Antigenic cartography using sera from sequence-confirmed SARS-CoV-2 variants of concern infections reveals antigenic divergence of Omicron.

Large-scale vaccination campaigns have prevented countless hospitalizations and deaths due to COVID-19. However, the emergence of SARS-CoV-2 variants that escape from immunity challenges the effectiveness of current vaccines. Given this continuing evolution, an important question is when and how to update SARS-CoV-2 vaccines to antigenically match circulating variants, similarly to seasonal influenza viruses where antigenic drift necessitates periodic vaccine updates. Here, we studied SARS-CoV-2 antigenic drift by assessing neutralizing activity against variants of concern (VOCs) in a set of sera from patients infected with viral sequence-confirmed VOCs. Infections with D614G or Alpha strains induced the broadest immunity, whereas individuals infected with other VOCs had more strain-specific responses. Omicron BA.1 and BA.2 were substantially resistant to neutralization by sera elicited by all other variants. Antigenic cartography revealed that Omicron BA.1 and BA.2 were antigenically most distinct from D614G, associated with immune escape, and possibly will require vaccine updates to ensure vaccine effectiveness.

Improving emergency department flow by introducing a simple time out moment (The TRAFFIC LIGHT study).

BACKGROUND AND IMPORTANCE: Long waiting times in the emergency department (ED) is an increasing problem in the recent years and is expected to become an even bigger problem in the future Objective: We aimed to test the hypothesis whether increasing awareness of the time lapse with the treating physician, 2 hours after patient arrival, can reduce long patient turnaround time (TAT). METHOD: In this prospective single-center cohort study we compared and analyzed patient TAT in the ED before and after implementation of a so called 'traffic light' moment 2 hours after patient arrival. At this 'traffic light' moment a team member contacted the treating physician to increased awareness over the time lapse. Difference in percentage of patients who stayed more than 4 hours in the ED before and after intervention was the primary outcome Results: Between October 2nd 2021 and January 2nd,2022 1494 patients were included for primary outcome analysis. A total of 419 patients (n=740, 56.6%) had a TAT of less than 4 hour in the ED before intervention, compared to 497 (n=754, 65.9%) after intervention (p <0.001). Median time spent in de ED before intervention was 3:40 (IQR 2:24 - 5:04) compared to 3:15 (IQR 2:03 - 4:38) after intervention (p<0.001). CONCLUSION: This simple and low-cost intervention reduces the ED length of stay significantly. Although multiple interventions will be required to ensure less patients spending more than 4-hours in the ED, a 'traffic light' moment can be a simple and an effective tool.

Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands: A prospective cohort study.

BACKGROUND: Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants. METHODS AND FINDINGS: In a prospective cohort of 165 SARS-CoV-2 naive health care workers in the Netherlands, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of mRNA-1273, followed by recipients of BNT162b2 (geometric mean titers (GMT) of 358 [95% CI 231-556] and 214 [95% CI 153-299], respectively; p<0.05), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 18 [95% CI 11-30] and 14 [95% CI 8-25] IU/ml, respectively; p<0.001). VOCs neutralization was reduced in all vaccine groups, with the greatest reduction in neutralization GMT observed against the Omicron variant (fold change 0.03 [95% CI 0.02-0.04], p<0.001). The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. We used linear regression and linear mixed model analysis. All results were adjusted for possible confounding of age and sex. Study limitations include the lack of cellular immunity data. CONCLUSIONS: Overall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination, which implies the use of mRNA vaccines for both initial and booster vaccination.

E-learning on antibiotic prescribing-the role of autonomous motivation in participation: a prospective cohort study.

