Cardiac Computed Tomography: Application in Valvular Heart Disease

The incidence and prevalence of valvular heart disease (VHD) is increasing and has been described as the next cardiac epidemic. Advances in imaging and therapeutics have revolutionized how we assess and treat patients with VHD. Although echocardiography continues to be the first-line imaging modality to assess the severity and the effects of VHD, advances in cardiac computed tomography (CT) now provide novel insights into VHD. Transcatheter valvular interventions rely heavily on CT guidance for procedural planning, predicting and detecting complications, and monitoring prosthesis. This review focuses on the current role and future prospects of CT in the assessment of aortic and mitral valves for transcatheter interventions, prosthetic valve complications such as thrombosis and endocarditis, and assessment of the myocardium

Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstratedthat heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shownto be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intraislet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxideinduced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/ heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.: This work was supported by a National Health and Medical Research Council of Australia (NHMRC; https://www.nhmrc.gov.au/)/Juvenile Diabetes Research Foundation (JDRF) Special Program Grant in Type 1 Diabetes (#418138), The Canberra Hospital Private Practice Fund (http:// www.health.act.gov.au/research-publications/research/ppf-major-grants), JDRF nPOD Research Grant (#25-2010-716; http://www.jdrf.org), JDRF Research Grant (#47-2012-746) and NHMRC Project Grant (#1043284

Securing Safe Supply During COVID-19 and Beyond: Scoping Review and Knowledge Mobilization

Background Safe supply is defined as the legal and regulated provision of drugs with mind and/or body altering properties that have been typically accessible only through the illegal drug market. In response to the coronavirus disease 2019 (COVID-19) pandemic and related social/physical distancing measures, efforts have been made to scale up and increase access to safe supply programs in an effort to reduce overdose and other drug- and drug policy-related risks. However, it remains unclear whether these efforts taken thus far have meaningfully mitigated the barriers to safe supply experienced by People Who Use Drugs (PWUD), both during and beyond the context of COVID-19. We thus undertook a scoping review to identify key concepts, strategies and gaps in evidence with respect to the provision of safe supply during pandemics and other emergencies. Methods We conducted three searches across Scopus, Medline, Embase, CINAHL, and The Cochrane Central Register of Controlled Trials (CENTRAL) for peer-reviewed and grey literature articles to understand barriers/facilitators to both accessing and prescribing legal, pharmaceutical-grade drugs, including opioids, benzodiazepines, and/or stimulants during public health emergencies from January 1 2002 to June 30 2020. We also included opioid agonist therapies (OAT) during emergency conditions. All potential sources underwent title/abstract screening and duplicate full- text review to determine eligibility for inclusion. Three reviewers extracted characteristics and barriers/facilitators to accessing or prescribing drugs for each study, and these were then inductively analyzed to identify common themes. Key stakeholders (PWUD, prescribers, and policymakers/regulators) informed the search strategy and validated findings and interpretations. Input from PWUD and prescribers was gathered through Advisory Committee meetings and one-on-one consultations, respectively. Results We screened 9,839 references and included 169 studies (135 peer-reviewed articles and 36 grey literature reports). From 119 articles, we identified 35 themes related to barriers/facilitators to prescribing safe supply or OAT. Few studies (n=24) focused on emergency or pandemic contexts. Among the most frequently reported barriers were restrictive laws or policies (n= 33; 28%). The most frequently cited facilitator was temporary legal or regulatory exemptions (n= 16; 13%). Further stakeholder consultation identified barriers/facilitators to safe supply absent in the reviewed literature: PWUD reported barriers including lack of access to desired substances, concerns about child apprehension, and a lack of cultural competency within safe supply/OAT programs; prescribers reported barriers including regional differences in service delivery, colleague support, and a lack of, or disagreement between, clinical guidance documents. Conclusion We identified multiple barriers and facilitators to accessing and/or prescribing safe supply or OAT. With few peer-reviewed studies on safe supply models, particularly in the context of emergencies, input from PWUD and other stakeholders offered crucial insights not reflected in the existing literature. To address the overdose epidemic stemming from the criminalization of an unregulated drug supply, prescribers, regulators, and public health authorities should focus on scaling up, and then evaluating, diverse safe supply frameworks that address the facilitators and barriers we have identified

