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Background: High basal plasma levels of inflammatory molecules are associated with a higher risk of cardiovascular events. It has been suggested that also the dynamic response to an inflammatory trigger is important in determining cardiovascular risk. The aim of the present study was to evaluate the use of vaccination against yellow fever as an in vivo model to study the interindividual variation in the response to inflammatory triggers. Methods: Ten healthy volunteers were vaccinated with 17D yellow fever vaccine. Blood samples were drawn each day, until Day 8 after vaccination. Automated blood cell counting was performed, and the plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen were determined. Results: In most individuals, CRP levels peaked slightly (45% increase from basal values) around Day 7 after vaccination, preceded by an IL-6 (30%) peak around Day 5. Fibrinogen levels showed a significant increase (10%) from Day 2 after vaccination, with a further rise (17%) around Day 5. The monocyte fraction showed a significant 2-fold increase on Day 7 after vaccination. The lymphocyte fraction increased slightly towards Day 7 (not significant). Conclusion: Our findings show that yellow fever vaccination can be used as a model to study the response to mild stimulation of the inflammatory system. [Copyright &y& Elsevier]

The article discusses the methodology behind joint malaria prevention recommendations from Switzerland, Germany, Belgium, and The Netherlands. These countries have collaborated to align their recommendations based on epidemiological data quality and refined methodology. The process involves defining malaria risk categories, compiling data on malaria incidence, creating raw risk maps, adjusting maps based on expert discussions, and publishing final recommendations. The aim is to provide transparent and evidence-based recommendations for travel medicine advisors and travelers. [Extracted from the article]

This case report describes a patient diagnosed with ongoing portal venous gas, initiated by a rather common Campylobacter enterocolitis and maintained by septic thrombophlebitis and possibly by chronic cholecystitis. Cholecystectomy attenuated the patient''s septic condition. The etiology of portal venous gas determines both the patient''s prognosis and the choice for either conservative or surgical treatment. This report describes persistence of portal venous gas for a long period and a possible role for chronic cholecystitis as a cause. [Copyright &y& Elsevier]

Background: Electronic informed consent (eConsent) usage has expanded in recent years in Europe, especially during the pandemic. Slow recruitment rate and limitations in participant outreach are the challenges often faced in clinical research. Given the benefits of eConsent and group counselling reported in the literature, group eConsent was implemented in recruitment for the SWITCH-ON study. We aim to explore the experience of participants who attended group eConsent for the SWITCH-ON study and evaluate its potential for future use. Methods: SWITCH-ON study aims to analyse the immunogenicity of a healthy population following bivalent COVID-19 booster vaccination. Four hundred thirty-four healthcare workers aged 18–65 were successfully recruited and sent a questionnaire about their experience with group eConsent. Out of 399 completed questionnaires (response rate 92%), 39 participants did not join group eConsent. The remaining 360 responses were included in the final analysis. Quantitative and qualitative data were reported using descriptive statistical analysis and thematic analysis respectively. Results: Participants found that group eConsent was an efficient method that it allowed them to hear each other's questions and concerns and created a sense of togetherness. However, limited privacy, barriers to asking questions in a group, and peer pressure can limit the use of group eConsent. One hundred sixty-five (46%) participants thought that group eConsent was suitable to recruit participants with diseases or conditions, while 87 (24%) reported limitations with this method. The remaining participants suggested that applicability of group eConsent depended on the diseases or conditions of the study population, and one-to-one conversation should always be available. Participants who had experienced both one-to-one and group eConsent shared different preferred consent formats for future studies. Conclusion: Group eConsent was positively evaluated by the participants of a low-risk vaccination study. Participants advised using webinars to provide general information about the study, followed by an individual session for each participant, would retain the benefits of group eConsent and minimise the limitations it posed. This proposed setting addresses privacy questions and makes group eConsent easier to implement. Trial registration: ClinicalTrials.gov NCT05471440 (registered on 22nd of July, 2022). [ABSTRACT FROM AUTHOR]

The absence of a consensus-based reference standard for urinary tract infection (UTI) research adversely affects the internal and external validity of diagnostic and therapeutic studies. This omission hinders the accumulation of evidence for a disease that imposes a substantial burden on patients and society, particularly in an era of increasing antimicrobial resistance. We did a three-round Delphi study involving an international, multidisciplinary panel of UTI experts (n=46) and achieved a high degree of consensus (94%) on the final reference standard. New-onset dysuria, urinary frequency, and urinary urgency were considered major symptoms, and non-specific symptoms in older patients were not deemed indicative of UTI. The reference standard distinguishes between UTI with and without systemic involvement, abandoning the term complicated UTI. Moreover, different levels of pyuria were incorporated in the reference standard, encouraging quantification of pyuria in studies done in all health-care settings. The traditional bacteriuria threshold (105 colony-forming units per mL) was lowered to 104 colony-forming units per mL. This new reference standard can be used for UTI research across many patient populations and has the potential to increase homogeneity between studies. [ABSTRACT FROM AUTHOR]

Background: In 2013, the World Health Organization (WHO) revised their position on yellow fever vaccination, in which revaccination every 10 years was no longer required, and that a single-dose provided life-long protection. However, research data on the immunogenicity of YF vaccine in people aged 60 years and over are scarce. Indeed, immunosenescence may result in lower virus neutralizing antibody titers after primary vaccination and a more rapid waning immunity. Therefore, we tested the hypothesis that older travelers, vaccinated at 60 years or older are more likely to become seronegative in comparison to young adults 10 years after primary YF vaccination.Methods: This is a 10-year follow-up study of an earlier prospective controlled cohort study. In the original trial, the neutralizing antibody response was measured in older travelers (aged 60-81 years, N = 28) and young adults (aged 18-28 years, N = 30) up to 28 days after a primary yellow fever vaccination. Ten years later, we collected serum samples of 22/28 (78%) elderly (71-85 years) and 14/30 (47%) controls (29-40 years), and determined their neutralizing antibody titers by plaque reduction neutralization test (PRNT80). Seropositivity was defined as plaque formation reduction of 80% at a serum dilution of 10 or more (PRNT80 ≥ 10).Results: All participants (36/36) were still seropositive 10 years after primary vaccination. The geometric mean concentrations were not statistically different between the older and younger participants (6.7 IU/mL vs. 8.6 IU/mL, P = 0.5).Conclusions: All older travelers were seropositive, 10 years after a primary YF vaccination at the age of ≥60 years. These data suggest that in older travelers a single vaccination is sufficient to convey long-lasting immunity for at least 10 years, and is in support the position of the WHO on a single-dose yellow fever vaccination. [ABSTRACT FROM AUTHOR]

