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The purpose of this study was to evaluate whether pre-recorded video-based lectures (VBLs) covering a range of paediatric topics are an acceptable means of providing ongoing education for consultant and trainee paediatricians in Australia.Previous participants (paediatric consultants and junior medical officers) of a neurology outreach teleconference programme offered by a paediatric neurologist between 2017 and 2020 were invited to participate in a multi-specialty pre-recorded video-based education programme. Acceptability was explored by assessing relevance, likelihood of utilising VBL's in the future, uptake and learning activity preferences. The impact of VBLs on confidence, currency and practice was also explored. Additional data including topics of interest, preferred video format, duration, viewing method and frequency of delivery were captured, to better understand participant preferences to inform future efforts.A total of 135 consented; 116 returned baseline; 94 returned follow-up surveys. Preferred learning activities included a live/interactive component. Videos were considered relevant. Preferences for pre-recorded videos improved from ninth to sixth most preferred learning activity post-intervention. VBL convenience and accessibility were valued. Practice was altered in: approach to management, use of treatments, confidence in decision-making, and discussion with families and patients. The average view duration was 16 min. Longer videos yielded slightly lower audience retention rates. For future offerings, the majority endorsed a preference for a 'mixed' video format and duration of 20-40 min, offered monthly.Video-based medical education is an appealing and sustainable alternative, given the convenience of unrestricted accessibility, in meeting ongoing learning needs of Australian paediatricians and trainees.

Familial forms of the severe immunoregulatory disease Haemophagocytic Lymphohistiocytosis (HLH) arise from bi-allelic 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 bi-allelic 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 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 where 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/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 HLH/FHL patients who inherit mutations of undetermined pathogenicity.

CD11c+ atypical B cells (ABC) are an alternative memory B cell lineage identified both in normal immune responses as well as pathogenic responses in autoimmunity. While it is clear that ABCs have a distinct transcriptional program, the factors that direct this program have not been identified. Here, we generated a human tonsil single-cell RNA-seq dataset and identified candidate transcription factors associated with the ABC population. We selected 8 of these transcription factors for further analysis based on their conserved expression in mouse ABC bulk RNA-seq datasets. Using an optimized CRSPR-Cas9 knockdown method we found that only zinc finger E-box binding homeobox 2 (Zeb2) knock-out impaired ABC formation. To assess the role of Zeb2 in ABC formation in vivo we used Zeb2fl/fl mice crossed to a CD23Cre line. Germinal center and plasma cell responses in these mice after Plasmodium sporozoite immunization were largely unaltered but we observed a specific defect in ABC formation. We further determined that ZEB2 haploinsufficient Mowat Wilson syndrome patients also have decreased circulating ABCs in the blood, supporting a role for this transcription factor in humans as well as mice. In sum, we identified Zeb2 as a key TF governing the formation of ABCs.

Anaphylaxis in pregnancy is rare but can potentially be associated with significant morbidity and mortality for the mother, fetus and neonate. With appropriate and timely management, even severe anaphylaxis can be managed with excellent maternal and fetal outcomes.The aim of this article is to provide an illustrative case and highlight current recommendations for diagnosis and management of acute maternal anaphylaxis, which have recently been reviewed and developed into a guideline by the Australasian Society of Clinical Immunology and Allergy.An understanding of management of anaphylaxis in pregnancy is essential knowledge in the general practice setting. The recommended dosage and administration of adrenaline (epinephrine) for anaphylaxis is the same in pregnant and non-pregnant patients: 0.5 mg adrenaline intramuscularly in the mid-outer thigh (or dose of 0.01 mg/kg if50 kg). The use of adrenaline in maternal anaphylaxis is supported by various international guidelines.

Peanut allergy is increasingly prevalent and for most patients is a life-long condition, with the potential to cause life-threatening reactions. Accurate diagnosis and appropriate management are essential to minimise risks due to accidental peanut exposure. Current management strategies focus on strict allergen avoidance and access to emergency medicines to treat potential reactions; however, active approaches are an area of intense research. Promising new methods of food allergen immunotherapy are set to change the approach to managing peanut allergic patients in the near future.

