Search

ObjectiveProtracted international conflict has seen escalating numbers of displaced and resettled Syrian and Iraqi refugees, raising concerns for their health and well-being. This paper describes the demographic and clinical profiles of recently resettled Syrian and Iraqi refugee children and adolescents across physical, psychosocial, developmental and educational domains using standardised multidisciplinary assessments.DesignA cross-sectional observational study was undertaken of initial specialist paediatric multidisciplinary Refugee Health Service assessments completed at the tertiary paediatric hospital (Western Australia) between June 2015 and September 2019.ResultsThree hundred and twenty-seven children and adolescents (264 Syrian, 63 Iraqi) were assessed following resettlement. Witnessed trauma (86%) and disclosed adversity (median Refugee Adverse Childhood Experiences score 3, range 1–14) were universally high. Almost all patients had health issues identified across physical (99%), psychosocial (76%) and developmental/educational (75%) domains. Interrupted education (65%) and death of a family member (16%) were significantly associated with psychological morbidities. Common comorbidities included dental caries (78%), non-infectious disease (76%), vitamin D deficiency (72%), malnutrition (46%; overweight/obesity 23%), and psychological (32%; post-traumatic stress disorder 4.3%) and developmental (9.5%) concerns. Emerging and alarming child protection concerns were prevalent (17%), with females demonstrating especially high risks.ConclusionThis is the largest comprehensive study demonstrating the complex and cross-dimensional health needs and specific vulnerabilities of resettled Syrian and Iraqi refugee children and adolescents. Early comprehensive standardised multidisciplinary paediatric assessments, and culturally safe, trauma-informed interventions and follow-up are required to optimise resettlement outcomes and promote well-being.

This single-centre retrospective study explores demographics and outcomes of patients who underwent a modified Blalock-Taussig shunt (MBTS) over a 22-year period. The predominant surgical approach in this study is a lateral thoracotomy, in contrast to a midline sternotomy. Risks and outcomes of this approach are compared with national and international literature.Demographic, anatomical, clinical, surgical and outcome data of all patients who underwent a MBTS between 2000 and 2022 were collected and analysed, excluding Norwood procedures, which are not performed at this institution. Short- and long-term morbidity and mortality is described.Over the 22-year study period, 185 MBTS were performed in 162 patients, at a median age of 16 days (interquartile range [IQR] 5-59 days) and weight of 3.47 kg (IQR 3-4.25 kg, minimum weight 2 kg). Of these, 79% of patients had a biventricular circulation. Cardiac diagnoses included both univentricular and biventricular anatomy; tetralogy of Fallot (TOF) (36%), transposition of the great arteries/ventricular septal defect/pulmonary stenosis (TGA/VSD/PS) (11%), pulmonary atresia with intact ventricular septum (PA/IVS) (23%), pulmonary atresia with ventricular septal defect (PA/VSD) (14%), other (16%). The most common size of MBTS was 4 mm (71%); 93% were performed via a lateral thoracotomy. There were 47 cases of major operative morbidity, which did not differ significantly with cardiac diagnosis. Overall all-cause mortality was 13.5%. Early operative mortality was 4.3%. Mortality varied with cardiac diagnosis, 6% with TOF and 19% with PA/IVS. There was no era effect on mortality rates, however a lower frequency of major morbidity (23% vs 7%, p=0.03) was observed in the most recent third of the study period. Risk factors for shunt reintervention or mortality included weight2.5 kg (HR=2.79 [1.37, 5.65], p=0.005), and pre- (HR=3.31 [1.86, 5.9], p0.001) or postoperative lactic acidosis (HR=1.37 [1.25,1.5], p0.001). These rates are comparable to those in the literature, with the predominant approach a midline sternotomy. Hobbes et al. from Royal Children's Hospital in Melbourne, Australia reported an overall and operative mortality rate of 12.8% and 5.2%, respectively, while Sasikumar et al. from The Hospital for Sick Children in Toronto, Canada reported an overall and operative mortality of 16% and 10%, respectively, for MBTS procedures over the same time period, however including smaller weight infants. Petrucci et al. described outcomes from the multi-institutional Society of Thoracic Surgeons Congenital Heart Surgery database reporting an overall mortality in MBTS of 7.2% in 1,273 patients with both single and double ventricle anatomy.Mortality rates and risk factors for adverse outcomes are comparable to those previously reported for both univentricular and biventricular groups. These results highlight that outcomes of MBTS performed via lateral thoracotomy are comparable to those by midline sternotomy as reported in the literature. Operating via the lateral approach may be advantageous as it avoids the complications of a midline sternotomy.

Background There is increasing interest in the association between perinatal depression and diet including whether diet may have an impact on depressive symptoms and equally whether depression influences diet. Furthermore, whether pharmacological treatment of depression with antidepressant medication also may influence diet. Methods We examine diet, perinatal depression, and antidepressant use in 442 women recruited in early pregnancy and followed until 12 months postpartum as part of the Mercy Pregnancy Emotional Wellbeing Study. Measures included Structured Clinical Interview for the DSM at recruitment in early pregnancy and comprehensive dietary intake questions, Edinburgh Postnatal Depression Scale, and self-report and recorded antidepressant use at third trimester and 6 and 12 months postpartum. Results This study found that those women with untreated, current depression in pregnancy had higher unhealthy takeaway food intake across the perinatal period compared to those taking antidepressant medication or healthy control women, albeit the overall effects were small and the clinical significance unknown. Higher depressive symptoms in the postpartum were also associated with higher takeaway intake. There was no difference in fruit and vegetable intake between the three groups and intake was highest for all women late in pregnancy and declined in the postpartum period. In all, women's takeaway food intake increased from pregnancy across the postpartum. Limitations Lack of information on pre-pregnancy diet. Conclusions Unhealthy takeaway intake was found to be associated with depression; however, for those women who took antidepressant treatment, their diet patterns were similar to healthy controls. Future research should examine the relationship of treatments for depression in addition to depression and associated dietary behaviours.

