The carbon monoxide prodrug oCOm-21 increases Ca2+ sensitivity of the cardiac myofilament.

Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low-dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO-releasing pro-drug, oCOm-21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of -log [Ca2+ ] (pCa) in the range of 9.0-4.5 under five conditions: vehicle, oCOm-21, the oCOm-21 control BP-21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50 ). oCOm-21, but not BP-21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm-21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm-21. These results support the hypothesis that oCOm-21-derived CO increases myofilament Ca2+ sensitivity through a heme-dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.

Eosinophilia and wheeze: thinking beyond asthma.

Primary idiopathic hypereosinophilic syndrome is a rare condition that can cause end-organ damage in multiple systems. The advent of targeted monoclonal antibodies, such as mepolizumab, provides a safe and effective steroid-sparing treatment. https://bit.ly/4bgDP1u.

Oral health and cystic fibrosis in pediatrics: A survey of health professionals.

BACKGROUND: Children with cystic fibrosis (CF) are usually managed by hospital-based, multidisciplinary teams (MDTs). This study aimed to investigate oral health perspectives, training, and practices of health professionals working with children with CF. METHODS: Data were collected through an online survey distributed to health professionals caring for children with CF by the CF Director in 12 Australian hospitals. The questions related to perspectives, training, and dental referral/advice relating to oral health for children with CF. The data were analyzed using descriptive statistics. RESULTS: Forty-four participants (26 physicians, 8 nurses, 6 physiotherapists, 2 dieticians, 1 psychologist, and 1 pharmacist) completed the survey. Most (n = 33, 75%) indicated they rarely/never check or discuss dental health. Of those who did, most reported lacking skills to inspect teeth and discuss dental health. Frequently reported barriers were lack of skills, training, knowledge, and time. Most respondents (n = 30, 68%) indicated they rarely/never recommend patients to see the dentist. The most frequently reported barrier to referrals was not considering it part of their role (43%). CONCLUSIONS: Closer working relations between CF units and dental teams may remove barriers that prevent non-dental clinicians from supporting patients with CF maintain oral health. Better integration of dental care within the MDT through improved professional training, increased referral practices, and availability of digital resources may help to improve dental care for all children, including children and adolescents with CF.

The role of exome sequencing in childhood interstitial or diffuse lung disease.

BACKGROUND: Children's interstitial and diffuse lung disease (chILD) is a complex heterogeneous group of lung disorders. Gene panel approaches have a reported diagnostic yield of ~ 12%. No data currently exist using trio exome sequencing as the standard diagnostic modality. We assessed the diagnostic utility of using trio exome sequencing in chILD. We prospectively enrolled children meeting specified clinical criteria between 2016 and 2020 from 16 Australian hospitals. Exome sequencing was performed with analysis of an initial gene panel followed by trio exome analysis. A subset of critically ill infants underwent ultra-rapid trio exome sequencing as first-line test. RESULTS: 36 patients [median (range) age 0.34 years (0.02-11.46); 11F] were recruited from multiple States and Territories. Five patients had clinically significant likely pathogenic/pathogenic variants (RARB, RPL15, CTCF, RFXANK, TBX4) and one patient had a variant of uncertain significance (VIP) suspected to contribute to their clinical phenotype, with VIP being a novel gene candidate. CONCLUSIONS: Trio exomes (6/36; 16.7%) had a better diagnostic rate than gene panel (1/36; 2.8%), due to the ability to consider a broader range of underlying conditions. However, the aetiology of chILD in most cases remained undetermined, likely reflecting the interplay between low penetrant genetic and environmental factors.

Utilising fluorescent reporters to probe the mode of action of norbornen-7-one CO releasing molecules.

