Relapse of polymyalgia rheumatica following adjuvanted influenza vaccine: A case-based review

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatological condition affecting individuals aged >50 years. There have been rare reports of PMR and other vasculitides developing within 3 months of influenza vaccination. Influenza is a major public health issue associated with seasonal increased mortality and intensified health care service use. Annual vaccination is the most effective intervention to prevent influenza, especially in elderly individuals. We report a severe “flare” of PMR in a 70-year-old patient after receiving the adjuvanted trivalent influenza vaccine, as recommended by the Joint Committee on Vaccination and Immunisations for this age group in the UK National Health Service in 2018-2019. The adverse event (AE) could be interpreted as the newly described autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome) as both PMR and ASIA display hyperactive immune responses. Caution is warranted in the use of vaccine adjuvants in patients with PMR with pre-existing imbalance of B and T cell homeostasis. Rare AEs are important to individuals, and personalized medicine means we should move away from “one size fits all” for vaccines, as well as for therapeutics

Evaluating the effectiveness of the Disability Discrimination (NI) Order (2006) duties

This report evaluates the effectiveness of the Disability Discrimination (NI) Order (2006) duties. These duties require public authorities in Northern Ireland to promote positive attitudes towards disabled people and to encourage the participation of disabled people in public life. The duties also require public authorities to produce disability action plans and to report annually on progress towards disability equality. The report provides a framework for evaluation of progress and applies this to provide an assessment of the implementation of these duties up to 2009 and makes recommendations to improve the effectiveness and implementation of the duties

Questioning conventional enterprise wisdom

Government (and academic) interest in enterprise (including entrepreneurs and small businesses) largely emerged in the early 1980s when unemployment was rising and research suggested that small businesses were the main source of new jobs. Therefore there was a desire to know more about enterprise in order to encourage it but, like any emerging subject, its early understanding was based more on myth and supposition than ‘scientifically’ established facts. Subsequently much of that understanding appears to have become the conventional wisdom about enterprise which is largely taken on trust and not questioned. But, to those who examine it, problems are apparent, not least because policy apparently based on it does not work. Studies of epistemology suggest that this is to be expected and the review of the links between enterprise research and policy indicates that a disconnect is to be expected there also. Therefore the purpose of this thesis is to identify the body of ‘knowledge’ that has formed the basis for received enterprise wisdom and examine the hypothesis that: Policy has been informed, guided and/or justified by this conventional wisdom – but the failure of policy raises questions about its veracity. This conventional wisdom has not just influenced policy but is also likely to be the foundation for other current thinking about enterprise. However the ‘conventional wisdom is itself based on, or consistent with, a set of assumptions, often not consciously made and therefore not recorded, but at least some of which may be questionable. The research identifies a set of assumptions and shows that they could have been and were adopted and do seem to provide a basis for the conventional wisdom but, nevertheless, are wrong. It therefore concludes that if enterprise understanding is to improve, and enterprise budgets not wasted, this paradigm needs to be changed

Chromosome segregation and recombination in human meiosis: Clinical applications and insight into disjunction errors

Chromosome copy number errors (or aneuploidy) of gametes and embryos occurs in humans more frequently than in any other studied species, with a spectrum of manifestations from implantation failure to affected live births. It is predominantly problem arising in maternal meiosis with at least 20% of oocytes being aneuploid, a proportion that increases dramatically with advancing maternal age. Currently the only intervention to reduce the chances of transmitting aneuploidy is by invasive embryo biopsy procedures in high-risk groups (mainly patients with advanced maternal age) undergoing in-vitro fertilisation. Despite the severity of this problem, aneuploidy of the human preimplantation embryo is relatively poorly understood. With this in mind the purpose of this thesis is to explore the premise underpinning the use of preimplantation genetic screening (PGS) in human embryos and investigate its clinical applications and current methodologies. A series of published works demonstrate what I believe to be a significant contribution to the development of applications for studying human preimplantation aneuploidy, also providing insight into its origins and mechanisms at the earliest stages of human development. Specifically, I present a novel standard set of protocols as a general reference work from practitioners in the fields of embryo biopsy and array comparative genomic hybridisation (CGH - the current ‘gold standard’ for preimplantation aneuploidy screening). I present a summary of work encapsulated in three published clinical papers using a linkage based analysis of Single Nucleotide Polymorphism (SNP) karyotypes (Karyomapping). Karyomapping was designed as a near-universal approach for the simultaneous detection of chromosomal and monogenic disorders in a PGS setting and these results demonstrate the utility of the technique in three separate scenarios. In order to study the underlying mechanisms of female meiosis I present my findings on the use of a calcium ionophore to activate human oocytes artificially. An algorithm based on Karyomapping (termed MeioMapping) is demonstrated for the first time specifically to investigate human female meiosis. By recovering all three products of human female meiosis (oocyte, and both polar biopsies – herein termed “Trios”) using calcium ionophore, I present a novel protocol (commissioned by Nature Protocols) to allow exploration of the full extent of meiotic chromosome recombination and segregation that occurs in the female germline. Finally I present a published set of experiments using this protocol to provide new insight into meiotic segregation patterns and recombination in human oocytes. This work uncovers a previously undescribed pattern of meiotic segregation (termed Reverse Segregation), providing an association between recombination rates and chromosome mis-segregation (aneuploidy). This work demonstrates that there is selection for higher recombination rates in the female germline and that there is a role for meiotic drive for recombinant chromatids at meiosis II in human female meiosis. The work presented in this thesis provides deeper understanding of meiotically derived maternal aneuploidy and recombination. More importantly it provides a vehicle within an ethical framework to continue to expand our knowledge and uncover new insights into the basis of meiotic errors that may aid future reproductive therapies