Rationale for review: The global yellow fever vaccine supply is insufficient to provide full-dose vaccination to millions threatened by outbreaks. Given the excess of live-attenuated 17D yellow fever virus in the current single dose vials, dose sparing would increase available vaccine doses manifold. Fractional-dose yellow fever vaccination is now accepted as an emergency solution, as short-term protection has been confirmed in an outbreak situation in the Democratic Republic of Congo, but broader application of this dose-sparing strategy is still not recommended. In this review, important knowledge gaps that hamper this application such as long-term protection after fractional-dose vaccination, safety, comparability across different genetic backgrounds and different World Health Organization-licensed yellow fever vaccines and immunogenicity in infants are addressed.Main findings: Recently, published results on long-term protection after fractional-dose vaccination in healthy young volunteers indicate that if a person mounts a protective response shortly after vaccination, the protective response will persist for 10 years and possibly longer. It also appears that fractional-dose vaccination does not elicit more serious adverse events than standard dose vaccination. Short-term immunogenicity studies are currently underway in specific populations (infants, human immunodeficiency virus (HIV)-infected persons and healthy adults living in Uganda and Kenya), of which the results will become available in 2021-22.Conclusions: Available results on long-lasting immunogenicity of fractional-dose yellow fever vaccination are encouraging, although confirmation is required in larger populations including young children living in yellow fever endemic areas. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the safety and immunogenicity of a dose-sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine. COVID-19 naive adults aged 18–30 years were recruited from a previous study on primary vaccination regimens that compared 20 μg ID vaccinations with 100 μg intramuscular (IM) vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 μg) or the standard-of-care intramuscular (IM) booster dose (50 μg) of the mRNA-1273 vaccine, 6 months after completing their primary series (ID-ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). In addition, COVID-19 naive individuals aged 18–40 years who had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti-spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored. In January 2022, 129 participants were included in the study. Fractional ID boosting was safe and well tolerated, with fewer systemic adverse events compared with IM boosting. At day 28 post-booster, anti-spike S1 IgG geometric mean concentrations were 9106 (95% CI, 7150–11 597) binding antibody units (BAU)/mL in the IM-IM group and 4357 (3003–6322) BAU/mL; 6629 (4913–8946) BAU/mL; and 5264 (4032–6873) BAU/mL in the ID-IM, ID-ID, and IM-ID groups, respectively. Intradermal boosting provides robust immune responses and is a viable dose-sparing strategy for mRNA COVID-19 vaccines. The favourable side-effect profile supports its potential to reduce vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness. [ABSTRACT FROM AUTHOR]

The article discusses methods on preventing yellow fever that is caused as a result of unchecked urbanisation which is a breeding group for the mosquito Aedes aegypti.

After rabies pre-exposure prophylaxis (PrEP) vaccination, scarcely available rabies immunoglobulins are not required for post-exposure prophylaxis (PEP). However, PrEP is not sufficiently accessible as it is cost-intensive and time-intensive. This study investigates whether rabies PrEP schedules can be shortened to one visit, removing some of these barriers. In a block-randomised (2:2:2:1) controlled, multicentre non-inferiority trial, healthy adult travellers (aged 18–50 years and >50 years) were randomly assigned to (A) single-visit intramuscular (1·0 mL); (B) single-visit intradermal (0·2 mL); (C) standard two-visit intramuscular (1·0 mL; day 0 and 7) PrEP; or (D) no rabies vaccination. 6 months later, participants received simulated intramuscular rabies PEP (1·0 mL; day 0 and 3). Rabies virus neutralising antibody (RVNA) concentrations were measured repeatedly. The primary outcome was the fold increase in geometric mean RVNA concentrations between day 0 and 7 after simulated PEP for all participants. The two main comparisons of this primary outcome are between the standard two-visit schedule and the one-visit intramuscular schedule, and between the standard two-visit schedule and the one-visit intradermal schedule. The non-inferiority margin was 0·67. This study is registered with EudraCT, 2017-000089-31. Between May 16, 2018, and March 26, 2020, 288 healthy adult travellers were randomly assigned and 214 participants were evaluated for the primary outcome. Single-visit intramuscular rabies PrEP induced an anamnestic antibody response non-inferior compared with the two-visit intramuscular schedule; single-visit intradermal PrEP did not. The fold increases in the single-visit intramuscular and the single-visit intradermal schedule were 2·32 (95% CI [1·43–3·77]) and 1·11 (0·66–1·87) times as high as the fold increase in the standard schedule, respectively. No vaccine-related serious adverse events were observed. Adverse events related to vaccination were mostly mild. Single intramuscular rabies vaccination can effectively prime travellers (aged 18–50 years), and potentially other populations, and could replace current standard two-visit rabies vaccination as PrEP. ZonMW. For the Dutch translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Urinary tract infection (UTI) is common among older women. However, diagnosis is challenging because of frequent chronic lower urinary tract symptoms, cognitive impairment, and a high prevalence of asymptomatic bacteriuria (ASB). Current urine diagnostics lack specificity, leading to unnecessary treatment and antimicrobial resistance. This study aimed to evaluate the diagnostic accuracy of 12 urine biomarkers for diagnosing UTI in older women. In this case-control study, cases were women ≥65 years with ≥2 new-onset lower urinary tract symptoms, pyuria, and one uropathogen ≥104 CFU/mL. Controls were asymptomatic and classified as ASB (one uropathogen ≥105 CFU/mL), negative culture, or mixed flora. Urine biomarker concentrations were measured through liquid chromatography-mass spectrometry and ELISA. Diagnostic accuracy parameters of individual biomarkers and a biomarker model were derived from receiver operating characteristic curves. We included 162 community-dwelling and institutionalized older women. Five urine inflammatory biomarkers demonstrated high discriminative ability (area under the curve ≥0.80): interleukin 6, azurocidin, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinases 2, and C-X-C motif chemokine 9. Azurocidin exhibited the highest diagnostic accuracy (sensitivity 86% [95% CI 75%–93%] and specificity 89% [95% CI 82%–94%] at 16.7 ng/mmol creatinine). A combined biomarker and pyuria model showed improved diagnostic accuracy in patients with UTI and ASB, compared with pyuria alone. We identified several urine biomarkers that accurately differentiated older women with UTI from asymptomatic women, including ASB. These findings represent a potential advancement towards improved diagnostics for UTI in older women and warrant validation in a diverse population. [ABSTRACT FROM AUTHOR]

Background: There is consistent evidence showing an interplay between psychological processes and immune function in health and disease processes.Objectives: The present systematic review and meta-analysis aims to provide a concise overview of the effectiveness of stress-reducing psychological interventions on the activation of immune responses in both healthy subjects and patients.Methods: Included are 3 types of challenges: in vivo, in vitro, and psychophysiological. Such challenges are designed to mimic naturally occurring immune-related threats.Results: A systematic literature search was conducted using PubMed, EMBASE, and PsychInfo, resulting in 75 eligible studies. The risk of bias was assessed with the Cochrane risk-of-bias tool. Across all studies, a small-to-medium effect size was found for the effects of psychological interventions on optimization of the immune function (g = 0.33; 95% CI 0.22-0.43). While the largest effects were found for in vivo immune-related challenges (g = 0.61; 95% CI 0.34-0.88; especially on studies that incorporated skin tests and wound healing), studies incorporating psychophysiological challenges and in vitro immune-related stimulations similarly suggest more optimal immune responses among those receiving stress-reducing interventions (g = 0.28; 95% CI 0.15-0.42).Conclusion: These findings showed substantial heterogeneity depending on the type of challenge, the study populations, and the intervention types. These data demonstrate support for the effectiveness of stress-reducing psychological interventions in improving immunity in studies that tested immune function by means of incorporating an in vivo,in vitro, or psychophysiological challenge. Future research should more consistently incorporate challenges into the study design to gather more insights in the mechanisms underlying the optimized immune function following a psychological intervention. This is also relevant for clinical practice, as psychological interventions can possibly supplement, or at least partially replace, current drug treatments in various somatic conditions to reduce side effects. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Special infectious disease risks of expatriate and long-term travelers in tropical countries, Part I: Malaria," by S. Toovey, F. Moerman and A. van Gompel in the 2007 issue is presented.

