Rasch validation of the short form (8 item) PC-QoL questionnaire and applicability of use as a health state classification system for a new preference-based measure.

BACKGROUND: The parent-proxy paediatric chronic cough quality of life questionnaire (PC-QoL) is a commonly used measure of spillover quality of life in parents of children with chronic cough. To date, spillover health utility in these parents is not routinely estimated largely due to the lack of a suitable instrument. Their perspective is not included in economic evaluations of interventions for their children. We explored developing a health state classification system based on the PC-QoL for measuring health utility spill over in this population. METHODS: This study included PC-QoL 8-item responses of 653 parents participating in a prospective cohort study about paediatric chronic cough. Exploratory factor analysis (EFA) and Rasch analysis were used to examine dimensionality and select potential items and level structure. RESULTS: EFA indicated that the PC-QoL had one underlying domain. Rasch analysis indicated threshold disordering in all items which improved when items were collapsed from seven to four levels. Two demonstrated differential item functioning (DIF) by diagnosis or ethnicity and were excluded from the final scale. This scale satisfied Rasch assumptions of local independence and unidimensionality and demonstrated acceptable fit to the Rasch model. It was presented to and modified by an expert panel and a consumer panel. The resulting classification system had six items, each with four levels. DISCUSSION: The PC-QoL can conform to a Rasch model with minor modifications. It may be a good basis for the classification system of a child cough-specific PBM. A valuation study is required to estimate preference weights for each item and to estimate health utility in parents of children with chronic cough.

Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence.

BACKGROUND: Transitioning from a genetic association signal to an effector gene and a targetable molecular mechanism requires the application of functional fine-mapping tools such as reporter assays and genome editing. In this report, we undertook such studies on the osteoarthritis (OA) risk that is marked by single nucleotide polymorphism (SNP) rs34195470 (A > G). The OA risk-conferring G allele of this SNP associates with increased DNA methylation (DNAm) at two CpG dinucleotides within WWP2. This gene encodes a ubiquitin ligase and is the host gene of microRNA-140 (miR-140). WWP2 and miR-140 are both regulators of TGFß signaling. METHODS: Nucleic acids were extracted from adult OA (arthroplasty) and foetal cartilage. Samples were genotyped and DNAm quantified by pyrosequencing at the two CpGs plus 14 flanking CpGs. CpGs were tested for transcriptional regulatory effects using a chondrocyte cell line and reporter gene assay. DNAm was altered using epigenetic editing, with the impact on gene expression determined using RT-qPCR. In silico analysis complemented laboratory experiments. RESULTS: rs34195470 genotype associates with differential methylation at 14 of the 16 CpGs in OA cartilage, forming a methylation quantitative trait locus (mQTL). The mQTL is less pronounced in foetal cartilage (5/16 CpGs). The reporter assay revealed that the CpGs reside within a transcriptional regulator. Epigenetic editing to increase their DNAm resulted in altered expression of the full-length and N-terminal transcript isoforms of WWP2. No changes in expression were observed for the C-terminal isoform of WWP2 or for miR-140. CONCLUSIONS: As far as we are aware, this is the first experimental demonstration of an OA association signal targeting specific transcript isoforms of a gene. The WWP2 isoforms encode proteins with varying substrate specificities for the components of the TGFß signaling pathway. Future analysis should focus on the substrates regulated by the two WWP2 isoforms that are the targets of this genetic risk.

Osteoarthritis as an Enhanceropathy: Gene Regulation in Complex Musculoskeletal Disease.

PURPOSE OF REVIEW: Osteoarthritis is a complex and highly polygenic disease. Over 100 reported osteoarthritis risk variants fall in non-coding regions of the genome, ostensibly conferring functional effects through the disruption of regulatory elements impacting target gene expression. In this review, we summarise the progress that has advanced our knowledge of gene enhancers both within the field of osteoarthritis and more broadly in complex diseases. RECENT FINDINGS: Advances in technologies such as ATAC-seq have facilitated our understanding of chromatin states in specific cell types, bolstering the interpretation of GWAS and the identification of effector genes. Their application to osteoarthritis research has revealed enhancers as the principal regulatory element driving disease-associated changes in gene expression. However, tissue-specific effects in gene regulatory mechanisms can contribute added complexity to biological interpretation. Understanding gene enhancers and their altered activity in specific cell and tissue types is the key to unlocking the genetic complexity of osteoarthritis. The use of single-cell technologies in osteoarthritis research is still in its infancy. However, such tools offer great promise in improving our functional interpretation of osteoarthritis GWAS and the identification of druggable targets. Large-scale collaborative efforts will be imperative to understand tissue and cell-type specific molecular mechanisms underlying enhancer function in disease.