Differential efficacy of vaccinia virus envelope proteins administered by DNA immunisation in protection of BALB/c mice from a lethal intranasal poxvirus challenge

DNA vaccines might offer an alternative to the live smallpox vaccine in providing protective efficacy in an orthopoxvirus (OPV) lethal respiratory challenge model. BALB/c mice were immunised with DNA vaccines coding for 10 different single vaccinia virus (VACV) membrane proteins. After an intranasal challenge with the VACV IHD strain, three gene candidates B5R, A33R and A27L produced > or =66% survival. The B5R DNA vaccine consistently produced 100% protection and exhibited greatest efficacy after three 50 microg intramuscular doses in this model. Sero-conversion to these vaccines was often inconsistent, implying that antibody itself was not a correlate of protection. The B5R DNA vaccine induced a strong and consistent gamma interferon (IFNgamma) response in BALB/c mice given a single DNA vaccine dose. Strong IFNgamma responses were also measured in pTB5R immunised C57BL6 mice deficient for MHC class I molecules, suggesting that the memory response was mediated by a CD4+ T cell population

HCV and the hepatic lipid pathway as a potential treatment target

Atherosclerosis has been described as a liver disease of the heart. The liver is the central regulatory organ of lipid pathways but since dyslipidaemias are major contributors to cardiovascular disease and type 2 diabetes rather than liver disease, research in this area has not been a major focus for hepatologists. Virus-host interaction is a continuous co-evolutionary process involving the host immune system and viral escape mechanisms. One of the strategies HCV has adopted to escape immune clearance and establish persistent infection is to make use of hepatic lipid pathways. This review aims to: update the hepatologist on lipid metabolism; review the evidence that HCV exploits hepatic lipid pathways to its advantage; discuss approaches to targeting host lipid pathways as adjunctive therapy

Heterologous prime-boost-boost immunisation of Chinese cynomolgus macaques using DNA and recombinant poxvirus vectors expressing HIV-1 virus-like particles

Background: There is renewed interest in the development of poxvirus vector-based HIV vaccines due to the protective effect observed with repeated recombinant canarypox priming with gp120 boosting in the recent Thai placebo-controlled trial. This study sought to investigate whether a heterologous prime-boost-boost vaccine regimen in Chinese cynomolgus macaques with a DNA vaccine and recombinant poxviral vectors expressing HIV virus-like particles bearing envelopes derived from the most prevalent clades circulating in sub-Saharan Africa, focused the antibody response to shared neutralising epitopes. Methods: Three Chinese cynomolgus macaques were immunised via intramuscular injections using a regimen composed of a prime with two DNA vaccines expressing clade A Env/clade B Gag followed by boosting with recombinant fowlpox virus expressing HIV-1 clade D Gag, Env and cholera toxin B subunit followed by the final boost with recombinant modified vaccinia virus Ankara expressing HIV-1 clade C Env, Gag and human complement protein C3d. We measured the macaque serum antibody responses by ELISA, enumerated T cell responses by IFN-gamma ELISpot and assessed seroneutralisation of HIV-1 using the TZM-bl beta-galactosidase assay with primary isolates of HIV-1. Results: This study shows that large and complex synthetic DNA sequences can be successfully cloned in a single step into two poxvirus vectors: MVA and FPV and the recombinant poxviruses could be grown to high titres. The vaccine candidates showed appropriate expression of recombinant proteins with the formation of authentic HIV virus-like particles seen on transmission electron microscopy. In addition the b12 epitope was shown to be held in common by the vaccine candidates using confocal immunofluorescent microscopy. The vaccine candidates were safely administered to Chinese cynomolgus macaques which elicited modest T cell responses at the end of the study but only one out of the three macaques elicited an HIV-specific antibody response. However, the antibodies did not neutralise primary isolates of HIV-1 or the V3-sensitive isolate SF162 using the TZM-bl b-galactosidase assay. Conclusions: MVA and FP9 are ideal replication-deficient viral vectors for HIV-1 vaccines due to their excellent safety profile for use in humans. This study shows this novel prime-boost-boost regimen was poorly immunogenic in Chinese cynomolgus macaques

Revisiting the Elusive Hepatitis C Vaccine

The impactful discovery and subsequent characterisation of hepatitis C virus (HCV), an RNA virus of the flavivirus family, led to the awarding of the 2020 Nobel Prize in Physiology or Medicine to Harvey J. Alter, Michael Houghton and Charles M. Rice [...

Covid‐19 and co‐morbidities: a role for Dipeptidyl Peptidase 4 ( DPP4 ) in disease severity?

The coronavirus disease 2019 (COVID‐19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), similar to SARS‐CoV and Middle East respiratory syndrome (MERS‐CoV), which cause acute respiratory distress syndrome and case fatalities. COVID‐19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS‐CoV binds to the metalloprotease angiotensin‐converting enzyme 2 (ACE2), MERS‐CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS‐CoV‐2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane‐bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID‐19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID‐19 disease severity, which creates interest regarding the use of gliptins in management of COVID‐19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS‐CoV‐2