The transcription factor FOXP3 is essential for CD4

Aim Penicillin allergy labels are frequently encountered in children and are associated with significant harms. Most children are falsely labelled and can safely tolerate a penicillin but delabelling strategies are underutilised and paediatric-specific resources are lacking. The aim of this study was to evaluate an allergy assessment tool for children in hospital. Methods We evaluated a paediatric-adapted penicillin allergy assessment tool, using an online survey of clinicians in a tertiary paediatric hospital, with 10 hypothetical potential penicillin allergy or adverse reaction cases (including non-allergy reactions). For each case, respondents were asked to use the tool to assign a reaction phenotype and recommend management. We determined the tool's sensitivity, specificity and acceptability to end users. Results We evaluated 30 complete survey responses from senior and junior medical staff, nurses and pharmacists. The tool's overall sensitivity was 80.7% (95% confidence interval (CI) 74.2-87.1%) for assigning the correct reaction phenotype and 85.3% (95% CI 79.4-91.3%) for appropriate management. The tool had high sensitivity for identifying immediate hypersensitivity reactions at 95.6% (95% CI 90.2-100%). Most respondents agreed or strongly agreed that they would use the tool in their practice (22/30, 73.3%). Conclusion This survey evaluated a paediatric-adapted penicillin allergy assessment tool in a tertiary paediatric hospital among multidisciplinary clinician groups. The tool performed well overall and had high safety in identifying immediate hypersensitivity reactions. Further research to support implementation of allergy assessment and delabelling programmes among children is required.

SUMMARY Severe allergic reactions (anaphylaxis) are unpredictable, and initial signs of what could be fatal anaphylaxis can be mild Adrenaline (epinephrine) remains the first-line drug of choice for the acute management of anaphylaxis and should be administered early There are no contraindications to intramuscular adrenaline in the treatment of anaphylaxis Correct positioning of the patient is vital as death can occur within minutes if a patient stands, walks or sits up suddenly. Position the patient correctly first and then promptly administer intramuscular adrenaline Updated guidelines by the Australasian Society of Clinical Immunology and Allergy now recommend that the 0.15 mg adrenaline injector device may be prescribed for infants and children weighing 7.5–10 kg. The recommendation to use the 0.3 mg adrenaline injector device for those over 20 kg remains unchanged The adrenaline doses in Australian Prescriber’s anaphylaxis wallchart remain valid

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat–Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8, p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%, p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.

Ultrasound use has become an integral part of modern medical practice in the past two decades. Ultrasound technology allows clinicians to quickly, easily, and safely identify patient anatomy for diagnostic and therapeutic purposes. Diagnostic ultrasound utilization includes transthoracic, abdominal, and airway assessment. Therapeutic ultrasound utilization includes securing difficult intravenous access, central hemodynamic access, and peripheral nerve blocks. The ease, quickness, and safety of ultrasound use has made it an integral component of ambulatory surgical centers’ healthare. This chapter will review the wide utility of ultrasound in ambulatory surgical centers.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal allergic disorder. Large population-based FPIES studies are lacking.We sought to determine the incidence and clinical characteristics of FPIES in Australian infants.An Australia-wide survey (2012-2014) was undertaken through the Australian Paediatric Surveillance Unit, with monthly notification of new cases of acute FPIES in infants aged less than 24 months by 1400 participating pediatricians.Two hundred thirty infants with FPIES were identified. The incidence of FPIES in Australian infants (24 months) was 15.4/100,000/y. Median age of first episode, diagnosis, and notification were 5, 7, and 10 months, respectively. There was no sex predilection. Seven percent of infants had siblings with a history of FPIES, and 5% reacted during exclusive breast-feeding. Sixty-eight had a single food trigger (20% had 2 and 12% had ≥3 food triggers). The most common FPIES triggers were rice (45%), cow's milk (33%), and egg (12%). Fifty-one percent of infants reacted on their first known exposure. Infants with FPIES to multiple versus single food groups were younger at the initial episode (4.6 vs 5.8 months [mean], P = .001) and more frequently had FPIES to fruits, vegetables, or both (66% vs 21%, P .0001). Infants exclusively breast-fed for more than 4 months had a trend toward lower rates of FPIES to multiple food groups (23% vs 36%, P = .06). Sixty-four percent of infants with FPIES to multiple foods, which included cow's milk, had coassociated FPIES to solid foods. Forty-two percent of infants with FPIES to fish reacted to other food groups.FPIES is not rare, with an estimated incidence of 15.4/100,000/y. Rice is the most common food trigger in Australia. Factors associated with FPIES to multiple foods included early-onset disease and FPIES to fruits, vegetables, or both.

