ORCID Profile
0000-0002-8557-6433
Current Organisations
Royal Australasian College of Physicians
,
Royal Perth Hospital
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Publisher: Wiley
Date: 11-2016
DOI: 10.1111/IMJ.13223
Abstract: Patients frequently report antibiotic allergies however, only 10% of labelled patients have a true allergy. We investigated the documentation of antibiotic 'allergy' labels (AAL) and the effect of labelling on clinical outcomes, in a West Australian adult tertiary hospital. Retrospective cross-sectional analysis of patients captured in the 2013 and 2014 National Antimicrobial Prescribing Surveys was carried out. Data were collected on documented antibiotic adverse drug reactions, antibiotic cost, prescribing appropriateness, prevalence of multi-drug resistant organisms, length of stay, intensive care admission and readmissions. Of the 687 patients surveyed, 278 (40%) were aged 70 or above, 365 (53%) were male and 279 (41%) were prescribed antibiotics. AAL were recorded in 122 (18%) patients and the majority were penicillin labels (n = 87 71%). Details of AAL were documented for 80 of 141 (57%) in idual allergy labels, with 61 describing allergic symptoms. Patients with beta-lactam allergy labels received fewer penicillins (P = 0.0002) and more aminoglycosides (P = 0.043) and metronidazole (P = 0.021) than patients without beta-lactam labels. Five patients received an antibiotic that was contraindicated according to their allergy status. Patients with AAL had significantly more hospital readmissions within 4 weeks (P = 0.001) and 6 months (P = 0.025) of discharge, compared with unlabelled patients. The majority (81%) of readmitted labelled patients had major infections. AAL are common, but poorly documented in hospital records. Patients with AAL are significantly more likely to require alternative antibiotics and hospital readmissions. There may be a role for antibiotic allergy delabelling to mitigate the clinical and economic burdens for patients with invalid allergy labels.
Publisher: Elsevier BV
Date: 02-2019
Publisher: Rockefeller University Press
Date: 17-02-2014
DOI: 10.1084/JEM.20131424
Abstract: MYD88L265P has recently been discovered as an extraordinarily frequent somatic mutation in benign monoclonal IgM gammopathy, Waldenström’s macroglobulinemia, and diffuse large B cell lymphoma. In this study, we analyze the consequences for antigen-activated primary B cells of acquiring MYD88L265P. The mutation induced rapid B cell ision in the absence of exogenous TLR ligands and was inhibited by Unc93b13d mutation and chloroquine or TLR9 deficiency, indicating continued dependence on upstream TLR9 activation. Proliferation and NF-κB activation induced by MYD88L265P were nevertheless rapidly countered by the induction of TNFAIP3, an NF-κB inhibitor frequently inactivated in MYD88L265P–bearing lymphomas, and extinguished by Bim-dependent apoptosis. MYD88L265P caused self-reactive B cells to accumulate in vivo only when apoptosis was opposed by Bcl2 overexpression. These results reveal checkpoints that fortify TLR responses against aberrant B cell proliferation in response to ubiquitous TLR and BCR self-ligands and suggest that tolerance failure requires the accumulation of multiple somatic mutations.
Publisher: Informa UK Limited
Date: 08-2013
DOI: 10.2147/BLCTT.S35292
Publisher: Springer Science and Business Media LLC
Date: 18-09-2019
DOI: 10.1038/S41590-019-0492-0
Abstract: Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Rockefeller University Press
Date: 24-12-2013
DOI: 10.1084/JEM.20121076
Abstract: Druggable proteins required for B lymphocyte survival and immune responses are an emerging source of new treatments for autoimmunity and lymphoid malignancy. In this study, we show that mice with an inactivating mutation in the intramembrane protease signal peptide peptidase–like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell–activating factor (BAFF). Accumulation of Sppl2a-deficient B cells was rescued by overexpression of the BAFF-induced survival protein B cell lymphoma 2 (BCL2) but not BAFF and was distinguished by low surface BAFF receptor and IgM and IgD B cell receptors. CD8-negative dendritic cells were also greatly decreased. SPPL2A deficiency blocked the proteolytic processing of CD74 MHC II invariant chain in both cell types, causing dramatic build-up of the p8 product of Cathepsin S and interfering with earlier steps in CD74 endosomal retention and processing. The findings illuminate an important role for the final step in the CD74–MHC II pathway and a new target for protease inhibitor treatment of B cell diseases.
