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Background: Ten percent of the population is labeled as allergic to penicillin(s), when in fact 90% of these labels are inappropriate. Recent studies have shown that inpatient delabeling by a direct drug challenge (dDC) is safe in low-risk patients. However, there is a need for outpatient and nonallergist delabeling., Objective: To assess the safety of delabeling low-risk adults by means of dDC in primary care., Methods: We searched the MEDLINE, Embase, and Cochrane Library databases from inception to March 15, 2022 (updated June 5, 2023) for studies performing dDC in adults in primary care or other outpatient settings. Two researchers independently screened studies for eligibility. The data extraction and critical appraisal were performed by 1 reviewer, and we pooled the results in a meta-analysis., Results: Of 2138 results, 12 studies (1070 participants) were eligible for inclusion. Three studies evaluated delabeling in primary care and 9 studies in an outpatient hospital setting. There were no critical adverse events during dDC. No reaction occurred in 97.13% of the 1070 patients, who previously labeled as penicillin-allergic, and were safely delabeled. Ten patients (<1%) developed an immediate reaction: 3 had self-limiting reactions and 7 needed antihistaminics, steroids, epinephrine, and/or salbutamol., Conclusions: No serious allergic reactions are observed during direct amoxicillin challenge in adults in an outpatient setting. However, with the exception of 1 recent report, these studies are of low to moderate quality. Nonspecialist delabeling is promising, but further research is required on correct risk stratification and safety assessment in large cohort studies evaluating dDC in primary care., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

When COVID-19 vaccines were implemented, nursing home residents (NHRs) and staff (NHS) in Belgium were prioritized for vaccination. To characterize the vaccine response over time in this population and to identify poorly responding groups, we assessed antibody concentrations two (T1), four (T2) and six months (T3) after primary course BNT162b2 vaccination in six groups of infection-naive/infection-primed NHRs/NHS, with/without comorbidity (NHRs only). Participant groups (N = 125 per group) were defined within a national serosurveillance study in nursing homes, based on questionnaire data. Dried blood spots were analyzed using ELISA for the quantification of SARS-CoV-2 S1RBD IgG antibodies. Among all groups, antibody concentrations significantly decreased between T1 and T2/T3, all with a ≥70% decrease at T3, except for infection-primed staff (-32%). Antibody concentrations among infection-naive NHRs were 11.96 times lower than those among infection-primed NHR, while the latter were comparable (x1.05) to infection-primed NHS. The largest proportion [13% (95% CI: 11-24%)] of vaccine non-responders was observed in the group of infection-naive NHRs with comorbidities. A longer interval between infection and vaccination (≥3 months) elicited higher antibody responses. Our data retrospectively show the necessity of timely COVID-19 booster vaccination. Infection-naive NHRs require special attention regarding immune monitoring in future epidemics or pandemics., Competing Interests: The authors have no conflicts of interest to declare.

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., (Copyright © 2024, The Authors.)

Background: Chronic Fatigue Syndrome patients suffer from symptoms that cannot be explained by a single underlying biological cause. It is sometimes claimed that these symptoms are a manifestation of a disrupted autonomic nervous system. Prior works studying this claim from the complex adaptive systems perspective, have observed a lower average complexity of physical activity patterns in chronic fatigue syndrome patients compared to healthy controls. To further study the robustness of such methods, we investigate the within-patient changes in complexity of activity over time. Furthermore, we explore how these changes might be related to changes in patient functioning., Methods: We propose an extension of the allometric aggregation method, which characterises the complexity of a physiological signal by quantifying the evolution of its fractal dimension. We use it to investigate the temporal variations in within-patient complexity. To this end, physical activity patterns of 7 patients diagnosed with chronic fatigue syndrome were recorded over a period of 3 weeks. These recordings are accompanied by physicians' judgements in terms of the patients' weekly functioning., Results: We report significant within-patient variations in complexity over time. The obtained metrics are shown to depend on the range of timescales for which these are evaluated. We were unable to establish a consistent link between complexity and functioning on a week-by-week basis for the majority of the patients., Conclusions: The considerable within-patient variations of the fractal dimension across scales and time force us to question the utility of previous studies that characterise long-term activity signals using a single static complexity metric. The complexity of a Chronic Fatigue Syndrome patient's physical activity signal does not suffice to characterise their high-level functioning over time and has limited potential as an objective monitoring metric by itself., (© 2024. The Author(s).)