Abstract: Objectives: Blood cultures (BCs) are essential in the evaluation of neutropenic fever. Modern BC systems have significantly reduced the time‐to‐positivity (TTP) of BC. This study explores the probability of bacteraemia when BCs have remained negative for different periods of time. Methods: All adult patients with neutropenia and bacteraemia were included (January 2012‐February 2016). Predictive clinical factors for short (≤16 hours) and long (>24 hours) TTP were determined. The residual probability of bacteraemia was estimated for the scenario of negative BC 24 hours after collection. Results: The cohort consisted of 154 patients, accounting for 190 episodes of bacteraemia. Median age of 61 years, 60.5% were male. In 123 (64.7%) episodes, BC yielded a single Gram‐positive micro‐organism and in 49 (25.8%) a Gram‐negative micro‐organism (median TTP 16.7, 14.5 hours respectively, P < .01). TTP was ≤24 hours in 91.6% of episodes. Central line‐associated bacteraemia was associated with long TTP. The probability of bacteraemia if BC had remained negative for 24 hours was 1%‐3%. Conclusions: The expected TTP offers guidance in the management of patients with neutropenia and suspected bacteraemia. The knowledge of negative BC can support a change in working diagnosis, and impact clinical decisions as soon as 24 hours after BC collection. [ABSTRACT FROM AUTHOR]

Background Despite being the leading cause of mortality from bloodstream infections worldwide, little is known about regional variation in treatment practices for Staphylococcus aureus bacteremia (SAB). The aim of this study was to identify global variation in management, diagnostics, and definitions of SAB. Methods During a 20-day period in 2022, physicians throughout the world were surveyed on SAB treatment practices. The survey was distributed through listservs, e-mails, and social media. Results In total, 2031 physicians from 71 different countries on 6 continents (North America [701, 35%], Europe [573, 28%], Asia [409, 20%], Oceania [182, 9%], South America [124, 6%], and Africa [42, 2%]) completed the survey. Management-based responses differed significantly by continent for preferred treatment of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacteremia, use of adjunctive rifampin for prosthetic material infection, and use of oral antibiotics (P <.01 for all comparisons). The 18F-FDG PET/CT scans were most commonly used in Europe (94%) and least frequently used in Africa (13%) and North America (51%; P <.01). Although most respondents defined persistent SAB as 3 – 4 days of positive blood cultures, responses ranged from 2 days in 31% of European respondents to 7 days in 38% of Asian respondents (P <.01). Conclusions Large practice variations for SAB exist throughout the world, reflecting the paucity of high-quality data and the absence of an international standard of care for the management of SAB. [ABSTRACT FROM AUTHOR]

Introduction: Remdesivir is a registered treatment for hospitalised patients with COVID-19 that has moderate clinical effectiveness. Anecdotally, some patients' respiratory insufficiency seemed to recover particularly rapidly after initiation of remdesivir. In this study, we investigated if this rapid improvement was caused by remdesivir, and which patient characteristics might predict a rapid clinical improvement in response to remdesivir. Methods: This was a multicentre observational cohort study of hospitalised patients with COVID-19 who required supplemental oxygen and were treated with dexamethasone. Rapid clinical improvement in response to treatment was defined by a reduction of at least 1 L of supplemental oxygen per minute or discharge from the hospital within 72 h after admission. Inverse probability of treatment-weighted logistic regression modelling was used to assess the association between remdesivir and rapid clinical improvement. Secondary endpoints included in-hospital mortality, ICU admission rate and hospitalisation duration. Results: Of 871 patients included, 445 were treated with remdesivir. There was no influence of remdesivir on the occurrence of rapid clinical improvement (62% vs 61% OR 1.05, 95% CI 0.79–1.40; p = 0.76). The in-hospital mortality was lower (14.7% vs 19.8% OR 0.70, 95% CI 0.48–1.02; p = 0.06) for the remdesivir-treated patients. Rapid clinical improvement occurred more often in patients with low C-reactive protein (≤ 75 mg/L) and short duration of symptoms prior to hospitalisation (< 7 days) (OR 2.84, 95% CI 1.07–7.56). Conclusion: Remdesivir generally does not increase the incidence of rapid clinical improvement in hospitalised patients with COVID-19, but it might have an effect in patients with short duration of symptoms and limited signs of systemic inflammation. [ABSTRACT FROM AUTHOR]

The association of biological female sex with outcome in patients with Staphylococcus aureus bacteraemia remains unresolved. The aim of this study was to determine the independent association of female sex with management and mortality in patients with S. aureus bacteraemia. This is a post hoc analysis of prospectively collected data from the S. aureus Bacteraemia Group Prospective Cohort Study. Adult patients with monomicrobial S. aureus bacteraemia at Duke University Medical Center were enrolled from 1994 to 2020. Univariable and multivariable Cox regression analyses were performed to assess differences in management and mortality between females and males. Among 3384 patients with S. aureus bacteraemia, 1431 (42%) were women. Women were, as compared with men, more often Black (581/1431 [41%] vs. 620/1953 [32%], p < 0.001), haemodialysis dependent (309/1424 [22%] vs. 334/1940 [17%], p 0.001) and more likely to be infected with methicillin-resistant S. aureus (MRSA) (697/1410 [49%] MRSA in women vs. 840/1925 [44%] MRSA in men, p 0.001). Women received shorter durations of antimicrobial treatment (median 24 [interquartile range 14–42] vs. 28 [interquartile range 14–45] days, p 0.005), and were less likely to undergo transesophageal echocardiography as compared with men (495/1430 [35%] vs. 802/1952 [41%], p < 0.001). Despite these differences, female sex was not associated with 90-day mortality in either univariable (388/1431 [27%] in women vs. 491/1953 [25%] in men, p 0.204) or multivariable analysis (adjusted hazard ratio for women 0.98 [95% CI, 0.85–1.13]). Despite significant differences in patient characteristics, disease characteristics, and management, women and men with S. aureus bacteraemia have a similar mortality risk. [ABSTRACT FROM AUTHOR]

