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Abstract 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 Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

Objectives This study aims to describe the incidence, symptom clusters and determinants of post-acute COVID symptoms using data from the COVID RADAR app in the Netherlands.Design Prospective cohort.Setting General population in the Netherlands from April 2020 to February 2022.Participants A total of 1478 COVID RADAR app users, with data spanning 40 days before to 100 days after positive SARS-CoV-2 test.Outcome measures Incidence and duration of 10 new symptoms that developed during acute infection, defined as 10 days prior and 10 days after positive test. Clustering of these post-acute COVID symptoms and associations between factors known in the acute phase and 100-day symptom persistence.Results The most frequent post-acute symptoms were cough, loss of smell or taste and fatigue. At 100 days postinfection, 86 (8%) participants still experienced symptoms. Three post-acute COVID symptom clusters were identified: non-respiratory (headache and fatigue; 49% of participants with post-acute COVID symptoms); olfactory (15%) and respiratory (8%). Vaccination was associated with a lower risk of post-acute COVID symptoms 100 days after infection, although CIs were wide (OR: 0.5; 95% CI: 0.2 to 1.5), but not with non-respiratory symptoms (OR: 1.0; 95% CI: 0.3 to 4.4). Severe acute disease increased the risk of post-acute COVID symptoms (OR: 1.4; 95% CI: 1.2 to 1.5; per additional acute symptom).Conclusions In this cohort of infected community-dwelling app users, 5%–10% experienced post-acute COVID symptoms. The symptoms cluster in several distinct entities, which differ in incidence, patient characteristics and vaccination effects. This suggests multiple mechanisms underlying the development of post-acute COVID symptoms.

Abstract Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK–STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.

Abstract Decades of research have demonstrated that a variety of cognitive biases can affect our judgment and ability to make rational decisions in personal and professional environments. The lengthy, risky, and costly nature of pharmaceutical research and development (R&D) makes it vulnerable to biased decision‐making. Moreover, cognitive biases can play a role in regulatory and clinical decision‐making, the latter impacting diagnostic and treatment decisions in the therapeutic use of medicines. These inherent and/or institutionalized biases (e.g., in assumptions, data, or decision‐making practices) could conceivably contribute to health inequities. In this mini‐review, we provide a broad perspective on how cognitive biases can affect pharmaceutical R&D, regulatory evaluation, and therapeutic decision‐making. Example approaches to mitigate the effect of common biases in the development, approval, and use of new therapeutics, such as quantitative decision criteria, multidisciplinary reviews, regulatory and treatment guidelines, and evidence‐based clinical decision support systems are illustrated. Mitigating the impact of cognitive biases could increase pharma R&D efficiency, change the perspective and prioritization of unmet medical needs, increase representativeness and quality of evidence generated through clinical trials and real‐world research, leading to higher quality insights and more effective medication use, and as such could eventually contribute to more equitable healthcare.

Background: Travellers visiting rabies-endemic countries are at risk of rabies infection. Assessing travellers’ knowledge and risk perception of rabies and risk behaviour during travel can help identify knowledge gaps and improve pre-travel risk education. Methods: Cohort study in Dutch adult travellers, using two surveys: one before travel to assess knowledge and perception of rabies, and one after return to identify risk behaviour during travel. Results: The pre-travel and post-travel survey were completed by 301 and 276 participants, respectively. 222 participants had travelled to a high-risk rabies-endemic country. 21.6 % of the participants scored their rabies knowledge as poor. Some participants were unaware cats or bats can transmit rabies (26.6 % and 13.6 %, respectively), or that post-exposure prophylaxis (PEP) is required for certain exposures such as skin abrasions without bleeding or licks on damaged skin (35.5 % and 18.9 %, respectively), while 27.9 % of participants did not know PEP needs to be administered within one day. 115 participants (51.8 %) reported any form of contact with any animal during travel. Two participants reported animal exposure, of which one took adequate PEP measures. Risk factors for animal contact abroad were regularly touching cats or dogs at home or abroad, longer travel duration, having pets during childhood and being an animal lover. Conclusions: Pre-travel rabies risk education currently does not meet travellers’ needs, which is reflected in knowledge gaps and engagement in risk behaviour during travel. During pre-travel health advice, avoiding animal contact abroad should be emphasized, and additional education is required about indications for PEP.