Objectives: E-learning is increasingly used in education on antimicrobial stewardship, but participation rates are often low. Insight into factors that affect participation is therefore needed. Autonomous motivation is associated with higher achievements in medical education and could also play a role in e-learning participation. We therefore aimed to investigate the role of residents' autonomous motivation in their participation in e-learning on antibiotic prescribing. Methods: We performed a multicentre cohort study in two academic and two teaching hospitals. Residents who filled out questionnaires on antibiotic knowledge, the perceived importance of antibiotics and motivation [Self-Regulation Questionnaire - Academic (SRQ-a)] received e-learning access. We used the SRQ-a to calculate relative autonomous motivation (RAM), an index that estimates the amount of autonomous motivation compared with the amount of controlled motivation. We then analysed associations between RAM and participation in e-learning with logistic regression. Results: Eighty-six residents participated (74% female, mean age 30 years). Overall e-learning participation was 58% (n = 50). Participation was 41% in residents with negative RAM (i.e. more controlled motivation) and 62% in residents with positive RAM (i.e. more autonomous motivation). RAM was positively associated with participation, adjusted for residency in an academic hospital (adjusted OR 2.6, 95% CI 1.5-4.6). Conclusions: Participation in non-obligatory e-learning on antibiotic prescribing is higher in residents with more autonomous motivation. Interventions to increase autonomous motivation could improve participation. Preceding e-learning on antibiotic prescribing with face-to-face education, to explain the importance of the subject, could enhance autonomous motivation and thus optimize e-learning efficiency.

The 'morning dip' in antimicrobial appropriateness: circumstances determining appropriateness of antimicrobial prescribing.

Objectives: Quality of care has been shown to vary depending on the time of day or day of the week and depending on caregivers' gender and experience. We aimed to study how these factors influence quality of antimicrobial prescribing. Methods: Prospective point-prevalence surveys were performed to determine the association between the above-mentioned prescription factors and antimicrobial appropriateness. Surveys included cases of patients admitted to a tertiary care hospital with a prescribed systemic antimicrobial drug and its prescribers. The main outcome was appropriateness of antimicrobial prescriptions. A post hoc qualitative survey among hospital physicians asked physicians to reflect on the results. Results: The study included 351 antimicrobial prescriptions by 150 physicians prescribed for 276 patients. Appropriateness of antimicrobial prescribing in the morning was significantly lower compared with the afternoon and evening/night [43% versus 68% versus 70%, crude OR afternoon versus morning = 3.00 (95% CI = 1.60-5.48), crude OR evening/night versus morning = 3.40 (95% CI = 1.64-6.69)]. First-year residents performed significantly worse than their more experienced colleagues [51% versus 69%, crude OR = 2.09 (95% CI = 1.26-3.38)]. Infectious disease expert consultation improved appropriateness [54% versus 81%, crude OR = 3.71 (95% CI = 2.05-6.23)]. No significant effects for gender or office hours versus non-office hours were found. Post hoc survey results suggest creating room to improve prescribing circumstances during mornings and for inexperienced physicians. Conclusions: Antimicrobial prescribing was less appropriate in the mornings and when prescribed by inexperienced physicians. Appropriateness may be increased by improving prescribing circumstances.

Improving antibiotic prescribing skills in medical students: the effect of e-learning after 6 months.

Background: Antimicrobial prescribing behaviour is first established during medical study, but teachers often cite lack of time as an important problem in the implementation of antimicrobial stewardship in the medical curriculum. The use of electronic learning (e-learning) is a potentially time-efficient solution, but its effectiveness in changing long-term prescribing behaviour in medical students is as yet unknown. Methods: We performed a prospective controlled intervention study of the long-term effects of a short interactive e-learning course among fourth year medical students in a Dutch university. The e-learning was temporarily implemented as a non-compulsory course during a 6 week period. Six months later, all students underwent an infectious disease-based objective structured clinical examination (OSCE) aimed at simulating postgraduate prescribing. If they passed, each student did the OSCE only once. We created a control group of students from a period when the e-learning was not implemented. Main outcomes were the OSCE pass percentage and knowledge, drug choice and overall scores. We used propensity scores to create equal comparisons. Results: We included 71 students in the intervention group and 285 students in the control group. E-learning participation in the intervention group was 81%. The OSCE pass percentage was 86% in the control group versus 97% in the intervention group (+11%, OR 5.9, 95% CI 1.7-20.0). OSCE overall, knowledge and drug choice grades (1-10) were also significantly higher in the intervention group (differences +0.31, +0.31 and +0.51, respectively). Conclusions: E-learning during a limited period can significantly improve medical students' performance of an antimicrobial therapeutic consultation in a situation simulating clinical practice 6 months later.