Morphoea induced by vaping.

Case report of Morphoea induced by the use of electronic cigarettes.

The Economic Burden of Bronchiectasis: A Systematic Review.

BACKGROUND: Bronchiectasis, a previously neglected condition, now has renewed research interest. There are a few systematic reviews that have reported on the economic and societal burden of bronchiectasis in adults, but none have reported on children. We undertook this systematic review to estimate the economic burden of bronchiectasis in children and adults. RESEARCH QUESTION: What is the health care resource utilization and economic burden of bronchiectasis in adults and children? STUDY DESIGN AND METHODS: We performed a systematic review identifying publications from Embase, PubMed, Web of Science, Cochrane (trials, reviews, and editorials), and EconLit about the economic burden and health care utilization in adults and children with bronchiectasis between January 1, 2001, and October 10, 2022. We used a narrative synthesis approach and estimated aggregate costs for several countries. RESULTS: We identified 53 publications reporting on the economic burden and/or health care utilization of people with bronchiectasis. Total annual health care costs per adult patient ranged from 2021 $3,579 to $82,545 USD and were predominantly driven by hospitalization costs. Annual indirect costs including lost income because of illness (reported in only five studies) ranged from $1,311 to $2,898 USD. Total health care costs in children with bronchiectasis were $23,687 USD annually in the one study that estimated them. Additionally, one publication found that children with bronchiectasis missed 12 school days per year. We estimated aggregate annual health care costs for nine countries, ranging from $101.6 million per year in Singapore to $14.68 billion per year in the United States. We also estimated the aggregate cost of bronchiectasis in Australian children to be $17.77 million per year. INTERPRETATION: This review highlights the substantial economic burden of bronchiectasis for patients and health systems. To our knowledge, it is the first systematic review to include the costs for children with bronchiectasis and their families. Future research to examine the economic impact of bronchiectasis in children and economically disadvantaged communities, and to further understand the indirect burden of bronchiectasis on individuals and the community, is needed.

SMS reminders to improve the uptake and timeliness of the primary immunisation series in infants: a multi-centre randomised controlled trial.

Background: Immunisation timeliness continues to present challenges to achieving optimal vaccine coverage in infancy, particularly in disadvantaged groups and Australian First Nations infants. We aimed to determine whether a tailored, educational SMS reminder improves the timeliness of immunisation in infants up to seven months of age. Methods: A pragmatic, three-arm, parallel-group, randomised controlled trial of immunisation reminders was conducted in two First-Nations-specific primary health care centres and two public hospital antenatal clinics in South East Queensland, Australia. Live-born infants of mothers enrolled during pregnancy were randomised at birth and followed to eight months of age. One group received a simple SMS reminder at two weeks before, the week of, and two weeks after the due date for immunisation at two, four and six months of age. The second group received a tailored SMS with an educational message at two weeks before and on the date immunisations were due; those not immunised two weeks following the due date were offered support to immunise the baby. Controls received no intervention or contact until the baby turned seven months of age. The primary outcome was the proportion of infants age-appropriately vaccinated at seven months of age as recorded on the Australian Immunisation Register. Secondary outcomes included vaccination status at three and five months of age. Results: Between 30 May 2016 and 24 May 2018, one hundred and ninety-six infants (31% First Nations infants) were randomised. At seven months of age, 54/65 (83.1%) infants in the educational SMS ± additional support group (ESMS±S) were age-appropriately immunised, compared to 45/64 (70.3%) in the simple SMS group and 45/67 (67.2%) in controls. Differences were most marked at five months of age: ESMS±S 95.5%; simple SMS 73.4%; controls 75.8%. The difference between the ESMS±S group and the other two groups at seven months of age was no longer apparent when those who received additional support beyond the SMS were assumed to have not been vaccinated if that support had not been received. Discussion: A tailored SMS reminder system using an educational message and with provision of additional support to mothers is more effective in improving immunisation timeliness in infants at three and five months of age than a simple message and no intervention. The additional support was required at seven months of age in order to achieve higher coverage in the ESMS±S group.