Bivalent mRNA-based COVID-19 vaccines encoding the ancestral and omicron spike (S) protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We aimed to assess the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent omicron (BA.1) vaccines in individuals who were primed with adenovirus-based or mRNA-based vaccines encoding the ancestral spike protein. We analysed results of the direct boost group of the SWITCH ON study, an open-label, multicentre, randomised controlled trial. Health-care workers from four academic hospitals in the Netherlands aged 18–65 years who had completed a primary COVID-19 vaccination regimen and received one booster of an mRNA-based vaccine, given no later than 3 months previously, were eligible. Participants were randomly assigned (1:1) using computer software in block sizes of 16 and 24 to receive an omicron BA.1 bivalent booster straight away (direct boost group) or a bivalent omicron BA.5 booster, postponed for 90 days (postponed boost group), stratified by priming regimen. The BNT162b2 OMI BA.1 boost was given to participants younger than 45 years, and the mRNA-1273.214 boost was given to participants 45 years or older, as per Dutch guidelines. The direct boost group, whose results are presented here, were divided into four subgroups for analysis: (1) Ad26.COV2.S (Johnson & Johnson) prime and BNT162b2 OMI BA.1 (BioNTech–Pfizer) boost (Ad/P), (2) mRNA-based prime and BNT162b2 OMI BA.1 boost (mRNA/P), (3) Ad26.COV2.S prime and mRNA-1273.214 (Moderna) boost (Ad/M), and (4) mRNA-based prime and mRNA-1273.214 boost (mRNA/M). The primary outcome was fold change in S protein S1 subunit-specific IgG antibodies before and 28 days after booster vaccination. The primary outcome and safety were assessed in all participants except those who withdrew, had a SARS-CoV-2 breakthrough infection, or had a missing blood sample at day 0 or day 28. This trial is registered with ClinicalTrials.gov , NCT05471440. Between Sept 2 and Oct 4, 2022, 219 (50%) of 434 eligible participants were randomly assigned to the direct boost group; 187 participants were included in the primary analyses; exclusions were mainly due to SARS-CoV-2 infection between days 0 and 28. From the 187 included participants, 138 (74%) were female and 49 (26%) were male. 42 (22%) of 187 participants received Ad/P and 44 (24%) mRNA/P (those aged <45 years), and 45 (24%) had received Ad/M and 56 (30%) mRNA/M (those aged ≥45 years). S1-specific binding antibody concentrations increased 7 days after bivalent booster vaccination and remained stable over 28 days in all four subgroups (geometric mean ratio [GMR] between day 0 and day 28 was 1·15 [95% CI 1·12–1·19] for the Ad/P group, 1·17 [1·14–1·20] for the mRNA/P group, 1·20 [1·17–1·23] for the Ad/M group, and 1·16 [1·13–1·19] for the mRNA/M group). We observed no significant difference in the GMR between the Ad/P and mRNA/P groups (p=0·51). The GMR appeared to be higher in the Ad/M group than in the mRNA/M group, but was not significant (p=0·073). Most side-effects were mild to moderate in severity and resolved within 48 h in most individuals. Booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 in adult healthcare workers resulted in a rapid recall of humoral and cellular immune responses independent of the priming regimen. Monitoring of SARS-CoV-2 immunity at the population level, and simultaneously antigenic drift at the virus level, remains crucial to assess the necessity and timing of COVID-19 variant-specific booster vaccinations. The Netherlands Organization for Health Research and Development (ZonMw). [ABSTRACT FROM AUTHOR]

Defining urinary tract infection (UTI) is complex, as numerous clinical and diagnostic parameters are involved. In this systematic review, we aimed to gain insight into how UTI is defined across current studies. We included 47 studies, published between January 2019 and May 2022, investigating therapeutic or prophylactic interventions in adult patients with UTI. Signs and symptoms, pyuria, and a positive urine culture were required in 85%, 28%, and 55% of study definitions, respectively. Five studies (11%) required all 3 categories for the diagnosis of UTI. Thresholds for significant bacteriuria varied from 103 to 105 colony-forming units/mL. None of the 12 studies including acute cystitis and 2 of 12 (17%) defining acute pyelonephritis used identical definitions. Complicated UTI was defined by both host factors and systemic involvement in 9 of 14 (64%) studies. In conclusion, UTI definitions are heterogeneous across recent studies, highlighting the need for a consensus-based, research reference standard for UTI. [ABSTRACT FROM AUTHOR]

Background Pre-existing lower urinary tract symptoms (LUTS), cognitive impairment, and the high prevalence of asymptomatic bacteriuria (ASB) complicate the diagnosis of urinary tract infection (UTI) in older women. The presence of pyuria remains the cornerstone of UTI diagnosis. However, >90% of ASB patients have pyuria, prompting unnecessary treatment. We quantified pyuria by automated microscopy and flowcytometry to determine the diagnostic accuracy for UTI and to derive pyuria thresholds for UTI in older women. Methods Women ≥65 years with ≥2 new-onset LUTS and 1 uropathogen ≥104 colony-forming units (CFU)/mL were included in the UTI group. Controls were asymptomatic and classified as ASB (1 uropathogen ≥105 CFU/mL), negative culture, or mixed flora. Patients with an indwelling catheter or antimicrobial pretreatment were excluded. Leukocyte medians were compared and sensitivity–specificity pairs were derived from a receiver operating characteristic curve. Results We included 164 participants. UTI patients had higher median urinary leukocytes compared with control patients (microscopy: 900 vs 26 leukocytes/µL; flowcytometry: 1575 vs 23 leukocytes/µL; P <.001). Area under the curve was 0.93 for both methods. At a cutoff of 264 leukocytes/µL, sensitivity and specificity of microscopy were 88% (positive and negative likelihood ratio: 7.2 and 0.1, respectively). The commonly used cutoff of 10 leukocytes/µL had a poor specificity (36%) and a sensitivity of 100%. Conclusions The degree of pyuria can help to distinguish UTI in older women from ASB and asymptomatic controls with pyuria. Current pyuria cutoffs are too low and promote inappropriate UTI diagnosis in older women. Clinical Trials Registration. International Clinical Trials Registry Platform: NL9477 (https://trialsearch.who.int/Trial2.aspx?TrialID=NL9477) [ABSTRACT FROM AUTHOR]

The emergence of SARS-CoV-2 variants raised questions regarding the durability of immune responses after homologous or heterologous boosters after Ad26.COV2.S-priming. We found that SARS-CoV-2–specific binding antibodies, neutralizing antibodies, and T cells are detectable 5 months after boosting, although waning of antibodies and limited cross-reactivity with Omicron BA.1 was observed. [ABSTRACT FROM AUTHOR]

Suspected allergic reactions after mRNA COVID-19 vaccination withheld multiple individuals from getting fully vaccinated during the pandemic. We vaccinated adults who had experienced possible allergic symptoms after their first intramuscular dose of a COVID-19 mRNA vaccine with a 1/5th fractional intradermal test dose of the mRNA-1273 (Moderna) COVID-19 vaccine. No anaphylactic reactions were observed after intradermal vaccination (n = 56). Serum anti-S1 IgG concentrations were measured using a bead-based multiplex assay four weeks after vaccinations. Antibody concentrations were compared with a previously collected nationwide cohort that had received two intramuscular doses of mRNA-1273. Antibody responses in all subjects tested (n = 47) were comparable to standard of care intramuscular dosing. Fractional intradermal dosing of mRNA COVID-19 vaccines may provide a pragmatic solution that is safe, time efficient compared to skin prick testing, dose sparing and immunogenic in individuals with suspected vaccine allergy. [ABSTRACT FROM AUTHOR]

An editorial is presented which discusses rabies booster injections, whether administered via the intradermal (ID) or intramuscular (IM) route following ID or IM preexposure prophylaxis (PrEP), elicited neutralizing antibodies. It mentions that World Health Organization (WHO) has updated its recommendation for preexposure prophylaxis (PrEP).

