Robust and persistent B-cell responses following SARS-CoV-2 vaccine determine protection from SARS-CoV-2 infection.

Introduction: A clear immune correlate of protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has not been defined. We explored antibody, B-cell, and T-cell responses to the third-dose vaccine and relationship to incident SARS-CoV-2 infection. Methods: Adults in a prospective cohort provided blood samples at day 0, day 14, and 10 months after the third-dose SARS-CoV-2 vaccine. Participants self-reported incident SARS-CoV-2 infection. Plasma anti-SARS-CoV-2 receptor-binding domain (RBD) and spike-subunit-1 and spike-subunit-2 antibodies were measured. A sub-study assessed SARS-CoV-2-specific plasma and memory B-cell and memory T-cell responses in peripheral blood mononuclear cells by enzyme-linked immunospot. Comparative analysis between participants who developed incident infection and uninfected participants utilised non-parametric t-tests, Kaplan-Meier survival analysis, and Cox proportional hazard ratios. Results: Of the 132 participants, 47 (36%) reported incident SARS-CoV-2 infection at a median 16.5 (16.25-21) weeks after the third-dose vaccination. RBD titres and B-cell responses, but not T-cell responses, increased after the third-dose vaccine. Whereas no significant difference in day 14 antibody titres or T-cell responses was observed between participants with and without incident SARS-CoV-2 infection, RBD memory B-cell frequencies were significantly higher in those who did not develop infection [10.0% (4.5%-16.0%) versus 4.9% (1.6%-9.3%), p = 0.01]. RBD titres and memory B-cell frequencies remained significantly higher at 10 months than day 0 levels (p < 0.01). Discussion: Robust antibody and B-cell responses persisted at 10 months following the third-dose vaccination. Higher memory B-cell frequencies, rather than antibody titres or T-cell responses, predicted protection from subsequent infection, identifying memory B cells as a correlate of protection.

Early inflammatory profiles predict maximal disease severity in COVID-19: An unsupervised cluster analysis.

Background: The inflammatory changes that underlie the heterogeneous presentations of COVID-19 remain incompletely understood. In this study we aimed to identify inflammatory profiles that precede the development of severe COVID-19, that could serve as targets for optimised delivery of immunomodulatory therapies and provide insights for the development of new therapies. Methods: We included individuals sampled <10 days from COVID-19 symptom onset, recruited from both inpatient and outpatient settings. We measured 61 biomarkers in plasma, including markers of innate immune and T cell activation, coagulation, tissue repair and lung injury. We used principal component analysis and hierarchical clustering to derive biomarker clusters, and ordinal logistic regression to explore associations between cluster membership and maximal disease severity, adjusting for known risk factors for severe COVID-19. Results: In 312 individuals, median (IQR) 7 (4-9) days from symptom onset, we found four clusters. Cluster 1 was characterised by low overall inflammation, cluster 2 was characterised by higher levels of growth factors and markers of endothelial activation (EGF, VEGF, PDGF, TGFα, PAI-1 and p-selectin). Cluster 3 and 4 both had higher overall inflammation. Cluster 4 had the highest levels of most markers including markers of innate immune activation (IL6, procalcitonin, CRP, TNFα), and coagulation (D-dimer, TPO), in contrast cluster 3 had the highest levels of alveolar epithelial injury markers (RAGE, ST2), but relative downregulation of growth factors and endothelial activation markers, suggesting a dysfunctional inflammatory pattern. In unadjusted and adjusted analysis, compared to cluster 1, cluster 3 had the highest odds of progressing to more severe disease (unadjusted OR (95%CI) 9.02 (4.53-17.96), adjusted OR (95%CI) 6.02 (2.70-13.39)). Conclusion: Early inflammatory profiles predicted subsequent maximal disease severity independent of risk factors for severe COVID-19. A cluster with downregulation of growth factors and endothelial activation markers, and early evidence of alveolar epithelial injury, had the highest risk of severe COVID-19.

Factors influencing medical students' decision to pursue a career in obstetrics and gynaecology.

