Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma

BACKGROUND: Cutaneous Malignant Melanoma causes over 75% of skin cancer-related deaths, and it is clear that many factors may contribute to the outcome. Matrix Metalloproteinases (MMPs) play an important role in the degradation and remodeling of the extracellular matrix and basement membrane that, in turn, modulate cell division, migration and angiogenesis. Some polymorphisms are known to influence gene expression, protein activity, stability, and interactions, and they were shown to be associated with certain tumor phenotypes and cancer risk. METHODS: We tested seven polymorphisms within the MMP-9 gene in 1002 patients with melanoma in order to evaluate germline genetic variants and their association with progression and known risk factors of melanoma. The polymorphisms were selected based on previously published reports and their known or potential functional relevance using in-silico methods. Germline DNA was then genotyped using pyrosequencing, melting temperature profiles, heteroduplex analysis, and fragment size analysis. RESULTS: We found that reference alleles were present in higher frequency in patients who tend to sunburn, have family history of melanoma, higher melanoma stage, intransit metastasis and desmoplastic melanomas among others. However, after adjustment for age, sex, phenotypic index, moles, and freckles only Q279R, P574R and R668Q had significant associations with intransit metastasis, propensity to tan/sunburn and primary melanoma site. CONCLUSION: This study does not provide strong evidence for further investigation into the role of the MMP-9 SNPs in melanoma progression

Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection

K. pneumoniae sequence type 258 (Kp ST258) is a major cause of healthcare-associated pneumonia. However, it remains unclear how it causes protracted courses of infection in spite of its expression of immunostimulatory lipopolysaccharide, which should activate a brisk inflammatory response and bacterial clearance. We predicted that the metabolic stress induced by the bacteria in the host cells shapes an immune response that tolerates infection. We combined in situ metabolic imaging and transcriptional analyses to demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation. This response creates an oxidant-rich microenvironment conducive to the accumulation of anti-inflammatory myeloid cells. In this setting, metabolically active Kp ST258 elicits a disease-tolerant immune response. The bacteria, in turn, adapt to airway oxidants by upregulating the type VI secretion system, which is highly conserved across ST258 strains worldwide. Thus, much of the global success of Kp ST258 in hospital settings can be explained by the metabolic activity provoked in the host that promotes disease tolerance. Keywords: immunometabolism, Klebsiella pneumoniae, immunosuppressive, anti-inflammatory, itaconate, Type Six Secretion Syste

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Examining the relationship between genetic variation at G6PD and severe malaria

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common heritable trait whose prevalence mirrors geographic patterns of historic malaria endemicity, is thought to confer a selective advantage owing to partial protection conferred against malaria. Direct evidence supporting this malaria protection hypothesis in the form of clinical association studies re- mains controversial, however, as conflicting results have been reported with respect to the strength and specificity of a protective effect, if any, conferred to carriers of G6PD deficiency- associated alleles. This thesis examines genetic diversity at the G6PD locus, and then considers how such variation impacts both immediate molecular phenotypes and multifactorial clinical phenotypes. First, Chapter 3 presents a survey of variation at G6PD in several malaria-endemic areas, while Chapter 4 describes a novel technique for polymorphism discovery using pooled massively parallel sequencing. Next, in Chapters 5 and 6, I evaluate the link between genetic variation at the locus and G6PD enzyme activity, identifying major and minor determinants of G6PD deficiency state in an association study conducted in Kenya, and demonstrating a new technique for assaying G6PD deficiency at the level of an individual erythrocyte in a pilot project in Mali. Finally, Chapter 7 addresses the malaria protection hypothesis directly by conducting a fine-mapping case-control association study of severe malaria in the Gambia, where I found that G6PD deficiency alleles exhibited differential direction of association with respect to two important clinical syndromes- trending towards risk conferred to severe malarial anemia, and protection with respect to cerebral malaria. Overall, these findings suggest that future clinical association studies should consider heterogeneity at the genetic level, as well as at the level of molecular and clinical phenotypes in order to achieve a better mechanistic understanding of the relationship between G6PD deficiency and severe malaria.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Examining the relationship between genetic variation at G6PD and severe malaria

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common heritable trait whose prevalence mirrors geographic patterns of historic malaria endemicity, is thought to confer a selective advantage owing to partial protection conferred against malaria. Direct evidence supporting this malaria protection hypothesis in the form of clinical association studies re- mains controversial, however, as conflicting results have been reported with respect to the strength and specificity of a protective effect, if any, conferred to carriers of G6PD deficiency- associated alleles. This thesis examines genetic diversity at the G6PD locus, and then considers how such variation impacts both immediate molecular phenotypes and multifactorial clinical phenotypes. First, Chapter 3 presents a survey of variation at G6PD in several malaria-endemic areas, while Chapter 4 describes a novel technique for polymorphism discovery using pooled massively parallel sequencing. Next, in Chapters 5 and 6, I evaluate the link between genetic variation at the locus and G6PD enzyme activity, identifying major and minor determinants of G6PD deficiency state in an association study conducted in Kenya, and demonstrating a new technique for assaying G6PD deficiency at the level of an individual erythrocyte in a pilot project in Mali. Finally, Chapter 7 addresses the malaria protection hypothesis directly by conducting a fine-mapping case-control association study of severe malaria in the Gambia, where I found that G6PD deficiency alleles exhibited differential direction of association with respect to two important clinical syndromes- trending towards risk conferred to severe malarial anemia, and protection with respect to cerebral malaria. Overall, these findings suggest that future clinical association studies should consider heterogeneity at the genetic level, as well as at the level of molecular and clinical phenotypes in order to achieve a better mechanistic understanding of the relationship between G6PD deficiency and severe malaria.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Case Report: Cardiovertor-Defibrillator Implantation in an Isolated PLSVC with Hypertrophic Cardiomyopathy

Persistent Left Superior Vena Cava (PLSVC) has an estimated incidence of 0.2-0.8% in the general population and 3-10% in patients with known congenital heart disease [1]. A rare anatomic variation of LSVC occurs in up to 0.13% of otherwise normal individuals where both brachiocephalic venous systems drain into a persistent LSVC [1]. We describe a patient with hypertrophic cardiomyopathy (HCM) and malignant ventricular arrhythmias in whom this rare malformation was discovered at the time of implantable cardioverter–defibrillator (ICD) implant