Qualitative interview study exploring the perspectives of pregnant women on participating in controlled human infection research in the UK.

INTRODUCTION: Pregnant women have been historically excluded from interventional research. While recent efforts have been made to improve their involvement, there remains a disparity in the evidence base for treatments available to pregnant women compared with the non-pregnant population. A significant barrier to the enrolment of pregnant women within research is risk perception and a poor understanding of decision-making in this population. OBJECTIVE: Assess the risk perception and influences on decision-making in pregnant women, when considering whether to enrol in a hypothetical interventional research study. DESIGN: Semistructured interviews were undertaken, and thematic analysis was undertaken of participant responses. PARTICIPANTS: Twelve pregnant women were enrolled from an antenatal outpatient clinic. RESULTS: Participants were unanimously positive about enrolling in the proposed hypothetical interventional study. Risk perception was influenced by potential risks to their fetus and their previous experiences of healthcare and research. Participants found the uncertainty in quantifying risk for new research interventions challenging. They were motivated to enrol in research by altruism and found less invasive research interventions more tolerable. CONCLUSION: It is vital to understand how pregnant women balance the perceived risks and benefits of interventional research. This may help clinicians and scientists better communicate risk to pregnant women and address the ongoing under-representation of pregnant women in interventional research.

A Questionnaire-based Study Exploring Participant Perspectives in a Perinatal Human Challenge Trial.

BACKGROUND: Pregnant women have historically been excluded from most medical research, including human challenge studies. The proof-of-concept Lactamica 9 human challenge study investigated whether nasal inoculation of pregnant women with commensal bacteria leads to horizontal transmission to the neonate. Given the unique practical and ethical considerations of both human challenge studies and interventional research involving pregnant women and their newborns, we sought to investigate the motivations, concerns and experiences of these volunteers. METHODS: Pre- and post-participation questionnaires were given to all participants in the Lactamica 9 study. These fully anonymized qualitative and Semi-quantitative questionnaires used forced Likert scales, word association and free-text questions. RESULTS: Pre- and post-participation questionnaires were completed by 87.1% (27/31) and 62.5% (15/24) of eligible participants, respectively. Almost all pre-participation respondents agreed with altruistic motivations for participation, and most concerns were related to discomfort from study procedures, with few concerned about the theoretical risks of inoculation to themselves (5/27; 18.5%) or their baby (6/27; 22.2%). Participants most frequently associated the study intervention with the terms "bacteria," "natural," "protective" and "safe." For the post-participation questionnaire, 93.3% (14/15) found all study procedures acceptable, and qualitative feedback was almost entirely positive, with particular emphasis on the research team's flexibility, approachability and friendliness. CONCLUSIONS: The successful completion of the Lactamica 9 study demonstrates that human challenge research in healthy pregnant women can be acceptable and feasible. Participants' initial concerns of potential discomfort were outweighed by predominantly altruistic motivations and perception of the intervention as "natural."

Managing challenges in congenital CMV: current thinking.

Congenital human cytomegalovirus (CMV) infection is the most common congenital infection, affecting around 1 in 200 infants in high-income settings. It can have life-long consequences for up to one in four children, including sensorineural hearing loss and neurodisability. Despite the frequency of congenital CMV and the severity for some children, it is a little-known condition by pregnant women, families and healthcare providers. Timely diagnosis of CMV infection in pregnancy is important to facilitate consideration of treatment with valaciclovir, which may reduce the risk of transmission to the fetus or reduce the severity of the outcomes for infected infants. Recognition of features of congenital CMV is important for neonatologists, paediatricians and audiologists to prompt testing for congenital CMV within the first 21 days of life. Early diagnosis gives the opportunity for valganciclovir treatment, where appropriate, to improve outcomes for affected infants. Further research is urgently needed to inform decisions about antenatal and neonatal screening, long-term outcomes for asymptomatic and symptomatic infants, predictors of these outcomes and optimal treatment for women and infants.

Improving uptake of vaccines in pregnancy: A service evaluation of an antenatal vaccination clinic at a tertiary hospital in the UK.