Broad Repertoire of T Cell Autoreactivity Directly from Islets of Donors with Type 1 Diabetes (T1D)

Type 1 diabetes (T1D) is an autoimmune disease characterized by the infiltration of lymphocytes into the insulin-producing β-cells in the pancreas. We have isolated live T cells sorted or grown directly from the isolated, handpicked islets of human donors with T1D. We received ~500 islet equivalent EQ of variable purity (10-90%) from 12 donors with T1D (disease duration 0.42-20 years) and from seven control donors and two donors with type 2 diabetes (T2D). A total of 321 T cell lines and clones were derived from the islets of donors with T1D (3 lines from the 9 control donors). These are 131 CD4+ lines and clones, 47 CD8+ lines and 143 lines that contain both CD4+ and CD8+ T cells. From 50 lines and clones examined to date, we have determined the autoreactivity of 19 and have seen a broad repertoire of T cell autoreactivity in the islets, including characterized targets and post-translationally modified targets. Autoreactivity of CD4+ T cell lines was to three different peptides from glutamic acid decarboxylase 65 (GAD; GAD115-127, GAD274-286, GAD555-567), proinsulin76-90, and to chromogranin A or proinsulin expressed by DR4+DQ8+ B cells transduced with lentivirus containing constructs with the open reading frames corresponding to whole autoantigens. Reactivity to modified peptides included the glucose-regulated protein 78 and islet amyloid polypeptide with arginine to citrulline modifications (GRP78292-305(Arg-Cit297) and IAPP65-84(Arg-Cit 73, 81)), deaminations (IA-2545-562(Gln-Glu 548, 551, 556), and to several insulin hybrid peptides. These autoreactive CD4+ T cell lines and clones secreted only pro-inflammatory cytokines (IFN-γ, TNFα) upon peptide stimulation. For CD8+ T cells from islets, from one donor with T1D, we saw binding of a pool of HLA-A2 pentamers loaded with insulin B10-18, IA-2797-805 and insulin specific glucose-6-phosphatase catalytic subunit related protein, IGRP265-273. These results have implications for the development of successful prevention and reversal therapeutic strategies in T1D

Activation of Insulin-Reactive CD8 T-Cells for Development of Autoimmune Diabetes

Objective: We have previously reported a highly diabetogenic CD8 T cell clone, G9C8, in the Non Obese Diabetic (NOD) mouse, specific to low avidity insulin peptide B15-23 and cells responsive to this antigen are among the earliest islet infiltrates. We aimed to study the selection, activation and development of diabetogenic capacity of these insulin-reactive T cells. Research Design and Methods: We generated a TCR transgenic mouse expressing the cloned TCR Vα18/Vβ6 receptor of the G9C8 insulin-reactive CD8 T cell clone. The mice were crossed to TCRCα−/− mice so that the majority of the T cells expressed the clonotypic TCR and the phenotype and function of the cells was investigated. Results: There was good selection of CD8 T cells with a predominance of CD8 single positive thymocytes, in spite of thymic insulin expression. Peripheral lymph node T cells had a naïve phenotype (CD44lo, CD62Lhi) and proliferated to insulin B15-23 peptide and to insulin. These cells produced interferon-γ and TNF-α in response to insulin peptide and were cytotoxic to insulin-peptide coated targets. In vivo, the TCR transgenic mice developed insulitis but not spontaneous diabetes. However, the mice developed diabetes on immunization, and the activated transgenic T cells were able to transfer diabetes to immunodeficient NOD.scid mice. Conclusion: Autoimmune CD8 T cells responding to a low affinity insulin B chain peptide escape from thymic negative selection, and require activation in vivo to cause diabetes

