Lessons learned from the investigation and management of an outbreak of Shigella flexneri associated with a restaurant in London, 2019-2020.

BACKGROUND: Foodborne outbreaks of Shigella flexneri infection are uncommon in the UK. In November 2019, the United Kingdom Health Security Agency investigated an outbreak of S. flexneri associated with a fast-food restaurant in London. METHODS: Epidemiological investigations included case ascertainment and interviewing suspected cases using enhanced surveillance questionnaires. Whole-genome sequencing (WGS) was used for characterisation of human isolates. Environmental investigations included a review of food safety processes at the implicated restaurant, administration of exposure questionnaires and stool sampling of staff. RESULTS: Between November 2019 and February 2020, 17 cases were confirmed as part of the outbreak by WGS in London. Among these, 15 were linked to the implicated restaurant. A review of the food safety processes at the restaurant was satisfactory. Despite initial suboptimal coverage of stool screening of staff, all staff members working at the restaurant during the sampling period were screened and an asymptomatic food handler tested positive for S.flexneri with the outbreak WGS profile. The individual underwent microbiological clearance, and no further cases were reported. It was not possible to confirm the direction of transmission for the community cases or the staff member. CONCLUSION: We report an outbreak of S. flexneri in a fast-food restaurant in London with previous inspection ratings indicating good compliance with food safety and hygiene standards. WGS was crucial in identifying cases linked to the outbreak. This outbreak highlights the importance of prompt testing of food handlers in outbreaks suspected to be associated with food businesses.

University students with attention deficit hyperactivity disorder (ADHD): a literature review.

OBJECTIVES: To review existing literature about university students with Attention Deficit Hyperactivity Disorder (ADHD). METHODS: A framework for scoping studies and content analysis were used to source and review selected publications from PubMed, ScienceDirect, Google Scholar and relevant bibliographies. RESULTS: Seventy-four publications were reviewed and key findings were categorised under six core themes that represent the issues germane to university students with ADHD. These themes are: academic, social and psychological functioning, giftedness, new media technologies, treatment, substance misuse and the non-medical use of prescription stimulants, and malingering. CONCLUSION: In Ireland and the United Kingdom (UK) young people with ADHD are unlikely to enrol into further education, and of those who do go to university, few will graduate at the same time as their non-ADHD peers. ADHD is associated with poor educational outcomes and it may be a hidden disability within institutions of higher education (e.g. universities). Surprisingly, in this topic area, there is a paucity of research in Ireland and the UK. Most studies originate from North America were research activity in the field has been ongoing since the 1990s. These studies however, tend to use relatively small samples of college (university) students recruited at a single institution. It is difficult to generalise the findings of these studies to student populations in North America, let alone in Ireland and the UK. At the very least, these North American studies provide insights into key areas of concern. This topic area straddles education and psychiatry. This means an inter-disciplinary approach is required to examine, better understand and address the impact of ADHD on the educational outcomes of university students. The philosophies of difference, equity and self-realisation can offer a conceptual framework for conducting further research and/or developing services to deliver more personalised learning support for university students with ADHD.

Outbreak of a South West Pacific clone Panton-Valentine leucocidin-positive meticillin-resistant Staphylococcus aureus infection in a UK neonatal intensive care unit.

BACKGROUND: Panton-Valentine leucocidin-positive meticillin-resistant Staphylococcus aureus (PVL-MRSA) has become a globally common cause of community-acquired infections. AIM: We report an outbreak of PVL-MRSA in a regional neonatal unit in the UK involving three babies and three staff members. METHODS: Quinolone susceptibility was helpful in identifying potential PVL-MRSA but toxin gene profiling and sequence-based typing were required to distinguish between two PVL-MRSA strains present in the unit. FINDINGS: All three symptomatic babies and two staff carriers, one of whom was symptomatic, were found to be carrying the South West Pacific (SWP) clone of PVL-MRSA (ST30). One of the staff carriers had recently visited the Philippines and was thought to be the source of the outbreak. Control was established using standard infection control procedures but one baby with relapsing MRSA colonization has required more than 100 days in isolation. CONCLUSION: This is the first reported neonatal outbreak associated with the SWP clone in the UK. Our study highlights the potential risk of further introductions of this organism by healthcare staff or patients epidemiologically linked with the Philippines.

Healthcare-associated infection in acute hospitals: which interventions are effective?

