Macrophage-enriched Sectm1a promotes efficient efferocytosis to attenuate ischemia/reperfusion-induced cardiac injury.

Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.

Treatment of multidrug-resistant or rifampicin-resistant tuberculosis with an all-oral 9-month regimen containing linezolid or ethionamide in South Africa: A retrospective cohort study.

BACKGROUND: In 2019, the South African tuberculosis program replaced ethionamide with linezolid as a part of an all-oral 9-month regimen. We evaluated treatment outcomes for patients assigned to regimens including linezolid in 2019 and ethionamide in 2017. METHOD: This retrospective cohort study included patients treated for multi-drug resistant/rifampicin-resistant tuberculosis throughout South Africa between 1 Jan to 31 Dec 2017 and from 1 Jan to 31 Dec 2019. The cohort treated with a 9-month regimen containing ethionamide for four months, was compared with a cohort treated with a 9-month regimen containing linezolid for two months. The regimens were otherwise identical. Inverse probability weighting of propensity scores was used to adjust for potential confounding. A log-binomial regression model was used to estimate adjusted relative risk (aRR) comparing 24-month outcomes between cohorts including treatment success, death, loss to follow up, and treatment failure. Adverse event data were available for the linezolid cohort. FINDINGS: 817 patients were included in the cohort receiving ethionamide and 4244 in the cohort receiving linezolid. No evidence for a difference was observed between linezolid and ethionamide regimens for treatment success (aRR = 0·96, 95%CI 0·91-1·01), death (aRR = 1·01, 95%CI 0·87-1·17) or treatment failure (aRR = 0·87, 95%CI 0·44-1·75). Loss to follow up was more common in the linezolid group, although estimates were imprecise (aRR = 1·22, 95%CI 0·99-1·50). INTERPRETATION: No significant differences in treatment success and survival were observed with substitution of linezolid for ethionamide as a part of an all-oral 9-month regimen. Linezolid is an acceptable alternative to ethionamide in this shorter regimen for treatment of multi-drug resistant/rifampicin resistant tuberculosis.

Audiovestibular adverse events following COVID-19 vaccinations.

INTRODUCTION: Evidence regarding audiovestibular adverse events post COVID-19 vaccination to date has been inconclusive regarding a potential association. This study aimed to determine if there was an increase in audiovestibular events following COVID-19 vaccination in South-eastern Australia during January 2021-March 2023. METHODS: A multi-data source approach was applied. First, a retrospective observational analysis of spontaneous reports of audiovestibular events to a statewide vaccine safety surveillance service, SAEFVIC. Second, a self-controlled case series analysis using general practice data collected via the POpulation Level Analysis and Reporting (POLAR) tool. RESULTS AND CONCLUSIONS: This study is the first to demonstrate an increase in general practice presentations of vertigo following mRNA vaccines (RI = 1.40, P <.001), and tinnitus following both the Vaxzevria® adenovirus vector and mRNA vaccines (RI = 2.25, P <.001 and 1.53, P <.001 respectively). There was no increase in hearing loss following any COVID-19 vaccinations. Our study, however, was unable to account for the potential of concurrent COVID-19 infections, which literature has indicated to be associated with audiovestibular events. Healthcare providers and vaccinees should be alert to potential audiovestibular complaints after COVID-19 vaccination. Our analysis highlights the importance of using large real-world datasets to gather reliable evidence for public health decision making.

Acute disseminated encephalomyelitis and transverse myelitis following COVID-19 vaccination - A self-controlled case series analysis.

