Background In 2009, England experienced an increase in serogroup W (MenW) invasive meningococcal disease (IMD) caused by the hypervirulent ST-11 clonal complex (MenW:cc11) South American strain sublineage. The ‘original UK strain’ that emerged in 2009 evolved into the ‘2013 strain’ in 2013 resulting in further increases in case numbers. Here, we compare demographics, co-morbidities, clinical characteristics and outcomes of patients with MenW IMD caused by the original UK, 2013, and other MenW strains during 2010-2019 in England. Methods The UK Health Security Agency (UKHSA) conducts enhanced national IMD surveillance in England and provides a national reference laboratory service for diagnosis confirmation and meningococcal characterisation. All confirmed cases are followed-up with general practitioners for additional information, including comorbidities, clinical presentation and outcomes. Results Between 2009/10 and 2018/2019 epidemiological years, there were 1,126 MenW IMD cases in England, of which 947 (84.1%) were confirmed by culture and 174 (15.9%) by PCR only. Cultured isolates were characterised as the original UK strain (n=361, 38.1%), 2013 strain (n=481, 50.8%), and other MenW strains (n=105, 11.1%). There were no significant differences in age, sex, risk factors, comorbidities, clinical presentation or intensive care requirement between MenW strain groups. For the cases between 2011-2017, clinical data analysis was performed. MenW IMD case fatality rate (CFR) was 12.7% (110/877) overall, but significantly higher for the 2013 strain (15.0%, 51/340) than for the original UK strain (9.8%, 30/305) for the 2013 strain and for other MenW strains (7.2%, 6/83) (p=0.05). In a multivariable logistic regression model, the 2013 strain, age ≥25 years compared to <5 year-olds and clinical presentation with septicaemia compared to other clinical presentations were independently associated with death. Implementation of an emergency adolescent MenACWY immunisation programme in 2015 was associated with large declines in MenW IMD cases and deaths across all age-groups. Conclusion The emergence of the original UK and 2013 MenW strains led to large increases in MenW IMD cases across all age groups and the latter was associated with higher case fatality. This has important implications for countries where the 2013 strain continues to circulate.

BACKGROUND:Asplenia and splenic dysfunction is associated with an increased risk of severe and fatal infections, especially due to encapsulated bacteria including Streptococcus pneumoniae, Haemophilus influenzae serotype b (Hib) and Neisseria meningitidis. People with sickle cell disease (SCD) develop recurrent splenic infarcts rendering them functionally asplenic. Consequently, additional vaccination against these three pathogens is recommended. There is robust evidence of an increased risk for invasive pneumococcal (IPD) and Hib disease, in people with SCD, but for not invasive meningococcal disease (IMD). METHODS:We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) recommendations. Studies published in any language before June 2024 and including people with SCD of all ages and from all geographical locations were included. Studies were included if they documented bacterial culture and/or PCR in patients with SCD with suspected infection. The primary outcome was to estimate IMD risk in people with SCD. Secondary outcomes included estimating the risk of IMD and Hib disease in people with SCD. FINDINGS:We identified 3804 publications and included 86 in the final analyses. Among 74 cohort studies published during 1971-2023, there were three IMD cases among 26,404 persons with SCD compared with 570 IPD and 113 Hib cases. Eight case-control studies published during 1983-2022 reported one IMD case among 932 people with SCD (0.1%) compared to 118 IMD cases among 7143 people without SCD (1.65%). In contrast, there were 126 IPD cases (126/932, 13.5%) in people with SCD compared to 588 (588/7143, 8.2%) in those without SCD. For Hib, the rates were 32/932 (3.4%) and 316/7143 (4.4%), respectively. After including all published studies, we identified five IMD cases in people with SCD across studies published worldwide during 1965-1995 and all five survived their infection. INTERPRETATION:We found no evidence of any increased risk of IMD in people with SCD. This has important implications for policymakers in countries and organisations that currently recommend meningococcal vaccination for people with SCD.