Assessment of appropriate antimicrobial prescribing: do experts agree?

OBJECTIVES: Little is known about the validity and reliability of expert assessments of the quality of antimicrobial prescribing, despite their importance in antimicrobial stewardship. We investigated how infectious disease doctors' assessments compared with a reference standard (modal expert opinion) and with the assessments of their colleagues. METHODS: Twenty-four doctors specialized in infectious diseases or clinical microbiology (16 specialists and 8 residents) from five hospitals were asked to assess the appropriateness of antimicrobial agents prescribed for a broad spectrum of indications in 56 paper cases. They were instructed how to handle guideline applicability and deviations. We created a reference standard of antimicrobial appropriateness using the modal assessment of 16 specialists. We calculated criterion validity and interrater and intrarater overall and specific agreement with an index expert (senior infectious disease physician) and analysed the influence of doctor characteristics on validity. RESULTS: Specialists agreed with the reference standard in 80% of cases (range 75%-86%), with a sensitivity and specificity of 75% and 84%, respectively. This did not differ by clinical specialty, hospital or years of experience, and residents had similar results. Specialists agreed with the index expert in 76% of cases and the index expert agreed with his previous assessments in 71% of cases. CONCLUSIONS: Doctors specialized in infectious diseases and clinical microbiology assess the appropriateness of antimicrobials prescribed for a broad spectrum of indications with acceptable agreement and validity, regardless of their experience or hospital of employment. However, there is room for improvement, which merits attention in multidisciplinary discussions and education.

Participatory action research in antimicrobial stewardship: a novel approach to improving antimicrobial prescribing in hospitals and long-term care facilities.

It is challenging to change physicians' antimicrobial prescribing behaviour. Although antimicrobial prescribing is determined by contextual (e.g. a lack of guidelines), cultural (e.g. peer practice) and behavioural (e.g. perceived decision making autonomy) factors, most antimicrobial stewardship programmes fail to consider these factors in their approach. This may lead to suboptimal intervention effectiveness. We present a new approach in antimicrobial stewardship programme development that addresses relevant determinants of antimicrobial prescribing: participatory action research (PAR). PAR is a collaborative process that aims to bring about change in social situations by producing practical knowledge that is useful in local practice. It requires substantial involvement of relevant stakeholders to address determinants of the studied behaviour and to facilitate empowerment. PAR is well suited for complex problems in multidisciplinary settings as it adapts to local needs, delivering a tailored approach to improving local practice. We describe how PAR can be applied to antimicrobial stewardship, and describe the PAR design of two ongoing multicentre antimicrobial stewardship projects, in the acute care setting and the long-term care setting, respectively.

The Impact of First-Time SARS-CoV-2 Infection on Human Anelloviruses.

Members of the Anelloviridae family dominate the blood virome, emerging early in life. The anellome, representing the variety of anelloviruses within an individual, stabilizes by adulthood. Despite their supposedly commensal nature, elevated anellovirus concentrations under immunosuppressive treatment indicate an equilibrium controlled by immunity. Here, we investigated whether anelloviruses are sensitive to the immune activation that accompanies a secondary infection. As a model, we investigated 19 health care workers (HCWs) with initial SARS-CoV-2 infection, with blood sampling performed pre and post infection every 4 weeks in a 3-month-follow-up during the early 2020 COVID-19 pandemic. A concurrently followed control group (n = 27) remained SARS-CoV-2-negative. Serum anellovirus loads were measured using qPCR. A significant decrease in anellovirus load was found in the first weeks after SARS-CoV-2 infection, whereas anellovirus concentrations remained stable in the uninfected control group. A restored anellovirus load was seen approximately 10 weeks after SARS-CoV-2 infection. For five subjects, an in-time anellome analysis via Illumina sequencing could be performed. In three of the five HCWs, the anellome visibly changed during SARS-CoV-2 infection and returned to baseline in two of these cases. In conclusion, anellovirus loads in blood can temporarily decrease upon an acute secondary infection.

[Glycemia reduction in type 2 diabetes patients with low cardiovascular risk]. / Patiënten met type 2-diabetes en een laag cardiovasculair risico.