In Belgium, nursing home (NH) staff (NHS) and residents were prioritised for the initial COVID-19 vaccination and successive booster doses. The vaccination campaign for the first booster started in September 2021 in Belgian NH. Our first study about vaccine hesitancy towards the COVID-19 vaccine in Belgian NHS already showed a degree of fear for the primary vaccination course (T1). This new study aims to evaluate vaccine hesitancy to get the first booster (T2) in a population of fully vaccinated (with two doses) NHS. A random stratified sample of NHS who received the primary vaccination course ( N  = 954) completed an online questionnaire on COVID-19 booster hesitancy (between 25/11/2021 and 22/01/2022). NHS who hesitated or refused the booster were asked for the main reason for their hesitation/refusal. Overall, 21.0 % of our population hesitated before, were still hesitating or refused the booster, NHS that were not hesitant at T1 being 5.7 times less likely to hesitate to get the first booster dose (Adjusted OR 0.179, 95 % CI: 0.120, 0.267). Although there was a slight reduction (23.5 % to 20.1 %) in the proportion of NHS who hesitated/refused vaccination at T1 compared to T2 ( p  = 0.034), the fear of unknown effects was the principal reason for hesitation/refusal, already mentioned in our first study. NHS were not reassured concerning their initial fears. Given the likelihood that booster vaccinations will be necessary over the coming years, a communication strategy specific to NHS should be implemented., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: Develop a consensus on the content and form of safety netting advice (SNA) for parents of acutely ill children., Design: Four-round modified e-Delphi using online questionnaires and feedback among clinical and research experts., Setting: Ambulatory care in high-income countries., Participants: Forty-one experts from 13 countries: 3 emergency physicians, 15 general practitioners, 4 nurses and 19 paediatricians., Results: The experts defined the content of SNA as advice on the normal, expected disease course of the provisional diagnosis, diagnostic uncertainty, alarm signs that indicate the need for medical help and information on where and how to find such help. Regarding the form of the SNA, the experts agree that a reliable source should give SNA verbally with paper or digital written or video/image resources at every appropriate healthcare encounter in a short and simple empowering fashion, specific to the child's situation and seek confirmatory feedback from parents., Conclusions: SNA needs to contain advice on the expected disease course, alarm signs and where and how to find help. It should be given verbally with written resources by a reliable healthcare professional or digital platform. Short, simple and specific, SNA needs to empower the parent whose understanding of the advice should be checked. The effectiveness of SNA resources coproduced by parents and experts should be assessed in different settings and those providing SNA require up-to-date and reliable training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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).

In a previous study in Belgian nursing homes (NH) during the first wave of the COVID-19 pandemic, we found a SARS-CoV-2 seroprevalence of 17% with a large variability (0-45%) between NH. The current exploratory study aimed to identify nursing home-specific risk factors for high SARS-CoV-2 seroprevalence. Between October 19th, 2020 and November 13th, 2020, during the second COVID-19 wave in Belgium, capillary blood was collected on dried blood spots from 60 residents and staff in each of the 20 participating NH in Flanders and Brussels. The presence of SARS-CoV-2-specific IgG antibodies was assessed by ELISA. Risk factors were evaluated using a questionnaire, filled in by the director or manager of the NH. Assessed risk factors comprised community-related factors, resident-related factors, management and performance features as well as building-related aspects. The relation between risk factors and seroprevalence was assessed by applying random forest modelling, generalized linear models and Bayesian linear regression. The present analyses showed that the prevalence of residents with dementia, the scarcity of personal protective equipment (surgical masks, FFP2 masks, glasses and face shields), and inadequate PCR test capacity were related to a higher seroprevalence. Generally, our study put forward that the various aspects of infection prevention in NH require more attention and investment. This exploratory study suggests that the ratio of residents with dementia, the availability of test capacity and personal protective equipment may have played a role in the SARS-CoV-2 seroprevalence of NH, after the first wave. It underscores the importance of the availability of PPE and education in infection prevention. Moreover, investments may also yield benefits in the prevention of other respiratory infections (such as influenza)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Janssens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

During the SARS-CoV-2 pandemic, rapid and sensitive detection of SARS-CoV-2 has been of high importance for outbreak control. Reverse transcriptase polymerase chain reaction (RT-PCR) is the current gold standard, however, the procedures require an equipped laboratory setting and personnel, which have been regularly overburdened during the pandemic. This often resulted in long waiting times for patients. In contrast, reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) is a simple, cost-efficient, and fast procedure, allowing for rapid and remote detection of SARS-CoV-2. In the current study, we performed a clinical evaluation of a new point-of-care test system based on LAMP-technology for SARS-CoV-2 detection, providing a result within 25 min (1copy™ COVID-19 MDx Kit Professional system). We tested 112 paired nasopharyngeal swabs, collected in the COVID-19 Ghent University Hospital test center, using the 1copy™ COVID-19 MDx Kit Professional system, and RT-PCR as the reference method. The test system was found to have a clinical sensitivity of 93.24% (69/74) (95% confidence interval [CI]: 84.93%-97.77%) and specificity of 97.37% (37/38) (95% CI: 86.19%-99.93%). Due to its easy smartphone operation and ready-to-use reagents, it ought to be easily applied in for instance general practices, pharmacies, nursing homes, schools, and companies. This would facilitate an efficient SARS-CoV-2 outbreak control and quarantine policy, as diagnosis can occur sooner in a near-patient setting., (© 2023 Wiley Periodicals LLC.)