INTRODUCTION: The career intentions of medical students can exert influence on service provision and medical staffing in the health services. It is vital for a specialty's development and sustainability that it has a constant stream of trainees into it annually. An appreciation of how a specialty is viewed by medical students can be used as an opportunity for early intervention in order to improve perception of the specialty and reduce future workforce problems, such as retention and attrition within obstetrics and gynaecology (O&G). We aimed to analyse positive and negative factors of the specialty of O&G as perceived by medical students in order to gain insight into changes that need to be made to improve recruitment and retention into the specialty. METHODS: A 70-item structured questionnaire consisting of demographic information and 5-point Likert scale questions relating to O&G was administered to final year medical students in the Republic of Ireland. Data were analysed with descriptive statistics, logistic regression, and odds ratios as appropriate. RESULTS: Of 195 medical students approached, 134 completed the questionnaire, a response rate of 68.7%. The majority were female (55.2%, n = 74) and 76.1% of respondents (n = 102) were Direct Entry Medicine students, with the remainder Graduate Entry Medicine students. 30.8% (n = 41) of students who responded scored 6 or more on a 10-point Likert scale when asked about their likelihood of considering a career in O&G. Students' clerkship experience factored heavily into their perception of the specialty and was more likely to be positive if they experienced direct consultant engagement and the opportunity for hands-on experience. Lifestyle factors, litigation and media were found to be deterrents to considering the specialty after graduation. CONCLUSIONS: This study demonstrates the importance of good clerkship experience in fostering an interest amongst undergraduates in O&G. Educators and those working within the specialty should showcase the strengths of the specialty during undergraduate education, and work on ameliorating deterrents to ultimately provide a structured approach to improving recruitment into O&G.

Distinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time.

SARS-CoV-2 neutralising antibodies provide protection against COVID-19. Evidence from early vaccine trials suggested binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether these thresholds predict sufficient neutralising capacity against variants of concern (VOCs), and whether this is impacted by vaccine or infection history remains unclear. Here we analyse individuals recovered from, vaccinated or with hybrid immunity against SARS-CoV-2. An NT50 ≥ 100 IU confers protection in vaccine trials, however, as VOC induce a reduction in NT50, we use NT50 ≥ 1000 IU as a cut off for WT NT50 that would retain neutralisation against VOC. In unvaccinated convalescent participants, a receptor binding domain (RBD) IgG of 456 BAU/mL predicts an NT50 against WT of 1000 IU with an accuracy of 80% (95%CI 73-86%). This threshold maintains accuracy in determining loss of protective immunity against VOC in two vaccinated cohorts. It predicts an NT50 < 100 IU against Beta with an accuracy of 80% (95%CI 67-89%) in 2 vaccine dose recipients. In booster vaccine recipients with a history of COVID-19 (hybrid immunity), accuracy is 87% (95%CI 77-94%) in determining an NT50 of <100 IU against BA.5. This analysis provides a discrete threshold that could be used in future clinical studies.

Development of a novel medium throughput flow-cytometry based micro-neutralisation test for SARS-CoV-2 with applications in clinical vaccine trials and antibody screening.

Quantifying neutralising capacity of circulating SARS-COV-2 antibodies is critical in evaluating protective humoral immune responses generated post-infection/post-vaccination. Here we describe a novel medium-throughput flow cytometry-based micro-neutralisation test to evaluate Neutralising Antibody (NAb) responses against live SARS-CoV-2 Wild Type and Variants of Concern (VOC) in convalescent/vaccinated populations. Flow Cytometry-Based Micro-Neutralisation Test (Micro-NT) was performed in 96-well plates using clinical isolates WT-B, WT-B.1.177.18 and/or VOCs Beta and Omicron. Plasma samples (All Ireland Infectious Diseases (AIID) Cohort) were serially diluted (8 points, half-log) from 1:20 and pre-incubated with SARS-CoV-2 (1h, 37°C). Virus-plasma mixture were added onto Vero E6 or Vero E6/TMPRSS2 cells for 18h. Percentage infected cells was analysed by automated flow cytometry following trypsinisation, fixation and SARS-CoV-2 Nucleoprotein intracellular staining. Half-maximal Neutralisation Titres (NT50) were determined using non-linear regression. Our assay was compared to Plaque Reduction Neutralisation Test (PRNT) and validated against the First WHO International Standard for anti-SARS-CoV-2 immunoglobulin. Both Micro-NT and PRNT achieved comparable NT50 values. Further validation showed adequate correlation with PRNT using a panel of secondary standards of clinical convalescent and vaccinated plasma samples. We found the assay to be reproducible through measuring both repeatability and intermediate precision. Screening 190 convalescent samples and 11 COVID-19 naive controls (AIID cohort) we demonstrated that Micro-NT has broad dynamic range differentiating NT50s <1/20 to >1/5000. We could also characterise immune-escape VOC Beta and Omicron BA.5, achieving fold-reductions in neutralising capacity similar to those published. Our flow cytometry-based Micro-NT is a robust and reliable assay to quantify NAb titres, and has been selected as an endpoint in clinical trials.