In persons with type 2 diabetes without established cardiovascular complications data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to glycemic outcomes as well as microvascular and cardiovascular disease outcomes. The GRADE trial compared the ability of four glucose-lowering remedies to achieve and maintain a defined glycated hemoglobin target and to protect the participant from microvascular and macrovascular complications. In this article, we comment on the relevance of this trial with specific attention for the notion that GLP-1 receptor agonists seem to have a primary preventive effect.

Why not to pick your nose: Association between nose picking and SARS-CoV-2 incidence, a cohort study in hospital health care workers.

BACKGROUND: Hospital health care workers (HCW) are at increased risk of contracting SARS-CoV-2. We investigated whether certain behavioral and physical features, e.g. nose picking and wearing glasses, are associated with infection risk. AIM: To assess the association between nose picking and related behavioral or physical features (nail biting, wearing glasses, and having a beard) and the incidence of SARS-CoV-2-infection. METHODS: In a cohort study among 404 HCW in two university medical centers in the Netherlands, SARS-CoV-2-specific antibodies were prospectively measured during the first phase of the pandemic. For this study HCW received an additional retrospective survey regarding behavioral (e.g. nose picking) and physical features. RESULTS: In total 219 HCW completed the survey (response rate 52%), and 34/219 (15.5%) became SARS-CoV-2 seropositive during follow-up from March 2020 till October 2020. The majority of HCW (185/219, 84.5%) reported picking their nose at least incidentally, with frequency varying between monthly, weekly and daily. SARS-CoV-2 incidence was higher in nose picking HCW compared to participants who refrained from nose picking (32/185: 17.3% vs. 2/34: 5.9%, OR 3.80, 95% CI 1.05 to 24.52), adjusted for exposure to COVID-19. No association was observed between nail biting, wearing glasses, or having a beard, and the incidence of SARS-CoV-2 infection. CONCLUSION: Nose picking among HCW is associated with an increased risk of contracting a SARS-CoV-2 infection. We therefore recommend health care facilities to create more awareness, e.g. by educational sessions or implementing recommendations against nose picking in infection prevention guidelines.

Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection.

BACKGROUND: Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, led us to determine, in an exploratory observational study, whether IDO2 is expressed and active in PASC, and may correlate with pathophysiology. METHODS: Plasma or serum, and peripheral blood mononuclear cells (PBMC) were obtained from well-characterized PASC patients and SARS-CoV-2-infected individuals without PASC. We assessed tryptophan and its degradation products by UPLC-MS/MS. IDO2 activity, its potential consequences, and the involvement of the aryl hydrocarbon receptor (AHR) in IDO2 expression were determined in PBMC from another PASC cohort by immunohistochemistry (IHC) for IDO2, IDO1, AHR, kynurenine metabolites, autophagy, and apoptosis. These PBMC were also analyzed by metabolomics and for mitochondrial functioning by respirometry. IHC was also performed on autopsy brain material from two PASC patients. FINDINGS: IDO2 is expressed and active in PBMC from PASC patients, as well as in brain tissue, long after SARS-CoV-2 infection. This is paralleled by autophagy, and in blood cells by reduced mitochondrial functioning, reduced intracellular levels of amino acids and Krebs cycle-related compounds. IDO2 expression and activity is triggered by SARS-CoV-2-infection, but the severity of SARS-CoV-2-induced pathology appears related to the generated specific kynurenine metabolites. Ex vivo, IDO2 expression and autophagy can be halted by an AHR antagonist. INTERPRETATION: SARS-CoV-2 infection triggers long-lasting IDO2 expression, which can be halted by an AHR antagonist. The specific kynurenine catabolites may relate to SARS-CoV-2-induced symptoms and pathology. FUNDING: None.

Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial.

BACKGROUND: Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. METHODS: This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 109/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329. FINDINGS: Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections. INTERPRETATION: Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating. FUNDING: The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

Decreased Passive Immunity to Respiratory Viruses through Human Milk during the COVID-19 Pandemic.

