Development and validation of a simplified risk prediction model for preterm birth: a prospective cohort study in rural Ethiopia.

Preterm birth is one of the most common obstetric complications in low- and middle-income countries, where access to advanced diagnostic tests and imaging is limited. Therefore, we developed and validated a simplified risk prediction tool to predict preterm birth based on easily applicable and routinely collected characteristics of pregnant women in the primary care setting. We used a logistic regression model to develop a model based on the data collected from 481 pregnant women. Model accuracy was evaluated through discrimination (measured by the area under the Receiver Operating Characteristic curve; AUC) and calibration (via calibration graphs and the Hosmer-Lemeshow goodness of fit test). Internal validation was performed using a bootstrapping technique. A simplified risk score was developed, and the cut-off point was determined using the "Youden index" to classify pregnant women into high or low risk for preterm birth. The incidence of preterm birth was 19.5% (95% CI:16.2, 23.3) of pregnancies. The final prediction model incorporated mid-upper arm circumference, gravidity, history of abortion, antenatal care, comorbidity, intimate partner violence, and anemia as predictors of preeclampsia. The AUC of the model was 0.687 (95% CI: 0.62, 0.75). The calibration plot demonstrated a good calibration with a p-value of 0.713 for the Hosmer-Lemeshow goodness of fit test. The model can identify pregnant women at high risk of preterm birth. It is applicable in daily clinical practice and could contribute to the improvement of the health of women and newborns in primary care settings with limited resources. Healthcare providers in rural areas could use this prediction model to improve clinical decision-making and reduce obstetrics complications.

One Health surveillance of colistin-resistant Enterobacterales in Belgium and the Netherlands between 2017 and 2019.

BACKGROUND: Colistin serves as the last line of defense against multidrug resistant Gram-negative bacterial infections in both human and veterinary medicine. This study aimed to investigate the occurrence and spread of colistin-resistant Enterobacterales (ColR-E) using a One Health approach in Belgium and in the Netherlands. METHODS: In a transnational research project, a total of 998 hospitalized patients, 1430 long-term care facility (LTCF) residents, 947 children attending day care centres, 1597 pigs and 1691 broilers were sampled for the presence of ColR-E in 2017 and 2018, followed by a second round twelve months later for hospitalized patients and animals. Colistin treatment incidence in livestock farms was used to determine the association between colistin use and resistance. Selective cultures and colistin minimum inhibitory concentrations (MIC) were employed to identify ColR-E. A combination of short-read and long-read sequencing was utilized to investigate the molecular characteristics of 562 colistin-resistant isolates. Core genome multi-locus sequence typing (cgMLST) was applied to examine potential transmission events. RESULTS: The presence of ColR-E was observed in all One Health sectors. In Dutch hospitalized patients, ColR-E proportions (11.3 and 11.8% in both measurements) were higher than in Belgian patients (4.4 and 7.9% in both measurements), while the occurrence of ColR-E in Belgian LTCF residents (10.2%) and children in day care centres (17.6%) was higher than in their Dutch counterparts (5.6% and 12.8%, respectively). Colistin use in pig farms was associated with the occurrence of colistin resistance. The percentage of pigs carrying ColR-E was 21.8 and 23.3% in Belgium and 14.6% and 8.9% in the Netherlands during both measurements. The proportion of broilers carrying ColR-E in the Netherlands (5.3 and 1.5%) was higher compared to Belgium (1.5 and 0.7%) in both measurements. mcr-harboring E. coli were detected in 17.4% (31/178) of the screened pigs from 7 Belgian pig farms. Concurrently, four human-related Enterobacter spp. isolates harbored mcr-9.1 and mcr-10 genes. The majority of colistin-resistant isolates (419/473, 88.6% E. coli; 126/166, 75.9% Klebsiella spp.; 50/75, 66.7% Enterobacter spp.) were susceptible to the critically important antibiotics (extended-spectrum cephalosporins, fluoroquinolones, carbapenems and aminoglycosides). Chromosomal colistin resistance mutations have been identified in globally prevalent high-risk clonal lineages, including E. coli ST131 (n = 17) and ST1193 (n = 4). Clonally related isolates were detected in different patients, healthy individuals and livestock animals of the same site suggesting local transmission. Clonal clustering of E. coli ST10 and K. pneumoniae ST45 was identified in different sites from both countries suggesting that these clones have the potential to spread colistin resistance through the human population or were acquired by exposure to a common (food) source. In pig farms, the continuous circulation of related isolates was observed over time. Inter-host transmission between humans and livestock animals was not detected. CONCLUSIONS: The findings of this study contribute to a broader understanding of ColR-E prevalence and the possible pathways of transmission, offering insights valuable to both academic research and public health policy development.