Publisher: Rockefeller University Press
Date: 12-07-2017
DOI: 10.1084/JEM.20161454
Abstract: CD79B and MYD88 mutations are frequently and simultaneously detected in B cell malignancies. It is not known if these mutations cooperate or how crosstalk occurs. Here we analyze the consequences of CD79B and MYD88L265P mutations in idually and combined in normal activated mouse B lymphocytes. CD79B mutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-κB responsive markers. Conversely, B cells expressing MYD88L265P decreased surface IgM coupled with accumulation of endoglycosidase H–sensitive IgM intracellularly, resembling the trafficking block in anergic B cells repeatedly stimulated by self-antigen. Mutation or overexpression of CD79B counteracted the effect of MYD88L265P. In B cells chronically stimulated by self-antigen, CD79B and MYD88L265P mutations in combination, but not in idually, blocked peripheral deletion and triggered differentiation into autoantibody secreting plasmablasts. These results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against B cell dysregulation by MYD88L265P and provide an explanation for the co-occurrence of MYD88 and CD79B mutations in lymphomas.
Publisher: Rockefeller University Press
Date: 10-2012
DOI: 10.1084/JEM.20112744
Abstract: Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing in idual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell–independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo.
Publisher: American Society of Hematology
Date: 10-2015
DOI: 10.1182/BLOOD-2015-03-631374
Abstract: Functional reversion of a germline CARD11 mutation in T cells is associated with the development of Omenn syndrome. Defective thymic T-cell development and peripheral lymphopenia are no prerequisite for the development of Omenn syndrome.
Publisher: American Society of Hematology
Date: 06-12-2014
DOI: 10.1182/BLOOD.V124.21.3038.3038
Abstract: Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with ~30% of cases failing treatment or relapsing after R-CHOP chemotherapy. Treatment options for refractory/ relapsed DLBCL are limited and often have a poor outcome. Tumour evolution and selection of a chemo resistant clone are likely explanations making it important to understand clonal heterogeneity at diagnosis and relapse. Green et al have noted a hierarchical acquisition of mutations with disease progression in follicular lymphoma (FL), with BCL2 and CREBBP mutations seen in earlier precursors and MLL2 and TNFRSF14 mutations proposed to be later events. Notably, 1 case analysed at diagnosis and at relapse had variable IgVH indicating origin in a more immature precursors. [Green, M.R., Blood, 2013]. More recent studies indicate that the dominant clone of FL and transformed FL arise by either convergent or ergent evolution from a common mutated precursor through the acquisition of additional genetic events [Pasqualucci, L., Cell Rep, 2014]. Defining the deregulated pathways and oncogenic mutations at diagnosis and later at relapse could help identify novel therapeutic targets for treatment at relapse. We aimed to map clonal evolution at relapse using immunophenotyping, sequencing for the Immunoglobulin variable heavy chain gene (IGHV) and genotyping for known somatic mutations in key lymphoma genes, within matched diagnostic and relapsed DLBCL pairs. Methods: Six matched diagnostic and relapsed DLBCL cryopreserved s les were subjected to comprehensive immunophenotyping using 10-colour B-cell flow cytometry panels based on normal ontogeny. PCR on initial and relapsed s les was performed to lify clonally rearranged IgHV genes from fresh araffin embedded primary diagnostic s les. Sanger sequencing was done for IgHV mutation status by targeting the conserved framework regions (FR) FR1 [IGHA: VHFR1-JH] or FR3 [IGHC: VHFR3-JH] using the Invivoscribe kit based on the Biomed-2 protocols. A custom Haloplex library preparation kit designed and ordered from Agilent was used to capture the exons of ~40 genes commonly mutated in DLBCL. Targeted fragments were PCR lified and target enriched s les sequenced on an Illumina