Infants may develop severe viral respiratory tract infections because their immune system is still developing in the first months after birth. Human milk provides passive humoral immunity during the first months of life. During the COVID-19 pandemic, circulation of common respiratory viruses was virtually absent due to the preventative measures resulting in reduced maternal exposure. Therefore, we hypothesized that this might result in lower antibody levels in human milk during the pandemic and, subsequently, decreased protection of infants against viral respiratory tract infections. We assessed antibody levels against respiratory syncytial virus (RSV), Influenza virus, and several seasonal coronaviruses in different periods of the COVID-19 pandemic in serum and human milk using a Luminex assay. IgG levels against RSV, Influenza, HCoV-OC43, HCoV-HKU1, and HCoV-NL63 in human milk were reduced with a factor of 1.7 (P < 0.001), 2.2 (P < 0.01), 2.6 (P < 0.05), 1.4 (P < 0.01), and 2.1 (P < 0.001), respectively, since the introduction of the COVID-19 restrictions. Furthermore, we observed that human milk of mothers that experienced COVID-19 contained increased levels of IgG and IgA binding to other respiratory viruses. Passive immunity via human milk against common respiratory viruses was reduced during the COVID-19 pandemic, which may have consequences for the protection of breastfed infants against respiratory infections. IMPORTANCE Passive immunity derived from antibodies in human milk is important for protecting young infants against invading viruses. During the COVID-19 pandemic, circulation of common respiratory viruses was virtually absent due to preventative measures. In this study, we observed a decrease in human milk antibody levels against common respiratory viruses several months into the COVID-19 pandemic. This waning of antibody levels might partially explain the previously observed surge of hospitalizations of infants, mostly due to RSV, when preventative hygiene measures were lifted. Knowledge of the association between preventative measures, antibody levels in human milk and subsequent passive immunity in infants might help predict infant hospital admissions and thereby enables anticipation to prevent capacity issues. Additionally, it is important in the consideration for strategies for future lockdowns to best prevent possible consequences for vulnerable infants.

Recent infection with HCoV-OC43 may be associated with protection against SARS-CoV-2 infection.

Antibodies against seasonal human coronaviruses (HCoVs) are known to cross-react with SARS-CoV-2, but data on cross-protective effects of prior HCoV infections are conflicting. In a prospective cohort of healthcare workers (HCWs), we studied the association between seasonal HCoV (OC43, HKU1, 229E and NL63) nucleocapsid protein IgG and SARS-CoV-2 infection during the first pandemic wave in the Netherlands (March 2020 - June 2020), by 4-weekly serum sampling. HCW with HCoV-OC43 antibody levels in the highest quartile, were less likely to become SARS-CoV-2 seropositive when compared with those with lower levels (6/32, 18.8%, versus 42/97, 43.3%, respectively: p = 0.019; HR 0.37, 95% CI 0.16-0.88). We found no significant association with HCoV-OC43 spike protein IgG, or with antibodies against other HCoVs. Our results indicate that the high levels of HCoV-OC43-nucleocapsid antibodies, as an indicator of a recent infection, are associated with protection against SARS-CoV-2 infection; this supports and informs efforts to develop pancoronavirus vaccines.

A single mRNA vaccine dose in COVID-19 patients boosts neutralizing antibodies against SARS-CoV-2 and variants of concern.

The urgent need for, but limited availability of, SARS-CoV-2 vaccines worldwide has led to widespread consideration of dose-sparing strategies. Here, we evaluate the SARS-CoV-2-specific antibody responses following BNT162b2 vaccination in 150 previously SARS-CoV-2-infected individuals from a population-based cohort. One week after first vaccine dose, spike protein antibody levels are 27-fold higher and neutralizing antibody titers 12-fold higher, exceeding titers of fully vaccinated SARS-CoV-2-naive controls, with minimal additional boosting after the second dose. Neutralizing antibody titers against four variants of concern increase after vaccination; however, overall neutralization breadth does not improve. Pre-vaccination neutralizing antibody titers and time since infection have the largest positive effect on titers following vaccination. COVID-19 severity and the presence of comorbidities have no discernible impact on vaccine response. In conclusion, a single dose of BNT162b2 vaccine up to 15 months after SARS-CoV-2 infection offers higher neutralizing antibody titers than 2 vaccine doses in SARS-CoV-2-naive individuals.