Abstract Fractional dosing can be a cost-effective vaccination strategy to accelerate individual and herd immunity in a pandemic. We assessed the immunogenicity and safety of primary intradermal (ID) vaccination, with a 1/5th dose compared with the standard intramuscular (IM) dose of mRNA-1273 in SARS-CoV-2 naïve persons. We conducted an open-label, non-inferiority, randomized controlled trial in the Netherlands between June and December 2021. One hundred and fifty healthy and SARS-CoV-2 naïve participants, aged 18–30 years, were randomized (1:1:1) to receive either two doses of 20 µg mRNA-1273 ID with a standard needle (SN) or the Bella-mu® needle (BM), or two doses of 100 µg IM, 28 days apart. The primary outcome was non-inferiority in seroconversion rates at day 43 (D43), defined as a neutralizing antibody concentration threshold of 465 IU/mL, the lowest response in the IM group. The non-inferiority margin was set at −15%. Neutralizing antibody concentrations at D43 were 1789 (95% CI: 1488–2150) in the IM and 1263 (951–1676) and 1295 (1020–1645) in the ID-SN and ID-BM groups, respectively. The absolute difference in seroconversion proportion between fractional and standard-dose groups was −13.95% (−24.31 to −3.60) for the ID-SN and −13.04% (−22.78 to −3.31) for the ID-BM group and exceeded the predefined non-inferiority margin. Although ID vaccination with 1/5th dose of mRNA-1273 did not meet the predefined non-inferior criteria, the neutralizing antibody concentrations in these groups are far above the proposed proxy for protection against severe disease (100 IU/mL), justifying this strategy in times of vaccine scarcity to accelerate mass protection against severe disease.

Introduction: Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus in vitro. We investigated the potential antiviral effects of voclosporin on SARS-CoV-2 in immunocompromised patients. Methods: First, we conducted a prospective, randomized, open-label, proof-of-concept study in 20 kidney transplant recipients (KTRs) on tacrolimus-based immunosuppression who contracted mild to moderate SARS-CoV-2 infection. Patients were randomized to continue tacrolimus or switch to voclosporin. Second, we performed a post hoc analysis on SARS-CoV-2 infections in 216 patients with lupus nephritis (LN) on standard immunosuppression who were randomly exposed to voclosporin or placebo as part of a clinical trial that was conducted during the worldwide COVID-19 pandemic. Results: The primary end point was clearance of SARS-CoV-2 viral load and that did not differ between voclosporin-treated KTRs (median 12 days, interquartile range [IQR] 8–28) and tacrolimus-treated KTRs (median 12 days, IQR 4–16) nor was there a difference in clinical recovery. Pharmacokinetic analyses demonstrated that, when voclosporin trough levels were on-target, SARS-CoV-2 viral load dropped significantly more (ΔCt 7.7 [3.4–10.7]) compared to tacrolimus-treated KTRs (ΔCt 2.7 [2.0-4.3]; P = 0.035). In voclosporin-exposed patients with LN, SARS-CoV-2 infection was detected in 6% (7/116) compared to 12% (12/100) in placebo-exposed patients (relative risk [RR] 1.4 [0.97–2.06]). Notably, no voclosporin-exposed patients with LN died from severe SARS-CoV-2 infection compared to 3% (3/100) in placebo-exposed patients (RR 2.2 [1.90–2.54]). Conclusion: This proof-of-concept study shows a potential positive risk-benefit profile for voclosporin in immunocompromised patients with SARS-CoV-2 infection. These results warrant further investigations on voclosporin to establish an equipoise between infection and maintenance immunosuppression.

Abstract Establishing a dosing regimen that maximizes clinical benefit and minimizes adverse effects for novel therapeutics is a key objective for drug developers. Finding an optimal dose and schedule can be particularly challenging for compounds with a narrow therapeutic window such as in oncology. Modeling and simulation tools can be valuable to conduct in silico evaluations of various dosing scenarios with the goal to identify those that could minimize toxicities, avoid unscheduled dose interruptions, or minimize premature discontinuations, which all could limit the potential for therapeutic benefit. In this tutorial, we present a stepwise development of an adaptive dose simulation framework that can be used for dose optimization simulations. The tutorial first describes the general workflow, followed by a technical description with basic to advanced practical examples of its implementation in mrgsolve and is concluded with examples on how to use this in decision‐making around dose and schedule optimization. The adaptive simulation framework is built with pharmacokinetic, pharmacodynamic (i.e., biomarkers, activity markers, target engagement markers, efficacy markers), and safety models that include evaluations of unexplained interindividual and intraindividual variability and covariate impact, which can be replaced and expanded (e.g., combination setting, comparator setting) with user‐defined models. Subsequent adaptive simulations allow investigation of the impact of starting dose, dosing intervals, and event‐driven (exposure or effect) dose modifications on any end point. The resulting simulation‐derived insights can be used in quantitatively proposing dose and regimens that better balance benefit and adverse effects for further evaluation, aiding dose selection discussions, and designing dose modification recommendations, among others.