The burden of bronchiectasis is disproportionately high in Aboriginal adults, with early mortality. Bronchiectasis precursors, that is, protracted bacterial bronchitis (PBB) and chronic suppurative lung disease (CSLD), often commence in early childhood. We previously reported a 10% prevalence of PBB in Aboriginal children aged 0 to 7 years, however there are no data on prevalence of chronic lung diseases in older children. Our study aimed to determine the prevalence of PBB, CSLD, bronchiectasis, and asthma in Aboriginal children living in four communities.A whole-population cross-sectional community co-designed study of Aboriginal children aged18-years in four remote communities in Western Australia across two-time points, a month apart. Children were assessed by pediatric respiratory clinicians with spirometry undertaken (when possible) between March-September 2021. Children with respiratory symptoms were followed up via medical record audit from either the local medical clinic or via a respiratory specialist clinic through to March 2022 to establish a final diagnosis.We recruited 392 (91.6%) of those in the selected communities; median age = 8.4 years (interquartile range [IQR] 5.1-11.5). Seventy children (17.9%) had a chronic respiratory pathology or abnormal spirometry results. PBB was confirmed in 30 (7.7%), CSLD = 13 (3.3%), bronchiectasis = 5 (1.3%) and asthma = 17 (4.3%). The prevalence of chronic wet cough significantly increased with increasing age.The prevalence of PBB, CSLD and bronchiectasis is high in Aboriginal children and chronic wet cough increases with age. This study highlights the high disease burden in Aboriginal children and the urgent need for strategies to address these conditions.

Evidence of autoimmune disease associated with hepatitis C virus (HCV)-infection has important clinical implications. A systematic profile of these autoantibodies in relevant clinical cohorts relative to healthy controls is needed to better inform current standard of care for chronic hepatitis C. Samples from an Australian cohort of chronic HCV-infected subjects (n=127) were tested for the presence of 19 diagnostic autoantibodies and compared with data available from a control cohort representing a general Caucasian population (n=198). Chronic HCV-infected individuals had a greater number of autoantibodies than controls (p

Objectives Systemic Lupus Erythematosus (SLE) is a serious autoimmune disease often resulting in major end-organ damage and increased mortality. Currently, no data exists focussing on the presentation, long-term management and progression of SLE in the Australian paediatric population. We conducted the first Australian longitudinal review of childhood SLE, focussing on response to treatment and outcomes. Methods Detailed clinical and laboratory data of 42 children diagnosed with SLE before 16 years from 1998 to 2018 resident in Western Australia was collected. Data was collected at diagnosis and key clinical review time points and compared using the Systemic Lupus Collaborating Clinics (SLICC) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) criteria. End organ damage was assessed against Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Incidence rates of disease complications and end organ damage were determined. Results Of the 42 children, 88% were female with average age at diagnosis of 12.5 years. Indigenous Australians were over represented with an incidence rate 18-fold higher than non-Indigenous, although most children were Caucasian, reflecting the demographics of the Australian population. Median duration of follow-up was 4.25 years. On final review, 28.6% had developed cumulative organ damage as described by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (incidence rate: 0.08/PY (95% CI 0.04–0.14)), and one child died. Twenty-nine children had renal involvement (incidence rate: 0.38/PY (95% CI 0.26–0.56)). Of the 27 patients with biopsy proven lupus nephritis, 70% had Class III or IV disease. Average length of prednisolone use from diagnosis was 32.5 months. Hydroxychloroquine ( n = 36) and mycophenolate mofetil ( n =21) were the most widely used steroid sparing agents. 61.9% received rituximab and/or cyclophosphamide. Conclusion This is the first longitudinal retrospective review of Australian children with SLE, with a markedly higher incidence in Indigenous children. Although improving, rates of end organ complications remain high, similar to international cohort outcomes. Longitudinal multi-centre research is crucial to elucidate risk factors for poor outcomes, and identifying those warranting early more aggressive therapy.

Background Despite the wide use of parenteral nutrition (PN) in neonatal intensive care units (NICU), there is limited evidence regarding the optimal time to commence PN in term and late preterm infants. The recommendations from the recently published ESPGHAN/ESPEN/ESPR/CPEN and NICE guidelines are substantially different in this area, and surveys have reported variations in clinical practice. The aim of this randomised controlled trial (RCT) is to evaluate the benefits and risks of early versus late PN in term and late preterm infants. Methods/design This study is a single-centre, non-blinded RCT in the NICU of Perth Children’s Hospital, Western Australia.A total of 60 infants born ≥34 weeks of gestation who have a high likelihood of intolerance to enteral nutrition (EN) for at least 3-5 days will be randomised to early (day 1 or day 2 of admission) or late commencement (day 6 of admission) of PN after informed parental consent. In both groups, EN will be commenced as early as clinically feasible. Primary outcomes are plasma phenylalanine and plasma F2-isoprostane levels on Day 4 and Day 8 of admission. Secondary outcomes are total and individual plasma amino acid profiles, plasma and red blood cell fatty acid profiles, in-hospital all-cause mortality, hospital-acquired infections, length of hospital/NICU stay, z scores and changes in z scores at discharge for weight, height and head circumference, time to full EN, duration of respiratory (mechanical, non-invasive) support, duration of inotropic support, the incidence of hyper and hypoglycaemia, incidence of metabolic acidosis, liver function, blood urea nitrogen, and C-reactive protein (CRP). Discussion This RCT will examine the effects of early versus late PN in term and late preterm infants by comparing key biochemical and clinical outcomes and has the potential to identify underlying pathways for beneficial or harmful effects related to the timing of commencement of PN in such infants. Trial registration ANZCTR; ACTRN12620000324910 (3rd March 2020)