Vitamin D is an essential nutrient for various physiological functions, including immunity. While it has been suggested that higher vitamin D levels/supplementation are associated with a better immune response to COVID-19 vaccination, conflicting data exist. Therefore, we aimed to investigate the association between vitamin D (25-hydroxyvitamin D) deficiency/supplementation, and SARS-CoV-2 antibody responses post-vaccination in nursing home residents (NHRs) and staff (NHS). Blood samples were collected from 115 NHRs and 254 NHS at baseline and 14 days after primary course BNT162b2 vaccination. Baseline samples were assessed for serum 25-hydroxyvitamin D levels, while follow-up samples were analyzed for spike protein S1 receptor-binding domain (S1RBD) IgG antibody concentrations and 50% pseudoneutralization titers. Vitamin D supplementation status was obtained from NHRs medical records. We compared immune responses between (severe) vitamin D-deficient and -sufficient NHRs/NHS and between supplemented and non-supplemented NHRs, stratified for history of SARS-CoV-2 infection and participant type. No significant differences in either binding or neutralizing COVID-19 vaccine antibody response were found between groups. The prevalence of vitamin D deficiency (<20 ng/mL) was 45% (95% CI: 36-54%) among NHRs and 60% (95% CI: 54-66%) among NHS. Although we showed that vitamin D status may not be related to a better COVID-19 vaccine antibody response, addressing the high prevalence of vitamin D deficiency in the nursing home population remains important.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Randomised controlled trials (RCTs) investigated analgesics, herbal formulations, delayed prescription of antibiotics, and placebo to prevent overprescription of antibiotics in women with uncomplicated urinary tract infections (uUTI)., Objectives: To estimate the effect of these strategies and to identify symptoms, signs, or other factors that indicate a benefit from these strategies., Data Sources: MEDLINE, EMBASE, Web of Science, LILACS, Cochrane Database of Systematic Reviews and of Controlled Trials, and ClinicalTrials., Study Eligibility Criteria, Participants and Interventions: RCTs investigating any strategies to reduce antibiotics vs. immediate antibiotics in adult women with uUTI in primary care., Methods: We extracted individual participant data (IPD) if available, otherwise aggregate data (AD). Bayesian random-effects meta-analysis of the AD was used for pairwise comparisons. Candidate moderators and prognostic indicators of treatment effects were investigated using generalised linear mixed models based on IPD., Results: We analysed IPD of 3524 patients from eight RCTs and AD of 78 patients. Non-antibiotic strategies increased the rates of incomplete recovery (OR 3.0; 95% credible interval (CrI), 1.7-5.5; Bayesian p-value (p B ) = 0.0017; τ = 0.6), subsequent antibiotic treatment (OR 3.5; 95% CrI, 2.1-5.8; p B  = 0.0003) and pyelonephritis (OR 5.6; 95% CrI, 2.3-13.9; p B  = 0.0003). Conversely, they decreased overall antibiotic use by 63%. Patients positive for urinary erythrocytes and urine culture were at increased risk for incomplete recovery (OR 4.7; 95% CrI, 2.1-10.8; p B  = 0.0010), but no difference was apparent where both were negative (OR 0.8; 95% CrI, 0.3-2.0; p B  = 0.667). In patients treated using non-antibiotic strategies, urinary erythrocytes and positive urine culture were independent prognostic indicators for subsequent antibiotic treatment and pyelonephritis., Conclusions: Compared to immediate antibiotics, non-antibiotic strategies reduce overall antibiotic use but result in poorer clinical outcomes. The presence of erythrocytes and tests to confirm bacteria in urine could be used to target antibiotic prescribing., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the rate and appropriateness of antibiotic prescribing for acutely ill children in ambulatory care in high-income countries., Design: On 10 February 2021, we systematically searched articles published since 2000 in MEDLINE, Embase, CENTRAL, Web Of Science and grey literature databases. We included cross-sectional and longitudinal studies, time-series analyses, randomised controlled trials and non-randomised studies of interventions with acutely ill children up to and including 12 years of age in ambulatory care settings in high-income countries. Pooled antibiotic prescribing and appropriateness rates were calculated using random-effects models. Meta-regression was performed to describe the relationship between the antibiotic prescribing rate and study-level covariates., Results: We included 86 studies comprising 11 114 863 children. We found a pooled antibiotic prescribing rate of 45.4% (95% CI 38.2% to 52.8%) for all acutely ill children, and 85.6% (95% CI 73.3% to 92.9%) for acute otitis media, 37.4% (95% CI 30.9% to 44.3%) for respiratory tract infections, and 40.4% (95% CI 29.9% to 51.9%) for other diagnoses. Considerable heterogeneity can only partly be explained by differences in diagnoses. The overall pooled appropriateness rate is 68.5% (95% CI 55.8% to 78.9%, I²=99.8%; 19 studies, 119 995 participants). 38.3% of all prescribed antibiotics were aminopenicillins., Conclusions: Antibiotic prescribing rates for acutely ill children in ambulatory care in high-income countries remain high. Large differences in prescription rates between studies can only partly be explained by differences in diagnoses. Better registration and further research are needed to investigate patient-level data on diagnosis and appropriateness., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Introduction: Overdiagnosis is the diagnosis of a disease that would never have caused any symptom or problem. It is a harmful side effect of screening and may lead to unnecessary treatment, costs and emotional drawbacks. Doctors and other healthcare professionals (HCPs) have the opportunity to mitigate these consequences, not only by informing their patients or the public but also by adjusting screening methods or even by refraining from screening. However, it is unclear to what extent HCPs are fully aware of overdiagnosis and whether it affects their screening decisions. With this systematic review, we aim to synthesise all available research about what HCPs know and think about overdiagnosis, how it affects their position on screening policy and whether they think patients and the public should be informed about it., Methods and Analysis: We will systematically search several databases (MEDLINE, Embase, Web of Science, Scopus, CINAHL and PsycArticles) for studies that directly examine HCPs' knowledge and subjective perceptions of overdiagnosis due to health screening, both qualitatively and quantitatively. We will optimise our search by scanning reference and citation lists, contacting experts in the field and hand searching abstracts from the annual conference on 'Preventing Overdiagnosis'. After selection and quality appraisal, we will analyse qualitative and quantitative findings separately in a segregated design for mixed-method reviews. The data will be examined and presented descriptively. If the retrieved studies allow it, we will review them from a constructivist perspective through a critical interpretive synthesis., Ethics and Dissemination: For this type of research, no ethical approval is required. Findings from this systematic review will be published in a peer-reviewed journal and presented at the annual congress of 'Preventing Overdiagnosis'. In addition, the results will serve as guidance for further research on this topic., Prospero Registration Number: CRD42021244513., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Dried Blood Spots (DBS) are broadly used in SARS-CoV-2 surveillance studies, reporting either the presence or absence of SARS-CoV-2 antibodies. However, quantitative follow-up has become increasingly important to monitor humoral vaccine responses. Therefore, we aimed to evaluate the performance of DBS for the detection of anti-spike SARS-CoV-2 antibody concentrations using a commercially available assay, reporting in a standardised unitage (International Units/mL; IU/mL). To assess the sensitivity and specificity of the ImmunoDiagnostics ELISA on serum and DBS for SARS-CoV-2 antibody detection, we analysed 72 paired DBS and serum samples. The SARS-CoV-2 S1 IgG ELISA kit (EUROIMMUN) on serum was used as the reference method. We performed a statistical assessment to optimise the cut-off value for DBS and serum and assessed the correlation between DBS and serum antibody concentrations. We found that anti-spike SARS-CoV-2 antibody concentrations detected in DBS are highly correlated to those detected in paired serum (Pearson correlation 0.98; p-value < 0.0001), allowing to assess serum antibody concentration using DBS. The optimal cut-off for antibody detection on DBS was found to be 26 IU/mL, with 98.1% sensitivity and 100% specificity. For serum, the optimal cut-off was 14 IU/mL, with 100% sensitivity and 100% specificity. Therefore, we conclude that the ImmunoDiagnostics ELISA kit has optimal performance in the detection of SARS-CoV-2 antibodies on both DBS and serum. This makes DBS ideal for large-scale follow-up of humoral SARS-CoV-2 immune responses, as it is an easy but valuable sampling method for quantification of SARS-CoV-2 antibodies, compared to serum., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2022. Published by Elsevier B.V.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In Belgium, nursing home staff (NHS) and residents were prioritised for COVID-19 vaccination. However, vaccine hesitancy may have impacted vaccination rates. In this study, a random stratified sample of NHS ( N = 1142), vaccinated and unvaccinated, completed an online questionnaire on COVID-19 vaccine hesitancy (between 31 July and 15 November 2021). NHS who hesitated or refused the vaccine were asked for the main reason for their hesitation/refusal. Those who hesitated, but eventually accepted vaccination, were asked why they changed their minds. Overall, 29.5% of all respondents hesitated before accepting vaccination, were still hesitating, or refused vaccination. Principal reasons were fear of unknown future effects (55.1% of vaccinated participants that hesitated and 19.5% who refused), fear of side-effects (12.7% of vaccinated participants that hesitated and 12.2% who refused), and mistrust in vaccination (10.5% of vaccinated participants that hesitated and 12.2% who refused). For vaccinated participants who hesitated initially, protecting the vulnerable was the main reason they changed their minds. Given this degree of fear and proposals to mandate vaccination among healthcare workers, communicating with NHS on the safety and efficacy of the vaccine should be prioritised.

