A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.

Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.

Self-determination in programmes of perinatal health for Aboriginal Communities: A systematic review.

OBJECTIVE: The importance of self-determination in restoring the wellbeing of Australian First Nations peoples is becoming understood. For thousands of years, Aboriginal women gave birth on Country and Grandmothers' Lore and Women's Business facilitated the survival of the oldest living civilisations on earth. Following colonisation, however, Aboriginal and Torres Strait Islander practices of maternal and perinatal care were actively dismantled, and self-determination by Aboriginal people was destroyed. This had significant implications for the wellbeing of Aboriginal and Torres Strait Islander people and their Cultures and practices. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-based systematic review of research about programmes of birthing and perinatal health care for Australian Aboriginal and Torres Strait Islander women and their children was undertaken. The review's primary aim was to assess the Cultural context of programme development and delivery, its secondary aim was to assess the Cultural appropriateness of programme components. Electronic databases SCOPUS, PsycINFO, Medline, and CINAHL were searched for peer-reviewed studies published in English in Australia between 2000 and 2023. RESULTS: Twenty-eight publications met inclusion criteria. Included studies were assessed for their methodological characteristics, birthing-support characteristics, perinatal care and continuity of care characteristics. Overall, programmes were limited in meeting the Cultural needs of women, children, and individual Communities. The role of Aboriginal Communities in identifying, delivering, and reviewing programmes was also limited. CONCLUSIONS: Findings articulate the importance of self-determination in maintaining strong Indigenous Cultures and informing the Culturally appropriate development and delivery of Culturally safe programmes of perinatal care for Aboriginal women, children, and Communities. IMPLICATIONS FOR PUBLIC HEALTH: Programmes and services for use by Aboriginal and Torres Strait Islander people must involve Aboriginal and Torres Strait Islander people and their Communities in processes of programme planning, delivery, and review. The evaluation of a programme or service as "Culturally safe" represents a determination that is most appropriately made by service users based on their experience of that programme or service.

Dominant negative OTULIN-related autoinflammatory syndrome.

OTU deubiquitinase with linear linkage specificity (OTULIN) regulates inflammation and cell death by deubiquitinating linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC). Biallelic loss-of-function mutations causes OTULIN-related autoinflammatory syndrome (ORAS), while OTULIN haploinsuffiency has not been associated with spontaneous inflammation. However, herein, we identify two patients with the heterozygous mutation p.Cys129Ser in OTULIN. Consistent with ORAS, we observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. While the C129S mutation did not affect OTULIN protein stability or binding capacity to LUBAC and linear ubiquitin chains, it did ablate OTULIN deubiquitinase activity. Loss of activity facilitated the accumulation of autoubiquitin chains on LUBAC. Altered ubiquitination of LUBAC inhibits its recruitment to the TNF receptor signaling complex, promoting TNF-induced cell death and disease pathology. By reporting the first dominant negative mutation driving ORAS, this study expands our clinical understanding of OTULIN-associated pathology.

Filaggrin-Associated Atopic Skin, Eye, Airways, and Gut Disease, Modifying the Presentation of X-Linked Reticular Pigmentary Disorder (XLPDR).