The DAWN antivirals trial: process evaluation of a COVID-19 trial in general practice.

BACKGROUND: The DAWN antivirals trial was a multicentric, randomised placebo-controlled trial evaluating antiviral medication for COVID-19 in general practice. The trial was prematurely terminated because of insufficient recruitment. AIM: To explore which factors contributed to the premature termination. DESIGN & SETTING: General practice in Belgium. METHOD: Patients were randomised to camostat or placebo (patients and physicians blinded) between June 2021 and July 2022; a third arm evaluating molnupiravir (open label) was opened in March 2022. The outcome assessor was blinded for all comparisons except for the patient reported outcomes in case of molnupiravir. The authors analysed available trial data and evaluated trial context, implementation, and mechanisms of impact based on semi-structured interviews with trial stakeholders. RESULTS: The trial recruited 44 participants; 19 were allocated to camostat (median age 55 years), 8 to molnupiravir (median age 60 years), and 17 to placebo (median age 56 years). There were no serious adverse events in either group. Most difficulties were related to the pandemic context: disruption to routine clinical services; multiple changes to the service model for COVID-19 patients; overwhelmed clinical staff; delays of trial medication; and staff shortages in the sponsor and clinical team. In addition, regulatory approval processes were lengthy and led to additional study procedures. It was felt that the trial started too late, when vaccinations had already begun. CONCLUSION: The DAWN antivirals trial was stopped prematurely. Although many barriers were related to the pandemic itself, hurdles such as a small and inexperienced sponsor and clinical teams, delays in regulatory processes, and research capacity in routine settings could be overcome by established research infrastructure and standardisation of processes.

Improving antibiotic prescribing quality in out-of-hours primary care: a mixed-methods study using participatory action research.

Background: During out-of-hours (OOH) primary care, GPs overprescribe antibiotics for respiratory tract infections (RTIs). Many interventions have been shown to improve antibiotic prescribing quality, but their implementation in practice remains difficult. Participatory action research (PAR) aims to explore, implement and evaluate change in practice with an active involvement of local stakeholders, while generating knowledge through experience. Objectives: To evaluate whether PAR improves antibiotic prescribing quality for RTIs during OOH primary care and simultaneously identify the pivotal lessons learned. Methods: A mixed-methods study with a PAR approach in three OOH GP cooperatives (GPCs). Each GPC co-created a multifaceted intervention focusing on improving antibiotic use for RTIs through plan-do-study-act cycles. We quantified antibiotic prescribing quality indicators and formulated the lessons learned from a qualitative process analysis. Results: Interventions were chosen with the GPs and adapted to be context-relevant. The willingness to work on quality and engagement of local stakeholders led to ownership of the project, but was time-consuming. In one GPC, antibiotic prescribing significantly decreased for tonsillitis, bronchitis, otitis media and acute upper RTI. In all three GPCs, use of guideline-recommended antibiotics for otitis media significantly increased. Conclusions: Implementing multifaceted interventions through PAR can lower total and increase guideline-recommended antibiotic prescribing for RTIs in OOH primary care. Co-creating interventions with GPs to suit local needs is feasible, but reaching all GPs targeted is challenging.

Using microbiological data to improve the use of antibiotics for respiratory tract infections: A protocol for an individual patient data meta-analysis.

BACKGROUND: Resistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence. AIM: To undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs. METHODS: A systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs. TRIAL REGISTRATION: PROSPERO Registration number: CRD42023376769.

T cells, more than antibodies, may prevent symptoms developing from respiratory syncytial virus infections in older adults.

Introduction: The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract. Methods: This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups. Results: Pre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+). Conclusion: The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults.

Impact of the COVID-19 pandemic on community antibiotic consumption in the EU/European Economic Area: a changepoint analysis.