Utility of a personalised Bronchiectasis Action Management Plan (BAMP) for children with bronchiectasis: protocol for a multicentre, double-blind parallel, superiority randomised controlled trial.

INTRODUCTION: Bronchiectasis is no longer considered rare or irreversible in children, yet it remains relatively under-researched and neglected in respiratory health globally. Bronchiectasis (including chronic suppurative lung disease) causes substantial morbidity for patients and significant impact on caregivers, especially during acute respiratory exacerbations. In other chronic respiratory diseases (eg, asthma), empowering consumers with an individualised plan for management of acute exacerbations improves clinical outcomes. However, in the absence of any such data specific to bronchiectasis, action management plans are rarely currently used in children or adults with bronchiectasis. We hypothesise that providing an individualised bronchiectasis action management plan (BAMP) to children with bronchiectasis reduces non-scheduled doctor consultations, compared with not having a BAMP. METHODS AND ANALYSIS: This multicentre, parallel, double-blind, randomised trial involving three urban Australian hospitals commenced in June 2018 and will include 198 children, aged <19 years with bronchiectasis who had 2 or more exacerbations in the previous 18 months. Children will be randomised to having an individualised BAMP or standard care (a decoy clinic letter). Primary caregivers will then be followed up monthly for 12 months. The primary outcome is the rate of acute non-scheduled doctor visits for respiratory exacerbations by 12 months. The main secondary outcomes are cough-specific quality of life scores at 6 and 12 months, overall exacerbation rate over 12 months, and proportion of children who received timely influenza vaccination by 30 May annually. ETHICS AND DISSEMINATION: The Human Research Ethics Committees of the Northern Territory Department of Health and Menzies School of Heath Research and Queensland Children's Hospital approved the study. The results of the trial will be submitted for publication and the BAMP made available free online. TRIAL REGISTRATION NUMBER: Australia and New Zealand Clinical Trials Register ACTRN12618000604202.

Burden of Care for Children with Bronchiectasis from Parents/Carers Perspective.

Bronchiectasis is a neglected chronic respiratory condition. In children optimal appropriate management can halt the disease process, and in some cases reverse the radiological abnormality. This requires many facets, including parental/carer bronchiectasis-specific knowledge, for which there is currently no such published data. Further, the importance of patient voices in guiding clinical research is becoming increasingly appreciated. To address these issues, we aimed to describe the voices of parents of children with bronchiectasis relating to (a) burden of illness and quality of life (QoL), (b) their major worries/concerns and (c) understanding/management of exacerbations. The parents of 152 children with bronchiectasis (median age = 5.8 years, range 3.5-8.4) recruited from the Queensland Children's Hospital (Australia) completed questionnaires, including a parent-proxy cough-specific QoL. We found that parents of children with bronchiectasis had impaired QoL (median 4.38, range 3.13-5.63) and a high disease burden with median 7.0 (range 4.0-10.0) doctor visits in 12-months. Parental knowledge varied with only 41% understanding appropriate management of an exacerbation. The highest worry/concern expressed were long-term effects (n = 42, 29.8%) and perceived declining health (n = 36, 25.5%). Our study has highlighted the need for improved education, high parental burden and areas of concern/worry which may inform development of a bronchiectasis-specific paediatric QoL tool.

Genetic and Epigenetic Fine-Tuning of TGFB1 Expression Within the Human Osteoarthritic Joint.