Robust cross-cohort gut microbiome associations with COVID-19 severity.

Although many recent studies have examined associations between the gut microbiome and COVID-19 disease severity in individual patient cohorts, questions remain on the robustness across international cohorts of the biomarkers they reported. Here, we performed a meta-analysis of eight shotgun metagenomic studies of COVID-19 patients (comprising 1,023 stool samples) and 23 > 16S rRNA gene amplicon sequencing (16S) cohorts (2,415 total stool samples). We found that disease severity (as defined by the WHO clinical progression scale) was associated with taxonomic and functional microbiome differences. This alteration in gut microbiome configuration peaks at days 7-30 post diagnosis, after which the gut microbiome returns to a configuration that becomes more similar to that of healthy controls over time. Furthermore, we identified a core set of species that were consistently associated with disease severity across shotgun metagenomic and 16S cohorts, and whose abundance can accurately predict disease severity category of SARS-CoV-2 infected subjects, with Actinomyces oris abundance predicting population-level mortality rate of COVID-19. Additionally, we used relational diet-microbiome databases constructed from cohort studies to predict microbiota-targeted diet patterns that would modulate gut microbiota composition toward that of healthy controls. Finally, we demonstrated the association of disease severity with the composition of intestinal archaeal, fungal, viral, and parasitic communities. Collectively, this study has identified robust COVID-19 microbiome biomarkers, established accurate predictive models as a basis for clinical prognostic tests for disease severity, and proposed biomarker-targeted diets for managing COVID-19 infection.

A qualitative review of challenges in recruitment and retention in obstetrics and gynecology in Ireland: The consultants' solution based perspective.

AIM: Recruitment and retention remains a concern in obstetrics and gynecology, with consultants having a unique perspective on the daily challenges. We aimed to examine these and examine their solutions to future-proofing the workforce. METHODS: Primary data were collected from consultant obstetrician-gynecologists in the Republic of Ireland. Using a qualitative methodology, semi-structured interviews were conducted with 17 participants recruited through purposive sampling. Following transcription, deductive content analysis was conducted to identify themes and categories with respect to challenges and solutions in the specialty. RESULTS: Findings revealed four superordinate themes of professional and personal factors, opinions of the specialty and the role of the consultant. Respondents expressed fear about low morale in the specialty, but also threats posed by resource availability and training limitations, in addition to medico-legal and media challenges. Solutions centered around re-evaluating training pathways and implementing improved advocacy and support structures for the specialty and for those working within it. CONCLUSIONS: This study provides a unique standpoint from which to explore an international in obstetrics and gynecology. Its solution-based outlook provides the framework to implement changes to protect and retain the current workforce as well as future-proofing recruitment to secure the specialty.

Impact of Long COVID on health and quality of life.