Neurological disorders are a leading cause of disease burden worldwide, placing a heavy demand on health systems. This study evaluated the impacts and cost savings of a community-based nursing service providing supported discharge for neurological patients deemed high-risk for unplanned emergency department presentations and/or hospital readmissions. It focused on adult patients with stroke, epilepsy, migraine/headache or functional neurological disorders discharged from a Western Australian tertiary hospital. An observational design was used comprising prospective enrolment of patients receiving nurse-led supported discharge and follow-up (Neurocare), 21 August 2018 to 6 December 2019 (N = 81), and hospital administrative data, 1 February 2016 to 31 January 2018, for patients in previous care model (N = 740). Healthcare utilisation and annualised cost savings from reduced rehospitalisation and/or emergency department presentations within 28 days post discharge were compared. Neurocare patients' postdischarge functional and health-related quality of life outcomes, and perceived involvement in self-management and integrated care were surveyed. The hospital's total cost savings are A$101,639 per annum and A$275/patient/year with a return on investment of 2.01. There was no significant difference in hospital length of stay (LOS) between models, but older age was associated with longer length of hospital stay and a predictor for non-neurological readmissions. Neurocare patients showed improved functional status, less equipment and/or service needs, improved health-related quality of life. They felt involved in self-managing their condition with well-integrated postdischarge care. This nurse-led model of transitional care for neurology patients discharged from hospital produced cost savings and a positive return on investment compared with usual care. With service maturity, earlier supported hospital discharge and reduced LOS may follow. Patients' reduced service needs and improved functional status and health-related quality of life may positively impact healthcare utilisation. Future research should include larger patient samples and multiple sites.

BACKGROUND The consideration of health-related quality of life (HRQL) is a hallmark of best practice in HIV care. Information technology offers an opportunity to more closely engage patients with chronic HIV infection in their long-term management and support a focus on HRQL. However, the implementation of patient-reported outcome (PRO) measures, such as HRQL in routine care, is challenged by the need to synthesize data generated by questionnaires, the complexity of collecting data between patient visits, and the integration of results into clinical decision-making processes. OBJECTIVE Our aim is to design and pilot-test a multimedia software platform to overcome these challenges and provide a vehicle to increase focus on HRQL issues in HIV management. METHODS A multidisciplinary team in France and Australia conducted the study with 120 patients and 16 doctors contributing to the design and development of the software. We used agile development principles, user-centered design, and qualitative research methods to develop and pilot the software platform. We developed a prototype application to determine the acceptability of the software and piloted the final version with 41 Australian and 19 French residents using 2 validated electronic questionnaires, the Depression, Anxiety and Stress Scale-21 Items, and the Patient Reported Outcomes Quality of Life-HIV. RESULTS Testing of the prototype demonstrated that patients wanted an application that was intuitive and without excessive instruction, so it felt effortless to use, as well as secure and discreet. Clinicians wanted the PRO data synthesized, presented clearly and succinctly, and clinically actionable. Safety concerns for patients and clinicians included confidentiality, and the potential for breakdown in communication if insufficient user training was not provided. The final product, piloted with patients from both countries, showed that most respondents found the application easy to use and comprehend. The usability testing survey administered found that older Australians had reduced scores for understanding the visual interface (P=.004) and finding the buttons organized (P=.02). Three-fourths of the respondents were concerned with confidentiality (P=.007), and this result was more prevalent in participants with higher anxiety and stress scores (P=.01), as measured by the Depression, Anxiety and Stress Scale-21 Items. These statistical associations were not observed in 15 French patients who completed the same questionnaire. CONCLUSIONS Digital applications in health care should be safe and fit for purpose. Our software was acceptable to patients and shows potential to overcome some barriers to the implementation of PROs in routine care. The design of the clinicians’ interface presents a solution to the problem of voluminous data, both synthesizing and providing a snapshot of longitudinal data. The next stage is to conduct a randomized controlled trial to determine whether patients experience increased satisfaction with care and whether doctors perceive that they deliver better clinical care without compromising efficiency.