Abstract Single‐arm cohorts/trials are often used in early phase oncology programs to support preliminary clinical activity assessments for investigational products, administered alone or in combination with standard of care (SOC) agents. Benchmarking clinical activity of those combinations against other treatments, including SOC, requires indirect comparisons against external trials, which presents challenges including cross‐study differences in trial populations/other factors. To facilitate such nonrandomized comparisons, we developed a comprehensive model‐based meta‐analysis (MBMA) framework to quantitatively adjust for factors related to efficacy in metastatic non‐small cell lung cancer (mNSCLC). Data were derived from 15 published studies assessing key programmed cell death protein‐1 (PD‐1) inhibitors pembrolizumab (n = 8) and nivolumab (n = 7), representing current SOC in mNSCLC. In the first stage, a mixed‐effects logistic regression model for overall response rate (ORR) was developed accounting for effects of various population covariates on ORR. The ORR model results indicated an odds ratio (OR) of 1.02 for squamous versus non‐squamous histology and OR of 1.20 for PD‐ligand 1 tumor proportion score (TPS) per every 10% increase of TPS level. Next, a nonparametric mixed‐effects model for overall survival (OS) was developed with ORR/other clinical covariates as input. Subsequently, MBMA simulations of relevant hypothetical scenarios involving single‐arm trial design predicted OS hazard ratios as a function of ORR with matched patient characteristics. Findings from this MBMA and derived parameter estimates can be generally applied by the reader as a framework for interpreting efficacy data from early phase trials to support ORR‐based go/no‐go decisions and futility rules, illustrated through examples in this report.

Abstract 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 (

Abstract Background Prompt administration of post-exposure prophylaxis (PEP) is crucial to prevent a fatal rabies infection after an animal associated injury (AAI), preferably within 24 h. PEP, especially in case of a type III injury for which rabies immune globulin (RIG) is needed, is difficult to obtain abroad. This, along with the fear of potentially having contracted a lethal disease, might be an important source for anxiety and distress. We investigated the occurrence and extent of self-reported anxiety and distress at different timepoints among Dutch travellers after encountering an AAI, and the involved factors. Methods A retrospective quantitative observational study was conducted including insured Dutch travellers who actively contacted Eurocross Assistance after encountering an AAI abroad. An online questionnaire was designed to measure anxiety and distress levels, using the HADS (Hospital Anxiety and Depression Scale) and distress thermometer at three time points: departure from home (T1), post-AAI (T2), and treatment administration (T3). Statistical analyses included T-tests, Chi-square tests, and ANCOVA analyses. Results We showed a significant increase in mean anxiety and distress scores at T2, and a significant decrease at T3. Women were more often anxious and distressed. Between T1 and T2, PrEP, and being aware of the risks were positively associated with anxiety levels, and PrEP and WHO region Africa with distress levels. Between T2 and T3, anxiety levels remained higher for monkey-induced injury, thoracic injuries, and WHO region Southeast Asia. PEP-delay between 24–48 h resulted in decreased distress levels at this time period, while type II injury elevated distress levels. Conclusions This study showed significant anxiety and distress levels after an AAI among the vast majority of travellers, which is detrimental to their health-related quality of life (HR-QOL). This highlights the importance of proper pre-travel information. In the context of rabies prevention, these results suggest that pre-travel advice and policy makers should also take aspects of HR-QOL into consideration.