Background: The aim of this study was to measure the impact of post-acute sequelae of COVID-19 (PASC) on quality of life, mental health, ability to work and return to baseline health in an Irish cohort. Methods: We invited individuals with symptoms of COVID-19 lasting more than 14 days to participate in an anonymous online questionnaire. Basic demographic data and self-reported symptoms were recorded. Internationally validated instruments including the patient health questionnaire somatic, anxiety and depressive symptom scales (PHQ-SADS), the Patient Health Questionnaire-15 (PHQ-15) and Chadler fatigue scale (CFQ) were used. Results: We analysed responses from 988 participants with self-reported confirmed (diagnostic/antibody positive; 81%) or suspected (diagnostic/antibody negative or untested; 9%) COVID-19. The majority of respondents were female (88%), white (98%), with a median age of 43.0 (range 15 - 88 years old) and a median BMI of 26.0 (range 16 - 60). At the time of completing this survey, 89% of respondents reported that they have not returned to their pre-COVID-19 level of health. The median number of symptoms reported was 8 (range 0 to 33 symptoms), with a median duration of 12 months (range 1 to 20 months) since time of acute infection. A high proportion of PASC patients reported that they have a moderate or severe limitation in their ability to carry out their usual activities, 38% report their ability to work is severely limited and 33% report a moderate, or higher, level of anxiety or depression. Conclusion: The results of this survey of an Irish cohort with PASC are in line with reports from other settings, and we confirm that patients with PASC reported prolonged, multi-system symptoms which can significantly impact quality of life, affect ability to work and cause significant disability. Dedicated multidisciplinary, cross specialty supports are required to improve outcomes of this patient group.

A high-risk gut microbiota configuration associates with fatal hyperinflammatory immune and metabolic responses to SARS-CoV-2.

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and associated clinical sequelae requires well-coordinated metabolic and immune responses that limit viral spread and promote recovery of damaged systems. However, the role of the gut microbiota in regulating these responses has not been thoroughly investigated. In order to identify mechanisms underpinning microbiota interactions with host immune and metabolic systems that influence coronavirus disease 2019 (COVID-19) outcomes, we performed a multi-omics analysis on hospitalized COVID-19 patients and compared those with the most severe outcome (i.e. death, n = 41) to those with severe non-fatal disease (n = 89), or mild/moderate disease (n = 42), that recovered. A distinct subset of 8 cytokines (e.g. TSLP) and 140 metabolites (e.g. quinolinate) in sera identified those with a fatal outcome to infection. In addition, elevated levels of multiple pathobionts and lower levels of protective or anti-inflammatory microbes were observed in the fecal microbiome of those with the poorest clinical outcomes. Weighted gene correlation network analysis (WGCNA) identified modules that associated severity-associated cytokines with tryptophan metabolism, coagulation-linked fibrinopeptides, and bile acids with multiple pathobionts, such as Enterococcus. In contrast, less severe clinical outcomes are associated with clusters of anti-inflammatory microbes such as Bifidobacterium or Ruminococcus, short chain fatty acids (SCFAs) and IL-17A. Our study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection. These features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to SARS-CoV-2 and other infectious agents.

Development of a risk assessment profile tool to determine appropriate use of SARS-CoV-2 rapid antigen detection tests for different activities and events in Ireland, since October 2021.

We describe the development of a risk assessment profile tool that incorporates data from multiple domains to help determine activities and events where rapid antigen detection tests (Ag-RDT) could be used to screen asymptomatic individuals to identify infectious cases as an additional mitigation measure to reduce transmission of SARS-CoV-2. The tool aims to stratify, in real time, the overall risk of SARS-CoV-2 transmission associated with common activities and events, and this can be matched to an appropriate Ag-RDT testing protocol.

Seroprevalence study of SARS-CoV-2 antibodies in healthcare workers following the first wave of the COVID-19 pandemic in a tertiary-level hospital in the south of Ireland.