Background The consideration of health-related quality of life (HRQL) is a hallmark of best practice in HIV care. Information technology offers an opportunity to more closely engage patients with chronic HIV infection in their long-term management and support a focus on HRQL. However, the implementation of patient-reported outcome (PRO) measures, such as HRQL in routine care, is challenged by the need to synthesize data generated by questionnaires, the complexity of collecting data between patient visits, and the integration of results into clinical decision-making processes. Objective Our aim is to design and pilot-test a multimedia software platform to overcome these challenges and provide a vehicle to increase focus on HRQL issues in HIV management. Methods A multidisciplinary team in France and Australia conducted the study with 120 patients and 16 doctors contributing to the design and development of the software. We used agile development principles, user-centered design, and qualitative research methods to develop and pilot the software platform. We developed a prototype application to determine the acceptability of the software and piloted the final version with 41 Australian and 19 French residents using 2 validated electronic questionnaires, the Depression, Anxiety and Stress Scale-21 Items, and the Patient Reported Outcomes Quality of Life-HIV. Results Testing of the prototype demonstrated that patients wanted an application that was intuitive and without excessive instruction, so it felt effortless to use, as well as secure and discreet. Clinicians wanted the PRO data synthesized, presented clearly and succinctly, and clinically actionable. Safety concerns for patients and clinicians included confidentiality, and the potential for breakdown in communication if insufficient user training was not provided. The final product, piloted with patients from both countries, showed that most respondents found the application easy to use and comprehend. The usability testing survey administered found that older Australians had reduced scores for understanding the visual interface (P=.004) and finding the buttons organized (P=.02). Three-fourths of the respondents were concerned with confidentiality (P=.007), and this result was more prevalent in participants with higher anxiety and stress scores (P=.01), as measured by the Depression, Anxiety and Stress Scale-21 Items. These statistical associations were not observed in 15 French patients who completed the same questionnaire. Conclusions Digital applications in health care should be safe and fit for purpose. Our software was acceptable to patients and shows potential to overcome some barriers to the implementation of PROs in routine care. The design of the clinicians’ interface presents a solution to the problem of voluminous data, both synthesizing and providing a snapshot of longitudinal data. The next stage is to conduct a randomized controlled trial to determine whether patients experience increased satisfaction with care and whether doctors perceive that they deliver better clinical care without compromising efficiency.

There is increasing interest in the association between perinatal depression and diet including whether diet may have an impact on depressive symptoms and equally whether depression influences diet. Furthermore, whether pharmacological treatment of depression with antidepressant medication also may influence diet.We examine diet, perinatal depression, and antidepressant use in 442 women recruited in early pregnancy and followed until 12 months postpartum as part of the Mercy Pregnancy Emotional Wellbeing Study. Measures included Structured Clinical Interview for the DSM at recruitment in early pregnancy and comprehensive dietary intake questions, Edinburgh Postnatal Depression Scale, and self-report and recorded antidepressant use at third trimester and 6 and 12 months postpartum.This study found that those women with untreated, current depression in pregnancy had higher unhealthy takeaway food intake across the perinatal period compared to those taking antidepressant medication or healthy control women, albeit the overall effects were small and the clinical significance unknown. Higher depressive symptoms in the postpartum were also associated with higher takeaway intake. There was no difference in fruit and vegetable intake between the three groups and intake was highest for all women late in pregnancy and declined in the postpartum period. In all, women's takeaway food intake increased from pregnancy across the postpartum.Lack of information on pre-pregnancy diet.Unhealthy takeaway intake was found to be associated with depression; however, for those women who took antidepressant treatment, their diet patterns were similar to healthy controls. Future research should examine the relationship of treatments for depression in addition to depression and associated dietary behaviours.

Neurocognitive impairment (NCI) is common in people aging with HIV and can adversely affect health-related quality of life. However, early NCI may be largely asymptomatic and neurocognitive function is rarely assessed in the context of routine clinical care. In this study, we considered the utility of two assessment tools as screens for NCI in patients attending a community-based clinic (N = 58; mean age = 57 years): the Montreal Cognitive Assessment (MoCA) and a 3-item cognitive concerns questionnaire derived from the HIV Dementia Scale. Health-related quality of life and depression/anxiety were also measured. Indication of NCI using the MoCA was more prevalent compared to the 3-item questionnaire and was associated with the patients' initial antiretroviral therapy commencing between the years of 1997 and 2001, independently of age. Findings of the MoCA were not confounded by existing mood disorders, unlike the 3-item questionnaire. Therefore, we suggest implementing the MoCA as an initial screen for NCI.

BACKGROUND Concurrent upper limb injuries can occur with hip fractures, and its incidence and effect on outcomes are unclear. The objective of this study was to review the number and types of upper limb injuries sustained by patients with hip fractures, and investigate how acute hospital stay, rehabilitation and patient outcomes are affected. METHODS A retrospective study was performed on 820 patients with traumatic fracture of the hip over the age of 50. We reviewed the patients with concurrent upper limb injuries and compared patient outcomes - including mortality, acute length of stay in the orthopaedic ward, rehabilitation outcomes and rehabilitation length of stay. RESULTS Thirty-four patients (4.1%) with a hip fracture had a concurrent upper limb injury. Patients with and without concurrent upper limb injuries had similar acute length of stays on the orthopaedic ward (mean 5.2 versus 5.5 days, P = 0.4), and no significant difference in mortality rates at time of discharge (0% versus 3.8%, P = 0.4) and at 30 days (2.9% versus 9.1%, P = 0.2). However, they also required significantly longer rehabilitation (mean 34.6 versus 19.9 days, P = 0.009) even after other demographic factors including upper limb injury, older age and dementia were taken into consideration (multivariate linear model: concurrent upper limb injury, P = 0.0003; older age, P = 0.05; dementia, P = 0.09). CONCLUSION A concurrent upper limb injury is infrequent in the hip fracture population. Overall, these patients were previously higher functioning than the average hip fracture patient and required longer stays in inpatient rehabilitation than patients with isolated hip fractures.