Aim Haematopoietic stem cell transplantation (HSCT) is a central therapy in the treatment of primary immunodeficiency diseases (PIDs). Over the past 5 years, outcomes have been greatly improved due to earlier diagnosis, improved donor availability, advancements in graft manipulation and the use of less toxic preparative regimens. We present a 5-year audit of HSCT for PID at a single Australian tertiary hospital. Methods Retrospective case note review identified diagnosis, pre-transplant medical morbidity, transplant protocol, engraftment, adverse events, post-transplant immune reconstitution and general health. Results A total of 22 patients with PID underwent 24 HSCTs at our institution between 2012 and 2016. The most common indications were severe combined immunodeficiency, chronic granulomatous disease and familial haemophagocytic lymphohistiocytosis, with a genetic diagnosis in all but two patients. Reduced intensity or reduced toxicity conditioning was used in 91% of cases, and 75% of the donors were unrelated. Transplant-related mortality at day +100 was 9.5%, and cumulative overall survival was 86%. There were three mortalities, all secondary to viral infection, one of which occurred in the context of graft failure. Two patients remained on immune support, with the remainder achieving adequate immune reconstitution. Conclusions The outcomes for HSCT for PIDs performed at Sydney Children's Hospital were in line with the world's best practice. HSCT should be considered a potential therapeutic option for all Australian PID patients with a valid disease indication.

Aim To examine the long-term follow-up and health outcomes of patients who have undergone haematopoietic stem cell transplant (HSCT) for severe combined immunodeficiency (SCID). Methods Through a structured questionnaire, we examined follow-up arrangements and long-term health outcomes in 22 children who have had a successful HSCT for SCID during the period of 1984–2012 at the Sydney Children's Hospital, Sydney, Australia. Results Most children considered themselves healthy and ‘cured’ from SCID. Whilst many children enjoy relatively good bio-social health outcomes, specific negative health outcomes and absenteeism from school were perceived negatively. Two-thirds of children see their general practitioner or specialist regularly; however, there did not appear to be consistency with the nature of this follow-up. Conclusion The findings from our study highlight the complex bio-psychosocial health needs of post-HSCT SCID children and encourage SCID centres to consider a multidisciplinary approach to their follow-up. Further studies into the determinants of patients’ perceptions of their health are needed.

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

Haematopoietic stem cell transplantation (HSCT) is a central therapy in the treatment of primary immunodeficiency diseases (PIDs). Over the past 5 years, outcomes have been greatly improved due to earlier diagnosis, improved donor availability, advancements in graft manipulation and the use of less toxic preparative regimens. We present a 5-year audit of HSCT for PID at a single Australian tertiary hospital.Retrospective case note review identified diagnosis, pre-transplant medical morbidity, transplant protocol, engraftment, adverse events, post-transplant immune reconstitution and general health.A total of 22 patients with PID underwent 24 HSCTs at our institution between 2012 and 2016. The most common indications were severe combined immunodeficiency, chronic granulomatous disease and familial haemophagocytic lymphohistiocytosis, with a genetic diagnosis in all but two patients. Reduced intensity or reduced toxicity conditioning was used in 91% of cases, and 75% of the donors were unrelated. Transplant-related mortality at day +100 was 9.5%, and cumulative overall survival was 86%. There were three mortalities, all secondary to viral infection, one of which occurred in the context of graft failure. Two patients remained on immune support, with the remainder achieving adequate immune reconstitution.The outcomes for HSCT for PIDs performed at Sydney Children's Hospital were in line with the world's best practice. HSCT should be considered a potential therapeutic option for all Australian PID patients with a valid disease indication.

