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Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR. Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites. Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%). Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro/in vivo diagnostic strategies to ascertain drug causality. Trial registration: ANZCTR ACTRN1261900024113

Anurans are known to detect vibrations, but few studies explore relationships between vibrations and resultant behaviors. We studied the reaction of calling captive-bred male midwife toads (Alytes obstetricans) to the randomized playback of a vibrational crescendo stimulus train. We considered two sources of natural abiotic vibrational stimuli: rainfall and wind. Rainfall was expected to induce calling and wind was expected to inhibit it. Playback experiments with two synthetic tones (200 Hz and 300 Hz) tested the sensitivity to pure tones and could possibly reveal a hearing sensitivity trend between these frequencies. The toads did not increase call rate in response to rainfall vibrations and only one of the five wind stimulus levels caused a significant decrease in call rate. This limited response could be explained, because the tested toads came from a captive population, where emergence may not be mediated by rainfall vibrations. We found that A. obstetricans is highly sensitive to very low frequencies, which could explain the sensitivity observed to vibrational stimuli. Playback of a random crescendo stimulus train proves to be a valid approach for addressing behavioral questions. However, the use of a captive population may have been a limitation in the clarity of the results.

Inpatient direct oral challenge programs are increasingly deployed as part of antimicrobial stewardship initiatives to reduce the burden and impacts of penicillin allergy labels on antibiotic prescribing. Using data from a prospective, multicenter cohort inpatient penicillin allergy program, we identify the key targets for delabeling to aid health service implementation.

The Victorian Specialist Immunization Services (VicSIS) was established in Victoria, Australia, in February 2021, aiming to enhance vaccine safety services for Coronavirus disease (COVID-19) vaccines. VicSIS supports practitioners and patients with complex vaccine safety questions, including those who experience adverse events following immunization (AEFI) after COVID-19 vaccines. VicSIS provides individual vaccination recommendations, allergy testing, vaccine challenges, and vaccination under supervision. VicSIS initially comprised of eight adult COVID-19 specialist vaccination clinics, subsequently, expanding to better support pediatric patients as the Australian vaccine roll-out extended to adolescents and children. Since their establishment to September 2021, the inaugural VicSIS clinics received a total of 26,401 referrals and reviewed 6,079 patients. Consults were initially predominantly for pre-vaccination reviews, later predominantly becoming post-vaccination AEFI reviews as the program progressed. Regardless of the type of consult, the most common consult outcome was a recommendation for routine vaccination (73% and 55% of consult outcomes respectively). VicSIS is an integral component of the COVID-19 vaccination program and supports confidence in COVID-19 vaccine safety by providing consistent advice across the state. VicSIS aims to strengthen the health system through the pandemic, bolstering specialist immunization services beyond COVID-19 vaccines, including training the next generation of vaccinology experts.

Primary Immunodeficiency diseases (PID) are a heterogeneous group of conditions with variable clinical features that are frequently associated with significant diagnostic delay. Accurate diagnosis has significant therapeutic benefit and may lead to personalized therapies. We established the Immunology Flagship of Melbourne Genomics Health Alliance in Australia to determine the clinical utility of genomic sequencing for diagnosis and management of individuals with suspected and confirmed cases of PID. 198 adults and children with suspected or confirmed PID (n=153), autoinflammatory disease (n=33) and hereditary angioedema (HAE, n=11) were recruited to the Melbourne Genomics Immunology Flagship.Whole-exome sequencing (WES) was performed, with targeted gene analysis. Variant curation and reporting was performed according to the American Council of Medical Genetics guidelines. Overall, WES was diagnostic in 15% (30/198), confirming a preexisting diagnosis in 7% (14/198), and offering a new or more specific diagnosis in 8% (16/198). Variants of uncertain significance were identified in a further 28 patients (14%) in genes known to be associated with their clinical diagnosis, that warrant further functional validation. In the HAE group, diagnosis was confirmed in only 5 patients (45%), suggesting thatWES may not be the appropriate technique for genetic diagnosis in this condition. A higher diagnostic rate was observed for autoinflammatory disorders (20%; 8/40) compared to PID (12%; 18/146). Of those who received a diagnosis, immediate changes to patient management and treatment occurred for 17/29 patients (59%), including HSCT for 3 and specific targeted therapy for 11 (38%) individuals. We have demonstrated the utility ofWES for accurate diagnosis of complex immune diseases, with the potential to change diagnoses, guide therapeutic intervention and provide opportunities for genetic counseling. Further longitudinal analysis will determine clinical outcomes and health econ