Human immunodeficiency virus (HIV) can adapt to an individual’s T cell immune response via genomic mutations that affect antigen recognition and impact disease outcome. These viral adaptations are specific to the host’s human leucocyte antigen (HLA) alleles, as these molecules determine which peptides are presented to T cells. As HLA molecules are highly polymorphic at the population level, horizontal transmission events are most commonly between HLA-mismatched donor/recipient pairs, representing new immune selection environments for the transmitted virus. In this study, we utilised a deep sequencing approach to determine the HIV quasispecies in 26 mother-to-child transmission pairs where the potential for founder viruses to be pre-adapted is high due to the pairs being haplo-identical at HLA loci. This scenario allowed the assessment of specific HIV adaptations following transmission in either a non-selective immune environment, due to recipient HLA mismatched to original selecting HLA, or a selective immune environment, mediated by matched donor/recipient HLA. We show that the pattern of reversion or fixation of HIV adaptations following transmission provides insight into the replicative cost, and likely compensatory networks, associated with specific adaptations in vivo. Furthermore, although transmitted viruses were commonly heavily pre-adapted to the child’s HLA genotype, we found evidence of de novo post-transmission adaptation, representing new epitopes targeted by the child’s T cell response. High-resolution analysis of HIV adaptation is relevant when considering vaccine and cure strategies for individuals exposed to adapted viruses via transmission or reactivated from reservoirs., Author summary Highly mutable pathogens utilise genetic variations within T cell epitopes as a mechanism of immune escape (viral adaptation). The diversity of the human leucocyte antigen (HLA) molecules that present viral targets to T cells in human populations partially protects against rapid population-level accumulation of human immunodeficiency virus (HIV) adaptations through horizontal transmissions. In contrast, vertical transmissions occur between haplo-identical mother/child pairs, and potentially include adaptive changes through father-mother-child transmission, representing a pathway to complete pre-adaptation to HLA alleles in child hosts over only two transmission events. We utilised next-generation sequencing to examine HIV evolution in the unique setting of vertical HIV transmission. We predict the in vivo replicative cost and immune benefit of specific HIV adaptations that could be used to inform vaccine design and cure strategies to combat viral immune adaptation.

Background & Aims Non-alcoholic fatty liver disease (NAFLD) is common and related to obesity and insulin resistance. Iron metabolism is impaired in obese individuals and iron deficiency has been associated with physical inactivity. We investigated whether iron bioavailability is reduced in patients with NAFLD and contributes to reduced cardiorespiratory fitness. Methods We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study—a longitudinal study of disease development in 2868 children in Western Australia. X2 and linear regression analyses were used to compare characteristics of study participants according to NAFLD status at age 17 years. Results Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI]). Iron bioavailability (assessed by mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], transferrin saturation, and serum levels of iron) was inversely correlated with BMI in adolescents with NAFLD (P ≤ .01 for all, adjusted for sex) but not in adolescents without NAFLD (P > .30). MCV and MCH correlated with PWC (MCV, P = .002 for female and P = .0003 male participants; MCH, P = .004 for female and P = .01 for male participants), irrespective of NAFLD status. Reduced PWC was associated with lower transferrin saturation in adolescents with NAFLD (reduction of 0.012 W/kg per unit decrease in transferrin saturation, P = .007) but not in adolescents without NAFLD (reduction of 0.001 W/kg, P = .40), adjusted for sex. This association was independent of MCV or MCH. Conclusions In a well-defined cohort of adolescents, we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.

INTRODUCTION: HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist. METHODS: We compared the HLA class I (A, B, C) and class II (DR, DQ, DP) typing between patients with well-characterized AIH and healthy controls by high resolution sequencing of the HLA region. Seventy-three patients with AIH and 87 healthy controls were included. Association between HLA alleles and AIH was considered singly and in clusters and adjusted for age, gender, and DRB1*03:01. RESULTS: DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01. Significant HLA class I alleles were associated with AIH including those belonging to the A03 (OR: 0.4, P = 0.01) and B44 supertype (OR: 0.44, P = 0.03). Further refinement of HLA-A by binding pocket structure revealed that the sequence Y(F/T)AVMENV(H/Q)Y, corresponding to HLA-A alleles A*03:01-02; *31:01; *32:02, was protective for AIH (OR: 0.3, P = 0.002). A protective association also existed for alleles belonging to the HLA-B binding pocket structure Y(H/Y)TVKEISNY (OR: 0.35, P = 0.01), corresponding to HLA-B alleles: B*40:01-02; *41:02; *44:02-03; *45:01; *49:01; *50:01-02. Associations with specific class I alleles belonging to the 8.1 ancestral haplotype (HLA-A*01:01, HLA-B*08:01, HLA-C*07:01) were not significant when considered jointly with DRB1*03:01 and reported protective class I alleles. DISCUSSION: Our study identified novel supertypes and HLA-A and B peptide binding structures protective against AIH. Further risk assessment of class I molecules remains important in AIH as they are key mediators of adaptive immunity.