BACKGROUND: X-linked reticular pigmentary disorder (XLPDR) is a rare condition characterized by skin hyperpigmentation, ectodermal features, multiorgan inflammation, and recurrent infections. All probands identified to date share the same intronic hemizygous POLA1 hypomorphic variant (NM_001330360.2(POLA1):c.1393-354A > G) on the X chromosome. Previous studies have supported excessive type 1 interferon (IFN) inflammation and natural killer (NK) cell dysfunction in disease pathogenesis. Common null polymorphisms in filaggrin (FLG) gene underlie ichthyosis vulgaris and atopic predisposition. CASE: A 9-year-old boy born to non-consanguineous parents developed eczema with reticular skin hyperpigmentation in early infancy. He suffered recurrent chest infections with chronic cough, clubbing, and asthma, moderate allergic rhinoconjunctivitis with keratitis, multiple food allergies, and vomiting with growth failure. Imaging demonstrated bronchiectasis, while gastroscopy identified chronic eosinophilic gastroduodenitis. Interestingly, growth failure and bronchiectasis improved over time without specific treatment. METHODS: Whole-genome sequencing (WGS) using Illumina short-read sequencing was followed by both manual and orthogonal automated bioinformatic analyses for single-nucleotide variants, small insertions/deletions (indels), and larger copy number variations. NK cell cytotoxic function was assessed using 51Cr release and degranulation assays. The presence of an interferon signature was investigated using a panel of six interferon-stimulated genes (ISGs) by QPCR. RESULTS: WGS identified a de novo hemizygous intronic variant in POLA1 (NM_001330360.2(POLA1):c.1393-354A > G) giving a diagnosis of XLPDR, as well as a heterozygous nonsense FLG variant (NM_002016.2(FLG):c.441del, NP_0020.1:p.(Arg151Glyfs*43)). Compared to healthy controls, the IFN signature was elevated although the degree moderated over time with the improvement in his chest disease. NK cell functional studies showed normal cytotoxicity and degranulation. CONCLUSION: This patient had multiple atopic manifestations affecting eye, skin, chest, and gut, complicating the presentation of XLPDR. This highlights that common FLG polymorphisms should always be considered when assessing genotype-phenotype correlations of other genetic variation in patients with atopic symptoms. Additionally, while the patient exhibited an enhanced IFN signature, he does not have an NK cell defect, suggesting this may not be a constant feature of XLPDR.

Restoration from out-of-home care for Aboriginal children: Evidence from the pathways of care longitudinal study and experiences of parents and children.

BACKGROUND: Restoration of Aboriginal children (also called reunification) is an under-researched area despite being the preferred permanency outcome for children. OBJECTIVE: To investigate the rate of restoration for Aboriginal children, the factors that influence restoration, and to explore the experiences of parents whose Aboriginal children have been restored, and their children. PARTICIPANTS AND SETTING: Analyses were conducted using data from the NSW Department of Communities and Justice Pathways of Care Longitudinal Study (POCLS). METHODS: The quantitative sample includes all Aboriginal children in NSW who were on final Children's Court care and protection orders by 30 April 2013. Qualitative data were extracted from the POCLS survey instruments. RESULTS: Of the 1018 Aboriginal children in the study, 15.2% were restored. Around 40 % of children entered care following just one (or no) substantiated Risk of Significant Harm reports. Children entering care under the age of 2 years were the least likely to be restored. Parents expressed dissatisfaction with child protection agencies and family support services both at the time their child was removed and in the restoration period. Parents and children expressed the importance of being supported to maintain family relationships while children are in care. CONCLUSIONS: Despite policy priorities to the contrary, few Aboriginal children are considered for restoration. More support is needed for Aboriginal parents interfacing with all stages of the care system and following restoration. Additional research is needed to understand the factors underlying decisions to remove Aboriginal children from their families and whether restoration to their family is considered or achieved.

Pyrin variant E148Q potentiates inflammasome activation and the effect of pathogenic mutations in cis.

OBJECTIVE: The p.E148Q variant in pyrin is present in different populations at a frequency of up to 29%, and has been associated with diseases, including vasculitis and FMF. The pathogenicity of p.E148Q in FMF is unclear, even when observed in cis or in trans to a single, typically recessive, pathogenic mutation. We performed functional validation to determine whether p.E148Q increases the ability of pyrin to form an active inflammasome complex in cell lines. METHODS: We interrogated the Australian Autoinflammatory Disease RegistrY (AADRY) to find candidate inheritance patterns for the p.E148Q variant in pyrin. Different pyrin variant combinations were tested in HEK293T cells stably expressing the adaptor protein apoptosis-associated speck-like (ASC), which were analysed by flow cytometry to visualize inflammasome formation, with and without stimulation by Clostridioides difficile toxin B (TcdB). Inflammasome-dependent cytokine secretion was also quantified by ELISA of supernatants from THP-1 cells transduced with lentiviral expression vectors. RESULTS: In AADRY, we observed the p.E148Q allele in individuals with autoinflammatory diseases alone or in conjunction with other pyrin variants. Two FMF families harboured the allele p.E148Q-M694I in cis with dominant heritability. In vitro, p.E148Q pyrin could spontaneously potentiate inflammasome formation, with increased IL-1ß and IL-18 secretion. p.E148Q in cis to classical FMF mutations provided significant potentiation of inflammasome formation. CONCLUSION: The p.E148Q variant in pyrin potentiates inflammasome activation in vitro. In cis, this effect is additive to known pathogenic FMF mutations. In some families, this increased effect could explain why FMF segregates as an apparently dominant disease.