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objective(s): To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Method(s): We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Result(s): 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the c

Background and aims: Immune diseases are a heterogeneous group of conditions with variable clinical features, therefore frequently associated with significant diagnostic delay. Accurate genetic diagnosis has significant therapeutic benefit and may lead to personalized therapies. Access to genetic testing has previously been limited by cost and a limited number of Australian laboratories offering testing. We established the Immunology Flagship of Melbourne Genomics Health Alliance to determine the clinical utility of genomic sequencing for diagnosis and management of 3 groups of immune diseases. Method(s): 197 adults and children with suspected or confirmed Primary Immunodeficiency (PID; n = 153), systemic auto-inflammatory disease (SAID; n = 33) and hereditary angioedema (HAE; n = 11) were recruited to the Melbourne Genomics Immunology Flagship. Whole-exome sequencing (WES) was performed at the Australian Genomic Research Facility (AGRF), with targeted gene analysis. Variant curation and reporting was performed according to the American Council of Medical Genetics guidelines. Result(s): Overall, WES was diagnostic in 30 patients (15%), confirming a preexisting diagnosis in 14 (7%), and offering a more specific diagnosis in 16 (8%). A further 29 patients (14%) had variants of uncertain significance (VUS) identified in genes known to be associated with their clinical diagnosis, that warrant further functional validation. In the HAE group, diagnosis was confirmed in only 5 patients (45%), suggesting that WES may not be the appropriate technique for genetic diagnosis in this condition. SAIDs had a higher diagnostic rate than PIDs, at 20% and 12% respectively. Conclusion(s): WES is a useful tool for accurate diagnosis of complex immune diseases, and has the potential to change diagnoses, guide therapeutic intervention and provide opportunities for genetic counseling. Further longitudinal analysis, and continuing progress of the Australian Genomics Health Alliance, Geneti

BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. OBJECTIVES: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. METHODS: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. RESULTS: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort.

Background: This study examined whether patellar tendon vascularity could be quantified accurately in the clinical setting using colour Doppler ultrasonography. Methods: A sonographer and two radiologists visually estimated tendon vascularity in millimetres in 74 tendons during ultrasound (US) examination and from hard copy films. These estimates were then compared to the length of vessels measured from the digital image in millimetres and the correlation between them was determined. A subset of 16 tendons was used to compare the estimates of vascularity by two examiners at US examination. Results: The estimation of vascular length at US examination correlated highly with the measured vascular length (r = 0.92; 95% confidence interval (CI) 0.87 to 0.94), as did the length estimated from the films (r = 0.94; 95% CI 0.9 to 0.96). The correlation between examiners was 0.84 (95% CI 0.51 to 0.94) for the estimates made during US examination and 0.85 (95% CI 0.59 to 0.95) for the vessel lengths measured from the digital images. Conclusions: These excellent correlations indicate that tendon vascularity can be reliably estimated using colour Doppler ultrasonography and tendon vascularity could therefore be used by clinicians to rate clinical change. This method of quantifying tendon vascularity could also be used in research to investigate the effects of tendon treatments on vascularity.

Background: This study investigated changes in tendon vascularity in 102 (67 men and 35 women) volleyball players over a 6 month competitive season. Methods: Athletes were examined with both grey scale ultrasound and standardised colour Doppler settings. Vessel length and pain were measured each month on five separate occasions. Vascular tendons were divided into (i) those that were vascular on all occasions (persistent vascularity) and (ii) those that were vascular on more than two but less than five occasions (intermittent vascularity). Results: A total of 41 of the 133 abnormal tendons were vascular on two or more occasions. Of these, 16 had persistent vascularity and 25 had intermittent vascularity. There was no significant difference in the prevalence of vascularity between men and women. None of the tendons had a pattern of vascularity over the season that could be clearly interpreted as the onset or resolution of vascularity. Subjects with changes in both tendons were more likely to have persistent vascularity (p = 0.045). Vessels were longer in tendons with persistent vascularity (p<0.000) and pain was significantly greater (p = 0.043) than in tendons with intermittent vascularity. Tendons with intermittent vascularity had similar pain scores on all days, whether or not they had detectable blood flow.