Objective: To estimate the rate and type of downstream activities (DAs) after laboratory testing in primary care, with a specific focus on check-up laboratory panels, and to explore the effect of a clinical decision support system (CDSS) for laboratory ordering on these DAs., Design: Cluster randomised clinical trial., Setting: 72 primary care practices in Belgium, with 272 general practitioners (GPs), randomly assigned to the intervention arm or the control arm., Participants: The study included 10 270 lab panels from 9683 primary care patients (women 55.1%, mean age 56.5). All adult patients who consulted one of the participating GPs during the trial period and needed a laboratory exam were eligible for participation., Interventions: GPs in the intervention group used a CDSS integrated into their online laboratory ordering system, while GPs in the control arm used their lab ordering system as usual. The trial duration was 6 months, with another 6 months follow-up., Main Outcome Measures: This publication reports on the exploratory outcome of DAs after an initial laboratory exam and the effect of the CDSS on these DAs., Results: 19.7% of all laboratory panels resulted in further diagnostic procedures (95% CI 18.9% to 20.5%) and 19% (95% CI 18.2% to 19.7%) in treatment changes. Check-up laboratory exams showed similar rates of DAs, with 17.5% (95% CI 13.8% to 21.2%) diagnostic DAs and 18.9% (95% CI 13.9% to 23.9%) treatment changes. Using the CDSS resulted in a significant reduction in downstream referrals (-2.4%; 95% CI -4.2% to -0.6%; p=0008), imaging and endoscopies (-0.9%; 95% CI -1.6% to -0.1%; p=0026) and treatment changes (-5.4%; 95% CI -9.5% to -1.2%; p=0.01)., Conclusion: This is the largest study so far to examine DAs after laboratory testing. It shows that almost one in three laboratory exams leads to further DAs, even in check-up panels. Using a CDSS for laboratory orders may reduce the rate of some DAs., Trial Registration Number: NCT02950142., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the high efficacy of the BNT162b2 vaccine in the general population, data on its immunogenicity among frail elderly individuals are limited. Recently, levels of anti-SARS-CoV-2 spike IgG antibodies and serum neutralization titers were confirmed as good immune markers of protection against the virus, with evidence showing a reverse correlation between these two parameters and susceptibility to infection. Here we analyzed sera from 138 nursing home residents (median age of 88.9 years) and 312 nursing home staff (median age of 50.7 years) to determine the humoral response to two doses of the BNT162b2 vaccine, and found markedly decreased serum anti-spike antibody levels and neutralization titers in the nursing home resident (NHR) group, with over 11% non-responders compared to only 1.3% among the controls. Moreover, three months post-vaccination, a significant decrease in antibody titers was observed in COVID-19-naive nursing home residents. Subsequent flow cytometry and interferon gamma secretion analyses indicated that antibody non-responders among NHRs also failed to mount cellular responses. The presented data emphasize that additional measures are needed in the population of frail elderly individuals. Given the high proportion of non-responders among NHRs, continued monitoring should be considered in this group.