This study investigated the potential factors linked to healthcare-associated infection (HCAI) rates in acute National Health Service hospitals, analysing mandatory surveillance data with existing data available to the Healthcare Commission, and supplemented by a bespoke questionnaire. A questionnaire was developed to cover important elements related to the management and control of HCAI. Additional data were collated from other sources. Infection outcomes comprised the mandatory surveillance data, for both meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia and Clostridium difficile-associated diarrhoea (CDAD). The response rate was 90%. A lower MRSA rate was linked to hand hygiene and isolation and a lower rate of CDAD to cleanliness, good antimicrobial prescribing practices and surveillance of infections. Lower rates of both organisms were related to strategic planned interventions, such as the inclusion of infection control in the staff development programme. However, certain interventions, for example increased levels of training, were related to a higher infection rate. These findings for MRSA and CDAD are supported by evidence from the infection control literature. We have found relationships between interventions and higher infection rates that are counterintuitive and that may represent examples of what we call 'reactive practice' to higher rates of infection. Whilst it is interesting to hypothesise that these interventions may be swift and simple to introduce and may not be sustained compared to more strategic and planned interventions linked to lower infection rates, they most probably simply represent the beginning of a culture change and embedding of infection control practice.

Human airway and peripheral blood eosinophils enhance Th1 and Th2 cytokine secretion.

BACKGROUND: The effector function of eosinophils involves their release of toxic granule proteins, reactive oxygen species, cytokines, and lipid mediators. Murine studies have demonstrated that eosinophils can also enhance T cell function. Whether human eosinophils, in particular, airway eosinophils, have similar immunoregulatory activity has not been fully investigated. The aim of this study was to determine whether human blood and airway eosinophils can contribute to Th1 and Th2 cytokine generation from CD4+ T cells stimulated with superantigen. METHODS: Eosinophils were obtained from blood or bronchoalveolar lavage fluid 48 h after segmental allergen bronchoprovocation. Purified eosinophils were co-cultured with autologous CD4+ blood T cells in the presence of staphylococcal enterotoxin B (SEB). Cytokine levels in the supernatant fluid were determined by enzyme-linked immunosorbent assay (ELISA). Eosinophil expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules was assessed by flow cytometry before culture, 24 h after granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, and 24 h after co-culture with CD4+ T cells and SEB. RESULTS: Interleukin (IL)-5, IL-13, and interferon (IFN)-gamma generation increased when CD4+ T cells were co-cultured with either blood or airway eosinophils in the presence of SEB. The ability of eosinophils to enhance cytokine generation was independent of their source (blood vs airway), activation by GM-CSF, or detectable expression of human leukocyte antigen (HLA)-DR, CD80, or CD86. CONCLUSION: Our data demonstrate that SEB-induced generation of Th1 and Th2 cytokines is increased in the presence of human blood and airway eosinophils. Thus, eosinophils can have an immunoregulatory function in pathogen-associated allergic diseases such as atopic dermatitis, chronic sinusitis, and asthma exacerbations.

Cigarette smoking, health status, socio-economic status and access to health care in diabetes mellitus: a cross-sectional survey.

BACKGROUND: In diabetes mellitus, cigarette smoking is associated with increased risk of cardiovascular mortality and microvascular complications. We evaluated cigarette smoking in people with diabetes mellitus in a socio-economically deprived area. METHODS: We carried out a cross-sectional survey of people registered with diabetes mellitus at 29 general practices in inner London. Responses were analysed for 1,899 (64%) respondents out of 2,983 eligible. RESULTS: There were 1,899 respondents of whom 968 (51%) had never smoked, 296 (16%) were current smokers and 582 (31%) were ex-smokers. Smoking was more frequent in white Europeans (men 22%, women 20%), than in African Caribbeans (men 15%, women 10%) or Africans (men 8%, women 2%). Smoking prevalence decreased with age. Smokers were more likely to be living in rented accommodation (odds ratio, OR 2.02, 95% confidence interval 1.48 to 2.74). After adjusting for confounding, current smokers had lower SF-36 scores than subjects who had never smoked (mean difference in physical functioning score -5.6, 95% confidence interval -10.0 to -1.2; general health -6.1, -9.7 to -2.5). Current smokers were less likely to have attended a hospital diabetic clinic in the last year (OR 0.59, 0.44 to 0.79), and their hypertension was less likely to be treated (OR 0.47, 0.30 to 0.74). CONCLUSIONS: Compared with non-smokers, smokers had lower socio-economic status and worse health status, but were less likely to be referred to hospital or treated for their hypertension. People with diabetes who smoke can be regarded as a vulnerable group who need more intensive support and treatment.