BACKGROUND: Vaccination against pertussis and seasonal influenza is recommended for all pregnant women in the UK. More recently COVID-19 vaccination has also been offered to women in pregnancy. OBJECTIVES: To evaluate the uptake of vaccines in pregnant women within a midwife-led immunisation clinic and to assess factors influencing pregnant women's decisions about accepting vaccination. METHODS: Uptake of vaccines amongst pregnant women referred to a single UK centre for antenatal care between 01/01/19 and 02/10/19 was assessed. Interviews with 20 pregnant women explored views of antenatal vaccination and experiences of the vaccination service. FINDINGS: Amongst 4420 women, uptake was 90.6% for pertussis and 78.8% for influenza vaccines. Factors influencing vaccine-related decision-making amongst 20 interviewed women were: healthcare professional recommendation, perceived susceptibility and risk of infection, and previous experience of vaccination and vaccine-preventable disease. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Uptake of pertussis and influenza vaccines within a secondary care immunisation service was higher than the national or regional average. The model of vaccine delivery was associated with high levels of satisfaction. This model of vaccine delivery could be implemented elsewhere to increase vaccine uptake, and should be considered for delivery of COVID-19 vaccines in the future.

Manipulating the infant respiratory microbiomes to improve clinical outcomes: A review of the literature.

BACKGROUND: The association between infant respiratory microbiota and disease (including respiratory tract infections and asthma) is increasingly recognised, although the mechanism remains unclear. Respiratory infections and asthma account for a large proportion of infant morbidity and mortality, so the possibility of preventing disease or modifying clinical outcomes by manipulating microbiome development warrants investigation. OBJECTIVES AND METHODS: We identified studies that investigated the efficacy of live bacteria (probiotics or human challenge) or their substrates to modify respiratory colonisation or clinical outcomes in infants. ELIGIBILITY CRITERIA: Interventional studies involving infants under one year of age, administration of live bacteria or their substrates, and outcome measures including bacterial colonisation, microbiome profile, or respiratory disease phenotypes. RESULTS AND LIMITATIONS: Some bacterial interventions can reduce infant respiratory infections, although none have been shown to reduce asthma incidence. The literature is heterogeneous in design and quality, precluding meaningful meta-analysis. CONCLUSIONS: Upper respiratory tract infant microbiome manipulation may alter outcomes in respiratory tract infection, but further well-conducted research is needed to confirm this. Improved regulation of proprietary bacterial products is essential for further progress.

Influenza vaccination: protecting the most vulnerable.

Influenza virus infection causes seasonal epidemics and occasional pandemics, leading to huge morbidity and mortality worldwide. Vaccination against influenza is needed annually as protection from constantly mutating strains is required. Groups at high risk of poor outcomes include the elderly, the very young, pregnant women and those with chronic health conditions. However, vaccine effectiveness in the elderly is generally poor due to immunosenescence and may be altered due to "original antigenic sin". Strategies to overcome these challenges in the elderly include high-dose or adjuvant vaccines. Other options include vaccinating healthcare workers and children as this reduces community-level influenza transmission. Current guidelines in the UK are that young children receive a live attenuated nasal spray vaccine, adults aged >65 years receive an adjuvanted trivalent inactivated vaccine and adults aged <65 years with comorbidities receive a quadrivalent inactivated vaccine. The goal of a universal influenza vaccine targeting conserved regions of the virus and avoiding the need for annual vaccination is edging closer with early-phase trials under way.

The infant pharyngeal microbiomes: origin, impact and manipulation.

PURPOSE OF REVIEW: There has been an exponential increase in research into infant microbiome evolution, and it appears that pharyngeal microbiota are associated with clinical phenotypes (e.g. infection and asthma). Although broad consensus views are emerging, significant challenges and uncertainties remain. RECENT FINDINGS: Infant pharyngeal microbiome research is limited by low biomass, high temporal diversity and lack of agreed standards for sampling, DNA sequencing and taxonomic reporting. Analysis of amplicon sequence variants and improved cost and availability of whole-genome sequencing are promising options for improving taxonomic resolution of such studies. Infant respiratory microbiomes arise, at least in part, from maternal flora (e.g. the respiratory tract and breastmilk), and are associated with environmental and clinical factors (e.g. mode of feeding and delivery, siblings, daycare attendance, birth season and antibiotic usage). Interventional research to modify the infant pharyngeal microbiota has recently been reported, using dietary supplements. SUMMARY: Further work is needed to improve characterization of the infant pharyngeal microbiomes, including routes of bacterial acquisition, role of environmental factors and associations with disease phenotypes. Methodological standards are desirable to facilitate more reproducible, comparable research. Improved understanding may enable manipulation of infant pharyngeal microbiota to improve clinical outcomes.