OBJECTIVE: Osteoarthritis (OA) is an age-related disease characterized by articular cartilage degeneration. It is largely heritable, and genetic screening has identified single-nucleotide polymorphisms (SNPs) marking genomic risk loci. One such locus is marked by the G>A SNP rs75621460, downstream of TGFB1. This gene encodes transforming growth factor ß1, the correct expression of which is essential for cartilage maintenance. This study investigated the regulatory activity of rs75621460 to characterize its impact on TGFB1 expression in disease-relevant patient samples (n = 319) and in Tc28a2 immortalized chondrocytes. METHODS: Articular cartilage samples from human patients were genotyped, and DNA methylation levels were quantified using pyrosequencing. Gene reporter and electrophoretic mobility shift assays were used to determine differential nuclear protein binding to the region. The functional impact of DNA methylation on TGFB1 expression was tested using targeted epigenome editing. RESULTS: The analyses showed that SNP rs75621460 was located within a TGFB1 enhancer region, and the OA risk allele A altered transcription factor binding, with decreased enhancer activity. Protein complexes binding to A (but not G) induced DNA methylation at flanking CG dinucleotides. Strong correlations between patient DNA methylation levels and TGFB1 expression were observed, with directly opposing effects in the cartilage and the synovium at this locus. This demonstrated biologic pleiotropy in the impact of the SNP within different tissues of the articulating joint. CONCLUSION: The OA risk SNP rs75621460 impacts TGFB1 expression by modulating the function of a gene enhancer. We propose a mechanism by which the SNP impacts enhancer function, providing novel biologic insight into one mechanism of OA genetic risk, which may facilitate the development of future pharmacologic therapies.

Risk Factors for Chronic Cough in Young Children: A Cohort Study.

Background and Objective: Data on the predictors of chronic cough development in young children are scarce. Our primary objective was to examine the factors associated with young children developing a chronic cough, with a focus on childcare attendance. Methods: A secondary analysis of data collected in a prospective cohort study of children presenting to three emergency departments and three primary healthcare centers in southeast Queensland, Australia. Eligible children where those aged <6-years presenting with cough and without known underlying chronic lung disease other than asthma. Children were followed for 4 weeks to ascertain cough duration. The primary outcome was persistent cough at day-28. Logistic regression models were undertaken to identify independent predictors of chronic cough including sensitivity analyses that accounted for children with unknown cough status at day-28. Results: In 362 children, 95 (26.2%) were classified as having chronic cough. In models that included only children for whom cough status was known at day-28, symptom duration at enrolment, age <12 months [adjusted odds ratio (aOR) 4.5, 95% confidence interval (CI) 1.1, 18.7], gestational age (aOR 3.2, 95%CI 1.4, 7.9), underlying medical conditions (aOR 2.6, 95% CI 1.3, 5.5), a history of wheeze (aOR 2.6, 95% CI 1.4, 4.8) and childcare attendance (aOR 2.3, 95% CI 1.2, 4.4) were independent predictors of chronic cough. Amongst childcare attendees only, 64 (29.8%) had chronic cough at day-28. The strongest predictor of chronic cough amongst childcare attendees was continued attendance at childcare during their illness (aOR = 12.9, 95% CI 3.9, 43.3). Conclusion: Gestational age, underlying medical conditions, prior wheeze and childcare attendance are risk factors for chronic cough in young children. Parents/careers need to be aware of the risks associated with their child continuing to attend childcare whilst unwell and childcare centers should reinforce prevention measures in their facilities.

Effectiveness of a chronic cough management algorithm at the transitional stage from acute to chronic cough in children: a multicenter, nested, single-blind, randomised controlled trial.