Acute Disseminated Encephalomyelitis (ADEM) and Transverse Myelitis (TM) are within the group of immune mediated disorders of acquired demyelinating syndromes. Both have been described in temporal association following various vaccinations in case reports and case series and have been evaluated in observational studies. A recent analysis conducted by The Global Vaccine Data Network (GVDN) observed an excess of ADEM and TM cases following the adenoviral vectored ChAdOx1 nCoV-19 (AZD1222) and mRNA-1273 vaccines, compared with historically expected background rates from prior to the pandemic. Further epidemiologic studies were recommended to explore these potential associations. We utilized an Australian vaccine datalink, Vaccine Safety Health-Link (VSHL), to perform a self-controlled case series analysis for this purpose. VSHL was selected for this analysis as while VSHL data are utilised for GVDN association studies, they were not included in the GVDN observed expected analyses. The VSHL dataset contains vaccination records sourced from the Australian Immunisation Register, and hospital admission records from the Victorian Admitted Episodes Dataset for 6.7 million people. These datasets were used to determine the relative incidence (RI) of G040 (ADEM) and G373 (TM) ICD-10-AM coded admissions in the 42-day risk window following COVID-19 vaccinations as compared to control periods either side of the risk window. We observed associations between ChAdOx1 adenovirus vector COVID-19 vaccination and ADEM (all dose RI: 3.74 [95 %CI 1.02,13.70]) and TM (dose 1 RI: 2.49 [95 %CI: 1.07,5.79]) incident admissions. No associations were observed between mRNA COVID-19 vaccines and ADEM or TM. These findings translate to an extremely small absolute risk of ADEM (0.78 per million doses) and TM (1.82 per million doses) following vaccination; any potential risk of ADEM or TM should be weighed against the well-established protective benefits of vaccination against COVID-19 disease and its complications. This study demonstrates the value of the GVDN collaboration leveraging large population sizes to examine important vaccine safety questions regarding rare outcomes, as well as the value of linked population level datasets, such as VSHL, to rapidly explore associations that are identified.

BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs. METHODS: By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFß/Activin-SMAD2/3 signaling pathway. RESULTS: Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. CONCLUSIONS: Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

The Safety and Tolerability of Linezolid in Novel Short-Course Regimens Containing Bedaquiline, Pretomanid, and Linezolid to Treat Rifampicin-Resistant Tuberculosis: An Individual Patient Data Meta-analysis.

BACKGROUND: Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials. METHODS: A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. RESULTS: Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3-4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid. CONCLUSIONS: Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.

The PfRCR complex bridges malaria parasite and erythrocyte during invasion.

The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex1, containing PfRH5 (refs. 2,3), PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies3-6 or nanobodies1 against each of these conserved proteins, making them the leading blood-stage malaria vaccine candidates. However, little is known about how PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex7,8, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane9, instead showing that a rigid, disulfide-locked PfRH5 can mediate efficient erythrocyte invasion. We show, through modelling and an erythrocyte-binding assay, that PfCyRPA-binding antibodies5 neutralize invasion through a steric mechanism. We determine the structure of PfRIPR, showing that it consists of an ordered, multidomain core flexibly linked to an elongated tail. We also show that the elongated tail of PfRIPR, which is the target of growth-neutralizing antibodies6, binds to the PfCSS-PfPTRAMP complex on the parasite membrane. A modular PfRIPR is therefore linked to the merozoite membrane through an elongated tail, and its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides fresh insight into the molecular mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.

Genetic mapping of the p47 L.3.2 mutation in Drosophilamelanogaster.

An EMS-based forward genetic screen was conducted in an apoptotic null background to identify genetic aberrations that contribute to regulation of cell growth in Drosophila melanogaster . The current work maps the genomic location of one of the identified mutants, L.3.2 . Genetic crosses conducted through the Fly-CURE consortium determined that the gene locus for the L.3.2 mutation is p47 on chromosome 2R.

Exosome-associated lysophosphatidic acid signaling contributes to cancer pain.