OBJECTIVES: A decrease in community antibiotic consumption in Europe has been observed during the COVID-19 pandemic. The magnitude of this decrease, how fast after the outbreak it occurred, whether it was sustained during the pandemic and whether the seasonal variation in antibiotic consumption was affected, have not yet been evaluated in detail. METHODS: Data on community antibiotic consumption were available from the European Surveillance of Antimicrobial Consumption Network for 28 EU/European Economic Area (EEA) countries between 2010 and 2021. Antibiotic consumption was expressed as DDDs per 1000 inhabitants per day (DID). The impact of the pandemic on antibiotic consumption was investigated using descriptive statistics and non-linear mixed changepoint models for quarterly and yearly data. RESULTS: The decrease in overall antibiotic consumption between 2019 and 2020 (-3.4 DID; -18.6%) was mainly due to a decrease in the consumption of penicillins [Anatomical Therapeutic Chemical (ATC) code J01C] (-1.9 DID; -23.0%), other ß-lactam antibacterials (J01D) (-0.6 DID; -25.8%) and macrolides, lincosamides and streptogramins (J01F) (-0.5 DID; -17.4%) and was sustained during 2021. The changepoint analysis of yearly data (28 countries) estimated a decrease of 3.3 DID in overall antibiotic consumption (J01) between 2019 and 2020. The analysis of quarterly data (16 countries) estimated a decrease in overall antibiotic consumption (J01) of 4.0 DID and a decrease in seasonal variation of 1.2 DID between the first and second quarters of 2020. CONCLUSIONS: The changepoint analysis indicated a significant, sudden and steep decrease in community antibiotic consumption in the EU/EEA immediately after the start of the COVID-19 outbreak in Europe, as well as a decrease in its seasonal variation.

Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT.

Background: Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives: To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design: Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting: UK general practices. Participants: Children aged 1-12 years with acute uncomplicated lower respiratory tract infections. Outcomes: The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2-4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods: Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results: A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child's cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when 'necessary', and clinicians noted a reduction in parents' expectations for antibiotics. Limitations: The study was underpowered to detect small benefits in key subgroups. Conclusion: Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child's illness and safety-netting. Future work: The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN79914298. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

Children are commonly prescribed antibiotics for chest infections, but such infections are becoming resistant to antibiotics, and it is not clear if antibiotics work in treating them. A total of 432 children who saw their general practitioner with a chest infection were given either an antibiotic (amoxicillin) or a placebo (no antibiotic) for 7 days. Symptom diaries documented the infection's duration and its side effects. Children not in the placebo study were able to participate in another study that documented the same outcomes (an 'observational study'). We interviewed parents, doctors and nurses about their observations and concerns. Our patient and public involvement and engagement work with parents indicated that a 3-day symptom reduction was required to justify giving antibiotics. After seeing the doctor, parents whose children received antibiotics rated infective symptoms as moderately bad or worse for 5 days, and parents whose children received the placebo rated these for 6 days. Side effects and complications were similar in the two groups. Findings were similar when including the results of the observational study, and for children in whose chest the doctor could hear wheeze or rattles; who had fever; who were rated by the doctor as more unwell, who were short of breath, or who had had bacteria detected in the throat. The costs to the NHS per child were similar (antibiotics, £29; placebo, £26), and the wider costs to society were the same (antibiotics, £33; placebo, £33). Parents found it difficult to interpret their child's symptoms, and commonly used the sound of the cough to judge severity. Parents commonly consulted to receive an examination and reassurance, and accepted that antibiotics should be used only when 'necessary'. Clinicians noted a reduction in parents' expectations for antibiotics. Amoxicillin for chest infections in children is unlikely to be effective. General practitioners should support parents to self-manage at home and give clear communication about when and how to seek medical help if they continue to be concerned.

Validation of a rapid SARS-CoV-2 antibody test in general practice.