Systemic immunosuppressive therapy (IS) renders patients with inflammatory bowel disease (IBD) vulnerable to fulminant hepatitis B virus (HBV) infection. Seroprotection against HBV through a full vaccination scheme is preferably obtained before IS is initiated, but often conflicts with the clinical need to initiate therapy rapidly. Consequently, the vast majority of patients will use IS during booster vaccinations. In this retrospective cohort study, we examined the serological response after a modified vaccination schedule which includes an initial double dose of Fendrix in patients with IBD and compared the results with the serological responses of patients with IBD who received the standard schedule. Seroprotection rates were 86.2 % and 88.9 % in the modified and standard schedule groups respectively. One-third of patients obtained seroprotection after only one double dose vaccine. A double dose may be considered in patients with IBD at high short-term risk of HBV infection when a rapid protective response is warranted. [ABSTRACT FROM AUTHOR]

Background Treatment of staphylococcal prosthetic joint infection (PJI) usually consists of surgical debridement and prolonged rifampicin combination therapy. Tailored antimicrobial treatment alternatives are needed due to frequent side effects and drug-drug interactions with rifampicin combination therapy. We aimed to assess the effectiveness of several alternative antibiotic strategies in patients with staphylococcal PJI. Methods In this prospective, multicenter registry-based study, all consecutive patients with a staphylococcal PJI, treated with debridement, antibiotics and implant retention (DAIR) or 1-stage revision surgery between January 1, 2015 and November 3, 2020, were included. Patients were treated with a long-term rifampicin combination strategy (in 2 centers) or a short-term rifampicin combination strategy (in 3 centers). Antimicrobial treatment strategies in these centers were defined before the start of the registry. Patients were stratified in different groups, depending on the used antimicrobial strategy. Cox proportional hazards models were used to compare outcome between the groups. Results Two hundred patients were included and stratified in 1 long-term rifampicin group (traditional rifampicin combination therapy) or 1 of 3 short-term rifampicin groups (clindamycin or flucloxacillin or vancomycin monotherapy, including rifampicin for only 5 postoperative days). Adjusted hazard ratios (aHRs) for failure in patients treated with short-term rifampicin and either flucloxacillin or clindamycin were almost equal to patients treated with long-term rifampicin combination therapy (aHR = 1.21; 95% confidence interval,.34–4.40). Conclusions A short-term rifampicin strategy with either clindamycin or flucloxacillin and only 5 days of rifampicin was found to be as effective as traditional long-term rifampicin combination therapy. A randomized controlled trial is needed to further address efficacy and safety of alternative treatment strategies for staphylococcal PJI. [ABSTRACT FROM AUTHOR]

• The baseline anti-HBs titre in non-responders affects the seroconversion rate after revaccination. • Agreement of assays to differentiate between presence or absence of anti-HBs below the titre of 10 IU/L was substantial, except for ADVIA. • The limit of detection is a reliable cutoff to differentiate between a zero- and poor- responder. • The titre-based strategy results in a reduction of revaccinations needed compared to the standard series. The detection of low levels of antibodies against HBsAg (anti-HBs) below 10 IU/L in non-responders after a primary hepatitis B vaccination, is associated with seroconversion after revaccination. We compared the diagnostic performance of four anti-HBs assays in non-responders in their ability to differentiate between absence or presence of low levels of anti-HBs and propose a revaccination strategy guided by anti-HBs titres. Non-responders were revaccinated with Fendrix 20 μg at 0, 1 and 2 months. Anti-HBs titres were determined by Abbott Architect, Diasorin Liaison, Roche Cobas and Siemens ADVIA Centaur. Inter-assay agreement was evaluated with Cohen's Kappa (k) in baseline samples between zero-responders without detectable antibodies and poor-responders with detectable antibodies < 10 IU/L. Seroconversion rates and geometric mean titres were analysed at 0, 1 and 3 months. A titre-based strategy (one revaccination dose and anti-HBs measurement followed by two more revaccination doses if required) was compared with the standard revaccination series of 3 doses. 57 participants were included in the analysis. k was ≥ 0.65 for all assays except ADVIA (k ≤ 0.41). After one revaccination dose all assays detected a mean seroconversion rate in zero-responders of 42.9%, compared to 85.1% in poor-responders. The difference between zero- and poor-responders in seroconversion rate per assay was significant (p < 0.05). After three revaccination doses the mean seroconversion rate was 88.2% in zero-responders and 98.5% in poor-responders (p > 0.286 per assay). A titre-based strategy reduced the amount of revaccinations by 17% compared with the standard. All assays demonstrated a comparable difference in seroconversion rate between zero- and poor-responders after one revaccination dose. The revaccination strategy could be optimised by differentiation between zero- and poor-responders followed by a titre-guided schedule. [ABSTRACT FROM AUTHOR]

Background: The Ad26.COV2.S vaccine, which was approved as a single-shot immunization regimen, has been shown to be effective against severe coronavirus disease 2019. However, this vaccine induces lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)-specific antibody levels than those induced by messenger RNA (mRNA)-based vaccines. The immunogenicity and reactogenicity of a homologous or heterologous booster in persons who have received an Ad26.COV2.S priming dose are unclear.Methods: In this single-blind, multicenter, randomized, controlled trial involving health care workers who had received a priming dose of Ad26.COV2.S vaccine, we assessed immunogenicity and reactogenicity 28 days after a homologous or heterologous booster vaccination. The participants were assigned to receive no booster, an Ad26.COV2.S booster, an mRNA-1273 booster, or a BNT162b2 booster. The primary end point was the level of S-specific binding antibodies, and the secondary end points were the levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity. A post hoc analysis was performed to compare mRNA-1273 boosting with BNT162b2 boosting.Results: Homologous or heterologous booster vaccination in 434 participants resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration.Conclusions: The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting. (Funded by the Netherlands Organization for Health Research and Development ZonMw; SWITCH ClinicalTrials.gov number, NCT04927936.). [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a frequent complication in patients with Staphylococcus aureus bacteremia (SAB), with a significant impact on patient management and outcome. This study aimed to provide insight in the proportion of patients with SAB that develop AKI, the risk factors for developing AKI in this population, and its reversibility. In this retrospective, multicenter cohort study, adult patients with SAB were eligible for inclusion. Patient characteristics, clinical variables, and laboratory results were retrieved from the electronic patient files. Primary outcome was development of AKI, defined as 1.5 times baseline creatinine. Secondary outcomes were reversibility of AKI and risk factors for AKI. A total of 315 patients with SAB were included, of whom 115/315 (37%) developed acute kidney injury. In 68/115 (59%), the AKI was reversible. If kidney function recovered, this occurred within 7 days in 56/68 (82%) of patients. In multivariable logistic regression analyses, independent risk factors for AKI were as follows: complicated SAB, use of diuretics, and hemodynamic instability. Development of AKI was associated with 30-day mortality (OR 3.9; CI 2.2–6.9; p < 0.01). Acute kidney injury is a frequent complication in patients with Staphylococcus aureus bacteremia. Considering the irreversibility in a relevant proportion of patients, future research into the underlying pathophysiology and potential interventions is warranted. [ABSTRACT FROM AUTHOR]

Yellow fever outbreaks have continued to occur and caused infection and deaths in travelers from non-endemic regions. Yellow fever vaccine has proven effective, but vaccination decisions require balancing benefits with risks. Of concern is the continued vaccine shortage worldwide, including of the YF-VAX® stockout in North America, which has presented many challenges. [ABSTRACT FROM AUTHOR]