BACKGROUND:People living with HIV have been shown to have an increased risk of invasive meningococcal disease. In some countries, meningococcal vaccines are now routinely recommended to all people living with HIV, but no study has yet assessed the immunogenicity and safety of a meningococcal serogroup B vaccine or the co-administration of a MenB and MenACWY vaccine in people living with HIV.METHODS:This phase IV open-label clinical trial investigated the immunogenicity and safety of two doses of a four-component recombinant protein-based MenB vaccine (4CMenB) and a quadrivalent conjugate polysaccharide MenACWY vaccine (MenACWY-CRM197) given 1 month apart in a population of people living with HIV. Immunogenicity analysis was performed before vaccination and 1 month after the second doses of 4CMenB and MenACWY. Primary outcome measures were serum bactericidal assay geometric mean titres against three MenB reference strains at baseline and 1 month post vaccination, the proportion of participants achieving a putative protective titre of ≥4, and the proportion of participants with a ≥4-fold rise in titre from baseline. Secondary outcome measures were serum bactericidal assay geometric mean titres against MenA, C, W, and Y reference strains at baseline and 1 month post vaccination, the proportion achieving a putative protective titre of ≥8, and the proportion with a ≥4-fold rise in titre from baseline. Safety outcomes were solicited and unsolicited adverse events in the 7 days following vaccination. The trial was registered with clinicaltrials.gov (NCT03682939).FINDINGS:In total, 55 participants aged 20-45 years were enrolled. All participants (100%; 95% confidence interval [CI] 93-100) achieved putative protective titres for two of the three MenB strains and for MenA, W, and Y. A total of 98% (95% CI 89-100) achieved a protective titre for the third MenB strain and 94% (95% CI 83-99) for MenC. No serious adverse events were reported.INTERPRETATION:4CMenB and MenACWY were immunogenic and well-tolerated in a population of people living with HIV 1 month after two doses.

BACKGROUND:People living with HIV have an increased risk of meningococcal disease. The Propositive trial evaluated co-administration of two doses of a four-component recombinant protein-based MenB vaccine (4CMenB) and a quadrivalent conjugate polysaccharide MenACWY vaccine (MenACWY-CRM197) given 1 month apart in people with HIV. The follow-up trial assessed the immunogenicity of these vaccines at 1.5 and 2.5 years after primary vaccination. METHODS:Participants who completed the parent Propositive trial were invited to the follow-up study. Immunogenicity analysis was performed at 18 and 30 months after primary vaccination. Primary outcome measures were serum bactericidal antibody (SBA) geometric mean titres (GMTs) against three MenB reference strains and the proportion of participants maintaining a protective SBA titre of ≥4 at 18 and 30 months. Secondary outcome measures were SBA GMTs against MenA, C, W, and Y serogroups and the proportion of participants maintaining a protective SBA titre of ≥8 at 18 and 30 months. The trial is registered with Clinicaltrials.gov (NCT042394300). RESULTS:A total of 40 participants aged 22-47 years were enrolled. Geometric mean titres waned by 18 and 30 months but remained higher than pre-vaccination for all MenB strains and MenA, C, W, and Y. In total, 75%-85% of participants retained protective SBA titres by 30 months against individual MenB strains, whereas 68.8% of patients retained protective antibody titres against all three MenB strains. Antibodies against MenC waned more rapidly than did those against MenA, W, and Y. The proportion of participants with protective titres against MenC at 30 months was also lower (46.9%) than that with protective titres against MenA (87.5%), W (78.1%), and Y (87.5%). CONCLUSIONS:Immune responses against MenB in our cohort of people living with HIV at 2.5 years of follow-up were reassuring, with 68.8% of participants retaining protection against all three reference strains. However, responses against MenC were lower than those against MenA, W, and Y serogroups.

Group B Streptococcus (GBS) is a leading cause of adverse pregnancy outcomes due to invasive infection. This study investigated longitudinal variation in GBS rectovaginal colonization, serum and vaginal GBS capsular polysaccharide (CPS)-specific antibody levels. Non-pregnant women were recruited in the UK and were sampled every 2 weeks over a 12-week period. GBS isolates were taken from recto-vaginal swabs and serotyped by polymerase chain reaction. Serum and vaginal immunoglobulin G (IgG) and nasal immunoglobulin A (IgA) specific to CPS were measured by Luminex, and total IgG/A by ELISA. Seventy women were enrolled, of median age 26. Out of the 66 participants who completed at least three visits: 14/47 (29.8%) women that were GBS negative at screening became positive in follow-up visits and 16/19 (84.2%) women who were GBS positive at screening became negative. There was 50% probability of becoming negative 36 days after the first positive swab. The rate of detectable GBS carriage fluctuated over time, although serum, vaginal, and nasal CPS-specific antibody levels remained constant. Levels of CPS-specific antibodies were higher in the serum of individuals colonized with GBS than in non-colonized, but similar in the vaginal and nasal mucosa. We found correlations between antibody levels in serum and the vaginal and nasal mucosa. Our study demonstrates the feasibility of elution methods to retrieve vaginal and nasal antibodies, and the optimization of immunoassays to measure GBS-CPS-specific antibodies. The difference between the dynamics of colonization and antibody response is interesting and further investigation is required for vaccine development.