OBJECTIVES: To validate a rapid serological test (RST) for SARS-CoV-2 antibodies used in seroprevalence studies in healthcare providers, including primary healthcare providers (PHCPs) in Belgium. DESIGN: A phase III validation study of the RST (OrientGene) within a prospective cohort study. SETTING: Primary care in Belgium. PARTICIPANTS: Any general practitioner (GP) working in primary care in Belgium and any other PHCP from the same GP practice who physically manages patients were eligible in the seroprevalence study. For the validation study, all participants who tested positive (376) on the RST at the first testing timepoint (T1) and a random sample of those who tested negative (790) and unclear (24) were included. INTERVENTION: At T2, 4 weeks later, PHCPs performed the RST with fingerprick blood (index test) immediately after providing a serum sample to be analysed for the presence of SARS-CoV-2 immunoglobulin G antibodies using a two-out-of-three assay (reference test). PRIMARY AND SECONDARY OUTCOME MEASURES: The RST accuracy was estimated using inverse probability weighting to correct for missing reference test data, and considering unclear RST results as negative for the sensitivity and positive for the specificity. Using these conservative estimates, the true seroprevalence was estimated both for T2 and RST-based prevalence values found in a cohort study with PHCPs in Belgium. RESULTS: 1073 paired tests (403 positive on the reference test) were included. A sensitivity of 73% (a specificity of 92%) was found considering unclear RST results as negative (positive). For an RST-based prevalence at T1 (13.9), T2 (24.9) and T7 (70.21), the true prevalence was estimated to be 9.1%, 25.9% and 95.7%, respectively. CONCLUSION: The RST sensitivity (73%) and specificity (92%) make an RST-based seroprevalence below (above) 23% overestimate (underestimate) the true seroprevalence. TRIAL REGISTRATION NUMBER: NCT04779424.

Asthma occurrence in children and early life systemic antibiotic use: an incidence density study.

BACKGROUND: Results of studies evaluating the relationship between asthma occurrence and early life antibiotic use have been conflicting. The aim of this study was to investigate the relationship between occurrence of asthma in children and systemic antibiotic use in the first year of life based on an incidence density study with careful consideration of the temporal aspects of the determinant-outcome relationship. METHODS: We conducted an incidence density study nested in a data collection project with information on 1128 mother-child pairs. Systemic antibiotic use in the first year of life was defined as excessive (≥ 4 courses) vs. non-excessive (< 4 courses) use based on information from weekly diaries. Events (cases) were defined as the first parent-reported occurrence of asthma in a child between 1 and 10 years of age. Population time 'at risk' was probed by sampling population moments (controls). Missing data were imputed. Multiple logistic regression was used to assess the association between current first asthma occurrence (incidence density) and systemic antibiotic use in the first year of life, to evaluate effect modification and adjust for confounding. RESULTS: Forty-seven first asthma events and 147 population moments were included. Excessive systemic antibiotic use in the first year of life showed more than twice the incidence density of asthma compared to non-excessive use (adjusted IDR [95% CI]: 2.18 [0.98, 4.87], p = 0.06). The association was more pronounced in children who have had lower respiratory tract infections (LRTIs) in the first year of life compared to children who had no LRTIs in the first year of life (adjusted IDR [95% CI]: 5.17 [1.19, 22.52] versus 1.49 [0.54, 4.14]). CONCLUSIONS: Excessive use of systemic antibiotics in the first year of life may play a role in the genesis of asthma in children. This effect is modified by the occurrence of LRTIs in the first year of life, with a stronger association observed in children experiencing LRTIs in the first year of life.

Disease-Specific Quality Indicators for Outpatient Antibiotic Prescribing for Respiratory Infections (ESAC Quality Indicators) Applied to Point Prevalence Audit Surveys in General Practices in 13 European Countries.