Neuroinflammation in dementia with Lewy bodies: a human post-mortem study.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). It is now established that cerebral inflammation has a key role in the aetiology and progression of AD, but this has yet to be confirmed in DLB. We aimed to determine the neuroinflammatory profile in the cerebral cortex of a large cohort of DLB cases. Thirty post-mortem confirmed DLB cases and twenty-nine matched controls were immunolabelled (Brodmann area 21) and quantified for: neuropathology-αSYN, Aß, P-tau; microglial phenotype-Iba1, HLA-DR, CD68, FcÆ´R (CD64, CD32a, CD32b, CD16); presence of T lymphocytes-CD3; and anti-inflammatory markers-IL4R, CHI3L1. Status spongiosis, as a marker of neuropil degeneration, was quantified using Haematoxylin and Eosin staining. We found no significant difference between groups in protein load for Iba1, HLA-DR, CD68, CD64, CD32b, IL4R, or CHI3L1, despite increased neuropathology in DLB. CD32a load was significantly lower, and CD16 load higher, in DLB compared with controls. There was no difference in status spongiosis between groups. Significantly more DLB cases than controls showed T-lymphocyte recruitment. Overall, we conclude that microglial activation is not a prominent feature of DLB, and that this may be associated with the relatively modest neuropil degeneration observed in DLB. Our findings, based on the largest post-mortem cohort to date exploring neuroinflammation in DLB, demonstrate a dissociation between protein deposition, neurodegeneration and microglial activation. The relative preservation of cortical structures in DLB suggests the dementia could be more amenable to potential therapies.

High frequency of paediatric facial nerve palsy due to Lyme disease in a geographically endemic region.

INTRODUCTION: Idiopathic facial nerve palsy (FNP) is an uncommon but important presentation in children, with Lyme disease known to be a common cause. The UK county of Hampshire is a high incidence area of Lyme disease. We conducted a retrospective review of the investigation and management of paediatric FNP at a large University hospital, including serologic testing and treatment of Lyme disease. METHODS: We conducted a retrospective chart review of children under 18 presenting between January 1st, 2010 and December 31st, 2017 with a diagnosis of FNP. Patients with clear non-Lyme aetiology at presentation were excluded. Data was collected on demographics, initial presentation, investigations including Lyme serology, and management. RESULTS: A total of 93 children were identified, with an even proportion of male to female and median age 9.3 years (IQR 4.6-12 years). A history of rash was present in 5.4%, tick bite in 14% and recent travel to, or residence in the New Forest in 22.6%. Lyme serology was performed in 81.7% of patients, of which 29% were positive. Antibiotics were prescribed for 73.1% of patients, oral steroids for 44% and aciclovir for 17.2%. CONCLUSION: Lyme disease is a significant cause of FNP in this endemic area of the UK, and there was a large degree of variability in management prior to national guideline publication. Areas with endemic Lyme disease should consider introducing local guidelines supporting routine investigation and management for FNP, including empiric treatment for Lyme disease in accordance with NICE guidelines to improve care and reduce variability.

The nonpathogenic commensal Neisseria: friends and foes in infectious disease.

PURPOSE OF REVIEW: Nonpathogenic commensal Neisseria are rarely considered in the clinical setting despite evidence that they can cause invasive opportunistic infections. In contrast, they may offer protection against pathogenic Neisseria, and such relationships are being actively explored in experimental studies. RECENT FINDINGS: Recent case reports are presented of invasive infection caused by nonpathogenic Neisseria in patients on novel biologic therapies. On the other hand, Neisseria lactamica, a nonpathogenic commensal, has been shown in human challenge studies to inhibit colonization by Neisseria meningitidis. Experimental mouse models have also explored the inhibitory effects of nonpathogenic Neisseria on Neisseria gonnhoreae infection. Cutting-edge advances in metagenomics and microbiomics are being used to understand the mechanisms underpinning these effects. SUMMARY: Clinicians should have increased awareness of nonpathogenic Neisseria. First, as new immunomodulating therapies become licenced, the interactions that maintain balance between commensals and their human hosts may be altered. Second, these bacteria are showing promise in their capacity to exclude pathogenic Neisseria species from their anatomical niches.