The synthesis of the fluorescent organic carbon monoxide releasing molecules oCOm-57, oCOm-58, and oCOm-66 are reported. These oCOms are water soluble and exhibit a "turn-on" fluorescent behaviour when CO is released under physiological conditions. oCOm-66 also contains an additional nitro-naphthalimide moiety that functions as a fluorescent reporter. Delivery of CO released from these oCOms to the mitochondria of AC-16 cardiomyocytes was confirmed using confocal microscopy in conjuction with MitoTracker Red. While the neutral, PEGylated oCOm-57 was found to remain in the extracellular environment releasing CO to diffuse into the cellular compartments, the positively charged oCOm-58 and -66 are targeted to the mitochondria where they release CO. Notably, the use of the fluorescent oCOms in live cellular imaging, allows the intracellular CO delivery and oCOm localisation to be characterised. This cellular confocal study also shows that, subtoxic concentrations of CO released from these molecules preserved mitochondrial energetics as indicated by the membrane potential dependent MitoTracker Red.

Genomic testing for children with interstitial and diffuse lung disease (chILD): parent satisfaction, understanding and health-related quality of life.

OBJECTIVE: Research is needed to determine best practice for genomic testing in the context of child interstitial or diffuse lung disease (chILD). We explored parent's and child's health-related quality of life (HRQoL), parents' perceived understanding of a genomic testing study, satisfaction with information and the study and decisional regret to undertake genomic testing. METHODS: Parents of children with diagnosed or suspected chILD who were enrolled in a genomic sequencing study were invited to complete questionnaires pretesting (T1) and after receiving the result (T2). RESULTS: Parents' (T1, n=19; T2, n=17) HRQoL was lower than population norms. Study satisfaction (T1) and perceived understanding (T2) were positively correlated (rs=0.68, p=0.014). Satisfaction with information (T1 and T2) and decisional regret (T2) were negatively correlated (T1 rs=-0.71, p=0.01; T2 rs=-0.56, p=0.03). Parents reported wanting more frequent communication with staff throughout the genomic sequencing study, and greater information about the confidentiality of test results. CONCLUSIONS: Understanding of genomic testing, satisfaction with information and participation and decisional regret are inter-related. Pretest consultations are important and can allow researchers to explain confidentiality of data and the variable turnaround times for receiving a test result. Staff can also update parents when there will be delays to receiving a result.

Quality of life is poorly correlated to lung disease severity in school-aged children with cystic fibrosis.

BACKGROUND: There is no data exclusively on the relationship between health-related quality-of-life (HRQOL) and lung disease severity in early school-aged children with cystic fibrosis (CF). Using data from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) we assessed the relationships between HRQOL, lung function and structure. METHODS: 125 children aged 6.5-10 years enrolled in the AREST CF program were included from CF clinics at Royal Children's Hospital (RCH), Melbourne (n = 66) and Perth Children's Hospital (PCH), Perth (n = 59), Australia. Demographics, HRQOL measured by Cystic Fibrosis Questionnaire-Revised (CFQ-R), spirometry, multiple-breath washout (MBW) and chest CT were collected across two years. Correlation between CFQ-R scores and lung structure/function parameters and agreement between parent-proxy and child-reported HRQOL were evaluated. RESULTS: No correlation was observed between most CFQ-R domain scores and FEV1 z-scores, excepting weak-positive correlation with parent CFQ-R Physical (rho = 0.21, CI 0.02-0.37), and Weight (rho = 0.21, CI 0.03-0.38) domain and child Body domain (rho = 0.26, CI 0.00-0.48). No correlation between most CFQ-R domain scores and LCI values was noted excepting weak-negative correlation with parent Respiratory (rho = -0.23, CI -0.41--0.05), Emotional (rho = -0.24, CI -0.43--0.04), and Physical (-0.21, CI -0.39--0.02) domains. Furthermore, structural lung disease on CT data demonstrated little to no association with CFQ-R parent and child domain scores. Additionally, no agreement between child self-report and parent-proxy CFQ-R scores was observed across the majority of domains and visits. CONCLUSION: HRQOL correlated poorly with lung function and structure in early school-aged children with CF, hence clinical trials should consider these outcomes independently when determining study end-points.