Up to 80% of antibiotics are prescribed in the community. An assessment of prescribing by indication will help to identify areas where improvement can be made. A point prevalence audit study (PPAS) of consecutive respiratory tract infection (RTI) consultations in general practices in 13 European countries was conducted in January-February 2020 (PPAS-1) and again in 2022 (PPAS-4). The European Surveillance of Antibiotic Consumption quality indicators (ESAC-QI) were calculated to identify where improvements can be made. A total of 3618 consultations were recorded for PPAS-1 and 2655 in PPAS-4. Bacterial aetiology was suspected in 26% (PPAS-1) and 12% (PPAS-4), and an antibiotic was prescribed in 30% (PPAS-1) and 16% (PPAS-4) of consultations. The percentage of adult patients with bronchitis who receive an antibiotic should, according to the ESAC-QI, not exceed 30%, which was not met by participating practices in any country except Denmark and Spain. For patients (≥1) with acute upper RTI, less than 20% should be prescribed an antibiotic, which was achieved by general practices in most countries, except Ireland (both PPAS), Croatia (PPAS-1), and Greece (PPAS-4) where prescribing for acute or chronic sinusitis (0-20%) was also exceeded. For pneumonia in adults, prescribing is acceptable for 90-100%, and this is lower in most countries. Prescribing for tonsillitis (≥1) exceeded the ESAC-QI (0-20%) in all countries and was 69% (PPAS-1) and 75% (PPAS-4). In conclusion, ESAC-QI applied to PPAS outcomes allows us to evaluate appropriate antibiotic prescribing by indication and benchmark general practices and countries.

Initial symptoms and three months follow-up after acute COVID-19 in outpatients: An international prospective cohort study.

BACKGROUND: Most studies on long-term follow-up of patients with COVID-19 focused on hospitalised patients. No prospective study with structured follow-up has been performed in non-hospitalised patients with COVID-19. OBJECTIVES: To assess long-COVID and post-COVID (WHO definition: symptomatic at least 12 weeks), describe lingering symptoms, their impact on daily activities, and general practice visits and explore risk factors for symptom duration in outpatients. METHODS: A prospective study of adult outpatients with confirmed SARS-CoV-2 infection and symptoms consistent with COVID-19 in 11 European countries, recruited during 2020 and 2021 from primary care and the community. Structured follow-up by phone interviews (symptom rating, symptom impact on daily activities and general practice visits) was performed at weeks 2, 4, 8, and 12 by study personnel. Data was analysed descriptively by using correlation matrixes and Cox regression. RESULTS: Of 270 enrolled patients, 52% developed long-COVID and 32% post-COVID-syndrome. When only considering the presence of moderate or (very) severe symptoms at weeks 8 and 12, these percentages were 28% and 18%, respectively. Fatigue was the most often reported symptom during follow-up. The impact of lingering symptoms was most evident in sports and household activities. About half (53%) had at least one general practice contact during follow-up. Obese patients took twice as long to return to usual health (HR: 0.5, 95%CI: 0.3-0.8); no other risk profile could predict lingering symptoms. CONCLUSION: Long-COVID and post-COVID are also common in outpatients. In 32%, it takes more than 12 weeks to return to usual health.

Added value of patient- and drug-related factors to stratify drug-drug interaction alerts for risk of QT prolongation: Development and validation of a risk prediction model.

AIMS: Many clinical decision support systems trigger warning alerts for drug-drug interactions potentially leading to QT prolongation and torsades de pointes (QT-DDIs). Unfortunately, there is overalerting and underalerting because stratification is only based on a fixed QT-DDI severity level. We aimed to improve QT-DDI alerting by developing and validating a risk prediction model considering patient- and drug-related factors. METHODS: We fitted 31 predictor candidates to a stepwise linear regression for 1000 bootstrap samples and selected the predictors present in 95% of the 1000 models. A final linear regression model with those variables was fitted on the original development sample (350 QT-DDIs). This model was validated on an external dataset (143 QT-DDIs). Both true QTc and predicted QTc were stratified into three risk levels (low, moderate and high). Stratification of QT-DDIs could be appropriate (predicted risk = true risk), acceptable (one risk level difference) or inappropriate (two risk levels difference). RESULTS: The final model included 11 predictors with the three most important being use of antiarrhythmics, age and baseline QTc. Comparing current practice to the prediction model, appropriate stratification increased significantly from 37% to 54% appropriate QT-DDIs (increase of 17.5% on average [95% CI +5.4% to +29.6%], padj = 0.006) and inappropriate stratification decreased significantly from 13% to 1% inappropriate QT-DDIs (decrease of 11.2% on average [95% CI -17.7% to -4.7%], padj ≤ 0.001). CONCLUSION: The prediction model including patient- and drug-related factors outperformed QT alerting based on QT-DDI severity alone and therefore is a promising strategy to improve DDI alerting.

Development of a live biotherapeutic throat spray with lactobacilli targeting respiratory viral infections.