SARS: UK public health response--past, present and future.

The emergence of severe acute respiratory syndrome (SARS) in China, the occurrence of epidemics of SARS in China and a number of Southeast Asian countries, and its spread to countries elsewhere, have presented major challenges to public health systems throughout the world. Although very few true cases of SARS were detected in the United Kingdom, the public health response to the threat of SARS was considerable. The main components of this response were the early detection, isolation and reporting of cases, and the provision of comprehensive information to health professionals, cases, their contacts and the public. The development of the response to SARS raised a number of more general issues relevant to future infectious epidemic threats. Although the World Health Organisation has now declared SARS 'contained', the possibility of re-emergence is ever present. All countries will need to be vigilant and plan their response to the possibility of a renewed SARS epidemic.

Device-related sources of bacteraemia in English hospitals--opportunities for the prevention of hospital-acquired bacteraemia.

Between 1997 and 2001, 17 teaching and 56 non-teaching acute English hospitals conducted hospital-wide surveillance of hospital-acquired bacteraemia (HAB) using a standard protocol drawn up by the Nosocomial Infection National Surveillance Scheme (NINSS). The sources of organisms, the incidence of device-related HAB, and the distribution of HABs from individual device-related sources by specialty and type of hospital were determined for 6,956 HABs in order to identify where resources should best be targeted to reduce these infections. The overall incidence of HAB was higher in teaching than in non-teaching hospitals: 5.39 and 2.83 HABs per 1,000 patients at risk, respectively (P<0.001). Device-related sources were responsible for 52.4 and 43.2% of all HABs in teaching and non-teaching hospitals, respectively (P<0.001), and central lines were the commonest source, causing 38.3% of HABs in teaching versus 22.3% in non-teaching hospitals (P<0.001). In teaching hospitals, general intensive care units (ICUs), haematology, special care baby units (SCBUs), nephrology, and oncology accounted for only 6.1% of the population surveyed, but had the highest incidence of HAB, and contributed 47.8% of 2091 HABs and 56.9% of 1,095 device-related bacteraemias. Of 623 device-related bacteraemias in these high-risk specialties, 554 (88.9%) were from central lines. Thus, in teaching hospitals, resources should be targeted primarily at the prevention of central line-related bacteraemia in these five high-risk specialties, and the surveillance should include data on central line use. In non-teaching hospitals, nearly two thirds (63.3%) of 4,865 HABs and 60.7% of 2,103 device-related bacteraemias were from a few specialties with a low incidence of bacteraemia, but large numbers of patients, namely general medicine, general surgery, geriatric medicine and urology. These specialties accounted for 50.5% of the population surveyed. Central lines were the most common source of bacteraemia in general medicine and surgery, and together accounted for 23.3% of all device-related bacteraemias. However, in geriatric medicine and urology, central line sources were infrequent, accounting for only 1.7% of all device-related bacteraemias. On the other hand, bacteraemia from catheter-associated UTI were common in all these four specialties accounting for 20.9% of all device-related bacteraemias. Thus, in non-teaching hospitals, resources should be targeted primarily at these low-risk specialties and surveillance should include, at least, bacteraemia from central lines and from catheter-associated UTI. Further benefit can be obtained by including central line-related bacteraemias from general ICU and haematology patients, as they contributed 17.0% of all device-related bacteraemias in non-teaching hospitals.

Restricted weekend service inappropriately delays discharge after acute myocardial infarction.