OBJECTIVE: This study investigated seroprevalence of SARS-CoV-2-specific IgG antibodies, using the Abbott antinucleocapsid IgG chemiluminescent microparticle immunoassay (CMIA) assay, in five prespecified healthcare worker (HCW) subgroups following the first wave of the COVID-19 pandemic. SETTING: An 800-bed tertiary-level teaching hospital in the south of Ireland. PARTICIPANTS: Serum was collected for anti-SARS-CoV-2 nucleocapsid IgG using the Abbott ARCHITECT SARS-CoV-2 IgG CMIA qualitative assay, as per the manufacturer's specifications.The groups were as follows: (1) HCWs who had real-time PCR (RT-PCR) confirmed COVID-19 infection (>1-month postpositive RT-PCR); (2) HCWs identified as close contacts of persons with COVID-19 infection and who subsequently developed symptoms (virus not detected by RT-PCR on oropharyngeal/nasopharyngeal swab); (3) HCWs identified as close contacts of COVID-19 cases and who remained asymptomatic (not screened by RT-PCR); (4) HCWs not included in the aforementioned groups working in areas determined as high-risk clinical areas; and (5) HCWs not included in the aforementioned groups working in areas determined as low-risk clinical areas. RESULTS: Six of 404 (1.49%) HCWs not previously diagnosed with SARS-CoV-2 infection (groups 2-5) were seropositive for SARS-CoV-2 at the time of recruitment into the study.Out of the 99 participants in group 1, 72 had detectable IgG to SARS-CoV-2 on laboratory testing (73%). Antibody positivity correlated with shorter length of time between RT-PCR positivity and antibody testing.Quantification cycle value on RT-PCR was not found to be correlated with antibody positivity. CONCLUSIONS: Seroprevalence of SARS-CoV-2 antibodies in HCWs who had not previously tested RT-PCR positive for COVID-19 was low compared with similar studies.

Microbial clues lead to a diagnosis of cystic fibrosis in late adulthood.

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder among Caucasian populations. The majority of CF cases are diagnosed in childhood; however, increasing numbers of adults are being diagnosed with the condition. We present the case of a 65-year-old Irish woman presenting with a chronic cough and a history of recurrent respiratory tract infections. Staphylococcus aureus, Scedosporium apiospermum and Stenotrophomonas maltophilia were grown from bronchoalveolar lavage raising suspicion for CF. Sweat testing was negative; however, genetic testing revealed the presence of ∆F508 and R117H CF mutations, the latter mutation conferring a milder form of CF. The patient commenced treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator medication ivacaftor to good effect. Novel CFTR potentiators and modulators have significant potential to benefit morbidity and mortality in this group. In this case, the microbiological results were key in pursuing genetic testing and diagnosing CF.

Implementing a National Approach to Research Ethics Review during a Pandemic - the Irish Experience.

The surge of coronavirus disease 2019 (COVID-19) research studies involving human participants in response to the pandemic has meant that research ethics committees across the world have been challenged to adapt their processes to meet demand while retaining high standards of review. Ethics review during this pandemic remains essential to ensure the safety, dignity and well-being of research participants, however research ethics committees are now faced with new, and often complex, ethics considerations and logistical challenges. This Open Letter looks specifically at the Irish experience of establishing a national approach to research ethics review amidst a global pandemic. This represents Ireland's first National Research Ethics Committee, which provided the research community with an expedited and 'single national opinion' for ethics review for COVID-related research. The insights gleaned and lessons learned from the Irish experience may inform emergency responses to future pandemics or public health emergencies.

Doctors' attitudes to, beliefs about, and experiences of the regulation of professional competence: a scoping review protocol.

BACKGROUND: Historically, individual doctors were responsible for maintaining their own professional competence. More recently, changing patient expectations, debate about the appropriateness of professional self-regulation, and high-profile cases of malpractice have led to a move towards formal regulation of professional competence (RPC). Such programmes require doctors to demonstrate that they are fit to practice, through a variety of means. Participation in RPC is now part of many doctors' professional lives, yet it remains a highly contested area. Cost, limited evidence of impact, and lack of relevance to practice are amongst the criticisms cited. Doctors' attitudes towards RPC, their beliefs about its objectives and effectiveness, and their experiences of trying to meet its requirements can impact engagement with the process. We aim to conduct a scoping review to map the empirical literature in this area, to summarise the key findings, and to identify gaps for future research. METHODS: We will conduct our review following the six phases outlined by Arksey and O'Malley, and Levac. We will search seven electronic databases: Academic Search Complete, Business Source Complete, CINAHL, PsycINFO, PubMed, Social Sciences Full Text, and SocINDEX for relevant publications, and the websites of medical regulatory and educational organisations for documents. We will undertake backward and forward citation tracking of selected studies and will consult with international experts regarding key publications. Two researchers will independently screen papers for inclusion and extract data using a piloted data extraction tool. Data will be collated to provide a descriptive summary of the literature. A thematic analysis of the key findings will be presented as a narrative summary of the literature. DISCUSSION: We believe that this review will be of value to those tasked with the design and implementation of RPC programmes, helping them to maximise doctors' commitment and engagement, and to researchers, pointing to areas that would benefit from further enquiry. This research is timely; internationally existing programmes are evolving, new programmes are being initiated, and many jurisdictions do not yet have programmes in place. There is an opportunity for learning across different programmes and from the experiences of established programmes. Our review will support that learning. SYSTEMATIC REVIEW REGISTRATION: PROSPERO does not register scoping reviews.