Introduction: National SARS-CoV-2 seroprevalence data provide essential information about population exposure to the virus and help predict the future course of the epidemic. Early cohort studies have suggested declines in levels of antibodies in individuals associated with, for example, illness severity, age and comorbidities. This protocol focuses on the seroprevalence among primary healthcare providers (PHCPs) in Belgium. PHCPs manage the vast majority of (COVID-19) patients and therefore play an essential role in the efficient organisation of healthcare. Currently, evidence is lacking on (1) how many PHCPs get infected with SARS-CoV-2 in Belgium, (2) the rate at which this happens, (3) their clinical spectrum, (4) their risk factors, (5) the effectiveness of the measures to prevent infection and (6) the accuracy of the serology-based point-of-care test (POCT) in a primary care setting., Methods and Analysis: This study will be set up as a prospective cohort study. General practitioners (GPs) and other PHCPs (working in a GP practice) will be recruited via professional networks and professional media outlets to register online to participate. Registered GPs and other PHCPs will be asked at each testing point (n=9) to perform a capillary blood sample antibody POCT targeting IgM and IgG against the receptor-binding domain of SARS-CoV-2 and complete an online questionnaire. The primary outcomes are the prevalence and incidence of antibodies against SARS-CoV-2 in PHCPs during a 12-month follow-up period. Secondary outcomes include the longevity of antibodies against SARS-CoV-2., Ethics and Dissemination: Ethical approval has been granted by the ethics committee of the University Hospital of Antwerp/University of Antwerp (Belgian registration number: 3002020000237). Alongside journal publications, dissemination activities include the publication of monthly reports to be shared with the participants and the general population through the publicly available website of the Belgian health authorities (Sciensano)., Trial Registration Number: NCT04779424., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Primary health care providers (PHCPs) are assumed to be at high risk of a COVID-19 infection, as they are exposed to patients with usually less personal protective equipment (PPE) than other frontline health care workers (HCWs). Nevertheless, current research efforts focussed on the assessment of COVID-19 seroprevalence rates in the general population or hospital HCWs., Objective: We aimed to determine the seroprevalence in PHCPs during the second SARS-CoV-2 wave in Flanders (Belgium) and compared it to the seroprevalence in the general population. We also assessed risk factors, availability of PPE and attitudes towards the government guidelines over time., Methods: A prospective cohort of PHCPs (n = 698), mainly general practitioners, was asked to complete a questionnaire and self-sample capillary blood by finger-pricking at five distinct points in time (June-December 2020). We analysed the dried blood spots for IgG antibodies using a Luminex multiplex immunoassay., Results: The seroprevalence of PHCPs remained stable between June and September (4.6-5.0%), increased significantly from October to December (8.1-13.4%) and was significantly higher than the seroprevalence of the general population. The majority of PHCPs were concerned about becoming infected, had adequate PPE and showed increasing confidence in government guidelines., Conclusions: The marked increase in seroprevalence during the second COVID-19 wave shows that PHCPs were more at risk during the second wave compared to the first wave in Flanders. This increase was only slightly higher in PHCPs than in the general population suggesting that the occupational health measures implemented provided sufficient protection when managing patients., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