Background The Western Australian lung transplant programme commenced in 2004 to serve the growing demand of patients with end‐stage lung disease. Aim This report summarises our 11‐year experience in lung transplantation. Methods Data on 115 consecutive patients and their respective donors transplanted between 2004 and 2015 were collected. The Kaplan–Meier method was used to estimate survival. Cox regression was used to analyse the impact of donor and recipient characteristics on survival. Results A total of 88 bilateral, 22 single‐lung and 5 heart‐lung transplants were performed in Western Australia during the first 11 years of the lung transplant programme. The most common indications for transplantation were interstitial lung disease (30.4%), cystic fibrosis (27.8%) and chronic obstructive pulmonary disease (excluding alpha‐1 antitrypsin deficiency) (22.6%). Median recipient age was 50 years. Overall survival rates were 96% at 3 months, 93% at 1 year, 84% at 3 years and 70% at 5 years. Older age and higher BMI negatively impacted survival. Chronic lung allograft dysfunction was the leading cause of late mortality. Conclusion Lung transplantation is a treatment option in end‐stage lung disease, with annual transplant rates in Western Australia continuing to rise. Our patients enjoy survival rates that compare favourably against international standards.

Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.

Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.

Objective: To define the relative frequencies of different mechanisms of viral escape. Design: A population-based approach to examine the distribution of HIV polymorphism associated with diverse population human leucocyte antigens (HLAs) at sites within and flanking CD8 T-cell epitopes as a correlate of likely mechanisms of viral escape. Methods: Sequence windows surrounding 874 HLA allele-specific polymorphisms across the full HIV-1 proteomic consensus sequence were scanned by an epitope-prediction programme. Either already known or probable CD8 T-cell epitopes with HLA restriction matching that of the proximal HLA association were identified and synthesized. These peptides were used as stimulating antigens in automated enzyme-linked immunospot (ELISpot) assays. Peptide arrays were customized to each individual based on their HLA genotype. Results: Among HLA-associated HIV polymorphisms detected in the viral sequences of a cohort of 800 individuals with chronic subtype B HIV infection, those which were likely to affect HLA peptide binding were significantly more common than polymorphisms at nonanchor HLA binding sites. HIV epitopes with such polymorphisms were associated with reduced IFNγ responses in ELISpot assays. HIV escape at sites affecting T-cell receptor (TCR) engagement and epitope processing were also evident. Conclusion: HIV escape from HLA-peptide binding predominates as an effective viral evasion strategy and therefore has implications for inclusion of HLA-adapted epitopes in vaccine immunogens.

Infliximab (IFX) is an effective treatment for the management of moderate to severe inflammatory bowel disease (IBD). Low-serum IFX levels are associated with the development of antibodies to IFX (ATI), which subsequently associated with clinical relapse and increased morbidity. The primary purpose of this study is to examine the relation between dose and interval to IFX level. Secondary goal is to evaluate the relation between IFX level and ATI in a pediatric IBD population.We performed a retrospective chart review of all children diagnosed with IBD and treated with IFX at a tertiary care pediatric IBD center. We performed our analysis based on prescribed dosing intervals and rounded dose up to 5 or 10 mg/kg as indicated in clinical practice.Our study included 278 samples from 129 children on IFX. ATI were detected in 37 samples (13.3%). Low IFX levels (3 μg/mL) were detected in 37.2% of children receiving IFX. Samples with ATI present had significantly lower levels of IFX than samples in which ATI were not present. For the dose 5 mg/kg, Q6 dosing had significantly higher IFX levels than Q8 dosing (P = 0.009). Higher IFX levels were seen with interval shortening rather than dose escalation.We demonstrate that low IFX levels are associated with development of immunogenicity to IFX as measured by ATI. We demonstrate that interval shortening rather than dose escalation results in higher IFX levels. We suggest that given the high number of IFX levels below 3 μg/mL in patients, early IFX level evaluation or primary initiation of Q6 week dosing be considered.

Objective Vitamin D deficiency (VDD) is prevalent in HIV, and following antiretroviral therapy (ART), increased rates of lipoatrophy and metabolic abnormalities are described. We investigated the relationships between 25-hydroxyvitamin D [25(OH)D] and other metabolic parameters in a group of HIV patients with and without lipoatrophy to examine whether lipoatrophy could explain the high prevalence of VDD and metabolic abnormalities.

Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-γ responses in 290 individuals from the same cohort, which gave rise to 874 HLA–HIV associations in genetic analyses, taking into account autologous viral sequences and individual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this reverse-genomics approach. Many HLA-adapted epitopes elicited equivalent or higher-magnitude IFN-γ responses than did the nonadapted epitopes, particularly in Nef. At a population level, inclusion of all of the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef, and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins. We concluded that HLA–HIV associations mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations, as well as to test, train, and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA-adapted variant responses may have negative effects on natural and vaccine immunity against HIV and, therefore, has implications for diversity coverage approaches in HIV vaccine design.

Australian Gastroenterology Week 2014 Gold Coast Convention & Exhibition Centre, Broadbeach, Queensland, 22-24 October 2014

Since HLA-restricted cytotoxic T-cell responses select specific polymorphisms in HIV-1 sequences and HLA diversity is relatively static in human populations, we investigated the use of peptide epitopes based on sites of HLA-associated adaptation in HIV-1 sequences to stimulate and detect T-cell responses ex vivo. These "HLA-optimised" peptides captured more HIV-1 Nef-specific responses compared with overlapping peptides of a single consensus sequence, in interferon-gamma enzyme linked immunospot assays. Sites of immune selection can reveal more immunogenic epitopes in HLA-diverse populations and offer insights into the nature of HLA-epitope targeting, which could be applied in vaccine design.