BACKGROUND: Early discharge after myocardial infarction is safe and feasible. Factors that delay discharge need to be identified in order to improve care and reduce bed occupancy. OBJECTIVE: To investigate the potential of the restricted weekend service that operates in most hospitals to delay patient discharge. DESIGN: Prospective cohort study. SUBJECTS AND SETTING: 2541 consecutive patients with acute myocardial infarction admitted to the coronary care unit of three local district hospitals over a 12 year period. RESULTS: Clinical factors affecting the duration of stay were age, sex, and severity of infarction. Thus older patients and women stayed significantly longer, as did patients with enzymatically large infarcts. Day of week also had an important influence on duration of stay. Discharge occurred most often on a Friday (p = 0.006) and least often over the weekend (p = 0.0001). Patients were preferentially discharged on a Friday if the length of stay was more than 72 hours. Thus patients admitted on a Sunday or Monday were usually discharged the following Friday, corresponding to a median duration of stay of five or four days, respectively. For patients admitted on Tuesday to Saturday, weekend discharge was avoided and the median duration of stay was six to eight days. CONCLUSIONS: For patients with acute myocardial infarction, discharge decisions were influenced appropriately by clinical indicators of risk, but inappropriately by the day of the week. Thus weekend discharge was generally avoided, leading to variations in length of stay that were largely determined by the day of the week on which admission occurred rather than clinical need.

Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment.

Monocytes recruited from the blood are key contributors to the nature of an immune response. While monocyte recruitment in a subset of immunopathologies has been well studied and largely attributed to the chemokine monocyte chemoattractant protein (MCP)-1, mechanisms mediating such recruitment to other sites of inflammation remain elusive. Here, we showed that localized inflammation resulted in an increased binding of monocytes to perifollicular high endothelial venules (HEVs) of lymph nodes draining a local inflammatory site. Quantitative PCR analyses revealed the upregulation of many chemokines in the inflamed lymph node, including MCP-1 and MIG. HEVs did not express detectable levels of MCP-1; however, a subset of HEVs in inflamed lymph nodes in wild-type (but not tumor necrosis factor [TNF] null mice) expressed MIG and this subset of HEVs preferentially supported monocyte binding. Expression of CXCR3, the receptor for MIG, was detected on a small subset of peripheral blood monocytes and on a significant percentage of recruited monocytes. Most importantly, in both ex vivo and in vivo assays, neutralizing anti-MIG antibodies blocked monocyte binding to inflamed lymph node HEVs. Together, these results suggest that the lymph node microenvironment can dictate the nature of molecules expressed on HEV subsets in a TNF-dependent fashion and that inflammation-induced MIG expression by HEVs can mediate monocyte recruitment.

Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation.

Mice without secreted TNF but with functional, normally regulated and expressed membrane-bound TNF (memTNF(Delta/Delta) mice) were created by knocking-in the uncleavable Delta 1-9,K11E TNF allele. In contrast to TNF-deficient mice (TNF(-/-)), memTNF supported many features of lymphoid organ structure, except generation of primary B cell follicles. Splenic chemokine expression was near normal. MemTNF-induced apoptosis was mediated through both TNF-R1 and TNF-R2. That memTNF is suboptimal for development of inflammation was revealed in experimental autoimmune encephalomyelitis. Disease severity was reduced in memTNF(Delta/Delta) mice relative to wild-type mice, and the nature of spinal cord infiltrates resembled that in TNF(-/-) mice. We conclude that memTNF supports many processes underlying lymphoid tissue structure, but secreted TNF is needed for optimal inflammatory lesion development.

Lymphotoxin controls alphaEbeta7-integrin expression by peripheral CD8+ T cells.

Lymphotoxin (LT)-alpha, a member of the TNF family, is recognized as an important mediator in different aspects of lymphoid organ development. Targeted disruption of this molecule resulted in a substantial reduction in the proportion of alphaEbeta7-integrin(high) CD8+ T cells detectable in peripheral lymphoid organs. This defect, however, was not observed on mature CD4-CD8+ thymocytes. To determine whether this was due to downregulation of beta7-integrin expression by peripheral CD8+ T cells or a failure of thymic emigration of CD8+ beta7-integrin(high) T cells, beta7-integrin was examined on recent thymic emigrants (RTE). When analysed within 16 h after leaving the thymus CD4-CD8+ RTE in both LT-alpha-/- and wild type (wt) mice remained beta7-integrin(high) and were indistinguishable. However, within 3-5 days, emigration loss of beta7-integrin became evident in LT-alpha-/- mice. Despite this loss, the proportion of thymically derived alphabetaTCR+ T-cell populations in the intestinal epithelium, an important target tissue of CD8+ alphaEbeta7-integrin(high) T cells, was increased in the absence of LT-alpha. In contrast, B cells were detectable only rarely in the intestinal tissue of LT-alpha-/- mice. The expression of E-Cadherin remained unchanged. These results indicate that a LT-alpha-dependent process maintains a high level of alphaEbeta7-integrin expression by peripheral CD8+ T cells, and with this control mechanism LT-alpha may help to regulate CD8+ T-cell numbers in the tissues.