Background: Monitoring of symptoms and behavior may enable prediction of emerging COVID-19 hotspots. The COVID Radar smartphone app, active in the Netherlands, allows users to self-report symptoms, social distancing behaviors, and COVID-19 status daily. The objective of this study is to describe the validation of the COVID Radar. Methods: COVID Radar users are asked to complete a daily questionnaire consisting of 20 questions assessing their symptoms, social distancing behavior, and COVID-19 status. We describe the internal and external validation of symptoms, behavior, and both user-reported COVID-19 status and state-reported COVID-19 case numbers. Results: Since April 2nd, 2020, over 6 million observations from over 250,000 users have been collected using the COVID Radar app. Almost 2,000 users reported having tested positive for SARS-CoV-2. Amongst users testing positive for SARS-CoV-2, the proportion of observations reporting symptoms was higher than that of the cohort as a whole in the week prior to a positive SARS-CoV-2 test. Likewise, users who tested positive for SARS-CoV-2 showed above average risk social-distancing behavior. Per-capita user-reported SARS-CoV-2 positive tests closely matched government-reported per-capita case counts in provinces with high user engagement. Discussion: The COVID Radar app allows voluntarily self-reporting of COVID-19 related symptoms and social distancing behaviors. Symptoms and risk behavior increase prior to a positive SARS-CoV-2 test, and user-reported case counts match closely with nationally-reported case counts in regions with high user engagement. These results suggest the COVID Radar may be a valid instrument for future surveillance and potential predictive analytics to identify emerging hotspots. [ABSTRACT FROM AUTHOR]

Background: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)–piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. Methods: Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013–2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. Results: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). Conclusions: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942 [ABSTRACT FROM AUTHOR]

A 28-year old otherwise healthy Dutch male presented at the emergency department with fatigue, joint complaints and migratory subcutaneous swellings on back, and legs. These infestations include fascioliasis, gnathostomiasis, loaiasis, dirofilariasis, mansolelliasis, paragonimiasis and toxocariasis. However, fascioliasis, paragonimiasis and mansolelliasis are characterized by nodular subcutaneous swelling; loaiasis is only seen at the African continent and I G. spinigerum i larvae cannot mature in humans larger than 3 mm. [Extracted from the article]

Background: Controlled human hookworm infections could significantly contribute to the development of a hookworm vaccine. However, current models are hampered by low and unstable egg output, reducing generalizability and increasing sample sizes. This study aims to investigate the safety, tolerability, and egg output of repeated exposure to hookworm larvae.Methods: Twenty-four healthy volunteers were randomized, double-blindly, to 1, 2, or 3 doses of 50 Necator americanus L3 larvae at 2-week intervals. Volunteers were monitored weekly and were treated with albendazole at week 20.Results: There was no association between larval dose and number or severity of adverse events. Geometric mean egg loads stabilized at 697, 1668, and 1914 eggs per gram feces for the 1 × 50L3, 2 × 50L3, and 3 × 50L3 group, respectively. Bayesian statistical modeling showed that egg count variability relative to the mean was reduced with a second infectious dose; however, the third dose did not increase egg load or decrease variability. We therefore suggest 2 × 50L3 as an improved challenge dose. Model-based simulations indicates increased frequency of stool sampling optimizes the power of hypothetical vaccine trials.Conclusions: Repeated infection with hookworm larvae increased egg counts to levels comparable to the field and reduced relative variability in egg output without aggravating adverse events.Clinical Trials Registration: NCT03257072. [ABSTRACT FROM AUTHOR]

Background: Serological non-response can be present after hepatitis B vaccination in healthy adults. We aimed to establish which of three revaccination regimens is most effective at inducing protective immunity METHODS: Healthy adults (aged 18-80 years) from 16 Dutch centres (13 public health services, two university hospitals, and one travel clinic) were included in this multicentre, parallel group, randomised, controlled, superiority trial. The inclusion criterion was vaccine non-response (hepatitis B surface antibody [anti-HBs] titre <10 IU/L) after a primary series with three doses of one type of recombinant vaccine against hepatitis B virus (either HBVaxPro-10 or Engerix-B at months 0, 1, and 6). Participants were individually randomly assigned (1:1:1:1) to a vaccination series of repeated initial vaccination (HBVaxPro 10 μg or Engerix-B 20 μg) as the control, or to Twinrix 20 μg, Fendrix 20 μg, or HBVaxPro 40 μg. We used a web-based randomisation programme, stratified by centre, with a block size of four. Participants and centres were unmasked to assignment after randomisation. Laboratory staff and investigators were masked to vaccine-group assignment. All revaccination schedules were identical, with intramuscular vaccinations at 0, 1, and 2 months. Anti-HBs was measured at 0, 1, 2, and 3 months. The primary outcome was the percentage of responders (anti-HBs titres ≥10 IU/L) at 3 months. Immunogenicity and safety analyses were based on an intention-to-vaccinate analysis, the immunogenicity analysis with last observation carried forward for missing data, and the Bonferroni and the Benjamini-Hochberg method were applied to correct for multiple testing. The trial was registered in the Dutch National Trial Register and inclusion has been stopped (identifier NL3011; EudraCT-number 2011-005627-40).Findings: The participants were recruited between Nov 1, 2012, and Sept 1, 2017. 480 participants were randomly assigned and included in intention-to-vaccinate analyses: 124 (26%) to control, 118 (25%) to Twinrix, 114 (24%) to HBVaxPro-40, and 124 (26%) to Fendrix. At month 3 the percentage of responders was 83 (67%) of 124 (95% CI 57·9-75·1 in the control group, 94 (80%) of the 118 (71·3-86·5) in the Twinrix group, 95 (83%) of 114 (75·2-89·7) in the HBVaxPro-40 group, and 108 (87%) of 124 (79·9-92·4) in the Fendrix group. Compared with the control group, the percentage of responders was superior for the HBVaxPro-40 group (adjusted difference 21·6% [95% CI 10·4-32·7], p=0·0204 [Bonferroni corrected p value]) and the Fendrix group (26·3% [15·4-37·3], p=0·0006), but not the Twinrix group (25·0% [13·0-37·0]; p=0·0846). One serious adverse event occurred (herpes zoster ophthalmicus) in the Fendrix group, which was not attributed to the vaccine.Interpretation: Revaccinating healthy non-responders with Fendrix or HBVaxPro-40 resulted in significantly higher proportions of responders and therefore indication for these vaccines should be expanded to enable revaccination of non-responders.Funding: National Institute for Public Health and the Environment. [ABSTRACT FROM AUTHOR]

Four healthy volunteers were infected with 50 Necator americanus infective larvae (L3) in a controlled human hookworm infection trial and followed for 52 weeks. The kinetics of fecal egg counts in volunteers was assessed with Bayesian multilevel analysis, which revealed an increase between weeks 7 and 13, followed by an egg density plateau of about 1000 eggs/g of feces. Variation in egg counts was minimal between same-day measurements but varied considerably between days, particularly during the plateau phase. These analyses pave the way for the controlled human hookworm model to accelerate drug and vaccine efficacy studies. [ABSTRACT FROM AUTHOR]