In the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, testing for SARS-CoV-2-specific antibodies is paramount for monitoring immune responses in postauthorization vaccination and seroepidemiological studies. However, large-scale and iterative serological testing by venipuncture in older persons can be challenging. Capillary blood sampling using a finger prick and collection on protein saver cards, i.e., dried blood spots (DBSs), has already proven to be a promising alternative. However, elderly persons have reduced cutaneous microvasculature, which may affect DBS-based antibody testing. Therefore, we aimed to evaluate the performance of DBS tests for the detection of SARS-CoV-2 antibodies among nursing homes residents. We collected paired venous blood and DBS samples on two types of protein saver cards (Whatman and EUROIMMUN) from nursing home residents, as well as from staff members as a reference population. Venous blood samples were analyzed for the presence of SARS-CoV-2 IgG antibodies using the Abbott chemiluminescent microparticle immunoassay (CMIA). DBS samples were analyzed by the EUROIMMUN enzyme-linked immunosorbent assay (ELISA) for SARS-CoV-2 IgG antibodies. We performed a statistical assessment to optimize the ELISA cutoff value for the DBS testing using Youden's J index. A total of 273 paired DBS-serum samples were analyzed, of which 129 were positive, as assessed by the reference test. The sensitivities and specificities of DBS testing ranged from 95.0% to 97.1% and from 97.1% to 98.8%, respectively, depending on the population (residents or staff members) and the DBS card type. Therefore, we found that DBS sampling is a valid alternative to venipuncture for the detection of SARS-CoV-2 antibodies among elderly subjects. IMPORTANCE Since the implementation of newly developed SARS-CoV-2 vaccines in the general population, serological tests are of increasing importance. Because DBS samples can be obtained with a finger prick and can be shipped and stored at room temperature, they are optimal for use in large-scale SARS-CoV-2 serosurveillance or postauthorization vaccination studies, even in an elderly study population.