Recirculating and marginal zone B cell populations can be established and maintained independently of primary and secondary follicles.

In normal spleen, most recirculating naïve IgM+IgDhi B cells are located within primary follicles and mantle zones of secondary follicles. By contrast, the marginal zone contains a heterogeneous population of IgMhiIgDlo/- B cells that are mostly non-recirculating. Although these are dynamic populations they are maintained at a constant size, the fundamental homeostatic mechanisms remain uncertain. One possibility is that the presence and turnover of each of the B cell populations is dependent on their location within discrete splenic compartments. To investigate this, we have characterized immature, non-recirculating, mature recirculating, marginal zone and B-1 cell populations in TNF-/- and TNF/lymphotoxin(LT)-alpha-/- mice that have disorganized splenic architecture. Labelling with 5-bromo-2'-deoxyuridine revealed that turnover of B cells in TNF-/- mice is normal, but is diminished in TNF/LT-alpha-/- mice. The recirculating B cell populations in both mutant strains are normal in proportion and phenotype. Marginal zone B cells are not seen in TNF/LT-alpha-/- mice, but this population appears normal in TNF-/- mice, even though they lack germinal centres. These findings indicate that peripheral B cell subsets can be established and maintained independently of normal follicular architecture.

Down-regulation of the macrophage lineage through interaction with OX2 (CD200).

OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.

Experimental autoimmune cholangitis: a mouse model of immune-mediated cholangiopathy.

BACKGROUND: Primary biliary cirrhosis (PBC) is characterised by intra-hepatic immune-mediated cholangiopathy (non-suppurative destructive cholangitis (NSDC)). Although auto-reactive immune responses against pyruvate dehydrogenase complex (PDC) have been characterised in PBC, the lack of an animal model of the disease has limited study of the mechanisms of disease induction and the development of novel approaches to therapy. AIMS: To develop and validate a mouse model of immune-mediated cholangiopathy relevant for future use in the study of the aetio-pathogenesis and therapy of PBC. METHODS: Female SJL/J, C57BL/6, NOD and BALB/c mice were sensitised with PDC, its purified E2/E3BP component, and a PDC-E2 derived peptide p163 (a dominant T-cell epitope in humans) in complete Freund's adjuvant (CFA). Morphological changes were assessed under light microscopy by a hepatic histopathologist blinded to the experimental details. Antibody responses to PDC were studied by ELISA and PDC inhibition assay. RESULTS: An initial series of experiments was performed to survey the susceptibility of female mice of a range of strains to the induction of NSDC by i.p. sensitisation with PDC, PDC-E2/E3BP or p163 in CFA. Although each animal showed a specific antibody response following sensitisation, it was found that NSDC development (assessed at 30 weeks post-sensitisation) was restricted to SJL/J mice following sensitisation with any of the mitochondrial antigen preparations. A subsequent series of experiments was performed to examine the specificity and aetiology of this disease. Significant bile duct lesions were only seen in SJL/J animals following sensitisation with CFA containing PDC, and were absent from CFA only and un-sensitised controls. Kinetic analysis revealed that this pathology developed slowly, but a high incidence of animals with severe lesions was observed after 30 weeks. CONCLUSIONS: We have described a model of experimental autoimmune cholangitis (EAC) with immunological (anti-PDC antibodies) and histological (immune-mediated cholangiopathy) features suggestive of PBC. This model may be useful in further defining the role of self-tolerance breakdown in the development of this condition.

DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming.

DAP12 is an ITAM-bearing membrane adaptor molecule implicated in the activation of NK and myeloid cells. In mice rendered DAP12 deficient by targeted gene disruption, lymphoid and myeloid development was apparently normal, although the activating Ly49 receptors on NK cells were downregulated and nonfunctional. To analyze the consequences of DAP12 deficiency in vivo, we examined the susceptibility of DAP12-/- mice to experimental autoimmune encephalomyelitis (EAE). DAP12-/- mice were resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide. Resistance was associated with a strongly diminished production of IFNgamma by myelin-reactive CD4+ T cells due to inadequate T cell priming in vivo. These data suggest that DAP12 signaling may be required for optimal antigen-presenting cell (APC) function or inflammation.