this BP is present in vivo, further supporting the concept that IGF BPs may contribute to the regulation of growth in human CNS tumors.

Infection in cystic fibrosis: impact of the environment and climate.

In many countries numbers of adults with cystic fibrosis (CF) exceed that of children, with median survival predicted to surpass 50 years. Increasing longevity is, in part, due to intensive therapies including eradication of early infection and suppressive therapies and pulmonary exacerbations. Initial infections with common CF pathogens are thought to arise from the natural environment. We review the impact of climate and environment on infection in CF. Specifically, several studies indicate that higher ambient temperatures, proximity to the equator and the summer season may be linked to the increased prevalence of Pseudomonas aeruginosa in people with CF. The environment may also play an important role in the acquisition of Gram negative organisms other than P. aeruginosa. There is emerging data suggesting that climatic and environmental factors are likely to impact on the risk of infection with NTM and fungi in people which are found extensively throughout the natural environment.

Patterns of expression of Bax, Bcl-2 and Bcl-x(L) in the implantation site in rat during pregnancy.

The uterine endometrium responds to blastocyst implantation with extensive proliferation and differentiation of stromal cells into decidual cells, forming the antimesometrial and mesometrial decidua. These undergo regression by apoptosis but as this process occurs at different time periods suggest that there is spatially dependent temporal control of apoptosis in these specific regions. To elucidate the role of the mitochondrion-dependent signalling pathway in tissue regression, we investigated the spatial and temporal pattern of expression of the Bcl-2 family members in uterine tissues of the implantation site, from the post-implantation period to parturition. Furthermore, the activities of the initiator caspases-8 and -9, and of the executioner caspase-3 were determined. Overall Bax and Bcl-2 were expressed from day 8 till day 19, whilst Bcl-x(L) was extinguished by day 16. In the antimesometrial and in the mesometrial decidua both Bcl-2 and Bax declined from days 10 to 12. In the latter Bcl-2 immunoreactivity decreased till the end of pregnancy, whilst for Bax a constant level remained thereafter. The pattern of variation of enzymatic activities throughout pregnancy for all the enzymes was similar, increasing from days 10 to 14 and decreasing towards the end of pregnancy. The increased levels of active caspase-9 correlated with Bax/Bcl-2 and Bcl-x(L) expression suggesting that the apoptotic mitochondrion-dependent pathway is involved in decidual regression during pregnancy progression.

MRSA eradication in a health care worker with cystic fibrosis; re-emergence or re-infection?

Methicillin-resistant Staphylocosis aureus (MRSA) is an emerging infection in patients with cystic fibrosis (CF). MRSA may be a management dilemma for healthcare workers (HCWs) with CF. Eradication of MRSA with long-term rifampicin and fusidic acid can be achieved in patients with CF. We describe a case of recurrent MRSA infection in a HCW with CF. Molecular typing of the MRSA isolates supported re-infection rather than re-emergence of an earlier MRSA infection. Infection control advice for HCWs with CF who acquire MRSA remains controversial.

Immunoglobulin and peripheral B-lymphocyte concentrations in Fell pony foal syndrome.

REASONS FOR PERFORMING STUDY: Fell pony foals are affected by a congenital fatal disease that leads to profound anaemia and immunodeficiency. Previous studies comparing healthy and affected foals have shown normal T-cell populations, but a severe B-lymphopenia. OBJECTIVES: To measure the levels of individual immunoglobulin subisotypes in normal and affected Fell ponies and correlate these levels with the number of peripheral B-lymphocytes. METHODS: Serum levels of individual immunoglobulin subisotypes were measured by ELISA and correlated with the number of peripheral B-lymphocytes (measured by flow cytometry). RESULTS: Affected foals had significantly reduced serum levels of IgM, IgGa, IgGb and IgG(T) that coincided with the normal reduction in maternally derived immunoglobulin in foals and, with the exception of IgGb, correlated strongly with the B-lymphopenia. CONCLUSIONS: These data suggest that affected foals are unable to produce their own immunoglobulins. Therefore, once maternal immunity has waned, it may be the lack of specific foal-derived immunoglobulin that gives rise to the clinical signs of immunodeficiency. POTENTIAL RELEVANCE: Measurement of IgM after age 4 weeks may provide a more accessible means of confirming the status of future affected Fell pony foals than the measurement of B-lymphocytes (a technique limited to a few specialist laboratories).

N-terminal amino acid sequence of human pregnancy-associated endometrial alpha 1-globulin, an endometrial insulin-like growth factor (IGF) binding protein--evidence for two small molecular weight IGF binding proteins.

We have previously demonstrated that quantitatively the major secretory protein of the human endometrium from the latter half of the first trimester of pregnancy, pregnancy-associated endometrial alpha 1-globulin (alpha 1-PEG), is a small mol wt insulin-like growth factor binding protein (IGF BP) and is detected at high levels in amniotic fluid. N-terminal amino acid sequences have been determined for this protein purified from both these sources and a single N-terminal amino acid sequence Ala Pro Trp Gln Cys Ala Pro Cys Ser Ala Glu Lys Leu Ala Leu Pro Pro was obtained. The first ten residues are identical to those previously reported for the small mol wt IGF BP isolated from amniotic fluid and HEPG2 culture medium. However it was different to that reported for the IGF BP isolated from term placenta, placental protein 12 (PP12), a protein previously suggested to originate in the endometrium. These data suggest that at least two distinct forms of the small mol wt IGF BP exist and supports the hypothesis that the amniotic fluid form originates from the pregnancy endometrium.