MiSeq sequencer Results: Table 1. Immunophenotypic ersity was noted among cases but the phenotype did not change at relapse. IGHV sequencing showed that 3 cases with two distinct lymphoma clones at diagnosis evolved to a single detectable IGHV clonal population at relapse. Lymphoma-associated somatic mutations detected at diagnosis were preserved at relapse and in 4 cases, acquisition of additional mutations was observed. Table 1: Immunophenotype, IgHV sequence and somatic lymphoma mutations in paired DLBCL s les at diagnosis and relapse Patient number Disease course Immunophenotype IgHV sequence Lymphoma mutations DL157 Diagnosis IgM+, IgD+++, IgG-, CD27-, CD21+++, CD38++, CD10- N/A (not available) EP300 I- V EZH2 D- H NOTCH2 L- H TRAF2 A- T DL157 Relapse Same as diagnosis IgHV3-64 IgHV3-30 EZH2 D- H FOXO1G- D NOTCH2L- HTRAF2 A- T DL214 Diagnosis IgM+++,IgD++, IgG-, CD27-, CD21-, CD38+++, CD10+ IgHV4-30 IgHV4-39 N/A DL214 Relapse Same as diagnosis IgHV4-39 EP300 I- V MYD88 L- P NOTCH1 R- W PRDM1 C- Y SPEN D- E TP53 Y- N DL215 Diagnosis IgM-,IgD- IgG++, CD27++,CD21++, CD38-, CD10- IGHV3-23 IGHV3-23D KMT2D R- C MYD88 L- P NOTCH1 E- K DL215 Relapse Same as diagnosis IGHV3-23 BTG1 H- Y BTG1 Q- Stop BTG2 S- N FOXO1 V- E GNA13 R- H KMT2D R- C MYD88 L- P NOTCH1 E- K PIM1 L- F PIM1 K- N PIM1 V- L DL245 Diagnosis N/A IGHV3-11 IGHV3-33 EP300,I- V,997 NOTCH2,L- V,1559 DL245 Relapse N/A IGHV3-11 EP300,I- V,997 NOTCH2,L- V,1559 DL213 Diagnosis IgM+,IgD-, IgG-, CD27-,CD21+++, CD38+++, CD10++ IGHV3-15 ETS1 A- T EZH2 D- H PRDM1 L- F TNFRSF14 C- S DL213 Relapse Same as diagnosis IGHV3-15 ETS1 A- T EZH2 D- H KMT2D R- Stop PRDM1 L- FSTAT3 R- W DL252 Diagnosis IgM-,IgD++, IgG-, CD27-,CD21-, CD38+, CD10- IGHV1-2 NOTCH2,P- A,2359 TNFRSF14,V- I,241 DL252 Relapse Same as diagnosis IGHV1-2 N/A Conclusions: While multiple IGHV sub-clones are present at diagnosis of DLBCL, evolution of a single clone is noted at relapse (convergent model) with acquisition of additional somatic mutations. Immunophenotyping using B-cell maturation flow cytometry panels demonstrates heterogeneity of differentiation between cases but no change in immunophenotype at relapse. No relevant conflicts of interest to declare.
Publisher: Wiley
Date: 26-04-2011
DOI: 10.1038/ICB.2011.31
Publisher: Wiley
Date: 09-2014
DOI: 10.1111/JMWH.12249
Publisher: Wiley
Date: 20-11-2018
DOI: 10.1111/AJI.12784
Abstract: Advances in reproductive medicine have significantly increased the success of fertility treatments. Nevertheless, some women experience recurrent implantation failure (RIF) after in-vitro fertilization (IVF) or recurrent pregnancy loss (RPL). Imbalances in the immune system and failure to achieve immune tolerance to the foetus have been implicated as potentially modifiable causes of idiopathic RIF and RPL. As such, women are increasingly being treated with immunomodulatory agents in an attempt to achieve a successful pregnancy. This systematic review examines the published evidence on immune changes in these patients, the use of immunomodulation therapies and diagnostic testing modalities to guide their use or to identify patient subsets most likely to benefit. The PubMed database was searched for the terms "recurrent implantation failure" and "recurrent pregnancy loss" in conjunction with T-helper (Th) cells and their subsets in particular Th1, Th2, Th17 and T-regulatory (Treg) cells, natural killer (NK) cells, cytokine imbalance as well as immune modulators and immune suppressants. The reference lists of articles were examined to identify additional articles. There remains limited data on the immunological changes in cytokine and cellular profiles during the hormonal cycle as well as prior to, during and after implantation in health as well as idiopathic RIF and RPL. There is a need to advance immunological diagnostics to match the clinical need in this emerging field and to guide clinicians to make optimal and safe therapeutic choices. It is also imperative that the well-being of the infants conceived after such intervention is monitored.
No related grants have been discovered for Yogesh Jeelall.