ABSTRACT: Pain associated with bone cancer remains poorly managed, and chemotherapeutic drugs used to treat cancer usually increase pain. The discovery of dual-acting drugs that reduce cancer and produce analgesia is an optimal approach. The mechanisms underlying bone cancer pain involve interactions between cancer cells and nociceptive neurons. We demonstrated that fibrosarcoma cells express high levels of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA). Lysophosphatidic acid increased proliferation of fibrosarcoma cells in vitro. Lysophosphatidic acid is also a pain-signaling molecule, which activates LPA receptors (LPARs) located on nociceptive neurons and satellite cells in dorsal root ganglia. We therefore investigated the contribution of the ATX-LPA-LPAR signaling to pain in a mouse model of bone cancer pain in which fibrosarcoma cells are implanted into and around the calcaneus bone, resulting in tumor growth and hypersensitivity. LPA was elevated in serum of tumor-bearing mice, and blockade of ATX or LPAR reduced tumor-evoked hypersensitivity. Because cancer cell-secreted exosomes contribute to hypersensitivity and ATX is bound to exosomes, we determined the role of exosome-associated ATX-LPA-LPAR signaling in hypersensitivity produced by cancer exosomes. Intraplantar injection of cancer exosomes into naive mice produced hypersensitivity by sensitizing C-fiber nociceptors. Inhibition of ATX or blockade of LPAR attenuated cancer exosome-evoked hypersensitivity in an ATX-LPA-LPAR-dependent manner. Parallel in vitro studies revealed the involvement of ATX-LPA-LPAR signaling in direct sensitization of dorsal root ganglion neurons by cancer exosomes. Thus, our study identified a cancer exosome-mediated pathway, which may represent a therapeutic target for treating tumor growth and pain in patients with bone cancer.

Characterisation of the Paternal Influence on Intergenerational Offspring Cardiac and Brain Lipid Homeostasis in Mice.

There is growing evidence that poor paternal diet at the time of conception increase the risk of offspring developing a range of non-communicable metabolic diseases, such as obesity, diabetes and cardiovascular disease, in adulthood. We hypothesise that a paternal low protein-high carbohydrate diet perturbs offspring tissue lipid abundance through both sperm and seminal plasma-mediated mechanisms. To test our hypothesis, we fed male C57BL/6 mice either a control normal protein diet (NPD; 18% protein) or an isocaloric low protein diet (LPD; 9% protein) for a minimum of 8 weeks. We generated offspring through artificial insemination, in combination with vasectomised male mating. Using this approach, we derived offspring from either NPD or LPD sperm but in the presence of NPD or LPD seminal plasma. Using high resolution mass-spectrometry, we found that offspring derived from either LPD sperm or seminal fluid displayed perturbed cardiac and brain lipid abundance from just three weeks of age, typically associated with the altered abundance of tissue triglycerides. We also observed the differential sex-specific patterns of lipids between the control and experimental offspring's hearts and brains. These observations indicate that poor paternal diet at the time of conception affects offspring cardiac and brain lipid profiles in an age-, sex- and generation-specific manner.

Guillain-Barré syndrome temporally associated with COVID-19 vaccines in Victoria, Australia.

Guillain-Barré syndrome (GBS) is an adverse event of special interest (AESI) for surveillance systems monitoring adverse events following immunisation (AEFI) with COVID-19 vaccines. Emerging data support a temporal association between GBS and adenovirus-vector COVID-19 vaccines. We present a case series of GBS reports submitted between February and November 2021 to our enhanced spontaneous surveillance system (SAEFVIC) in Victoria, Australia, following vaccination with either the adenovirus-vector vaccine Vaxzevria ChadOx1-S (AstraZeneca) or an mRNA vaccine (Comirnaty BNT162b2 [Pfizer-BioNTech] or Spikevax mRNA-1273 [Moderna]). For each report, Brighton Collaboration case definitions were used to describe diagnostic certainty. Severity was graded using the GBS Disability Score. The observed incidence of GBS following immunisation against COVID-19 was compared to expected background ICD10-AM G61.0 coded hospitalisations. There were 41 total cases of GBS reported to SAEFVIC following Vaxzevria (n = 38), Comirnaty (n = 3), or Spikevax (n = 0) vaccines. The observed GBS incidence rate exceeded the expected background rate for Vaxzevria only, with 1.85 reports per 100,000 doses following dose 1, higher than the expected rate of 0.39 hospital admissions per 100,000 adults within 42 days of vaccination. Of 38 GBS reports following Vaxzevria, the median age at vaccination was 66 years and median onset of symptoms was 14 days following immunisation. There was one death. Four cases initially categorised as GBS were later reclassified as acute-onset chronic inflammatory demyelinating polyneuropathy. Fatigue was the predominant persisting symptom reported at follow up. Additional global studies are required to characterise risk factors, clinical variability, and to provide precision and generalizability regarding AEFI risks such as GBS associated with different vaccine platforms, which will help inform communication of the potential benefits and risks of COVID19 vaccination.