Rationale Non-IgE mediated mast-cell activation to fluoroquinolones (FQ) is prevalent and complicates both clinical and skin-test diagnosis of true IgE mediated reactions. Methods Consecutive patients(n=101) with immediate or accelerated reactions to FQ underwent prick (SPT)/intradermal skin (IDT) (0.005;0.025 mg/ml) testing to ciprofloxacin, levofloxacin, and moxifloxacin followed by single dose 250 mg oral challenge(OC) to the implicated FQ. Results 3/101 (2.97%) patients had immediate histories consistent with moxifloxacin anaphylaxis. 101/101(100%) were SPT negative. 2/3 patients with anaphylaxis were moxifloxacin IDT positive but negative to ciprofloxacin and levofloxacin at 0.005 mg/ml. Of 98/101 who were IDT 0.005 mg/ml negative to all FQ, 56/56(100%) of patients who underwent single dose OC to >1 FQ were tolerant, and 19/56 (34%) subsequently tolerated a therapeutic course of >1 FQ (5-41 days; median duration 12 days). Using OC as the gold standard, the performance of 0.005 mg/ml IDT FQ was: negative predictive (NPV) 98.25%(95%CI 91.9-99.6); positive predictive value (PPV) 100%; sensitivity (66.7%); specificity (100%). IDT 0.025 mg/ml was equally sensitive, however was positive in 7 patients who tolerated OC (PPV 22.2%[95%CI 9-45.2%; specificity 87.5%]. 76/101 (75%) of those FQ tested had been labeled as penicillin allergic prior to FQ exposure of which 100% were subsequently negative on penicillin SPT/IDT/OC, suggesting that FQ use is in part driven by history of penicillin allergy. Conclusions Negative IDT testing to FQ at 0.005 mg/ml followed by low dose FQ (250 mg) OC may be a useful testing strategy in allergy practice to define patients without true IgE-mediated reactions likely to be FQ tolerant.

The enzyme linked immunospot (ELISpot) assay is a fundamental tool in cellular immunology, providing both quantitative and qualitative information on cellular cytokine responses to defined antigens. It enables the comprehensive screening of patient derived peripheral blood mononuclear cells to reveal the antigenic restriction of T-cell responses and is an emerging technique in clinical laboratory investigation of certain infectious diseases. As with all cellular-based assays, the final results of the assay are dependent on a number of technical variables that may impact precision if not highly standardised between operators. When studies that are large scale or using multiple antigens are set up manually, these assays may be labour intensive, have many manual handling steps, are subject to data and sample integrity failure and may show large inter-operator variability. Here we describe the successful automated performance of the interferon (IFN)-γ ELISpot assay from cell counting through to electronic capture of cytokine quantitation and present the results of a comparison between automated and manual performance of the ELISpot assay. The mean number of spot forming units enumerated by both methods for limiting dilutions of CMV, EBV and influenza (CEF)-derived peptides in six healthy individuals were highly correlated (r > 0.83, p < 0.05). The precision results from the automated system compared favourably with the manual ELISpot and further ensured electronic tracking, increased through-put and reduced turnaround time.

Aim: The Major Histocompatibility Complex (MHC) is a highly polymorphic region on chromosome 6 encompassing the human leucocyte antigen (HLA)-DQ/DR loci most predictive of susceptibility to type 1 diabetes (T1D). To assess the contribution of other MHC genes, in this exploratory analysis of Type 1 Diabetes Genetics Consortium (T1DGC) family data we characterize association between susceptibility and MHC single nucleotide polymorphism (SNP) genotype, with an emphasis on effects of genetic variation additional to carriage of predisposing or protective MHC haplotypes. Methods: We use Cox regression analyses of age of onset, stratified by family, to jointly test both linkage and association. Analysis is restricted to children from families having both affected and unaffected siblings and is conducted with and without adjustment for known HLA class I and II effects. Model fits provide scores for each individual that are based on estimates of the probability of being affected by the age of 35, given the individual’s SNP genotype. The mean within-family variation in these scores provides a measure that closely reflects the relative size of the likelihood ratio test statistics, and their covariation provides a means of mapping patterns of association that incorporate both effect size and commonality of effect that is attributable to the strong linkage disequilibrium (LD) extending across the region. Results: Univariate analyses yielded strong associations with T1D susceptibility that are dominated by SNPs in the class II HLA-DR/DQ region but extend across the MHC. Similar effects are frequently observed across SNPs within multiple genes, sometimes spanning hundreds of kilobases. SNPs within a region at the telomeric end of the class II gene HLA-DRA yielded significant associations with and without adjustment for carriage of the predictive DR3, DR4, DR2 and DR7 HLA haplotypes, and remained highly prominent in a secondary analysis that was restricted to 66 families in whom at least one of the affected siblings carried neither the DR3 nor DR4 haplotype. Conclusions: While many of the associations can be attributed to LD between the SNPs and the dominant HLA-DRB/DQA/DQB loci, there is also evidence of additional modifying effects.