Horseradish peroxidase (HRP) was implanted in one maxillary canine of cats and the transganglionic transport to the brain stem studied and mapped. HRP-positive fibers and terminal granules are distributed ipsilaterally to each subdivision of the trigeminal complex but are heaviest in the main sensory nucleus, adjacent pars oralis and pars interpolaris near obex with somewhat less in the rest of pars oralis and least in pars caudalis. The distribution indicates a wider central representation than previous anatomical reports and corresponds well with certain physiological studies.

Meningococcal disease remains one of the most feared infectious diseases worldwide because of its sudden onset, rapid progression and high case fatality rates, while survivors are often left with severe long-term sequelae. Young children have the highest incidence of invasive meningococcal disease (IMD), and nearly all cases in the UK, as in most of Europe and many other industrialised countries, are due to group B meningococci (MenB). The licensure of a broad-coverage, recombinant protein-based MenB vaccine (4CMenB) in 2013 was, therefore, heralded a major breakthrough in the fight against IMD. This vaccine was, however, licensed on immunogenicity and reactogenicity studies only, raising uncertainties about field effectiveness, long--term safety and antibody persistence. In 2015, the UK became the first country to implement 4CMenB into the national infant immunisation schedule and, since then, several countries have followed suit. Seven years after licensure, a wealth of real-world data has emerged to confirm 4CMenB effectiveness, along with large-scale safety data, duration of protection in different age groups, successful strategies to reduce vaccine reactogenicity, impact on carriage in adolescents and the potential for 4CMenB to protect against other meningococcal serogroups and against gonorrhoea. A number of questions, however, remain unanswered, including the investigation and management of vaccine-associated fever in infants, as well as disease severity and assessment of breakthrough cases in immunised children. Increasing use of 4CMenB will provide answers in due course. We now have vaccines against all the major serogroups causing IMD worldwide. Next-generation and combination vaccines against multiple serogroups look very promising.

Syphilis infection in pregnancy is known to cause a number of severe adverse pregnancy outcomes, including second-trimester miscarriage, stillbirth, very pre-term delivery and neonatal death, in addition to congenital syphilis. A retrospective review of women with positive syphilis serology and a pregnancy outcome between 2005 and 2012 in Leeds, UK, was performed. In all, 57 cases of positive syphilis serology in pregnancy were identified: 24 with untreated syphilis treated in the current pregnancy (Group 1); seven with reported but unconfirmed prior treatment who were retreated (Group 2); and 26 adequately treated prior to pregnancy (Group 3). The rate of severe adverse pregnancy outcomes in Group 1 at 21% was significantly higher than the 0% outcome of Group 3 (p=0.02). The severe adverse pregnancy outcomes were two second-trimester miscarriages, two pre-term births at 25 and 28 weeks and one stillbirth at 32 weeks. There were no cases of term congenital syphilis or term neonatal death, but we observed high rates of other adverse pregnancy outcomes despite treatment during pregnancy. Rapid referral for treatment is needed before 18 weeks in order to minimise adverse pregnancy outcomes.

The 2008 UK syphilis guideline recommends infants born to women with any positive syphilis serology be followed up until both treponemal and nontreponemal tests are negative to exclude congenital syphilis, whereas Centers for Disease Control and Prevention guidelines recommend using only nontreponemal tests. Historically, we had low infant follow-up rates with no coherent pathways. We initiated a change in multidisciplinary team practice of infant testing for syphilis in 2011 and evaluated the results before and after by retrospective review of testing of infants born to women with positive syphilis serology between 2005 and 2012. A total of 28 infants' mothers were treated in pregnancy (termed high risk'); 26 had adequate treatment prior to pregnancy (termed low risk'). There was a significant increase in serological testing after 2011 compared with before (83% versus 48%; OR 5.07 [95% CI 1.22-22.77] p=0.01) but mainly in low risk infants with no significant improvement in high risk infants who are the priority group. Using nontreponemal tests only in the infants would have reduced the tests required by at least 50%, allowing health resources to be concentrated on achieving adequate follow-up for those infants most at risk.