Is cardiorespiratory disease associated with increased susceptibility of SARS-CoV-2 in children?

BACKGROUND: There are limited data in pediatric populations evaluating whether chronic cardiorespiratory conditions are associated with increased risk of coronavirus disease 2019 (COVID-19). We aimed to compare the rates of chronic cardiac and respiratory disease in children testing positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2[+]) compared with those testing negative (SARS-CoV-2[-]) at our institution. METHOD: Prospective cohort with nested case-control study of all children tested by polymerase chain reaction (PCR) for SARS-CoV-2 by nasopharyngeal/oropharyngeal sampling between March and October 2020. Children were identified prospectively via laboratory notification with age and sex-matching of SARS-CoV-2[+] to SARS-CoV-2[-] (1:2). Clinical data were extracted from the electronic medical record. RESULTS: In total, 179 SARS-CoV-2[+] children (44% females, median age 3.5 years, range: 0.1-19.0 years) were matched to 391 SARS-CoV-2[-] children (42% female, median age 3.7 years, range: 0.1-18.3 years). The commonest comorbidities showed similar frequencies in the SARS-CoV-2[+] and [-] groups: asthma (n = 9, 5% vs. n = 17, 4.4%, p = 0.71), congenital heart disease (n = 6, 3.4% vs. n = 7, 1.8%, p = 0.25) and obstructive sleep apnoea (n = 4, 2.2% vs. n = 10, 2.3%, p = 0.82). In the SARS-CoV-2[+] group, the prevalence of symptomatic disease was similar among children with and without cardiorespiratory comorbidities (n = 12, 75% vs. n = 103, 57%, p = 0.35). A high proportion of children hospitalized with SARS-CoV-2 infection had cardiac comorbidities (23.8%). CONCLUSIONS: In this single site data set, rates of pre-existing cardiorespiratory disease were similar in SARS-CoV-2[+] and SARS-CoV-2[-] children. Rates of symptomatic infection were similar between children with and without cardiorespiratory comorbidity. High rates of comorbid cardiac disease were observed among hospitalized children with COVID-19 warranting further research to inform vaccine prioritization.

Managing contacts of chlamydia: should clinics implement a test and wait process?

British guidelines recommend epidemiological treatment for all chlamydia contacts during the look back period. Some UK sexual health clinics follow a test and wait process for chlamydia contacts presenting after 14 days of exposure. The aim of this retrospective service evaluation was to determine the potential impact of implementing such a process for chlamydia contacts at our clinic. We reviewed the patient records of 548 chlamydia contacts over a 1-year period, and 588 patients with chlamydia over a 5-month period. Demographic and clinical characteristics data were collected.Chlamydia prevalence was 46% (254/548) in contacts, with prevalence varying by age (p=.008) and sexual risk (p=.04), but not by time since exposure (p=.29). For patients with chlamydia, there was a mean of 1.9 days between results notification and attending for treatment; a mean of 2.2 attempts were required to contact patients to return for treatment. Chlamydia prevalence in contacts is high. Not giving empirical treatment to contacts presenting after 14 days of exposure would result in 13.1% of the cohort needing to return for treatment. Patients found to have chlamydia returned promptly once informed of positive results.

BAL Inflammatory Markers Can Predict Pulmonary Exacerbations in Children With Cystic Fibrosis.

