Genomic evolution and niche adaption of Mycobacterium avium subspecies paratuberculosis

Mycobacterium avium subspecies paratuberculosis (MAP) is a highly specialised mycobacterial pathogen that has adapted to a unique niche. It is the causative agent of Johne’s disease and incurs significant economic and welfare costs to producers and livestock. Furthermore, MAP has been associated with human Crohn’s disease, making this pathogen a public health concern. To optimise control strategies against a zoonotic pathogen, a thorough understanding of its evolution, transmission patterns and specific virulence traits is essential. The underlying mechanisms that MAP utilises to survive in the gut in multiple host species is largely unknown. This thesis begins with broader investigations to identify genomic traits specific to MAP using a combined pan-genome and mapping approach. Transcription within these MAP-specific genomic traits and regions associated with niche adaptation is then assessed. Investigations then narrow down into MAP epidemiology and strain-specific characteristics to reveal insights into host specificity and vaccine persistence phenotypes. Collectively the studies within this thesis have unveiled potential mechanisms of MAP niche adaptation and investigated genomic markers of MAP isolates that persist despite vaccination. Subspecies-specific genes identified in this work may serve as valuable diagnostic or therapeutic targets and phylogenomic analysis enables new isolates to be placed into a context. Furthermore, improvements to our understanding of MAP-specific virulence mechanisms are integral to informing the development of new targeted diagnostic tests, therapeutics and management approaches

Serum prolactin monitoring in patients on risperidone admitted to the acute wards at Mount Carmel hospital

First-generation antipsychotics have been shown to increase prolactin levels in the body. Atypical antipsychotics have a lower tendency to produce hyperprolactinaemia due to a weaker and transient dopamine antagonistic effect. Despite being an atypical antipsychotic, Risperidone, tends to cause a higher increase in prolactin due to a stronger and more prolonged blockade on dopamine receptors. The purpose of this audit is to assess current practices at Mount Carmel Hospital (MCH) with regards to serum prolactin monitoring in patients taking Risperidone when compared to Maudsley Prescribing Guidelines in Psychiatry, 14th Edition (2021). The audit was based on patients acutely admitted between June and December 2021. Focus was placed on prolactin levels checked during admission in patients previously on Risperidone, prolactin levels checked in the preceding six months if no prolactin level was checked during admission and the appropriate action taken in cases where the serum Prolactin was noted to be high. From this audit it was concluded that there is inadequate monitoring of serum prolactin levels in patients prescribed Risperidone at MCH. Increased awareness of Risperidoneinduced hyperprolactinemia and associated guidelines are required to improve clinical practice. The recommendations suggested from this audit were to increase awareness of serum prolactin monitoring guidelines amongst all medical and nursing staff at MCH and to create a simple flow-chart outlining the appropriate serum prolactin monitoring guidelines and distribute this to MCH wards.peer-reviewe

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

SNP based phylogeny of the 15 closed genomes using Telford as a reference genome.

Metadata are indicated by coloured blocks. Reported IS1311 type, number of IS1311 sequences present in the genome, number of SNP-containing IS1311 sequences, year of isolation and country of origin are displayed from left to right respectively.</p

Nomenclature of MAP strains, adapted from Mizzi et al. (2021).

Nomenclature of MAP strains, adapted from Mizzi et al. (2021).</p

Schematic of the bioinformatic workflow used in this study.

Schematic of the bioinformatic workflow used in this study.</p

Details of closed MAP genome dataset used for verification purposes.

Note, this includes the closed reference genomes in Table 2.</p

Schematic of genomic rearrangements and the IS<i>1311</i> locations in the K10 (Type II) (top), S397 (Type III) (middle) and the Telford (Type I) (bottom) closed reference genomes.

Analysis conducted using MAUVE genome alignment tool: blocks of the same colour indicate homologous genomic regions; lines connect these regions between the different reference strains. Coloured arrows indicate the IS1311 loci; arrows with a grey outline indicate a locus that contains the C-strain specific SNP. The colour of the arrow heads indicates analogous loci, as shown in Table 4.</p