Background: Medical schools offer students the opportunity to perform international electives. This study aimed to assess health risks among medical students, to tailor institutional guidelines... Show moreBackground: Medical schools offer students the opportunity to perform international electives. This study aimed to assess health risks among medical students, to tailor institutional guidelines.Methods: Multicenter study at Dutch and Belgian universities, among medical students who visited low- or middle-income countries. Students completed four questionnaires: once before the elective and two weeks, three- and six months after return.Results: Data was complete for 479 students (follow-up rate 84%). Most traveled to Surinam (29%) and South-Africa (14%). Half of the students encountered difficulties in adapting to local culture. Almost 40% visited malaria endemic countries. Nearly all (87%) used chemoprophylaxis as prescribed. Definite needle-stick or splash injuries were reported by 7%. All were dealt with adequately in accordance with national guidelines. However, less than half of 24 possible incidents were handled adequately. Two-and-a-half percent had unprotected sex with a new partner. The incidence of travelers' diarrhea (TD) was 46%. In those with TD, the incidence of post-travel new-onset abdominal complaints was 3%. Three percent were involved in a minor traffic accident, 18% were injured during leisure activities, 5% were threatened or experienced physical violence. Only half of the students visiting a highly endemic country were screened for tuberculosis post-travel. For schistosomiasis this was 6%.Conclusions: Students abroad are exposed to medical and non-medical challenges, which should be addressed during pre-travel counseling. Contact details of a professional back home should be provided, so students can confer in case of problems while abroad. Lastly, we recommend a centrally organized post-travel health check. Show less
Background: More people on immunosuppression live in or wish to travel to yellow fever virus (YFV)-endemic areas. Data on the safety and immunogenicity of yellow fever vaccination (YFVV) during... Show moreBackground: More people on immunosuppression live in or wish to travel to yellow fever virus (YFV)-endemic areas. Data on the safety and immunogenicity of yellow fever vaccination (YFVV) during immunosuppression are scarce. The aim of this study was to compare the safety and immunogenicity of a primary YFVV between travellers on methotrexate and controls.Methods: We conducted a prospective multi-centre controlled observational study from 2015 to 2017 in six Swiss travel clinics. 15 adults (nine with rheumatic diseases, five with dermatologic conditions and one with a gastroenterological disease) on low-dose methotrexate (<= 20 mg/week) requiring a primary YFVV and 15 age and sex-matched controls received a YFVV. Solicited/unsolicited adverse reactions were recorded, YFV-RNA was measured in serum samples on Days 3, 7, 10, 14, 28 and neutralizing antibodies on Days 0, 7, 10, 14, 28.Results: Patients' and controls' median ages were 53 and 52 years; 9 patients and 10 controls were female. 43% of patients and 33% of controls showed local side effects (P = 0.71); 86% of patients and 66% of controls reported systemic reactions (P = 0.39). YFV-RNA was detected in patients and controls on Day 3-10 post-vaccination and was never of clinical significance. Slightly more patients developed YFV-RNAaemia (Day 3: n= 5 vs n= 2, Day 7: n= 9 vs n= 7, Day 10: n= 3 vs n= 2, all P > 0.39). No serious reactions occurred. On Day 10, a minority of vaccinees was seroprotected (patients: n= 2, controls: n= 6). On Day 28, all vaccinees were seroprotected.Conclusions: First-time YFVV was safe and immunogenic in travellers on low-dose methotrexate. Larger studies are needed to confirm these promising results. Show less
Background: Recently, internet-based cognitive behavioral therapy (ICBT) and serious gaming interventions have been suggested to enhance accessibility to interventions and engagement in... Show moreBackground: Recently, internet-based cognitive behavioral therapy (ICBT) and serious gaming interventions have been suggested to enhance accessibility to interventions and engagement in psychological interventions that aim to promote health outcomes. Few studies, however, have investigated their effectiveness in the context of simulated real-life challenges.Objective: We aimed to examine the effectivity of a guided ICBT combined with a serious gaming intervention in improving self-reported psychophysiological and immunological health endpoints in response to