Regulation of Glomerular Endothelial Cell Proteoglycans by Glucose

The presence of heparan sulfate proteoglycan (HSPG) in anionic sites in the lamina rara interna of glomerular basement membrane suggests that the proteoglycan may be deposited by the glomerular endothelial cells (GEndo). We have previously demonstrated that bovine GEndo in vitro synthesize perlecan, a species of glomerular basement membrane HSPG. In this study we examined whether high glucose medium regulates the GEndo metabolism of glycopeptides including perlecan. Metabolic labeling of glycoconjugates with 35S-SO4, sequential ion exchange and Sepharose CL-4B chromatography of labeled glycoconjugates, and northern analysis were performed. Incubation of GEndo for 8 to 14 weeks (but not for 1-2 weeks) in medium containing 30 mM glucose resulted in nearly 50% reduction in the synthesis of cell layer and medium 35SO4-labeled low anionic glycoproteins and proteoglycans, including that of basement membrane HSPG (Kav 0.42) compared to GEndo grown in 5 mM glucose medium; no changes in anionic charge density or hydrodynamic size of proteoglycans were noted. Northern analysis demonstrated that the mRNA abundance of perlecan was reduced by 47% in cells incubated with 30 mM glucose. Our data suggest that high glucose medium reduces the GEndo synthesis of perlecan by regulating its gene expression. Reduced synthesis of perlecan by GEndo may contribute to proteinuria seen in diabetic nephropathy

Melting of hybrid organic-inorganic perovskites.

Several organic-inorganic hybrid materials from the metal-organic framework (MOF) family have been shown to form stable liquids at high temperatures. Quenching then results in the formation of melt-quenched MOF glasses that retain the three-dimensional coordination bonding of the crystalline phase. These hybrid glasses have intriguing properties and could find practical applications, yet the melt-quench phenomenon has so far remained limited to a few MOF structures. Here we turn to hybrid organic-inorganic perovskites-which occupy a prominent position within materials chemistry owing to their functional properties such as ion transport, photoconductivity, ferroelectricity and multiferroicity-and show that a series of dicyanamide-based hybrid organic-inorganic perovskites undergo melting. Our combined experimental-computational approach demonstrates that, on quenching, they form glasses that largely retain their solid-state inorganic-organic connectivity. The resulting materials show very low thermal conductivities (~0.2 W m-1 K-1), moderate electrical conductivities (10-3-10-5 S m-1) and polymer-like thermomechanical properties

Acute maternal infection and risk of pre-eclampsia: a population-based case-control study.

BACKGROUND: Infection in pregnancy may be involved in the aetiology of pre-eclampsia. However, a clear association between acute maternal infection and pre-eclampsia has not been established. We assessed whether acute urinary tract infection, respiratory tract infection, and antibiotic drug prescriptions in pregnancy (a likely proxy for maternal infection) are associated with an increased risk of pre-eclampsia. METHODS AND FINDINGS: We used a matched nested case-control design and data from the UK General Practice Research Database to examine the association between maternal infection and pre-eclampsia. Primiparous women aged at least 13 years and registered with a participating practice between January 1987 and October 2007 were eligible for inclusion. We selected all cases of pre-eclampsia and a random sample of primiparous women without pre-eclampsia (controls). Cases (n=1533) were individually matched with up to ten controls (n=14236) on practice and year of delivery. We calculated odds ratios and 95% confidence intervals for pre-eclampsia comparing women exposed and unexposed to infection using multivariable conditional logistic regression. After adjusting for maternal age, pre-gestational hypertension, diabetes, renal disease and multifetal gestation, the odds of pre-eclampsia were increased in women prescribed antibiotic drugs (adjusted odds ratio 1.28;1.14-1.44) and in women with urinary tract infection (adjusted odds ratio 1.22;1.03-1.45). We found no association with maternal respiratory tract infection (adjusted odds ratio 0.91;0.72-1.16). Further adjustment for maternal smoking and pre-pregnancy body mass index made no difference to our findings. CONCLUSIONS: Women who acquire a urinary infection during pregnancy, but not those who have a respiratory infection, are at an increased risk of pre-eclampsia. Maternal antibiotic prescriptions are also associated with an increased risk. Further research is required to elucidate the underlying mechanism of this association and to determine whether, among women who acquire infections in pregnancy, prompt treatment or prophylaxis against infection might reduce the risk of pre-eclampsia