BACKGROUND: Chronic (lasting at least 4 weeks) cough in children is an important cause of morbidity. An algorithmic approach to the management of coughs in children evaluated in observational studies and a randomised controlled trial (RCT) enrolled children referred with median cough duration of 16 weeks to specialist centres. We investigated whether applying an evidence-based cough management algorithm in non-specialist settings earlier, once cough persisted for more than 4 weeks, improved cough resolution compared with usual care. METHODS: We undertook a multicentre, single-blind RCT nested within a prospective cohort study of children (<15 years) in Australia presenting to three primary care or three hospital emergency departments with an acute respiratory illness with cough. Children were excluded if they had a known diagnosis of an underlying chronic medical condition (excluding asthma) or had an immunosuppressive illness or were taking immunomodulating drugs for more than 2 weeks in the preceding 30 days, or had severe symptoms requiring inpatient hospitalisation. Children were followed up for 8 weeks; those with a persistent cough at day 28 were randomly assigned to the cough management algorithm or to usual care. Randomisation was stratified by reason for presentation, study site, and cough duration (4 weeks to <6 weeks vs ≥6 weeks) using computer-generated permuted blocks (block size of four) with a 1:1 allocation. The primary outcome was the proportion of children with cough resolution at day 56 (defined as resolved if the child did not cough for at least 3 days and nights since day 28 or a more than 75% reduction in their average day and night cough score). Absolute risk differences (RDabsolute) were calculated by modified intention-to-treat analysis (ITT). This trial is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12615000132549. FINDINGS: Between July 7, 2015, and Oct 31, 2018, 1018 children were screened, 509 were enrolled in the cohort study, and of 115 children in the ITT analysis, 57 were randomly assigned to the intervention group and 58 to the control group. Children had a median age of 1·6 years (IQR 1·0-4·5); 45 (39%) of 115 were Indigenous, and 59 (51%) were boys. By day 56, 33 (58%) of 57 children in the intervention group achieved cough resolution compared with 23 (40%) 58 in the control group; cough resolution was unknown in 12 (21%) of 57 children receiving the intervention and in 13 (22%) of 58 receiving the control. The RDabsolute assuming children with an unknown cough outcome were still coughing at day 56 was 18·3% (95% CI 0·3-36·2); the number needed-to-treat for benefit was five (95% CI 3-364); the adjusted odds ratio was 1·5 (95% CI 1·3-1·6), favouring the intervention group. INTERPRETATION: This study suggests an evidence-based cough management algorithm improves cough resolution in community-based children in the early phases of chronic cough. However, larger studies to confirm these findings in primary care are required. FUNDING: National Health and Medical Research Council.

The surprisingly facile formation of Pd(i)-phosphido complexes from ortho-biphenylphosphines and palladium acetate.

The widely-used ortho-biphenylphosphine ligands SPhos and RuPhos not only undergo facile orthometallation with palladium acetate, yielding strained, four-membered dimeric palladacycles but more surprisingly, in the presence of alcoholic solvents, along with the less encumbered analogue MePhos, yield unusual dinuclear Pd(i) complexes, in which the Pd-centers are bridged by both a phosphide ligand and by the arene of a coordinated phosphine donor.

Development of a Human Cranial Bone Surrogate for Impact Studies.

In order to replicate the fracture behavior of the intact human skull under impact it becomes necessary to develop a material having the mechanical properties of cranial bone. The most important properties to replicate in a surrogate human skull were found to be the fracture toughness and tensile strength of the cranial tables as well as the bending strength of the three-layer (inner table-diplöe-outer table) architecture of the human skull. The materials selected to represent the surrogate cranial tables consisted of two different epoxy resins systems with random milled glass fiber to enhance the strength and stiffness and the materials to represent the surrogate diplöe consisted of three low density foams. Forty-one three-point bending fracture toughness tests were performed on nine material combinations. The materials that best represented the fracture toughness of cranial tables were then selected and formed into tensile samples and tested. These materials were then used with the two surrogate diplöe foam materials to create the three-layer surrogate cranial bone samples for three-point bending tests. Drop tower tests were performed on flat samples created from these materials and the fracture patterns were very similar to the linear fractures in pendulum impacts of intact human skulls, previously reported in the literature. The surrogate cranial tables had the quasi-static fracture toughness and tensile strength of 2.5 MPa√ m and 53 ± 4.9 MPa, respectively, while the same properties of human compact bone were 3.1 ± 1.8 MPa√ m and 68 ± 18 MPa, respectively. The cranial surrogate had a quasi-static bending strength of 68 ± 5.7 MPa, while that of cranial bone was 82 ± 26 MPa. This material/design is currently being used to construct spherical shell samples for drop tower and ballistic tests.

Assessing behind armor blunt trauma (BABT) under NIJ standard-0101.04 conditions using human torso models.