Respiratory viruses such as influenza viruses, respiratory syncytial virus (RSV), and coronaviruses initiate infection at the mucosal surfaces of the upper respiratory tract (URT), where the resident respiratory microbiome has an important gatekeeper function. In contrast to gut-targeting administration of beneficial bacteria against respiratory viral disease, topical URT administration of probiotics is currently underexplored, especially for the prevention and/or treatment of viral infections. Here, we report the formulation of a throat spray with live lactobacilli exhibiting several in vitro mechanisms of action against respiratory viral infections, including induction of interferon regulatory pathways and direct inhibition of respiratory viruses. Rational selection of Lactobacillaceae strains was based on previously documented beneficial properties, up-scaling and industrial production characteristics, clinical safety parameters, and potential antiviral and immunostimulatory efficacy in the URT demonstrated in this study. Using a three-step selection strategy, three strains were selected and further tested in vitro antiviral assays and in formulations: Lacticaseibacillus casei AMBR2 as a promising endogenous candidate URT probiotic with previously reported barrier-enhancing and anti-pathogenic properties and the two well-studied model strains Lacticaseibacillus rhamnosus GG and Lactiplantibacillus plantarum WCFS1 that display immunomodulatory capacities. The three strains and their combination significantly reduced the cytopathogenic effects of RSV, influenza A/H1N1 and B viruses, and HCoV-229E coronavirus in co-culture models with bacteria, virus, and host cells. Subsequently, these strains were formulated in a throat spray and human monocytes were employed to confirm the formulation process did not reduce the interferon regulatory pathway-inducing capacity. Administration of the throat spray in healthy volunteers revealed that the lactobacilli were capable of temporary colonization of the throat in a metabolically active form. Thus, the developed spray with live lactobacilli will be further explored in the clinic as a potential broad-acting live biotherapeutic strategy against respiratory viral diseases.

Prevalence of SARS-CoV-2 antibodies among Belgian nursing home residents and staff during the primary COVID-19 vaccination campaign.

BACKGROUND: Nursing home residents (NHR) and staff have been disproportionally affected by the COVID-19 pandemic and were therefore prioritised in the COVID-19 vaccination strategy. However, frail older adults, like NHR, are known to have decreased antibody responses upon vaccination targeting other viral antigens. OBJECTIVES: As real-world data on vaccine responsiveness, we assessed the prevalence of SARS-CoV-2 antibodies among Belgian NHR and staff during the primary COVID-19 vaccination campaign. METHODS: In total, we tested 1629 NHR and 1356 staff across 69 Belgian NHs for the presence of SARS-CoV-2 IgM/IgG antibodies using rapid tests. We collected socio-demographic and COVID-19-related medical data through questionnaires. Sampling occurred between 1 February and 24 March 2021, in a randomly sampled population that received none, one or two BNT162b2 vaccine doses. RESULTS: We found that during the primary vaccination campaign with 59% of the study population fully vaccinated, 74% had SARS-CoV-2 antibodies. Among fully vaccinated individuals only, fewer residents tested positive for SARS-CoV-2 antibodies (77%) than staff (98%), suggesting an impaired vaccine-induced antibody response in the elderly, with lowest seroprevalences observed among infection naïve residents. COVID-19 vaccination status and previous SARS-CoV-2 infection were predictors for SARS-CoV-2 seropositivity. Alternatively, age ≥ 80 years old, the presence of comorbidities and high care dependency predicted SARS-CoV-2 seronegativity in NHR. CONCLUSION: These findings highlight the need for further monitoring of SARS-CoV-2 immunity upon vaccination in the elderly population, as their impaired humoral responses could imply insufficient protection against COVID-19. TRIAL REGISTRATION: This study was retrospectively registered on ClinicalTrials.gov (NCT04738695).

Cost-effectiveness of adding oseltamivir to primary care for influenza-like-illness: economic evaluation alongside the randomised controlled ALIC4E trial in 15 European countries.

BACKGROUND: Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries. METHODS: Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed. RESULTS: The healthcare payers' expected ICERs of oseltamivir were €22,459 per QALY gained in adults/adolescents and €13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is €8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged €1-€35 per patient). CONCLUSION: Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained > €22,459) and cost-saving in adults/adolescents from a societal perspective.