Impact of BCG vaccination on incidence of tuberculosis disease in southern Ireland.

BACKGROUND: Tuberculosis (TB) is the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Bacillus Calmette-Guerin (BCG) is the only licensed vaccine for TB, yet its efficacy remains debated with variations in vaccine sub-strains, policies, and practices observed across the world. Three BCG vaccination policies were implemented across adjoining regions in the South West of Ireland from 1972; neonatal vaccination (vaccinated Region-A), vaccination of children aged 10-12 years (vaccinated Region-B) and no vaccination (unvaccinated Region-C). The aim of this study is to examine the impact of different BCG vaccination policies on incidence of TB disease in the South of Ireland over a 13-year period. METHODS: Cases of active TB disease from 2003 to 2016 were identified through surveillance data. Residential addresses for each case were geocoded using the Google Maps API. Addresses were linked to 2011 census population data and to Local Health Offices BCG coverage data for study regions A-C. A steady-state population was assumed to calculate the 13-year incidence of TB disease. Using SatScan (v9.4.4), spatial clusters were identified at a small area level with the spatial scan statistic based on the discrete Poisson probability distribution. RESULTS: Of 621 TB disease cases identified, 510 could be linked to the study area based on the reported addresses. The median age was 42 years (range 4 months - 94 years), 65% male and 66% Irish born. The incidence of TB disease was higher in the unvaccinated population, region-C 132/100,000 (95% CI 116-150) versus vaccinated region-A 56/100,000 (95%CI 45-69) and region-B 44/100,000 (95%CI 29-63). A spatial cluster analysis identified a single high-risk cluster in region -C where the relative risk (vs. the areas outside of the cluster) was 4.94 (95% CI 4.03 to 5.96). CONCLUSION: Our study demonstrates significant regional variation in the incidence of TB in demographically similar populations based on BCG vaccination policy. This observation is particularly noteworthy in a country with low TB disease incidence such as Ireland. These findings strengthen existing data demonstrating efficacy of BCG vaccination for primary prevention of TB disease.

A national stakeholder consensus study of challenges and priorities for clinical learning environments in postgraduate medical education.

BACKGROUND: High quality clinical learning environments (CLE) are critical to postgraduate medical education (PGME). The understaffed and overcrowded environments in which many residents work present a significant challenge to learning. The purpose of this study was to develop a national expert group consensus amongst stakeholders in PGME to; (i) identify important barriers and facilitators of learning in CLEs and (ii) indicate priority areas for improvement. Our objective was to provide information to focus efforts to provide high quality CLEs. METHODS: Group Concept Mapping (GCM) is an integrated mixed methods approach to generating expert group consensus. A multi-disciplinary group of experts were invited to participate in the GCM process via an online platform. Multi-dimensional scaling and hierarchical cluster analysis were used to analyse participant inputs in regard to barriers, facilitators and priorities. RESULTS: Participants identified facilitators and barriers in ten domains within clinical learning environments. Domains rated most important were those which related to residents' connection to and engagement with more senior doctors. Organisation and conditions of work and Time to learn with senior doctors during patient care were rated as the most difficult areas in which to make improvements. CONCLUSIONS: High quality PGME requires that residents engage and connect with senior doctors during patient care, and that they are valued and supported both as learners and service providers. Academic medicine and health service managers must work together to protect these elements of CLEs, which not only shape learning, but impact quality of care and patient safety.