BACKGROUND: Although soft armor vests serve to prevent penetrating wounds and dissipate impact energy, the potential of nonpenetrating injury to the thorax, termed behind armor blunt trauma, does exist. Currently, the ballistic resistance of personal body armor is determined by impacting a soft armor vest over a clay backing and measuring the resulting clay deformation as specified in National Institute of Justice (NIJ) Standard-0101.04. This research effort evaluated the efficacy of a physical Human Surrogate Torso Model (HSTM) as a device for determining thoracic response when exposed to impact conditions specified in the NIJ Standard. METHODS: The HSTM was subjected to a series of ballistic impacts over the sternum and stomach. The pressure waves propagating through the torso were measured with sensors installed in the organs. A previously developed Human Torso Finite Element Model (HTFEM) was used to analyze the amount of tissue displacement during impact and compared with the amount of clay deformation predicted by a validated finite element model. All experiments and simulations were conducted at NIJ Standard test conditions. RESULTS: When normalized by the response at the lowest threat level (Level I), the clay deformations for the higher levels are relatively constant and range from 2.3 to 2.7 times that of the base threat level. However, the pressures in the HSTM increase with each test level and range from three to seven times greater than Level I depending on the organ. CONCLUSIONS: The results demonstrate the abilities of the HSTM to discriminate between threat levels, impact conditions, and impact locations. The HTFEM and HSTM are capable of realizing pressure and displacement differences because of the level of protection, surrounding tissue, and proximity to the impact point. The results of this research provide insight into the transfer of energy and pressure wave propagation during ballistic impacts using a physical surrogate and computational model of the human torso.

Assessing behind armor blunt trauma in accordance with the National Institute of Justice Standard for Personal Body Armor Protection using finite element modeling.

BACKGROUND: To assess the possibility of injury as a result of behind armor blunt trauma (BABT), a study was undertaken to determine the conditions necessary to produce the 44-mm clay deformation as set forth in the National Institute of Justice (NIJ) Standard 0101.04. These energy levels were then applied to a three-dimensional Human Torso Finite Element Model (HTFEM) with soft armor vest. An examination will be made of tissue stresses to determine the effects of the increased kinetic energy levels on the probability of injury. METHODS: A clay finite element model (CFEM) was created with a material model that required nonlinear properties for clay. To determine these properties empirically, the results from the CFEM were matched with experimental drop tests. A soft armor vest was modeled over the clay to create a vest over clay block finite element model (VCFEM) and empirical methods were again used to obtain material properties for the vest from experimental ballistic testing. Once the properties for the vest and clay had been obtained, the kinetic energy required to produce a 44-mm deformation in the VCFEM was determined through ballistic testing. The resulting kinetic energy was then used in the HTFEM to evaluate the probability of BABT. RESULTS: The VCFEM, with determined clay and vest material properties, was exercised with the equivalent of a 9-mm (8-gm) projectile at various impact velocities. The 44-mm clay deformation was produced with a velocity of 785 m/s. This impact condition (9-mm projectile at 785 m/s) was used in ballistic exercises of the HTFEM, which was modeled with high-strain rate human tissue properties for the organs. The impact zones were over the sternum anterior to T6 and over the liver. The principal stresses in both soft and hard tissue at both locations exceeded the tissue tensile strength. CONCLUSIONS: This study indicates that although NIJ standard 0101.04 may be a good guide to soft armor failure, it may not be as good a guide in BABT, especially at large projectile kinetic energies. Further studies, both numerical and experimental, are needed to assist in predicting injury using the NIJ standard.

Modeling the effect of non-penetrating ballistic impact as a means of detecting behind armor blunt trauma.

BACKGROUND: According to the National Institute of Justice (NIJ) Standard 0101.04, the maximum deformation a soft armor vest can undergo without penetration is 44 mm. However, this does not take into account the effect of the pressure wave or energy transferred to the organs within the torso due to behind armor blunt trauma (BABT). Therefore, a study was undertaken to develop a finite element model (FEM) to study these effects. METHODS: A finite element model (FEM) of the human thorax; complete with musculoskeletal structure and internal organs (heart, liver, lungs and stomach), intercostal muscle and skin, has been developed in LS-DYNA. A Kevlar vest was modeled on the chest to simulate non-penetrating ballistic impact. RESULTS: Using a projectile modeled with a size and mass equivalent to a 9 mm (124 grain) bullet at 360 and 425 m/s, four impacts were simulated against NIJ Level II and Level IIIa Kevlar vests at the midsternum and right thorax. At the same velocity, the pressures decreased by a factor of 3 and the energy absorbed by the organs decreased by a factor of 6 for the NIJ Level II and Level IIIa vests, respectively. As the projectile velocity increased, the peak pressures increased by a factor of 3 while the energy absorbed by the organs increased by a factor of 4. CONCLUSIONS: The resulting pressure profiles and kinetic energy exhibited by the respective organs indicate this model may be useful in identifying mechanisms of injury as well as organs at an elevated injury risk as a result of BABT.