Validation of self-reported folic acid use in a multiethnic population: results of the Amsterdam Born Children and their Development study.

OBJECTIVE: To assess folic acid supplementation rates and validate the self-reporting of folic acid supplement use among pregnant women in a multiethnic cohort. DESIGN: Secondary analysis of a prospective cohort study. SETTING: Self-reported folic acid supplement use in the Amsterdam Born Children and their Development study cohort was compared with serum folate concentrations using non-parametric trend analysis and linear and logistic regression. SUBJECTS: A total of 4234 pregnant women of various ethnic backgrounds. RESULTS: Serum folate levels showed a significant positive linear trend as reported use of folic acid increased (P < 0·001), which was supported by linear regression (r = 0·49). Odds of having low serum folate concentration decreased with reported early start of folic acid intake. Young, multiparous or non-Western women reported less pre-conception folic acid intake. Non-Western women showed lower serum folate concentrations. The overall rate of over-reporting, i.e. serum folate concentrations ≤20 nmol/l while reporting the use of folic acid supplements, was 20·7 %. Women of Surinamese and Moroccan ancestry had higher odds of over-reporting (OR = 2·3; 95 % CI 1·5, 3·5 and OR = 2·3; 95 % CI 1·3, 4·0, respectively). The odds for Surinamese women remained significant after adjusting for the onset of supplement use, parity and age (OR = 1·7; 95 % CI 1·1, 2·6). CONCLUSIONS: Although self-reporting is a valid method for assessing folic acid supplement use in a multiethnic population, some participants do over-report. Surinamese and possibly Moroccan women appear to over-report more often. Rates of supplementation are low, especially in non-Western women. This suggests the need for intensifying current campaigns or perhaps even additional advice to start or continue to use folic acid post-conceptionally.

[Research into diagnostic reasoning: significant, but also relevant?] / Onderzoek naar diagnostisch redeneren.

Research into diagnostic reasoning often focuses on diagnostic errors, while ignoring the also important concepts of overdiagnosis and cost of the diagnostic process. A popular theoretic model guiding studies on the subject is the dual process model in which cognitive errors play an important role. This paradigm is also used in the study of Mamede and colleagues, who studied the effect of disease specific knowledge on the occurrence of diagnostic errors due to availability bias in internal medicine residents. The study, which used case vignettes, is well set up but its experimental design cannot account for the influence of clinical context which limits its clinical value. Further research into this topic should be performed in actual clinical situations to provide more insight in how to improve diagnostic reasoning in medicine.

Time since SARS-CoV-2 infection and humoral immune response following BNT162b2 mRNA vaccination.

BACKGROUND: To optimise the use of available SARS-CoV-2 vaccines, some advocate delaying second vaccination for individuals infected within six months. We studied whether post-vaccination immune response is equally potent in individuals infected over six months prior to vaccination. METHODS: We tested serum IgG binding to SARS-CoV-2 spike protein and neutralising capacity in 110 healthcare workers, before and after both BNT162b2 messenger RNA (mRNA) vaccinations. We compared outcomes between participants with more recent infection (n = 18, median two months, IQR 2-3), with infection-vaccination interval over six months (n = 19, median nine months, IQR 9-10), and to those not previously infected (n = 73). FINDINGS: Both recently and earlier infected participants showed comparable humoral immune responses after a single mRNA vaccination, while exceeding those of previously uninfected persons after two vaccinations with 2.5 fold (p = 0.003) and 3.4 fold (p < 0.001) for binding antibody levels, and 6.4 and 7.2 fold for neutralisation titres, respectively (both p < 0.001). The second vaccine dose yielded no further substantial improvement of the humoral response in the previously infected participants (0.97 fold, p = 0.92), while it was associated with a 4 fold increase in antibody binding levels and 18 fold increase in neutralisation titres in previously uninfected participants (both p < 0.001). Adjustment for potential confounding of sex and age did not affect these findings. INTERPRETATION: Delaying the second vaccination in individuals infected up to ten months prior may constitute a more efficient use of limited vaccine supplies. FUNDING: Netherlands Organization for Health Research and Development ZonMw; Corona Research Fund Amsterdam UMC; Bill & Melinda Gates Foundation.