Abstract Background Cardiac rehabilitation in patients with chronic heart failure (CHF) has favourable effects on exercise capacity, the risk at hospital (re-)admission and quality of life. Although cardiac rehabilitation is generally recommended it is still under-utilised in daily clinical practice, particularly in frail elderly patients after hospital admission, mainly due to low referral and patient-related barriers. Cardiac telerehabilitation (CTR) has the potential to partially solve these barriers. The purpose of this study is to evaluate the effects of CTR as compared to standard remote care after hospital admission on physical functional capacity in CHF patients. Methods In this randomised controlled trial, 64 CHF patients will be recruited during hospitalisation for acute decompensated heart failure, and randomised to CTR combined with remote patient management (RPM) or RPM alone (1:1). All participants will start with RPM after hospital discharge for early detection of deterioration, and will be up titrated to optimal medical therapy before being randomised. CTR will start after randomisation and consists of an 18-week multidisciplinary programme with exercise training by physical and occupational therapists, supported by a (remote) technology-assisted dietary intervention and mental health guiding by a physiologist. The training programme consists of three centre-based and two home-based video exercise training sessions followed by weekly video coaching. The mental health and dietary programme are executed using individual and group video sessions. A wrist-worn device enables remote coaching by the physical therapist. The web application is used for promoting self-management by the following modules: 1) goal setting, 2) progress tracking, 3) education, and 4) video and chat communication. The primary outcome measure is physical functional capacity evaluated by the Short Physical Performance Battery (SPPB) score. Secondary outcome measures include frailty scoring, recovery after submaximal exercise, subjective health status, compliance and acceptance to the rehabilitation programme, and readmission rate. Discussion The Tele-ADHF trial is the first prospective randomised controlled trial designed for evaluating the effects of a comprehensive combined RPM and CTR programme in recently hospitalised CHF patients. We hypothesize that this intervention has superior effects on physical functional capacity than RPM alone. Trial registration Netherlands Trial Registry (NTR) NL9619, registered 21 July 2021.

Background: Differentiation between uncomplicated and complicated postoperative wound drainage after arthroplasty is crucial to prevent unnecessary reoperation. Prospective data about the duration and amount of postoperative wound drainage in patients with and without prosthetic joint infection (PJI) are currently absent. Methods: A multicentre cohort study was conducted to assess the duration and amount of wound drainage in patients after arthroplasty. During 30 postoperative days after arthroplasty, patients recorded their wound status in a previously developed wound care app and graded the amount of wound drainage on a 5-point scale. Data about PJI in the follow-up period were extracted from the patient files. Results: Of the 1019 included patients, 16 patients (1.6 %) developed a PJI. Minor wound drainage decreased from the first to the fourth postoperative week from 50 % to 3 %. Both moderate to severe wound drainage in the third week and newly developed wound drainage in the second week after a week without drainage were strongly associated with PJI (odds ratio (OR) 103.23, 95 % confidence interval (CI) 26.08 to 408.57, OR 80.71, 95 % CI 9.12 to 714.52, respectively). The positive predictive value (PPV) for PJI was 83 % for moderate to heavy wound drainage in the third week. Conclusion: Moderate to heavy wound drainage and persistent wound drainage were strongly associated with PJI. The PPV of wound drainage for PJI was high for moderate to heavy drainage in the third week but was low for drainage in the first week. Therefore, additional parameters are needed to guide the decision to reoperate on patients for suspected acute PJI.

We propose, test and apply a methodology integrating 1D magnetotelluric (MT) and magnetic data inversion, with a focus on the characterisation of the cover–basement interface. It consists of a cooperative inversion workflow relying on standalone inversion codes. Probabilistic information about the presence of rock units is derived from MT and passed on to magnetic inversion through constraints combining structural constraints with petrophysical prior information. First, we perform the 1D probabilistic inversion of MT data for all sites and recover the respective probabilities of observing the cover–basement interface, which we interpolate to the rest of the study area. We then calculate the probabilities of observing the different rock units and partition the model into domains defined by combinations of rock units with non-zero probabilities. Third, we combine these domains with petrophysical information to apply spatially varying, disjoint interval bound constraints (DIBC) to least-squares magnetic data inversion using the alternating direction method of multipliers (or ADMM). We demonstrate the proof-of-concept using a realistic synthetic model reproducing features from the Mansfield area (Victoria, Australia) using a series of uncertainty indicators. We then apply the workflow to field data from the prospective mining region of Cloncurry (Queensland, Australia). Results indicate that our integration methodology efficiently leverages the complementarity between separate MT and magnetic data modelling approaches and can improve our capability to image the cover–basement interface. In the field application case, our findings also suggest that the proposed workflow may be useful to refine existing geological interpretations and to infer lateral variations within the basement.