Introduction: Cardiovascular disease (CVD) being the leading cause of the morbidity and mortality in Vietnam, the objective of this study was to estimate the total 10-year CVD risk among adults aged 40-69 years by utilizing World Health Organization/International Society of Hypertension (WHO/ISH) risk prediction charts in Central Vietnam., Materials and Methods: In this cross-sectional study, multi-staged sampling was used to select 938 participants from a general population aged from 40 to 69. The CVD risk factors were then collected throughout the interviews with a standardized questionnaire, anthropometric measurements and a blood test. The cardiovascular risk was calculated using the WHO/ISH risk prediction charts., Results: According to the WHO/ISH charts, the proportion of moderate risk (10-20%) and high risk (>20%) among the surveyed participants were equal (5.1%). When "blood pressure of more than 160/100 mmHg" was applied, the proportion of moderate risk reduced to 2.3% while the high risk increased markedly to 12.8%. Those proportions were higher in men than in women (at 18.3% and 8.5% respectively, p-value <0.001, among the high-risk group), increasing with age. Male gender, smoking, ethnic minorities, hypertension and diabetes were associated with increased CVD risk., Conclusions: There was a high burden of CVD risk in Central Vietnam as assessed with the WHO/ISH risk prediction charts, especially in men and among the ethnic minorities. The use of WHO/ISH charts provided a feasible and affordable screening tool in estimating the cardiovascular risk in primary care settings., Competing Interests: The authors have no financial or personal relationships with other people or organizations that could inappropriately influence their work. The authors have declared that no competing interests exist. The authors do not receive any employment or consultancy from the China Medical Board of New York; the authors do not have to submit any patents, products in development, or marketed products to this funder, either. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Uncomplicated urinary tract infection (UTI) in women is a common reason to present in general practice and is usually treated with antibiotics to reduce symptom severity and duration. Results of recent clinical trials indicate that non-antibiotic treatment approaches can also be effective. However, it remains unclear which patients would benefit from antibiotic treatment and which can effectively and safely be treated without antibiotics. This systematic review and meta-analysis aims to estimate the effect of treatment strategies to reduce antibiotic use in comparison with immediate antibiotic treatment and to identify prognostic factors and moderators of treatment effects. A further aim is to identify subgroups of patients benefiting from a specific therapy., Methods and Analysis: A systematic literature search will be performed to identify randomised controlled trials which investigated the effect of treatment strategies to reduce antibiotic use in female adults with uncomplicated UTI compared with immediate antibiotic treatment. Therefore, the primary outcome of the meta-analysis is incomplete recovery. Anonymised individual patient data (IPD) will be collected. Aggregate data will be used for pairwise comparisons of treatment strategies using meta-analysis models with random effects accounting for potential between-study heterogeneity. Potential effect moderators will be explored in meta-regressions. For IPD, generalised linear mixed models will be used, which may be adjusted for baseline characteristics. Interactions of baseline variables with treatment effects will be explored. These models will be used to assess direct comparisons of treatment, but might be extended to networks., Ethics and Dissemination: The local institutional review and ethics board judged the project a secondary analysis of existing anonymous data which meet the criteria for waiver of ethics review. Dissemination of the results will be via published scientific papers and presentations. Key messages will be promoted for example, via social media or press releases., Prospero Registration Number: CRD42019125804., Competing Interests: Competing interests: IG, GF, TF, EH, MM are involved in the following studies: ‘REGATTA—reducing antibiotic use for uncomplicated urinary tract infection in general practice by treatment with uva-ursi’. Afshar K, Fleischmann N, Schmiemann G, Bleidorn J, Hummers-Pradier E, Friede T, Wegscheider K, Moore M, Gagyor I. 'Reducing antibiotic use for uncomplicated urinary tract infection in general practice by treatment with uva-ursi (REGATTA)—a double-blind, randomised, controlled comparative effectiveness trial'. BMC Complement Altern Med. 2018 Jul 3;18(1):203. doi: 10.1186/s12906-018-2266-x). IV was involved in the study: ‘Vik I, Bollestad M, Grude N, Bærheim A, Damsgaard E, Neumark T, Bjerrum L, Cordoba G, Olsen IC, Lindbæk M. Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women—a double-blind, randomised non-inferiority trial'. PLoS Med 15;5:e1002569. Doi.org/10.1371/journal.pmed.1002569. MM, ADH and PL are coauthors of the study: ‘Moore M, Trill J, Simpson C, Webley F, Radford M, Stanton L, Maishman T, Glanopoulou A, Flower A, Eyles C, Willcox M, Hay AD, van der Werf E, Gibbons S, Lewith G, Little P, Griffiths G. Uva-ursi extract and ibuprofen as alternative treatments for uncomplicated urinary tract infection in women (ATAFUTI): a factorial randomised trial. Clinical Microbiology and Infection'. Doi.org/10.1016/j.cmi.2019.01.011. SH was involved in the study with the reference number 11. PL and MM were involved in the study with the reference number 12. SF and TM were involved in the study with the reference number 13. IG, EH were involved in the studies with the reference numbers 14 and 15. AK was involved in the study with the reference number 16., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The diagnosis of urinary tract infections (UTIs) in institutionalized older adults is often based on vague symptoms and a positive culture. The high prevalence of asymptomatic bacteriuria (ABU), which cannot be easily discriminated from an acute infection in this population, is frequently neglected, leading to a vast over-prescription of antibiotics. This study aimed to identify subpopulations predisposed to transient or long-term ABU., Methods: Residents in a long-term care facility were screened for ABU. Mid-stream urine samples were collected during two sampling rounds, separated by 10 weeks, each consisting of an initial and a confirmative follow-up sample., Results: ABU occurred in approximately 40% of the participants and was mostly caused by Escherichia coli. Long-term ABU (> 3 months) was found in 30% of the subjects. The frailest women with urinary incontinence and dementia had drastically increased rates of ABU and especially long-term ABU. ABU was best predicted by a scale describing the functional independence of older adults., Conclusions: Institutionalized women with incontinence have ABU prevalence rates of about 80% and are often persistent carriers. Such prevalence rates should be considered in clinical decision making as they devalue the meaning of a positive urine culture as a criterion to diagnose UTIs. Diagnostic strategies are urgently needed to avoid antibiotic overuse and to identify patients at risk to develop upper UTI.

Objectives: Patients with medically unexplained physical symptoms suffer from chronic fatigue and/or pain in combination with a variety of other symptoms. A flexible, biopsychosocial approach is needed for diagnostic screening and global management. It is crucial to involve the direct patient environment, including family, friends, colleagues as well as health providers, evaluation, and reintegration sector. The aim of this paper is to review the importance of work in the management of medically unexplained physical symptoms., Methods: In this paper, different actors involved explain their views and handling concerning work in the management of MUPS., Results: Symptom severity and lack of understanding from the environment can negatively impact on earning an independent income from labor for years. Work, whether or not paid, is however, an important life domain with positive effects on physical, psychological, and social well-being. Therefore, health actors are pivotal in starting the professional reintegration process as soon as possible and should discuss this item from the early stage onward. Support services can be consulted in mutual interaction as required. A case manager, acting as a central intermediator within this multidisciplinary approach, may promote effective communication and coordination between the patients and their surrounding actors., Conclusion: The professional reintegration process should start as soon as possible within the management of medically unexplained physical symptoms. As such, the care sector, the evaluation sector, and the professional integration sector should collaborate and effectively communicate with each other.