Declining Prevalence of SARS-CoV-2 Antibodies among Vaccinated Nursing Home Residents and Staff Six Months after the Primary BNT162b2 Vaccination Campaign in Belgium: A Prospective Cohort Study.

In the SCOPE study, we monitored SARS-CoV-2 antibodies in a national sample of residents and staff from Belgian nursing homes. Here, we report the seroprevalence among infected and infection-naive residents and staff after the primary COVID-19 vaccination campaign. Among 1554 vaccinated nursing home residents and 1082 vaccinated staff from 69 nursing homes in Belgium, we assessed the proportion having SARS-CoV-2 antibodies approximately two (April 2021), four (June 2021), and six months (August 2021) after a two-dose regimen of the BNT162b2 vaccine. We measured the seroprevalence using SARS-CoV-2 antibody rapid tests and collected socio-demographic and COVID-19 medical data using an online questionnaire. Two months after vaccination (baseline), we found a seroprevalence of 91% (95% CI: 89-93) among vaccinated residents and 99% (95% CI: 98-99) among vaccinated staff. Six months after vaccination, the seroprevalence significantly decreased to 68% (95% CI: 64-72) among residents and to 89% (95% CI; 86-91) among staff (p < 0.001). The seroprevalence was more likely to decrease among infection-naive residents, older residents, or residents with a high care dependency level. These findings emphasize the need for close monitoring of nursing home residents, as a substantial part of this population fails to mount a persistent antibody response after BNT162b2 vaccination.

Prevalence, incidence and longevity of antibodies against SARS-CoV-2 among primary healthcare providers in Belgium: a prospective cohort study with 12 months of follow-up.

OBJECTIVES: To estimate the prevalence, incidence and longevity of antibodies against SARS-CoV-2 among primary healthcare providers (PHCPs). DESIGN: Prospective cohort study with 12 months of follow-up. SETTING: Primary care in Belgium. PARTICIPANTS: Any general practitioner (GP) working in primary care in Belgium and any other PHCP from the same GP practice who physically manages (examines, tests, treats) patients were eligible. A convenience sample of 3648 eligible PHCPs from 2001 GP practices registered for this study (3044 and 604 to start in December 2020 and January 2021, respectively). 3390 PHCPs (92,9%) participated in their first testing time point (2820 and 565, respectively) and 2557 PHCPs (70,1%) in the last testing time point (December 2021). INTERVENTIONS: Participants were asked to perform a rapid serological test targeting IgM and IgG against the receptor binding domain of SARS-CoV-2 and to complete an online questionnaire at each of maximum eight testing time points. PRIMARY AND SECONDARY OUTCOME MEASURES: The prevalence, incidence and longevity of antibodies against SARS-CoV-2 both after natural infection and after vaccination. RESULTS: Among all participants, 67% were women and 77% GPs. Median age was 43 years. The seroprevalence in December 2020 (before vaccination availability) was 15.1% (95% CI 13.5% to 16.6%), increased to 84.2% (95% CI 82.9% to 85.5%) in March 2021 (after vaccination availability) and reached 93.9% (95% CI 92.9% to 94.9%) in December 2021 (during booster vaccination availability and fourth (delta variant dominant) COVID-19 wave). Among not (yet) vaccinated participants the first monthly incidence of antibodies against SARS-CoV-2 was estimated to be 2.91% (95% CI 1.80% to 4.01%). The longevity of antibodies is higher in PHCPs with self-reported COVID-19 infection. CONCLUSIONS: This study confirms that occupational health measures provided sufficient protection when managing patients. High uptake of vaccination resulted in high seroprevalence of SARS-CoV-2 antibodies in PHCPs in Belgium. Longevity of antibodies was supported by booster vaccination and virus circulation. TRIAL REGISTRATION NUMBER: NCT04779424.

Randomized, Double-Blind, Placebo-Controlled Trial of a Throat Spray with Selected Lactobacilli in COVID-19 Outpatients.