Abstract Liquid xenon time projection chambers are promising detectors to search for neutrinoless double beta decay (0 $$\nu \beta \beta $$ ν β β ), due to their response uniformity, monolithic sensitive volume, scalability to large target masses, and suitability for extremely low background operations. The nEXO collaboration has designed a tonne-scale time projection chamber that aims to search for 0 $$\nu \beta \beta $$ ν β β of $$^{136}$$ 136 Xe with projected half-life sensitivity of $$1.35\times 10^{28}$$ 1.35 × 10 28 yr. To reach this sensitivity, the design goal for nEXO is $$\le $$ ≤ 1% energy resolution at the decay Q-value ( $$2458.07\pm 0.31$$ 2458.07 ± 0.31 keV). Reaching this resolution requires the efficient collection of both the ionization and scintillation produced in the detector. The nEXO design employs Silicon Photo-Multipliers (SiPMs) to detect the vacuum ultra-violet, 175 nm scintillation light of liquid xenon. This paper reports on the characterization of the newest vacuum ultra-violet sensitive Fondazione Bruno Kessler VUVHD3 SiPMs specifically designed for nEXO, as well as new measurements on new test samples of previously characterised Hamamatsu VUV4 Multi Pixel Photon Counters (MPPCs). Various SiPM and MPPC parameters, such as dark noise, gain, direct crosstalk, correlated avalanches and photon detection efficiency were measured as a function of the applied over voltage and wavelength at liquid xenon temperature (163 K). The results from this study are used to provide updated estimates of the achievable energy resolution at the decay Q-value for the nEXO design.

The rapid expansion of the human population is causing significant harm to giraffe (Giraffa camelopardalis giraffa) populations. The growth of the industrial and urban sectors leads to the release of harmful substances into the environment. This surge in pollution stands as one of the primary threats to giraffes and their constrained habitats, contributing to the fact that two of the nine giraffe subspecies are listed as Critically Endangered on the IUCN Red List of Threatened Species.Using the optimised hotspot analyses from a previous study of the browsing patterns of GPS-tagged male and female giraffes at the Rooipoort Nature Reserve (RNR) the frequent areas (hot spots) where they feed, and drink water could be identified.The aim of the study was to identify whether there is any form of heavy metal contamination in the plants or water sources. The leaves of all the tree species at RNR were collected from the 20 locations that were frequented the most and analysed for heavy metals. Six metals were found in significant concentrations in the leaves, with the thallium concentration higher than the permissible range.Water samples from the Vaal River and water holes were also quantitatively analysed and the presence of aluminium, thallium, chromium, copper, iron, manganese, and zinc was confirmed.We have gained knowledge on the factors influencing giraffe health that can ultimately be used to guide management and legislative/policy decisions by private and public conservation managers suitable for the well-being and survival of giraffes when exposed to metals and/or low-quality diet. We conclude that the giraffes in RNR (and other animal species) are constrained in an environment that has toxic levels of thallium in their diet and water sources they cannot avoid. This would be the first study to investigate the effect of thallium on giraffe distribution and habitat use.

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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. Clinical trial registry (on ClinicalTrial.gov): NCT05315362.

Introduction: In 2020, the first Dutch West Nile virus (WNV) infected birds were detected through risk-targeted surveillance of songbirds. Retrospective testing of patients with unexplained neurological disease revealed human WNV infections in July and August 2020. Bird ringers are highly exposed to mosquito bites and possibly avian excrements during ringing activities. This study therefore investigates whether bird ringers are at higher risk of exposure to WNV and Usutu virus (USUV). Methods: Dutch bird ringers were asked to provide a single serum sample (May – September 2021) and to fill out a survey. Sera were screened by protein microarray for presence of specific IgG against WNV and USUV non-structural protein 1 (NS1), followed by focus reduction virus neutralization tests (FRNT). Healthcare workers (2009–2010), the national immunity cohort (2016–2017) and blood donors (2021) were used as control groups without this occupational exposure. Results: The majority of the 157 participating bird ringers was male (132/157, 84%) and the median age was 62 years. Thirty-seven participants (37/157, 23.6%) showed WNV and USUV IgG microarray signals above background, compared to 6.4% (6/94) in the community cohort and 2.1% (2/96) in blood donors (p