Background: From a stewardship perspective it is recommended that antibiotic guidelines are adjusted to the local setting, accounting for the local epidemiology of pathogens. In many settings the prevalence of Gram-negative pathogens with resistance to empiric sepsis therapy is increasing. How and when to escalate standard sepsis therapy to a reserve antimicrobial agent, is a recurrent dilemma. The study objective was to develop decision strategies for empiric sepsis therapy based on local microbiological and clinical data, and estimate the number needed to treat with a carbapenem to avoid mismatch of empiric therapy in one patient (NNTC). Methods: We performed a nested case control study in patients (> 18 years) with Gram-negative bacteremia in 2013–2016. Cases were defined as patients with Gram-negative bacteremia with in vitro resistance to the combination 2nd generation cephalosporin AND aminoglycoside (C-2GC + AG). Control patients had Gram-negative bacteremia with in vitro susceptibility to cefuroxime AND/OR gentamicin, 1:2 ratio. Univariate and multivariable analysis was performed for demographic and clinical predictors of resistance. The adequacy rates of empiric therapy and the NNTC were estimated for different strategies. Results: The cohort consisted of 486 episodes of Gram-negative bacteremia in 450 patients. Median age was 66 years (IQR 56–74). In vitro resistance to C-2GC + AG was present in 44 patients (8.8%). Independent predictors for resistance to empiric sepsis therapy were hematologic malignancy (adjusted OR 4.09, 95%CI 1.43–11.62, p < 0.01), previously cultured drug resistant pathogen (adjusted OR 3.72. 95%CI 1.72–8.03, p < 0.01) and antibiotic therapy during the preceding 2 months (adjusted OR 12.5 4.08–38.48, p < 0.01). With risk-based strategies, an adequacy rate of empiric therapy of 95.2–99.3% could be achieved. Compared to treating all patients with a carbapenem, the NNTC could be reduced by 82.8% (95%CI 78.5–87.5%) using the targeted approaches. Conclusions: A risk-based approach in empiric sepsis therapy has the potential to better target the use of reserve antimicrobial agents aimed at multi-resistant Gram-negative pathogens. A structured evaluation of the expected antimicrobial consumption and antibiotic adequacy rates is essential to be able to weigh the costs and benefits of potential antibiotic strategies and select the most appropriate approach. [ABSTRACT FROM AUTHOR]

Background: Blood cultures are considered the gold standard to distinguish bacteremia from non-bacteremic systemic inflammation. In current clinical practice, bacteraemia is considered unlikely if blood cultures have been negative for 48–72 hours. Modern BC systems have reduced this time-to-positivity (TTP), questioning whether the time frame of 48–72 hrs is still valid. This study investigates the distribution of TTP, the probability of blood culture positivity after 24 hours, and identifies clinical predictors of prolonged TTP. Methods: Adult patients with monomicrobial bacteremia in an academic hospital were included retrospectively over a three-year period. Clinical data were retrieved from the medical records. Predictors of TTP >24 hours were determined by uni- and multivariate analyses. The residual probability of bacteremia was estimated for the scenario of negative BCs at 24 hours after bedside collection. Results: The cohort consisted of 801 patients, accounting for 897 episodes of bacteremia. Mean age was 65 years (IQR 54–73), 534 (59.5%) patients were male. Median TTP was 15.7 (IQR 13.5–19.3) hours. TTP was ≤24 hours in 85.3% of episodes. Antibiotic pre-treatment (adjusted OR 1.77; 95%CI 1.14–2.74, p<0.01) was independently associated with prolonged TTP. The probability of bacteremia, if BC had remained negative for 24 hours, was 1.8% (95% CI 1.46–2.14). Conclusion: With adequate hospital logistics, the probability of positive blood cultures after 24 hours of negative cultures was low. Combined with clinical reassessment, knowledge of this low probability may contribute to prioritization of the differential diagnosis and decisions on antimicrobial therapy. As a potential antibiotic stewardship tool, this strategy warrants further prospective investigation. [ABSTRACT FROM AUTHOR]

Background: Outbreaks of yellow fever and a frequently depleted vaccine stock increase demand for a dose-sparing strategy. A fractional dose of 17D yellow fever virus (17D-YFV) vaccine has been shown to be noninferior to the standard dose in inducing seroprotection.Objective: To evaluate whether fractional-dose vaccination can confer long-term immunity.Design: 10-year follow-up of a subgroup of a randomized, controlled, noninferiority trial. (Dutch Trial Register: NTR7094 [current study] and ISRCTN46326316 [original study]).Setting: The Netherlands.Participants: Seventy-five of 155 participants in the original trial provided a blood sample for this study. These 75 participants had received primary vaccination with 17D-YFV vaccine 10 years before. Forty received a 0.1-mL fractional dose intradermally, and 35 received the standard 0.5-mL dose subcutaneously.Measurements: Virus-neutralizing antibody responses were measured by a plaque reduction neutralization test.Results: Thirty-nine of 40 (98% [95% CI, 89% to 100%]) participants had protective levels of yellow fever-neutralizing antibodies more than 10 years after receiving a fractional dose of 17D-YFV vaccine compared with 34 of 35 (97% [CI, 87% to 100%]) in the standard-dose group.Limitation: Only 48% of participants from the original trial participated in this study.Conclusion: Intradermal administration of a one-fifth dose of yellow fever vaccine induced a protective immune response that lasted for 10 years after vaccination. Persons receiving a fractional dose of yellow fever vaccine do not require a booster vaccination for long-term protection against yellow fever.Primary Funding Source: Leiden University Medical Center and the International Society of Travel Medicine. [ABSTRACT FROM AUTHOR]

To accelerate the development of novel vaccines for schistosomiasis, we set out to develop a human model for Schistosoma mansoni infection in healthy volunteers. During natural infections, female schistosomes produce eggs that give rise to morbidity. Therefore, we produced single-sex, male Schistosoma mansoni cercariae for human infection without egg production and associated pathology. Cercariae were produced in their intermediate snail hosts in accordance with the principles of good manufacturing practice (GMP). The application of GMP principles to an unconventional production process is a showcase for the controlled production of complex live challenge material in the European Union or under Food and Drug Administration guidance. [ABSTRACT FROM AUTHOR]

Schistosomiasis is a parasitic disease affecting over 250 million people in the tropics. In non-endemic regions, imported Schistosoma infections are commonly diagnosed by serology, but based on antibody detection an active infection cannot be distinguished from a cured infection and it may take more than 8 weeks after exposure before seroconversion occurs. In endemic populations, excellent results have been described in diagnosing low-grade active Schistosoma infections by the detection of the adult worm-derived circulating anodic antigen (CAA) utilising robust lateral flow (LF) assays combined with up-converting phosphor (UCP) reporter technology. The purpose of this study is to explore the diagnostic value of the UCP-LF CAA assay in a non-endemic setting. CAA concentrations were determined in 111 serum samples originating from 81 serology-positive individuals. In nine individuals, serum could be collected before travel and an additional five provided samples before and after seroconversion occurred. Based on detectable CAA levels, an active infection was seen in 56/81 (69%) of the exposed individuals, while the 10 controls and the 9 sera collected before travel were tested negative for CAA. Positive CAA levels were observed starting 4 weeks after exposure and in four cases CAA was detected even before Schistosoma-specific antibodies became positive. Higher serum CAA levels were seen in migrants than in travellers and CAA concentrations dropped sharply when testing follow-up samples after treatment. This explorative study indicates the UCP-LF CAA serum assay to be a highly accurate test for detecting active low-grade Schistosoma infections in a non-endemic routine diagnostic setting. [ABSTRACT FROM AUTHOR]