Aim: The absence or ‘missingness’ of single nucleotide polymorphism (SNP) assay values because of genotype or related factors of interest may bias association and other studies. Missingness was determined for the Type 1 Diabetes Genetics Consortium (T1DGC) Major Histocompatibility Complex (MHC) data and was found to vary across the region, ranging up to 11.1% of the non-null proband SNPs, with a median of 0.3%. We consider factors related to missingness in the T1DGC data and briefly assess its possible influence on association studies. Methods: We assessed associations of missingness in the SNP assay data with human leucocyte antigen (HLA) genotype of the individual and with SNP genotypes of the parents. Within-cohort analyses were combined (over all cohorts) using (i) Mantel–Haenszel tests for two-by-two tables or (ii) by combining test statistics for larger tables and regression models. Mixed effect regression models were used to assess association of the SNP genotypes with affected status of the offspring after adjustment for parental SNP genotypes, cohort membership and HLA genotypes. Log-linear models were used to assess association of missingness in the unaffected sib assays with SNP genotypes of the probands. Results: Missingness of SNP values near the HLA class I (A, B and C) and class II (DR, DQ and DP) loci is strongly associated with carriage of corresponding HLA genotypes within these groups. Similar associations pertain to missing values among the microsatellite data. In at least some of these cases, regions of missingness coincided with known deletion regions corresponding to the associated HLA haplotype. We conjecture that other regions of associated missingness may point to similar haplotypic deletions. Analysis of association patterns of SNP genotypes with affected status of offspring does not indicate strong informative missingness. However, association of missingness in proband data with parental SNP genotypes may impact transmission disequilibrium test (TDT)-type analyses. Comparisons of affected and unaffected siblings point to possible susceptibility regions additional to the classical HLA-DR3/4 alleles near BAT4-LY6G5B-BAT5 and NOTCH4. Conclusions: Potentially informative missingness in SNP assay values in the MHC region may impact on association and related analyses based on the T1DGC data. These results suggest that it would be prudent to assess the degree to which missingness may abrogate assessed SNP disease markers in such studies. Initial analyses based on comparison of affected and unaffected status in offspring suggest that at least these may be little affected.

Objectives: HIV-infected patients responding to combination antiretroviral therapy (ART) after experiencing severe immunodeficiency may exhibit persistent immune defects and occasionally experience opportunistic infections (OIs) despite increased CD4 T-cell counts. The investigation of immune defects in such patients was examined in this study. Methods: CD4 effector memory T-cell (T em-cell) function [assessed by blood cytomegalovirus (CMV) interferon-γ (IFN-γ) enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) counts] and B-cell dysregulation [assessed by serum immunoglobulin A (IgA) and IgE levels] were examined in 27 patients with increased CD4 T-cell counts after receiving ART for over 2 years. Two of these patients and one other had developed OIs on ART and are described in detail. Results: Serum levels of IgA and IgE were higher than reference intervals (P

OBJECTIVES: Effective HIV therapy reflects suppression of plasma HIV RNA levels below assay detection thresholds, although lower levels of "residual viraemia" have also been demonstrated over extended periods of effective antiretroviral treatment. Here we examine the determinants of HIV RNA suppression below the standard assay threshold (40 HIV-1 RNA copies/mL) as well as factors associated with detectable HIV RNA below this reported detection limit. METHODS: Between 2007 and 2010, 11 575 consecutive viral load (VL) tests were obtained from 1540 patients, including 356 on effective antiretroviral therapy followed since initiation (1996-2001: n = 165; 2002-2009: n = 191). Analyses modelled the probability of an undetectable VL given successful suppression to < 200 copies/mL, and the probability of residual viraemia given an undetectable result. RESULTS: Detectable HIV RNA amplification was demonstrated in 20% of samples with a VL result < 40 copies/mL. Longitudinal analyses from 356 patients revealed that the likelihood of achieving results < 40 copies/mL was increased with current nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy [odds ratio (OR) 2.0; P < 0.05] and reduced with prior virological rebound (OR 0.5; P < 0.05). In contrast, the presence of detectable HIV RNA < 40 copies/mL was strongly associated with pretreatment HIV RNA levels among those on current protease inhibitor (PI) treatment (OR 1.5 per log10 copies/mL increase; P = 0.02) as well as those on NNRTIs (OR 1.7; P = 0.002). CONCLUSIONS: While HIV treatment history was associated with plasma HIV RNA levels below the detection limit, residual viraemia results were dominantly determined by pretreatment VL. These findings support the concept of a stable, long-lived reservoir of latently infected cells as a source of residual viraemia despite effective HIV treatment.

Variation in the host response to infection by pathogens including HIV-1 may be conferred by polymorphic genetic factors such as HLA and killer immunoglobulin-like receptors (KIR) genes. Here, we examined KIR and HLA genotype effects on pretreatment viral load, rate of CD4(+) T-cell decline and progression to AIDS among adult HIV-1-infected patients within the Western Australian HIV Study Cohort. In this study, carriage of KIR genes within the 'B' haplotype (eg KIR2DS2) was specifically associated with a more rapid CD4(+) T-cell decline over time and progression to AIDS. In contrast, KIR gene repertoire had no effect on pretreatment viral load while selected HLA alleles (eg HLA-B*5701, HLA-B*2705) demonstrated significant protective effects on viremia. Furthermore, interactions between specific HLA and KIR genes did appear to influence HIV disease progression. The results suggest that host genetic variation within the HLA and KIR gene complexes have clinically relevant effects on the course of HIV-1/AIDS, acting independently as well as synergistically to modify disease progression at multiple levels.

The Killer Ig-like receptors (KIRs) on NK cells regulate NK activity via the recognition of specific HLA class I products on the surface of target cells. To investigate the level at which these genetically polymorphic receptors and ligands influence HIV-1 disease progression, we examined the effect of KIR and HLA genotype on HIV outcome. We observed a significant association between particular combinations of KIR epitopes expressed by HLA-B/-C haplotypes and propose that the repertoire of KIR epitopes expressed by HLA-B and HLA-C alleles within the context of particular haplotypes may be an important component of the NK mediated immune response to HIV and/or other infectious pathogens.