The recent epidemics of pertussis (whooping cough) in parts of the USA and Australia have led to the largest numbers of annual cases reported in over half a century. These epidemics demonstrated a new pattern, with particularly high rates of disease among pre-adolescents and early adolescents. These high rates of pertussis coincided with the first cohorts vaccinated with purely acellular pertussis vaccine, which replaced whole-cell pertussis (wP) vaccine in the later 1990s in the USA and Australia. Studies undertaken during these epidemics provide new evidence of more rapid waning of acellular pertussis-containing vaccines and longer-term protection from effective wP-containing vaccines. There is evidence that receiving wP as at least the first dose of pertussis-containing vaccine provides greater and more long-lived protection, irrespective of the nature of subsequent doses. This evidence will be reviewed together with the immunobiology associated with both vaccines, and the implications for pertussis control discussed.

To examine the long-term follow-up and health outcomes of patients who have undergone haematopoietic stem cell transplant (HSCT) for severe combined immunodeficiency (SCID).Through a structured questionnaire, we examined follow-up arrangements and long-term health outcomes in 22 children who have had a successful HSCT for SCID during the period of 1984-2012 at the Sydney Children's Hospital, Sydney, Australia.Most children considered themselves healthy and 'cured' from SCID. Whilst many children enjoy relatively good bio-social health outcomes, specific negative health outcomes and absenteeism from school were perceived negatively. Two-thirds of children see their general practitioner or specialist regularly; however, there did not appear to be consistency with the nature of this follow-up.The findings from our study highlight the complex bio-psychosocial health needs of post-HSCT SCID children and encourage SCID centres to consider a multidisciplinary approach to their follow-up. Further studies into the determinants of patients' perceptions of their health are needed.

We describe the recent discovery of Alcathoe bat, Myotis alcathoe, at locations in the south and north of England. First described in 2001 from individuals caught in Greece, the species' known range has steadily been extended across much of Europe. Its presence in the UK was confirmed by mtDNA (ND1) and microsatellite analysis of wing biopsy samples collected between 2003–2009, primarily at swarming sites. Morphological and echolocation call data are consistent with the genetic interpretation. The presence of M. alcathoe at sites 350 km apart, and the probability that it makes up a significant proportion of the small Myotis bats at these sites, suggest it is a resident species. Preliminary assessment of its distribution in the UK will be facilitated by its distinctive echolocation call, an FM sweep that typically terminates at 43–46 kHz, above those of other Myotis species.

Objective. The goal was to examine the demographic characteristics, causative foods, clinical features, treatments, and outcomes for children presenting with acute food protein-induced enterocolitis syndrome. Methods. This was a retrospective study of children with food protein-induced enterocolitis syndrome who presented to the Children's Hospital at Westmead (Sydney, Australia) over 16 years. Results. Thirty-five children experienced 66 episodes of food protein-induced enterocolitis syndrome. The mean age at initial presentation was 5.5 months. Children frequently experienced multiple episodes before a correct diagnosis was made. Twenty-nine children reacted to 1 food, and 6 reacted to 2 foods. Causative foods for the 35 children were rice (n = 14), soy (n = 12), cow's milk (n = 7), vegetables and fruits (n = 3), meats (n = 2), oats (n = 2), and fish (n = 1). In the 66 episodes, vomiting was the most common clinical feature (100%), followed by lethargy (85%), pallor (67%), and diarrhea (24%). A temperature of 500 × 109 cells per L was recorded for 63% of episodes with blood count results. Only 2 of the 19 children who presented to an emergency department with their initial reactions were discharged with correct diagnoses. Additional investigations of food protein-induced enterocolitis syndrome episodes presenting to the hospital were common, with 34% of patients undergoing abdominal imaging, 28% undergoing a septic evaluation, and 22% having a surgical consultation. Prognosis was good, with high rates of resolution for the 2 most common food triggers (ie, rice and soy) by 3 years of age. Conclusions. Misdiagnosis and delays in diagnosis for children with food protein-induced enterocolitis syndrome were common, leading many children to undergo unnecessary, often painful investigations. Decreased body temperature and thrombocytosis emerge as additional features of the syndrome.