BACKGROUND: Pulmonary exacerbations in cystic fibrosis are characterized by airway inflammation and may cause irreversible lung damage. Early identification of such exacerbations may facilitate early initiation of treatment, thereby potentially reducing long-term morbidity. RESEARCH QUESTION: Is it possible to predict pulmonary exacerbations in children with cystic fibrosis, using inflammatory markers obtained from BAL fluid? STUDY DESIGN AND METHODS: A longitudinal analysis was conducted of children aged 0 to 7 years included in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) study between 2005 and 2015. The association between inflammatory markers from annual BAL fluid and time to pulmonary exacerbation requiring hospital admission in the 6-month period post-BAL was analyzed using Kaplan-Meier curves and Weibull regression, adjusting for annually repeated measurements. Admissions for Pseudomonas eradication were excluded in the main analysis, because of the standard policy in participating centers to treat Pseudomonas in-hospital. RESULTS: Nine hundred seventy-six BAL samples from 308 children were analyzed. After exclusion of admissions for Pseudomonas eradication (n = 43), there were 145 pulmonary exacerbations recorded within 6 months of BAL; median time to exacerbation was 31 days (interquartile range, 9-100). In univariate analyses, high IL-8 (hazard ratio [HR], 2.25 for 75th vs 25th percentile; 95% CI, 1.87-2.72), neutrophil elastase (HR, 3.00; 95% CI, 2.03-4.42), and high neutrophil percentage (HR, 1.80 for 75th vs 25th percentile; 95% CI, 1.56-2.04) were all significantly associated with risk for a pulmonary exacerbation (P < .001). The inflammatory markers remained significant predictors after adjustment for clinical predictive variables. INTERPRETATION: Inflammatory markers in BAL fluid are significant predictors of pulmonary exacerbations in young children with cystic fibrosis. The development of noninvasive measures of lung inflammation may facilitate routine surveillance of cystic fibrosis.

A Clinically Relevant Functional Model of Type-2 Cardio-Renal Syndrome with Paraventricular Changes consequent to Chronic Ischaemic Heart Failure.

Cardiorenal syndrome, de novo renal pathology arising secondary to cardiac insufficiency, is clinically recognised but poorly characterised. This study establishes and characterises a valid model representative of Type 2 cardiorenal syndrome. Extensive permanent left ventricular infarction, induced by ligation of the left anterior descending coronary artery in Lewis rats, was confirmed by plasma cardiac troponin I, histology and cardiac haemodynamics. Renal function and morphology was assessed 90-days post-ligation when heart failure had developed. The involvement of the paraventricular nucleus was investigated using markers of inflammation, apoptosis, reactive oxygen species and of angiotensin II involvement. An extensive left ventricular infarct was confirmed following coronary artery ligation, resulting in increased left ventricular weight and compromised left ventricular diastolic function and developed pressure. Glomerular filtration was significantly decreased, fractional excretion of sodium and caspase activities were increased and basement membrane thickening, indicating glomerulosclerosis, was evident. Interestingly, angiotensin II receptor I expression and reactive oxygen species levels in the hypothalamic paraventricular nucleus remained significantly increased at 90-days post-coronary artery ligation, suggesting that these hypothalamic changes may represent a novel, valuable pharmacological target. This model provides conclusive morphological, biochemical and functional evidence of renal injury consequent to heart failure, truly representative of Type-2 cardiorenal syndrome.

Pulmonary Mycobacterium abscessus complex in children with cystic fibrosis: A practical management guideline.

The treatment of Mycobacterium abscessus complex (MABSC) pulmonary infections is an emerging challenge in patients with cystic fibrosis (CF). Multidrug therapy for prolonged durations is required and carries the significant burden of drug-related toxicity, cost and selective pressure for multiresistant bacteria. International guidelines acknowledge that clinical and in vitro data to support treatment regimens are limited, particularly in children. As part of a collaboration between the infectious diseases and respiratory units at our institution, we have developed a modified treatment guideline that aims to balance the aims of MABSC eradication and slowing disease progression with minimising drug toxicity and resistance. The outcomes of this treatment approach will be monitored and reported. In this manuscript, we discuss the available evidence for treatment choices and present our treatment guideline for paediatric patients with CF and MABSC infection.

Changing Prevalence of Lower Airway Infections in Young Children with Cystic Fibrosis.