Primary care urgently needs treatments for coronavirus disease 2019 (COVID-19) patients because current options are limited, while these patients who do not require hospitalization encompass more than 90% of the people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we evaluated a throat spray containing three Lactobacillaceae strains with broad antiviral properties in a randomized, double-blind, placebo-controlled trial. Before the availability of vaccines, 78 eligible COVID-19 patients were randomized to verum (n = 41) and placebo (n = 37) within 96 h of a positive PCR-based SARS-CoV-2 diagnosis, and a per-protocol analysis was performed. Symptoms and severity were reported daily via an online diary. Combined nose-throat swabs and dried blood spots were collected at regular time points in the study for microbiome, viral load, and antibody analyses. The daily reported symptoms were highly variable, with no added benefit for symptom resolution in the verum group. However, based on 16S V4 amplicon sequencing, the acute symptom score (fever, diarrhea, chills, and muscle pain) was significantly negatively associated with the relative abundance of amplicon sequence variants (ASVs) that included the applied lactobacilli (P < 0.05). Furthermore, specific monitoring of these applied lactobacilli strains showed that they were detectable via quantitative PCR (qPCR) analysis in 82% of the patients in the verum group. At the end of the trial, a trend toward lower test positivity for SARS-CoV-2 was observed for the verum group (2/30; 6.7% positive) than for the placebo group (7/27; 26% positive) (P = 0.07). These data indicate that the throat spray with selected antiviral lactobacilli could have the potential to reduce nasopharyngeal viral loads and acute symptoms but should be applied earlier in the viral infection process and substantiated in larger trials. IMPORTANCE Viral respiratory tract infections result in significant health and economic burdens, as highlighted by the COVID-19 pandemic. Primary care patients represent 90% of those infected with SARS-CoV-2, yet their treatment options are limited to analgesics and antiphlogistics, and few broadly acting antiviral strategies are available. Microbiome or probiotic therapy is a promising emerging treatment option because it is based on the multifactorial action of beneficial bacteria against respiratory viral disease. In this study, an innovative topical throat spray with select beneficial lactobacilli was administered to primary COVID-19 patients. A remote study setup (reducing the burden on hospitals and general practitioners) was successfully implemented using online questionnaires and longitudinal self-sampling. Our results point toward the potential mechanisms of action associated with spray administration at the levels of viral loads and microbiome modulation in the upper respiratory tract and pave the way for future clinical applications of beneficial bacteria against viral diseases.

Economic Burden and Health-Related Quality of Life of Respiratory Syncytial Virus and Influenza Infection in European Community-Dwelling Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) and influenza virus infections result in a considerable mortality and morbidity among the aging population globally. Influenza vaccination for older adults before the seasonal influenza epidemic has been evaluated to be cost-effective in many countries. Interventions against RSV in older adults are in the pipeline, and evaluating their cost-effectiveness is crucial for decision making. To inform such evaluations, our aim was to estimate average costs and health-related quality of life (HRQoL) in older adults with RSV and influenza infection. METHODS: The European RESCEU observational cohort study followed 1040 relatively healthy community-dwelling older adults aged 60 years and older during 2 consecutive winter seasons. Health care resource use and HRQoL were collected and analyzed during RSV episodes, and also during influenza episodes. Country-specific unit cost data were mainly obtained from national databases. Direct costs were estimated from a patient, health care provider, and health care payers' perspective, whereas indirect costs were estimated from a societal perspective. Due to small sample size, no formal statistical comparisons were made. RESULTS: Thirty-six RSV and 60 influenza episodes were reported, including 1 hospitalization. Means (median; first-third quartile) of €26.4 (€5.5; 0-47.3) direct and €4.4 (€0; 0-0) indirect costs were reported per nonhospitalized RSV episode, and €42.5 (€36; 3.3-66.7) direct and €32.1 (€0; 0-0) indirect costs per nonhospitalized influenza episode. For RSV episodes, the utility value decreased from 0.896 (0.928; 0.854-0.953) to 0.801 (0.854; 0.712-0.937) from preseason to 1 week after symptom onset; for influenza, the change was from 0.872 (0.895; 0.828-0.953) to 0.664 (0.686; 0.574-0.797). CONCLUSIONS: The average costs and HRQoL estimates of older adults treated outside the hospital can be used to inform the design of future studies and the decision making regarding interventions to prevent RSV infection in older adults. Larger studies are needed to provide better country-specific and complementary cost estimates and to allow for formal statistical comparison of costs between RSV and influenza. CLINICAL TRIALS REGISTRATION: NCT03621930.