C-Reactive Protein (CRP) is Associated With Chronic Pain Independently of Biopsychosocial Factors.

Inflammation is linked with chronic pain but the extent to which this relationship is associated with biopsychosocial factors is not known. We investigated relationships between blood C-reactive protein (CRP) and regional chronic pain conditions adjusting for a large range and number of potential confounders. We performed cross-sectional analyses using the UK Biobank (N = 415,567) comparing CRP in people reporting any of 9 types of regional chronic pain with pain-free controls. Using logistic regression modelling, we explored relationships between CRP and the presence of chronic pain, with demographic, socioeconomic, psychological/lifestyle factors, and medical comorbidities as covariates. CRP was higher in chronic pain at any site compared with controls (Females: median [interquartile range] 1.60 mg/L [2.74] vs 1.17 mg/L [1.87], P < .001; Males: 1.44 mg/L [2.12] vs 1.15 mg/L [1.65], P < .001). In males, associations between CRP and all types of chronic pain were attenuated but remained significant after adjustment for biopsychosocial covariates (OR range 1.08-1.49, P ≤ .001). For females, adjusted associations between CRP and pain remained significant for most chronic pain types (OR range 1.07-1.34, P < .001) except for facial pain (OR 1.04, P = .17) and headache (OR 1.02, P = .07)-although these non-significant findings may reflect reduced sample size. The significant association between CRP and chronic pain after adjustment for key biopsychosocial confounders implicates an independent underlying biological mechanism of inflammation in chronic pain. The presence of yet unknown or unmeasured confounding factors cannot be ruled out. Our findings may inform better-targeted treatments for chronic pain. PERSPECTIVE: Using a large-scale dataset, this article investigates associations between chronic pain conditions and blood C-reactive protein (CRP), to evaluate the confounding effects of a range of biopsychosocial factors. CRP levels were higher in those with chronic pain versus controls after adjusting for confounders-suggesting a possible independent biological mechanism.

Yarning about pain: Evaluating communication training for health professionals at persistent pain services in Queensland, Australia.

Background: Providing cultural education to health professionals is essential in improving the quality of care and outcomes for Aboriginal and Torres Strait Islander patients. This study reports the evaluation of a novel training workshop used as an intervention to improve communication with Aboriginal and Torres Strait Islander patients of persistent pain services. Methods: In this single-arm intervention study, health professionals undertook a one-day workshop, which included cultural capability and communication skills training based on a clinical yarning framework. The workshop was delivered across three adult persistent pain clinics in Queensland. At the end of the training, participants completed a retrospective pre/post evaluation questionnaire (5 points Likert scale, 1 = very low to 5 = very high), to rate their perceived importance of communication training, their knowledge, ability and confidence to communicate effectively. Participants also rated their satisfaction with the training and suggested improvements for future trainings. Results: Fifty-seven health professionals were trained (N = 57/111; 51% participation rate), 51 completed an evaluation questionnaire (n = 51/57; 90% response rate). Significant improvements in the perceived importance of communication training, knowledge, ability and confidence to effectively communicate with Aboriginal and Torres Strait Islander patients were identified (p < 0.001). The greatest increase was in the perceived confidence pre-training mean of 2.96 (SE = 0.11) to the post-training mean of 4.02 (SE = 0.09). Conclusion: This patient-centred communication training, delivered through a novel model that combines cultural capability and the clinical yarning framework applied to the pain management setting, was highly acceptable and significantly improved participants' perceived competence. This method is transferrable to other health system sectors seeking to train their clinical workforce with culturally sensitive communication skills.

Inborn Errors of Immunity and Autoimmune Disease.

Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.

Early Life Maltreatment and Adolescent Interpretations of Ambiguous Social Situations: Investigating Interpersonal Cognitions and Emotional Symptoms.