Rationale: Historical studies suggest that airway infection in cystic fibrosis initiates with Staphylococcus aureus and Haemophilus influenzae, with later emergence of Pseudomonas aeruginosa. Aspergillus species are regarded as relatively infrequent, late-occurring infections.Objectives: To assess the prevalence and change in prevalence of early lower airway infections in a modern cohort of children with cystic fibrosis.Methods: All infants diagnosed with cystic fibrosis after newborn screening participating in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) cohort study between 2000 and 2018 were included. Participants prospectively underwent BAL at 3-6 months, 1 year, and annually up to 6 years of age. Lower airway infection prevalence was described. Changes in prevalence patterns were assessed longitudinally using generalized estimating equations controlling for age and repeated visits.Measurements and Main Results: A total of 380 infants underwent 1,759 BALs. The overall prevalence and median age of first acquisition of the most common infections were as follows: S. aureus, 11%, 2.5 years; P. aeruginosa, 8%, 2.4 years; Aspergillus species, 11%, 3.2 years; and H. influenzae, 9%, 3.1 years. During the study, a significant decrease in prevalence of P. aeruginosa (P < 0.001) and S. aureus (P < 0.001) was observed with a significant change toward more aggressive treatment. Prevalence of Aspergillus infections did not significantly change (P = 0.669).Conclusions:Aspergillus species and P. aeruginosa are commonly present in the lower airways from infancy. The decrease in prevalence of P. aeruginosa and S. aureus since 2000, coinciding with a more aggressive therapeutic approach, has resulted in Aspergillus becoming the most commonly isolated pathogen in young children. Further research is warranted to understand the implication of these findings.

Dual-energy X-ray absorptiometry scans accurately predict differing body fat content in live sheep.

BACKGROUND: There is considerable interest in implementing mobile scanning technology for on-farm body composition analysis on live animals. These experiments evaluated the use of dual energy X-ray absorptiometry (DXA) as an accurate method of total body fat measurement in live sheep. RESULTS: In Exp. 1, visceral and whole body fat analysis was undertaken in sheep with body condition scores (BCS) in the range 2 to 3.25 (scale 1: thin to 5: fat). The relationship of BCS was moderately correlated with visceral fat depot mass (r = 0.59, P < 0.01, n = 24) and whole body fat (r = 0.70, P < 0.001, n = 24). In Exp. 2, sheep with BCS in the range 2.25 to 3.75 were blood sampled to analyse circulating leptin concentrations, and were DXA scanned immediately post mortem for total body fat. Plasma leptin concentrations had low correlations with BCS (r = 0.50, P < 0.05, n = 17) and DXA body fat (r = 0.42, P < 0.05, n = 17), and no correlation with chemical body fat (r = 0.17, P > 0.05, n = 9). There was a moderate correlation between DXA body fat and BCS (r = 0.70, P < 0.01, n = 17), and DXA body fat was highly correlated with chemical body fat (r = 0.81, P < 0.001, n = 9). In Exp. 3, a series of five DXA scans, at 8-week intervals, was performed on growing sheep over a 32-week period. The average BCS ranged from 2.39 ± 0.07 (S.E.M.) to 3.05 ± 0.11 and the DXA body fat (%) ranged from 16.8 ± 0.8 to 24.2 ± 1.2. There was a moderate correlation between DXA body fat and BCS over the 32 weeks (r = 0.61, P < 0.001, n = 24). CONCLUSIONS: Overall, these experiments indicated that there was good agreement between BCS, DXA and chemical analysis for measuring total body fat in sheep, and that DXA scanning is a valid method for longitudinal measurement of total body fat in live sheep.

An approach to successful slide tracheoplasty in the low birth weight neonate with single lung.

The advent of the slide tracheoplasty technique and a multi-disciplinary approach has improved outcomes of congenital tracheal stenosis. However, tracheal surgery in younger patients with pulmonary malformations, especially low birth-weight neonates, has been associated with increased mortality. Patients with very low birth-weight, pulmonary malformations and prematurity may be palliated prior to definitive tracheal surgery due to the poor prognosis. We report a successful and unique approach of delaying tracheal reconstruction to allow growth and development in the premature, very low birth-weight neonate (1046g) with left lung agenesis.