Summary: The emergence of novel SARS-CoV-2 variants led to the recommendation of booster vaccinations after Ad26.COV2.S priming. It was previously shown that heterologous booster vaccination induces high antibody levels, but how heterologous boosters affect other functional aspects of the immune response remained unknown. Here, we performed immunological profiling of Ad26.COV2.S-primed individuals before and after homologous or heterologous (mRNA-1273 or BNT162b2) booster. Booster vaccinations increased functional antibodies targeting ancestral SARS-CoV-2 and emerging variants. Especially heterologous booster vaccinations induced high levels of functional antibodies. In contrast, T-cell responses were similar in magnitude following homologous or heterologous booster vaccination and retained cross-reactivity towards variants. Booster vaccination led to a minimal expansion of SARS-CoV-2-specific T-cell clones and no increase in the breadth of the T-cell repertoire. In conclusion, we show that Ad26.COV2.S priming vaccination provided a solid immunological base for heterologous boosting, increasing humoral and cellular responses targeting emerging variants of concern.

Vaccination against coronavirus disease 2019 (COVID-19) has contributed greatly to providing protection against severe disease, thereby reducing hospital admissions and deaths. Several studies have reported reduction in vaccine effectiveness over time against the Omicron sub-lineages. However, the willingness to receive regular booster doses in the general population is declining. To determine the need for repeated booster vaccinations in healthy individuals and to aid policymakers in future public health interventions for COVID-19, we aim to gain insight into the immunogenicity of the additional bivalent booster vaccination in a representative sample of the healthy Dutch population. The SWITCH ON study was initiated to investigate three main topics: i) immunogenicity of bivalent vaccines after priming with adenovirus- or mRNA-based vaccines, ii) immunological recall responses and reactivity with relevant variants after booster vaccination, and iii) the necessity of booster vaccinations for the healthy population in the future.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT05471440.

Abstract Backgrounds The large, international, randomized controlled NeoPInS trial showed that procalcitonin (PCT)-guided decision making was superior to standard care in reducing the duration of antibiotic therapy and hospitalization in neonates suspected of early-onset sepsis (EOS), without increased adverse events. This study aimed to perform a cost-minimization study of the NeoPInS trial, comparing health care costs of standard care and PCT-guided decision making based on the NeoPInS algorithm, and to analyze subgroups based on country, risk category and gestational age. Methods Data from the NeoPInS trial in neonates born after 34 weeks of gestational age with suspected EOS in the first 72 h of life requiring antibiotic therapy were used. We performed a cost-minimization study of health care costs, comparing standard care to PCT-guided decision making. Results In total, 1489 neonates were included in the study, of which 754 were treated according to PCT-guided decision making and 735 received standard care. Mean health care costs of PCT-guided decision making were not significantly different from costs of standard care (€3649 vs. €3616). Considering subgroups, we found a significant reduction in health care costs of PCT-guided decision making for risk category ‘infection unlikely’ and for gestational age ≥ 37 weeks in the Netherlands, Switzerland and the Czech Republic, and for gestational age

Abstract 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 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

Background: Total knee arthroplasty (TKA) in the setting of a prior contralateral above-knee amputation (AKA) represents a rare scenario with limited reported outcomes. As such, it is difficult for surgeons to effectively counsel these patients relative to risks and expected outcomes after TKA. We report outcomes for a series of 10 such patients. Methods: We retrospectively reviewed all patients at our institution from 2005 to 2018 who underwent a primary TKA and prior contralateral AKA and had a minimum 12-month follow-up. Data regarding complications, ambulatory status, reported pain, patient demographics, length of follow-up, and comorbidities were obtained. Results: Ten patients met criteria. Follow-up ranged from 1 to 8 years. Six reported no pain or improved pain with weight-bearing. Ambulatory status worsened for 5 patients, remained unchanged for 3, and improved for 2. Five patients had significant postoperative complications: infection requiring repeat surgery (3), quadriceps tendon rupture (1), and revision for implant failure and instability (1). Patients in this cohort had a median of 3 medical comorbidities known to affect postoperative outcomes and complication rates. Conclusions: While a contralateral AKA is not an absolute contraindication to TKA, these results should influence patient counseling. Most of our cohort benefited from improved pain, but only 2 of 10 had improved ambulation and half had significant complications. Medical comorbidities may have contributed to these complications. Surgeons contemplating TKA in this situation might consider modified postoperative recovery protocols and aggressive preoperative optimization of medical comorbidities to lower the risk of complication in this high-risk population.