In the general population, negative interpretations of social situations have been associated with risk of developing emotional disorders such as anxiety and depression. Given that childhood maltreatment poses risk for later emotional disorders, this study examined whether interpersonal cognitive style differentiated maltreated adolescents from their non-maltreated peers and correlated with emotional symptoms across each group. Forty-seven maltreated and 28 non-maltreated adolescents were recruited from New South Wales, Australia to complete a battery of questionnaires that assessed interpersonal cognitions and levels of anxiety and depression. Comparable endorsement of threatening interpretations of social situations between maltreated adolescents and their non-maltreated peers across measures was found. Furthermore, an association between anxiety and depressive symptoms and interpretation bias was found within the non-maltreatment group but not the maltreated group. Unlike general population samples, negative cognitions do not associate with emotional symptoms in victims of early maltreatment. More research is needed to investigate the cognitive factors maintaining emotional symptoms in adolescent victims of maltreatment.

Increased dendritic cell density and altered morphology in allergic conjunctivitis.

BACKGROUND: Corneal and conjunctival epithelial dendritic cells (DC) have an established role in vernal keratoconjunctivitis, however, their role in more prevalent forms of allergic eye disease remains unclear. This study evaluated corneal and conjunctival epithelial DC density, morphology, and distribution observed using in vivo confocal microscopy (IVCM) in allergic conjunctivitis. METHODS: In this prospective, observational study, 66 participants (mean age 36.6 ± 12.0 years, 56% female): 33 with allergic conjunctivitis and 33 controls were recruited. IVCM was performed at the corneal centre, inferior whorl, corneal periphery, corneal limbus, and temporal bulbar conjunctiva. DC were counted and their morphology was assessed as follows: largest cell body size, presence of dendrites, and presence of long and thick dendrites. Mixed model analysis (DC density) and non-parametric tests (DC morphology) were used. RESULTS: DC density was higher in allergic participants at all locations (p ≤ 0.01), (corneal centre median (IQR) 21.9 (8.7-50.9) cells/mm2 vs 13.1 (2.8-22.8) cells/mm2; periphery 37.5 (15.6-67.2) cells/mm2 vs 20 (9.4-32.5) cells/mm2; limbus 75 (60-120) cells/mm2 vs 58.1 (44.4-66.2) cells/mm2; conjunctiva 10 (0-54.4) cells/mm2 vs 0.6 (0-5.6) cells/mm2, but not at the inferior whorl 21.9 (6.2-34.4) cells/mm2 vs 12.5 (1.9-37.5) cells/mm2, p = 0.20. At the corneal centre, allergic participants had larger DC bodies (p = 0.02), a higher proportion of DC with dendrites (p = 0.02) and long dendrites (p = 0.003) compared to controls. CONCLUSIONS: Corneal and conjunctival DC density was increased, and morphology altered in allergic conjunctivitis. These findings imply that the ocular surface immune response was upregulated and support an increased antigen-capture capacity of DC in allergic conjunctivitis.

Dendritiform immune cells with reduced antigen-capture capacity persist in the cornea during the asymptomatic phase of allergic conjunctivitis.

BACKGROUND: Increased density and altered morphology of dendritic cells (DC) in the cornea and conjunctiva occur during active allergic conjunctivitis. This study investigated whether inflammation (characterised by altered DC density and morphology) persists during the symptom-free phase of allergic conjunctivitis. METHODS: Twenty participants (age 43.3 ± 14.3 years, 55% female) assessed during their active (symptomatic) phase of allergic conjunctivitis were re-examined during the asymptomatic phase. Ocular allergy symptoms and signs were evaluated during both phases, and five ocular surface locations (corneal centre, inferior whorl, corneal periphery, corneal limbus, and bulbar conjunctiva) were examined using in vivo confocal microscopy (HRT III). DC were counted manually, and their morphology was assessed for cell body size, presence of dendrites, presence of long dendrites and presence of thick dendrites using a grading system. Mixed model analysis (DC density) and non-parametric tests (DC morphology) were used to examine differences between phases. RESULTS: DC density at corneal locations did not change between the active and asymptomatic phases (p ≥ 0.22). However, corneal DC body size was smaller and fewer DC presented with long dendrites during the asymptomatic phase (p ≤ 0.02). In contrast, at the bulbar conjunctiva, DC density was reduced during the asymptomatic phase compared to the active phase (p = 0.01), but there were no changes in DC morphology. CONCLUSIONS: Dendritiform immune cell numbers persist in the cornea during the symptom-free phase of allergic conjunctivitis, whereas conjunctival DC appear to return to a baseline state. The morphology of these persisting corneal DC suggests their antigen-capture capacity is reduced during the asymptomatic phase.