Background: Although cystitis in women is very common in general practice, its evolution in symptoms has not been clearly studied. Qualitative research has pointed to other than the classic symptomatology., Methods: This was a prospective observational study of the symptomatology at presentation and the evolution of the symptoms in treated women with suspected uncomplicated urinary tract infection (UTI). Women consulting their general practitioner (GP) for dysuria, urgency, or frequency produced a urine sample (for bacteriologic processing) and kept a diary until the end of the symptoms. Exclusion criteria included complaints >1 week, fever, vaginal discharge, and known pathology., Results: Of the 300 asked to participate, 148 (49%) returned the diary. Although none of the patients developed acute pyelonephritis, a substantial number of the women had such complaints as feeling feverish (33% in culture-positive group, 38% in culture-negative group), back pains (44% vs. 56%), and feeling weak and tired (71% vs. 65%). Differences between the culture-positive and culture-negative groups were not statistically significant except for the duration of symptoms, which was shorter in the culture-positive group (4 vs. 6 days). More severe symptoms at inclusion were correlated with a longer duration of these symptoms., Conclusions: The spectrum of complaints in women with suspected uncomplicated UTI is broad and comprises a number of symptoms usually associated with an upper UTI. The occurrence of these symptoms should not automatically prompt GPs to prescribe broad-spectrum antibiotics. Moreover, the duration of symptoms exceeding the recommended duration of antibiotic therapy does not indicate therapy failure and, thus, the need for changing antibiotic therapy.

Objectives: For the empirical treatment of cystitis, clinicians are often guided by susceptibility data taken from urinary samples that sent to regional microbiological laboratories, which are not representatives for uncomplicated urinary tract infections (UTIs). To offer adequate recommendations, the distribution and susceptibility pattern of uropathogens in uncomplicated UTIs in women were compared with those obtained 10 years ago in our uropathogen surveillance in a primary healthcare setting., Methods: Sixty-six general practitioners in the region of the city of Ghent were asked to inoculate a dipslide with midstream urine from every adult female patient with complaints suggestive for cystitis, during a period of 1 year. The dipslides were further processed in a central microbiological laboratory, where counting, identification and susceptibility testing were performed., Results: Three hundred specimens were collected, of which 187 (62.3%) yielded a positive culture of 10(5) cfu/mL. In the age group of 18-54 years, Escherichia coli was the most frequently isolated uropathogen (77.5%), followed by Staphylococcus saprophyticus (13.5%) and Proteus spp. (2.7%). There were no statistically significant differences when compared with the data from 1996. In 2006, susceptibility of E. coli to nitrofurantoin was 100%, to quinolones 100%, to ampicillin 62.8% and to co-trimoxazole 86%, compared with 99.3%, 99.3%, 73.2% and 83.3%, respectively, in 1996 (no statistically significant differences)., Conclusions: Over a period of 10 years, a systematic surveillance of uropathogens in female patients with uncomplicated UTI in general practice could not demonstrate a significant change in species distribution or antimicrobial susceptibility.

Background: Urinary tract infections (UTIs) are very common and have been treated with apparent success with antimicrobials for many years. However, there is a paucity of placebo-controlled clinical trials., Aim: To measure the symptomatic and bacteriological short-term effect of nitrofurantoin treatment versus placebo, in the treatment of uncomplicated UTI in adult non-pregnant women., Design of Study: Randomised placebo-controlled trial in general practice., Setting: Non-pregnant women, aged between 15 and 54 years old, consulting a general practitioner for symtoms suggestive of uncomplicated lower UTI and with pyuria (positive for leucocyte esterase test)., Method: A dipslide was inoculated in first-void midstream urine and sent for examinion. The patients were randomised to receive nitrofurantoin 100 mg or placebo four times daily for three days. After three, seven, and 14 days a new dipslide was inoculated and symptoms of UTI were checked or improvement of symptoms and bacteriuria., Results: Of 166 women consulting with symptoms suggestive for UTI, 78 had pyuia and agreed to participate in the study (the clinically suspected UTI group); of these, 40 received nitrofurantoin and 38 received placebo. The result for combined symptomatic improvement and cure after three days was 27/35 in the nitrofurantoin group and 19/35 in the placebo group (c2 with Yates' correction P = 0.008; number needed to treat [NNT] = 4.4, 95% confidence interval [CI] = 2.3 to 79). After seven days, combined improvement and cure was observed in 30/34 and 17/33 respectively (P = 0.003, NNT = 2.7, 95% CI = 1.8 to 6.0). At inclusion, 56 women had bacteriuria of > or = 10(5) CFU/ml (the bacteriologically proven UTI group). Of these, 29 received nitrofurantoin and 27 received placebo. After three days the bacteriological cure was 21/26 in the treatment group, compared with 5/25 in the placebo group (P < 0.001; NNT = 1.6, 95% CI= 1.2 to 2.6). After seven days the bacteriological cure rate was 17/23 in the intervention group and 9/22 in the placebo group (P = 0.05, NNT = 3, 95% CI = 1.7 to 17)., Conclusion: In women with bacteriologically proven UTI, nitrofurantoin was significantly more effective than placebo in achieving bacteriological cure and symptomatic relief in just three days; this was still present after seven days. In patients with clinically suspected UTI the symptomatic effect was statistically significant after