Paternal low protein diet perturbs inter-generational metabolic homeostasis in a tissue-specific manner in mice.

The underlying mechanisms driving paternally-programmed metabolic disease in offspring remain poorly defined. We fed male C57BL/6 mice either a control normal protein diet (NPD; 18% protein) or an isocaloric low protein diet (LPD; 9% protein) for a minimum of 8 weeks. Using artificial insemination, in combination with vasectomised male mating, we generated offspring using either NPD or LPD sperm but in the presence of NPD or LPD seminal plasma. Offspring from either LPD sperm or seminal fluid display elevated body weight and tissue dyslipidaemia from just 3 weeks of age. These changes become more pronounced in adulthood, occurring in conjunction with altered hepatic metabolic and inflammatory pathway gene expression. Second generation offspring also display differential tissue lipid abundance, with profiles similar to those of first generation adults. These findings demonstrate that offspring metabolic homeostasis is perturbed in response to a suboptimal paternal diet with the effects still evident within a second generation.

Myocarditis and myopericarditis cases following COVID-19 mRNA vaccines administered to 12-17-year olds in Victoria, Australia.

IMPORTANCE: COVID-19 mRNA vaccine-associated myocarditis has previously been described; however specific features in the adolescent population are currently not well understood. OBJECTIVE: To describe myocarditis adverse events following immunisation reported following any COVID-19 mRNA vaccines in the adolescent population in Victoria, Australia. DESIGN: Statewide, population-based study. SETTING: Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC) is the vaccine-safety service for Victoria, Australia. PARTICIPANTS: All SAEFVIC reports of myocarditis and myopericarditis in 12-17-year-old COVID-19 mRNA vaccinees submitted between 22 February 2021 and 22 February 2022, as well as accompanying diagnostic investigation results where available, were assessed using Brighton Collaboration criteria for diagnostic certainty. EXPOSURES: Any mRNA COVID-19 vaccine. MAIN OUTCOMES/MMEASURE: Confirmed myocarditis as per Brighton Collaboration criteria (levels 1-3). RESULTS: Clinical review demonstrated definitive (Brighton level 1) or probable (level 2) diagnoses in 75 cases. Confirmed myocarditis reporting rates were 8.3 per 100 000 doses in this age group. Cases were predominantly male (n=62, 82.7%) and post dose 2 (n=61, 81.3%). Rates peaked in the 16-17-year-old age group and were higher in males than females (17.7 vs 3.9 per 100 000, p=<0.001).The most common presenting symptoms were chest pain, dyspnoea and palpitations. A large majority of cases who had a cardiac MRI had abnormalities (n=33, 91.7%). Females were more likely to have ongoing clinical symptoms at 1-month follow-up (p=0.02). CONCLUSION: Accurate evaluation and confirmation of episodes of COVID-19 mRNA vaccine-associated myocarditis enabled understanding of clinical phenotypes in the adolescent age group. Any potential vaccination and safety surveillance policies needs to consider age and gender differences.

Parental Programming of Offspring Health: The Intricate Interplay between Diet, Environment, Reproduction and Development.

As adults, our health can be influenced by a range of lifestyle and environmental factors, increasing the risk for developing a series of non-communicable diseases such as type 2 diabetes, heart disease and obesity. Over the past few decades, our understanding of how our adult health can be shaped by events occurring before birth has developed into a well-supported concept, the Developmental Origins of Health and Disease (DOHaD). Supported by epidemiological data and experimental studies, specific mechanisms have been defined linking environmental perturbations, disrupted fetal and neonatal development and adult ill-health. Originally, such studies focused on the significance of poor maternal health during pregnancy. However, the role of the father in directing the development and well-being of his offspring has come into recent focus. Whereas these studies identify the individual role of each parent in shaping the long-term health of their offspring, few studies have explored the combined influences of both parents on offspring well-being. Such understanding is necessary as parental influences on offspring development extend beyond the direct genetic contributions from the sperm and oocyte. This article reviews our current understanding of the parental contribution to offspring health, exploring some of the mechanisms linking parental well-being with gamete quality, embryo development and offspring health.