A cell-based functional assay that accurately links genotype to phenotype in familial HLH.

Familial forms of the severe immunoregulatory disease hemophagocytic lymphohistiocytosis (HLH) arise from biallelic mutations in the PRF1, UNC13D, STXBP2, and STX11 genes. Early and accurate diagnosis of the disease is important to determine the most appropriate treatment option, including potentially curative stem cell transplantation. The diagnosis of familial HLH (FHL) is traditionally based on finding biallelic mutations in patients with HLH symptoms and reduced natural killer (NK)-cell cytotoxicity. However, patients often have a low NK-cell count or receive immunosuppressive therapies that may render the NK-cell cytotoxicity assay unreliable. Furthermore, to fully understand the nature of a disease it is critical to directly assess the effect of mutations on cellular function; this will help to avoid instances in which carriers of innocuous mutations may be recommended for invasive procedures including transplantation. To overcome this diagnostic problem, we have developed a rapid and robust method that takes advantage of the functional equivalence of the human and mouse orthologues of PRF1, UNC13D, STX11, and STXBP2 proteins. By knocking out endogenous mouse genes in CD8+ T cells and simultaneously replacing them with their mutated human orthologues, we can accurately assess the effect of mutations on cell function. The wide dynamic range of this novel system allowed us to understand the basis of, otherwise cryptic, cases of FHL or HLH and, in some instances, to demonstrate that previously reported mutations are unlikely to cause FHL. This novel approach provides valuable new information to enable more accurate diagnosis and treatment of patients with HLH or FHL who inherit mutations of undetermined pathogenicity.

Use of sensory modulation approaches to improve compression garment adherence in adults after burn: An e-Delphi study.

BACKGROUND: Sensory over-responsiveness, identified through self-report and quantitative sensory testing, has been associated with compression garment non-adherence in a burn-injured cohort. This study sought expert consensus on the usefulness of, and recommendations for, sensory modulation strategies to improve compression garment adherence in sensory over-responsive adults after burn. METHOD: Experts in the field of sensory modulation were invited to participate in a mixed-methods, three-round electronic Delphi study. RESULTS: Experts (N = 18) agreed that sensory modulation therapy may be a useful clinical tool to improve compression garment adherence. Twenty-two items reached consensus as essential to assessment, treatment, or therapist training. CONCLUSION: With adequate therapist training and individualized assessment and treatment, sensory modulation strategies may be a useful clinical approach to improving compression garment adherence in those who are sensory over-responsive after burn. Further research is needed to gather perceptions from burns therapists, and to implement and evaluate the effectiveness in clinical practice.

Infliximab Reverses Symptoms and May Protect from Developing Chronic Restrictive Ophthalmopathy in Children with Familial Orbital Myositis: A Case Report.

BACKGROUND: Orbital myositis is a rare sporadic eye disease associated with extraocular eye muscle inflammation. To date, there have been two reports of familial orbital myositis (FOM), which demonstrate partially penetrant autosomal dominant inheritance. CASES: We report six new Australian cases of FOM, four of whom extend one of the reported pedigrees, as well as a separate mother and daughter manifesting orbital myositis, which constitutes a third report of familial occurrence. We can confirm that the disease has onset in childhood, appearing to go into remission in adult life, and that the inflammation is corticosteroid-responsive. However, one patient went on to develop permanent diplopia in upgaze. We also report two children suffering chronic pain and diplopia who demonstrated complete resolution of symptoms with the anti-TNF-α monoclonal infliximab. CONCLUSION: Uncontrolled FOM in childhood may result in permanent extraocular eye muscle damage, while TNF-α blockade provides an excellent steroid-sparing effect.

Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination.

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.

Communication and access to healthcare: Experiences of Aboriginal and Torres Strait Islander people managing pain in Queensland, Australia.