Adult subjects with systemic capillary leak syndrome (SCLS) present with acute and recurrent episodes of vascular leak manifesting as severe hypotension, hypoalbuminemia, hemoconcentration, and generalized edema. We studied clinical disease characteristics, serum cytokine profiles, and treatment modalities in a cohort of children with documented SCLS. Six children with SCLS were recruited from the United States, Australia, Canada, and Italy. Serum cytokines from SCLS subjects and a group of 10 healthy children were analyzed. Children with SCLS (aged 5–11 years old) presented with at least 1 acute, severe episode of hypotension, hypoalbuminemia, and hemoconcentration in the absence of underlying causes for these abnormalities. In contrast to what is observed in adult SCLS, identifiable infectious triggers precipitated most episodes in these children, and none of them had a monoclonal gammopathy. We found elevated levels of chemokine (C-C motif) ligand 2 (CCL2), interleukin-8, and tumor necrosis factor α in baseline SCLS sera compared with the control group. All patients are alive and well on prophylactic therapy, with 4 patients receiving intravenous or subcutaneous immunoglobulins at regular intervals. The clinical manifestations of pediatric and adult SCLS are similar, with the notable exceptions of frequent association with infections and the lack of monoclonal gammopathy. Prophylactic medication, including high dose immunoglobulins or theophylline plus verapamil, appears to be safe and efficacious therapy for SCLS in children.

Purpose of review To summarize the epidemiology of food protein-induced enterocolitis syndrome (FPIES). Recent findings FPIES is regarded as a rare non-IgE-mediated gastrointestinal allergic disorder. Older nonpopulation-based studies reported an average of 1–15 cases presenting to allergy clinics a year, but recent studies have reported figures as high as 90 cases a year. The yearly incidence of FPIES in one Australian study was one in 10,000 infants less than 2 years of age. Chronic FPIES typically presents in neonates, whereas acute FPIES is primarily a disorder of young infants. FPIES has a slight male predominance; eczema and a family history of atopy are commonly present at diagnosis; almost one in 10 infants have coexistent IgE food allergies and siblings are rarely affected. There is regional variation in common triggering foods, rates of combined cow milk and soy FPIES and multiple food group FPIES. Understanding of the epidemiology of FPIES is limited by the lack of a universally accepted definition and the publication of few prospective population-based case series. Summary FPIES is not as rare as once thought, but how common it is, what factors predispose to its development, and why there is regional variation needs to be addressed by future well designed population-based studies?

Policy makers and managers are increasingly called upon to assess the state of biodiversity, and make decisions regarding potential interventions. Genetic tools are well-recognised in the research community as a powerful approach to evaluate species and population status, reveal ecological and demographic processes, and inform nature conservation decisions. The wealth of genetic data and power of genetic methods are rapidly growing, but the consideration of genetic information and concerns in policy and management is limited by the currently low capacity of decision-makers to access and apply genetic resources. Here we describe a freely available, user-friendly online resource for decision-makers at local and national levels (http://congressgenetics.eu), which increases access to current knowledge, facilitates implementation of studies and interpretation of available data, and fosters collaboration between researchers and practitioners. This resource was created in partnership with conservation practitioners across the European Union, and includes a spectrum of taxa, ecosystems and conservation issues. Our goals here are to (1) introduce the rationale and context, (2) describe the specific tools (knowledge summaries, publications database, decision making tool, project planning tool, forum, community directory), and the challenges they help solve, and (3) summarise lessons learned. This article provides an outlook and model for similar efforts to build policy and management capacity

Paradoxically, rare diseases are common, collectively affecting 6–10% of the population and have a huge impact on patients and families, health services, clinicians and the wider community. Accurate data are required to inform clinical practice, government policy and health service planning. We recommend a national approach, similar to that adopted in the USA and Europe, to support research and promote advocacy and equitable access to services for children with rare diseases.