Paternal periconception metabolic health and offspring programming.

The association between maternal metabolic status at the time of conception and subsequent embryogenesis and offspring development has been studied in detail. However, less attention has been given to the significance of paternal nutrition and metabolism in directing offspring health. Despite this disparity, emerging evidence has begun to highlight an important connection between paternal metabolic well-being, semen quality, embryonic development and ultimately adult offspring health. This has established a new component within the Developmental Origins of Health and Disease hypothesis. Building on the decades of understanding and insight derived from the numerous models of maternal programming, attention is now becoming focused on defining the mechanisms underlying the links between paternal well-being, post-fertilisation development and offspring health. Understanding how the health and fitness of the father impact on semen quality is of fundamental importance for providing better information to intending fathers. Furthermore, assisted reproductive practices such as in vitro fertilisation rely on our ability to select the best quality sperm from a diverse and heterogeneous population. With considerable advances in sequencing capabilities, our understanding of the molecular and epigenetic composition of the sperm and seminal plasma, and their association with male metabolic health, has developed dramatically over recent years. This review will summarise our current understanding of how a father's metabolic status at the time of conception can affect sperm quality, post-fertilisation embryonic and fetal development and offspring health.

The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells.

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4+ T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory CD4+ T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory CD4+ T cells when compared with naive, central, and transitional memory CD4+ T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target.

Cellular Activation, Differentiation, and Proliferation Influence the Dynamics of Genetically Intact Proviruses Over Time.

Human immunodeficiency virus (HIV) persists in cells despite antiretroviral therapy; however, the influence of cellular mechanisms such as activation, differentiation, and proliferation upon the distribution of proviruses over time is unclear. To address this, we used full-length sequencing to examine proviruses within memory CD4+ T-cell subsets longitudinally in 8 participants. Over time, the odds of identifying a provirus increased in effector and decreased in transitional memory cells. In all subsets, more activated (HLA-DR-expressing) cells contained a higher frequency of intact provirus, as did more differentiated cells such as transitional and effector memory subsets. The proportion of genetically identical proviruses increased over time, indicating that cellular proliferation was maintaining the persistent reservoir; however, the number of genetically identical proviral clusters in each subset was stable. As such, key biological processes of activation, differentiation, and proliferation influence the dynamics of the HIV reservoir and must be considered during the development of any immune intervention.

Immune thrombocytopenia following immunisation with Vaxzevria ChadOx1-S (AstraZeneca) vaccine, Victoria, Australia.

Emerging evidence suggest a possible association between immune thrombocytopenia (ITP) and some formulations of COVID-19 vaccine. We conducted a retrospective case series of ITP following vaccination with Vaxzevria ChadOx1-S (AstraZeneca) and mRNA Comirnaty BNT162b2 COVID-19 (Pfizer-BioNTech) vaccines and compare the incidence to expected background rates for Victoria during the first six months of the Australian COVID-19 vaccination roll-out in 2021. Cases were identified by reports to the Victorian state vaccine safety service, SAEFVIC, of individuals aged 18 years or older presenting with thrombocytopenia following COVID-19 vaccination without evidence of thrombosis. Twenty-one confirmed or probable cases of ITP were identified following receipt of AstraZeneca (n = 17) or Pfizer-BioNTech (n = 4) vaccines. This translates to an observed incidence of 8 per million doses for AstraZeneca vaccine, twice the expected background rate of 4.1 per million. The observed rate for Pfizer-BioNTech was consistent with the expected background rate. The median time to onset for the cases post AstraZeneca vaccination was 10 days (range 1-78) and median platelet nadir 5 × 109/L (range 0-67 × 109/L). Hospital presentations or admissions for management of symptoms such as bleeding occurred in 18 (86%) of the cases. The majority of cases (n = 11) required intervention with at least 2 therapy modalities. In conclusion, we observed a substantially higher than expected rate of ITP following AstraZeneca vaccination. ITP is the second haematological adverse event, distinct from that of thrombosis with thrombocytopenia syndrome (TTS), observed following AstraZeneca vaccination.