OBJECTIVES:Skin graft failure is a recognised complication in the treatment of major burns. Little research to date has analysed the impact of the complex physiological management of burns patients on the success of skin grafting. We analysed surgical and anaesthetic variables to identify factors contributing to graft failure.METHODS:Inclusion criteria were admission to our Burns Intensive Care Unit (BICU) between January 2009 and October 2013 with a major burn. After exclusion for death before hospital discharge or prior skin graft at a different hospital, 35 patients remained and were divided into those with successful autografts (n=16) and those with a failed autograft (n=19). For the purposes of this study, we defined poor autograft viability as requiring at least one additional skin graft to the same site. Logistic regression of variables was performed using SPSS (Version 22.0 IBMTM).RESULTS:Age, Sex, %Total Burn Surface Area or Belgian Outcome Burns Injury score did not significantly differ between groups. No differences were found in any surgical factor at logistic regression (graft site, harvest site, infection etc.). When all operations were analysed, the use of colloids was found to be significantly associated with graft failure (p=0.035, CI 95%) and this remained significant when only split thickness skin grafts (STSGs) and debridement operations were included (p=0.034, CI 95%). No differences were found in crystalloid use, intraoperative temperature, pre-operative haemoglobin and blood products or vasopressor use.CONCLUSIONS:This analysis highlights an independent association between colloids and graft failure which has not been previously documented.

Recent editorials have discussed whether patients with burns require tracheal intubation 1, and the size of tracheal tube for those requiring intensive care generally 2. We wish to raise the issue of tracheal tube size for patients with burns in whom intubation is indicated. Patients admitted to a burns intensive care unit (BICU) often require bronchoscopy for the diagnosis and staging of airway burns, with subsequent therapeutic bronchoscopy for clearance of secretions. This is a key part of their specialist management. In order to perform bronchoscopy in these patients, a tracheal tube size of at least 8.0 mm internal diameter is required. A 7.0-mm tube does not allow the passage of a standard bronchoscope, whilst a tracheal tube with a 7.5-mm internal diameter allows passage of the bronchoscope but makes positive pressure ventilation difficult. Smaller bronchoscopes are available but these do not provide equivalent imaging or therapeutic efficacy. Therefore an 8.0-mm tracheal tube is the minimal size for safe and effective bronchoscopy. A recent study from an Australian BICU by Cheung et al. 3 found no significant differences in swallowing outcomes at 12 months in patients whose tracheas were intubated with 8.0-mm tracheal tubes, compared with those in whom smaller tubes were used. This suggests that the benefits to burns patients in the short to medium terms outweigh the risks of long-term complications. Anecdotally, we have noticed a trend at our Regional Burns Unit towards the use of smaller tracheal tubes (frequently size 7.0) in patients transferred from other sites. This practice has required exchange of the tracheal tube immediately after the patient's arrival, in order to allow diagnostic and therapeutic bronchoscopy. As part of a service evaluation, we are in the process of collating these data. Often, these patients arrive several hours after the initial injury, which means that the tube exchange has to be performed after airway swelling has begun. This exposes the patient to risks that could be prevented if an adequately-sized tube was inserted in the first instance. If patients require immediate surgery on arrival at our unit, the tracheal tube exchange may be delayed, by which time it may be impossible due to facial or airway swelling. This can result in patients’ being significantly disadvantaged for several days (or even weeks) while the swelling subsides. Because of the problems highlighted above, we would like to suggest consideration of the following when managing patients in need of BICU care: first, a tracheal tube of internal diameter 8.0 mm or more (if possible and if tracheal intubation is required); and second, maintainance of the head-up position (if possible), as this limits facial oedema. These steps would facilitate bronchoscopic assessment and treatment of inhalation injury.

Mycotoxins are toxic secondary metabolites that globally contaminate an estimated 25 % of cereal crops and thus exposure is frequent in many populations. Aflatoxins, fumonisins and deoxynivalenol are amongst those mycotoxins of particular concern from a human health perspective. A number of risks to health are suggested including cancer, growth faltering, immune suppression and neural tube defects; though only the demonstrated role for aflatoxin in the aetiology of liver cancer is widely recognised. The heterogeneous distribution of mycotoxins in food restricts the usefulness of food sampling and intake estimates; instead biomarkers provide better tools for informing epidemiological investigations. Validated exposure biomarkers for aflatoxin (urinary aflatoxin M(1), aflatoxin-N7-guaunine, serum aflatoxin-albumin) were established almost 20 years ago and were critical in confirming aflatoxins as potent liver carcinogens. Validation has included demonstration of assay robustness, intake v. biomarker level, and stability of stored samples. More recently, aflatoxin exposure biomarkers are revealing concerns of growth faltering and immune suppression; importantly, they are being used to assess the effectiveness of intervention strategies. For fumonisins and deoxynivalenol these steps of development and validation have significantly advanced in recent years. Such biomarkers should better inform epidemiological studies and thus improve our understanding of their potential risk to human health.