Each central platinum(II) atom in the crystal structures of chlorido[dihydroxybis(1-iminoethoxy)arsanido-κ3N,As,N′]platinum(II), [Pt(C4H10AsN2O4)Cl] (1), and of chlorido[dihydroxybis(1-iminopropoxy)arsanido-κ3N,As,N′]platinum(II), [Pt(C6H14AsN2O4)Cl] (2), is coordinated by two nitrogen donor atoms, a chlorido ligand and to arsenic, which, in turn, is coordinated by two oxygen donor ligands, two hydroxyl ligands and the platinum(II) atom. The square-planar and trigonal–bipyramidal coordination environments around platinum and arsenic, respectively, are significantly distorted with the largest outliers being 173.90 (13) and 106.98 (14)° for platinum and arsenic in (1), and 173.20 (14)° and 94.20 (9)° for (2), respectively. One intramolecular and four classical intermolecular hydrogen-bonding interactions are observed in the crystal structure of (1), which give rise to an infinite three-dimensional network. A similar situation (one intramolecular and four classical intermolecular hydrogen-bonding interactions) is observed in the crystal structure of (2). Various π-interactions are present in (1) between the platinum(II) atom and the centroid of one of the five-membered rings formed by Pt, As, C, N, O with a distance of 3.7225 (7) Å, and between the centroids of five-membered (Pt, As, C, N, O) rings of neighbouring molecules with distances of 3.7456 (4) and 3.7960 (6) Å. Likewise, weak π-interactions are observed in (2) between the platinum(II) atom and the centroid of one of the five-membered rings formed by Pt, As, C, N, O with a distance of 3.8213 (2) Å, as well as between the Cl atom and the centroid of a symmetry-related five-membered ring with a distance of 3.8252 (12) Å. Differences between (2) and the reported polymorph [Miodragović et al. (2013). Angew. Chem. Int. Ed. 52, 10749–10752] are discussed.

Vaccination is the most effective measure to prevent infections in the general population. Its efficiency strongly depends on the function and composition of the immune system. If the immune system lacks critical components, patients will not be fully protected despite a completed vaccination schedule. Antigen-specific serum immunoglobulin levels are broadly used correlates of protection. These are the products of terminally differentiated B cells – plasma cells. Here we reviewed the literature on how aberrancies in B-cell composition and function influence immune responses to vaccinations. In a search through five major literature databases, 6,537 unique articles published from 2000 and onwards were identified. 75 articles were included along three major research lines: extremities of life, immunodeficiency and immunosuppression. Details of the protocol can be found in the International Prospective Register of Systematic Reviews [PROSPERO (registration number CRD42021226683)]. The majority of articles investigated immune responses in adults, in which vaccinations against pneumococci and influenza were strongly represented. Lack of baseline information was the most common reason of exclusion. Irrespective of study group, three parameters measured at baseline seemed to have a predictive value in assessing vaccine efficacy: (1) distribution of B-cell subsets (mostly a reduction in memory B cells), (2) presence of exhausted/activated B cells, or B cells with an aberrant phenotype, and (3) pre-existing immunological memory. In this review we showed how pre-immunization (baseline) knowledge of circulating B cells can be used to predict vaccination efficacy. We hope that this overview will contribute to optimizing vaccination strategies, especially in immunocompromised patients.

The title compound, 2-(methylamino)cyclohepta-2,4,6-trien-1-one, C8H9NO, crystallizes in the monoclinic space group P21/c, with three independent molecules in the asymmetric unit. The planarity of the molecules is indicated by planes fitted through the seven ring carbon atoms. Small deviations from the planes, with an extremal r.m.s. deviation of 0.0345 Å, are present. In complexes of transition metals with similar ligands, the large planar seven-membered aromatic rings have shown to improve the stability of the complex. Two types of hydrogen-bonding interactions, C—H...O and N—H...O, are observed, as well as bifurcation of these interactions. The N—H...O interactions link molecules to form infinite chains. The packing of molecules in the unit cell shows a pattern of overlapping aromatic rings, forming column-like formations. π–π interactions are observed between the overlapping aromatic rings at 3.4462 (19) Å from each other.

Abstract Background Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. Methods Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. Results Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. Conclusion This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naïve CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naïve CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naïve CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19.