Background: Pain management requires a multidisciplinary approach and a collaborative relationship between patient-provider in which communication is crucial. This study examines the communication experiences of Aboriginal and Torres Strait Islander patients and Aboriginal and Torres Strait Islander Hospital Liaison Officers (ATSIHLOs), to improve understanding of how pain is managed in and through patient-health professional communication. Methods: This qualitative study involved a purposive sample of patients attending three persistent pain clinics and ATSIHLOs working in two hospitals in Queensland, Australia. Focus groups and in-depth interviews explored the communication experiences of patients managing pain and ATSIHLOs supporting patients with pain. This study adopted a descriptive phenomenological methodology, as described by Colaizzi (1978). Relevant statements (patient and ATSIHLOs quotes) about the phenomenon were extracted from the transcripts to formulate meanings. The formulated meanings were subsequently sorted into thematic clusters and then integrated into themes. The themes were then incorporated into a concise description of the phenomenon of communication within pain management. Findings were validated by participants. Results: A total of 21 Aboriginal and Torres Strait Islander participants were involved in this study. Exploration of the communication experiences of patients and ATSIHLOs revealed overlapping themes of important barriers to and enablers of communication that affected access to care while managing pain. Acknowledging historical and cultural factors were particularly important to build trust between patients and health professionals. Some patients reported feeling stigmatized for identifying as Aboriginal and Torres Strait Islander, while others were reluctant to disclose their background for fear of not having the same opportunity for treatment. Differences in the expression of pain and the difficulty to use standard pain measurement scales were identified. Communication was described as more than the content delivered, it is visual and emotional expressed through body language, voice intonation, language and the speed of the conversation. Conclusion: Communication can significantly affect access to pain management services. Aboriginal and Torres Strait Islander patients highlighted the burden of emotional pain caused by historical factors, negative stereotypes and the fear of discrimination. Pain management services and their health professionals need to acknowledge how these factors impact patients trust and care.

Study protocol: Clinical yarning, a communication training program for clinicians supporting aboriginal and Torres Strait Islander patients with persistent pain: A multicentre intervention feasibility study using mixed methods.

Objectives: Ineffective communication between healthcare clinicians and Aboriginal and Torres Strait Islander patients with persistent pain is a significant barrier to optimal pain management. This manuscript is a study protocol and describes the development and evaluation methods of a tailored, culturally-informed training program, to improve clinicians' communication with patients. Study design: This is a single-arm, multicentre (2 metropolitan and 1 regional persistent pain service) intervention feasibility study that will be evaluated using mixed methods. Methods: A communication training program will be developed informed by qualitative interviews with key stakeholders, and adapt the patient-centred 'clinical yarning' framework for the Queensland context. Evaluation of the effectiveness of the training will involve the analysis of quantitative data collected at three study sites over a 12-month period. At the patient level, communication experience will be rated at differing times of the training rollout to reflect participants' experience of communication either prior to or following the treating clinician attending the communication training. At the clinician level, evaluation of the training program will be based on changes of ratings in the importance of training, knowledge, ability and confidence to communicate with Aboriginal and Torres Strait Islander patients; satisfaction, acceptance and relevance to their clinical practice. This study will be grounded in the needs and preferences of communication of Aboriginal and Torres Strait Islander people living with pain. Conclusion: It is hypothesized that the patient-centred intervention will have immediate benefits for patients, improving patient experience of care. This research will focus on an area of unmet need in addressing persistent pain.

Supporting Aboriginal and Torres Strait Islander Families to Stay Together from the Start (SAFeST Start): Urgent call to action to address crisis in infant removals.

Reducing the rate of over-representation of Aboriginal and Torres Strait Islander children in out-of-home care (OOHC) is a key Closing the Gap target committed to by all Australian governments. Current strategies are failing. The "gap" is widening, with the rate of Aboriginal and Torres Strait Islander children in OOHC at 30 June 2020 being 11 times that of non-Indigenous children. Approximately, one in five Aboriginal and Torres Strait Islander children entering OOHC each year are younger than one year. These figures represent compounding intergenerational trauma and institutional harm to Aboriginal and Torres Strait Islander families and communities. This article outlines systemic failures to address the needs of Aboriginal and Torres Strait Islander parents during pregnancy and following birth, causing cumulative harm and trauma to families, communities and cultures. Major reform to child and family notification and service systems, and significant investment to address this crisis, is urgently needed. The Family Matters Building Blocks and five elements of the Aboriginal and Torres Strait Islander Child Placement Principle (Prevention, Participation, Partnership, Placement and Connection) provide a transformative foundation to address historical, institutional, well-being and socioeconomic drivers of current catastrophic trajectories. The time for action is now.

Human T-bet governs the generation of a distinct subset of CD11chighCD21low B cells.

High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as "age-associated B cells" (ABCs). T-bet-deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21loCD11chi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11chiCD21lo B cells.