Background Vaccination with conjugated meningococcal vaccines is the best way to prevent invasive meningococcal disease. Changes in serogroup epidemiology have led to the inclusion of quadrivalent vaccines in the national immunization programs of several countries, but vaccines are frequently in short supply. Intradermal administration has the potential to increase vaccine availability through dose reduction, without sacrificing efficacy. It has never before been investigated for glycoconjugate meningococcal vaccines. Methods Different fractional doses of two quadrivalent meningococcal conjugate vaccines (MenACWY-CRM 197 (Menveo®) and MenACWY-TT (Nimenrix®)) were administered intradermally to sequential groups of 4 participants, according to an adaptive dose escalation design, starting at 1/10th of the original dose. Booster doses were given after 4–6 months based on interim serology results using a multiplex bead-based assay (MIA). Final analyses were based on serum bactericidal antibody titers (rSBA). Results A total of 12 subjects were enrolled (average 25 years old, range 19–48). MenACWY-CRM 197 became unavailable during the course of the study and was only evaluated for a 1/10th dose. This dose resulted in less than complete seroprotection for serogroup A but complete protection against the other serogroups. MenACWY-TT was evaluated for a 1/10th and 1/5th dose level. Both fractional doses of MenACWY-TT resulted in complete seroprotection against all vaccine serogroups. Geometric mean titers 1 month after vaccination were lower and decayed faster in the MenACWY-CRM 197 group. Adverse events were mild and there were no serious adverse events. Conclusion Fractional intradermal vaccination against meningococcal disease with quadrivalent conjugate vaccine appears to be safe and effective in our small dose finding study. Tetanus toxoid conjugated vaccine (Nimenrix®) shows a trend towards higher antibody levels compared to CRM 197 -conjugated vaccine (Menveo®). The 1/5th fractional dose of MenACWY-TT appears to result in higher antibody levels than does the 1/10th dose. These results can be used for a larger non-inferiority study. This trial was registered in clinicaltrials.gov under NCT01782066. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to determine the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) and magnetic resonance imaging (MRI) in diagnosing vertebral osteomyelitis. Methods From November 2015 until December 2016, 32 patients with suspected vertebral osteomyelitis were prospectively included. All patients underwent both 18F-FDG-PET/CT and MRI within 48 h. All images were independently reevaluated by two radiologists and two nuclear medicine physicians who were blinded to each others' image interpretation. 18F-FDG-PET/CT and MRI were compared to the clinical diagnosis according to international guidelines. Results For 18F-FDG-PET/CT, sensitivity, specificity, PPV, and NPV in diagnosing vertebral osteomyelitis were 100%, 83.3%, 90.9%, and 100%, respectively. For MRI, sensitivity, specificity, PPV, and NPV were 100%, 91.7%, 95.2%, and 100%, respectively. MRI detected more epidural/spinal abscesses. An important advantage of 18F-FDG-PET/CT is the detection of metastatic infection (16 patients, 50.0%). Conclusion 18F-FDG-PET/CT and MRI are both necessary techniques in diagnosing vertebral osteomyelitis. An important advantage of 18F-FDG-PET/CT is the visualization of metastatic infection, especially in patients with bacteremia. MRI is more sensitive in detection of small epidural abscesses. [ABSTRACT FROM AUTHOR]

• This study is the first to describe the safety and immunogenicity of a nanoporous microneedle array for SARS-CoV-2 vaccination with the mRNA-1273 vaccine in healthy participants as a booster vaccination. • Nanoporous microneedle array for SARS-CoV-2 vaccination with 20 µg mRNA-1273 was safe but failed to induce an anamnestic antibody response, which is probably due to the used vaccine loading technique resulting in a very low amount of loaded vaccine on the microneedle tips. • As microneedle patch immunisation is a promising vaccination technique; it is worth to evaluate this novel technology further to be better prepared for pandemics in the future. Nanoporous microneedle arrays (npMNA) are being developed as skin patches for vaccine delivery. As alternative for needle-based immunisation, they may potentially result in higher vaccine acceptance, which is important for future mass vaccination campaigns to control outbreaks, such as COVID-19, and for public vaccination in general. In this study we investigated the safety and immunogenicity of needle-free intradermal delivery of a fractional third or fourth dose of mRNA-1273 vaccine by npMNA. This study was an open-label, randomised-controlled, proof-of-concept study. Healthy adults were eligible if they had received a primary immunisation series against SARS-CoV-2 with two doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) mRNA vaccine. A history of a COVID-19 infection or booster vaccination with mRNA-1273 or BNT162b2 was allowed if it occurred at least three months before inclusion. Participants were randomised in a 1:1 ratio to receive 20 µg mRNA-1273 vaccine, either through npMNA patch applied on the skin (ID-patch group), or through intramuscular (IM) injection (IM-control group). Primary outcomes were reactogenicity up to two weeks after vaccination, and fold-increase of SARS-CoV-2 spike S1-specific IgG antibodies 14 days post-vaccination. In April 2022, 20 participants were enroled. The geometric mean concentration (GMC) did not increase in the ID-patch group after vaccination, in contrast to the IM-control group (GMC was 1,006 BAU/mL (95% CI 599–1,689), 3,855 (2,800–5,306), and 3,513 (2,554–4,833) at day 1, 15 and 29, respectively). In addition, SARS-CoV-2-specific T cell responses were lower after ID vaccination through npMNA. Needle-free delivery of 20 µg mRNA-1273 vaccine by npMNA failed to induce antibody and T cell responses. As this is a potentially very useful vaccination method, it is important to determine which adjustments are needed to make this npMNA successful. NCT05315362. [ABSTRACT FROM AUTHOR]

Background: Previous research has provided evidence for the link between psychological processes and psychophysiological health outcomes. Psychological interventions, such as face-to-face or online cognitive behavioral therapy (CBT) and serious games aimed at improving health, have shown promising results in promoting health outcomes. Few studies so far, however, have examined whether Internet-based CBT combined with serious gaming elements is effective in modulating health outcomes. Moreover, studies often did not incorporate psychophysiological or immunological challenges in order to gain insight into physiological responses to real-life challenges after psychological interventions. The overall aim of this study is to investigate the effects of a psychological intervention on self-reported and physiological health outcomes in response to immune and psychophysiological challenges.Methods/design: In a randomized controlled trial, 60 healthy men are randomly assigned to either an experimental condition, receiving guided Internet-based (e-health) CBT combined with health-related serious gaming elements for 6 weeks, or a control condition receiving no intervention. After the psychological intervention, self-reported vitality is measured, and participants are given an immunological challenge in the form of a Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination. One day after the vaccination, participants are asked to perform several psychophysiological tasks in order to explore the effects of the psychological intervention on participants' stress response following the immune challenge. To assess the delayed effects of vaccination on self-reported and physiological health outcomes, a follow-up visit is planned 4 weeks later. Total study duration is approximately 14 weeks. The primary outcome measure is self-reported vitality measured directly after the intervention. Secondary outcome measures include inflammatory and endocrine markers, as well as psychophysiological measures of heart rate and skin conductance in response to the psychophysiological tasks after the BCG vaccination.Discussion: The innovative design features of this study - e.g., combining guided e-health CBT with health-related serious gaming elements and incorporating immunological and psychophysiological challenges - will provide valuable information on the effects of a psychological intervention on both self-reported and physiological health outcomes. This study will offer further insights into the mechanisms underlying the link between psychological factors and health outcomes and is anticipated to contribute to the optimization of health care strategies.Trial Registration: Nederlands Trial Register, NTR5610 . Registered on 4 January 2016. [ABSTRACT FROM AUTHOR]