The Dutch ‘search and destroy’ policy consists of screening patients with an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) carriership and subsequent decolonization treatment when carriership is found. Decolonization therapy of individual MRSA carriers is effective. However, the effectiveness of the national ‘search and destroy’ policy is dependent on the entire cascade of care, including identification, referral, and subsequent treatment initiation in MRSA carriers. The aim of this study was to evaluate the leakages in the cascade of MRSA decolonization care. We assessed familiarity with the ‘search and destroy’ policy and the barriers in the uptake of MRSA eradication care using a questionnaire among 114 Dutch general practitioners. The main reasons for treatment were planned hospital visits, occupational reasons, and infections. The main reasons for refraining from eradication treatment were unfamiliarity with the ‘search and destroy’ policy and the assumption that MRSA carriership is often self-limiting. To optimize the continuity of the cascade of care, interventions should be aimed at supporting general practitioners and facilitating treatment and referral.

Prosthetic joint infection (PJI) is a severe complication of arthroplasty. Due to biofilm and persister formation current treatment strategies often fail. Therefore, innovative anti-biofilm and anti-persister agents are urgently needed. Antimicrobial peptides with their broad antibacterial activities may be such candidates. An in vitro model simulating PJI comprising of rifampicin/ciprofloxacin-exposed, mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms on polystyrene plates, titanium/aluminium/niobium disks, and prosthetic joint liners were developed. Bacteria obtained from and residing within these biofilms were exposed to SAAP-148, acyldepsipeptide-4, LL-37, and pexiganan. Microcalorimetry was used to monitor the heat flow by the bacteria in these models. Daily exposure of mature biofilms to rifampicin/ciprofloxacin for 3 days resulted in a 4-log reduction of MRSA. Prolonged antibiotic exposure did not further reduce bacterial counts. Microcalorimetry confirmed the low metabolic activity of these persisters. SAAP-148 and pexiganan, but not LL-37, eliminated the persisters while ADEP4 reduced the number of persisters. SAAP-148 further eradicated persisters within antibiotics-exposed, mature biofilms on the various surfaces. To conclude, antibiotic-exposed, mature MRSA biofilms on various surfaces have been developed as in vitro models for PJI. SAAP-148 is highly effective against persisters obtained from the biofilms as well as within these models. Antibiotics-exposed, mature biofilms on relevant surfaces can be instrumental in the search for novel treatment strategies to combat biofilm-associated infections.

BackgroundMonitoring 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.MethodsCOVID 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.ResultsSince 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.DiscussionThe 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 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

The mechanisms by which measles virus infection induces transient immune suppression in humans are poorly understood. Here, Laksono and colleagues characterise the pathogenesis of measles-associated immune suppression in unvaccinated children, and shed new light on the long-term effects of measles on the host.

Abstract Background One third of travellers to low- and middle-income regions of the tropics and subtropics become colonized by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). The risk varies by destination and, for each traveller, may be substantially further increased by travellers’ diarrhoea (TD) and antibiotic use. Despite the risk of TD in Africa, ESBL-PE acquisition rates in all studies are lower there than in Asia. Africa has become increasingly popular as a destination for international travellers, yet minimal data are available from the continent’s subregions and countries. Methods We analysed subregion- and country-specific data on carriage and risk factors for ESBL-PE colonization pooled from three prospective studies conducted between 2009 and 2013 among Finnish and Dutch travellers. The data were subjected to multivariable analysis of risk factors. In addition, we compared our data to two recent large investigations reporting data by subregion and country. Results Our joint analysis comprised data on 396 travellers. The ESBL-PE colonization rate was highest in Northern Africa, followed by Middle and Eastern Africa, and lowest in Southern and Western Africa. Of individual countries with more than 15 visitors, the highest rates were seen for Egypt (12/17; 70.6%), Ghana (6/23; 26.1%), and Tanzania (14/81; 17.3%); the rates among travellers to Egypt were comparable to those reported in South and Southeast Asia. In a pooled multivariable analysis, travel destination, age, overnight hospitalisation abroad, TD, and use of fluoroquinolones were independently associated with increased ESBL-PE colonization rates. Conlusions Even in areas with relatively low risk of colonization, antimicrobials clearly predispose to colonization with ESBL-PE. Travellers to Africa should be cautioned against unnecessary use of antibiotics.

Abstract 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.

In the title compound, C12H8N4O2, the dihedral angle between the phenanthroline ring system and the nitro group is 23.75 (14)°. The molecule features intramolecular N—H...O and C—H...O hydrogen bonds. In the crystal, N—H...(N,N), C—H...N and C—H...O hydrogen bonds link the molecules into [100] chains.