psychophysiological and immune-related challenges.Methods: Sixty-nine healthy men were randomly assigned to the intervention condition, receiving ICBT combined with serious gaming for 6 weeks, or the control condition, receiving no intervention. Self-reported vitality was the primary endpoint. Other self-reported psychophysiological and immunological endpoints were assessed following various challenges, including a bacillus Calmette-Guerin vaccination evoking pro-inflammatory responses, 1 and 4 weeks after the intervention period.Results: Although the intervention did not affect vitality-associated parameters, self-reported sleep problems (P=.027) and bodily sensations (P=.042) were lower directly after the intervention compared with controls. Furthermore, wellbeing (P=.024) was higher in the intervention group after the psychophysiological challenges. Although no significant group differences were found for the psychophysiological and immunological endpoints, the data provided preliminary support for increased immunoglobulin antibody responses at the follow-up time points (P<.05). Differential chemokine endpoints between conditions were observed at the end of the test day.Conclusions: The present study provides some support for improving health endpoints with an innovative ICBT intervention. Future research should replicate and further extend the present findings by consistently including challenges and a wide range of immune parameters into the study design. Show less
Lambregts, M.M.C.; Molendijk, E.B.D.; Meziyerh, S.; Schippers, E.F.; Delfos, N.M.; Leendertse, M.; ... ; Boer, M.G.J. de 2020
Objective A cornerstone in the management ofStaphylococcus aureusbacteraemia (SAB) is the differentiation between a complicated and an uncomplicated SAB course. The ability to early and accurately... Show moreObjective A cornerstone in the management ofStaphylococcus aureusbacteraemia (SAB) is the differentiation between a complicated and an uncomplicated SAB course. The ability to early and accurately identify patients with - and without - complicated bacteraemia may optimise the utility of diagnostics and prevent unnecessary prolonged antibiotic therapy. Methods Development and validation of a prediction score in SAB using demographic, clinical, and laboratory data from two independent Dutch cohorts; estimating the risk of complicated disease at the time of the first positive blood culture. Models were developed using logistic regression and evaluated by c-statistics, ie area under the ROC-curve, and negative predictive values (NPV). Results The development- and validation cohorts included 150 and 183 patients, respectively. The most optimal prediction model included: mean arterial pressure, signs of metastatic infection on physical examination, leucocyte count, urea level and time to positivity of blood cultures (c-statistic 0.82, 95% CI 0.74-0.89). In the validation cohort, the c-statistic of the prediction score was 0,77 (95% CI 0.69-0.84). The NPV for complicated disease for patients with a score of <= 2 was 0.83 (95% CI 0.68-0.92), with a negative likelihood ratio of 0.14 (95% CI 0.06-0.31). Conclusion The early SAB risk score helps to identify patients with high probability of uncomplicated SAB. However, the risk score's lacked absolute discriminative power to guide decisions on the management of all patients with SAB on its own. The heterogenicity of the disease and inconsistency in definitions of complicated SAB are important challenges in the development of clinical rules to guide the management of SAB. Show less
'Immunity passport' (also called ''immunity certificate'' or ''immunity license'' has been suggested to certify traveler' protection from SARS-CoV-2 infection. Some data have demonstrated... Show more'Immunity passport' (also called ''immunity certificate'' or ''immunity license'' has been suggested to certify traveler' protection from SARS-CoV-2 infection. Some data have demonstrated development of neutralizing antibodies that may protect against reinfection and reduce disease severity in the short-term, and some tests correlate with virus neutralization. More evidence is needed on serologies for such certification to facilitate travel, to protect travelers and their destination countries. Show less
Roestenberg, M.; Walk, J.; Boor, S.C. van der; Langenberg, M.C.C.; Hoogerwerf, M.A.; Janse, J.J.; ... ; Sauerwein, R.W. 2020
Immunization with attenuated Plasmodium sporozoites can induce protection against malaria infection, as shown by Plasmodium fakiparum (Pf) sporozoites attenuated by radiation in multiple clinical... Show moreImmunization with attenuated Plasmodium sporozoites can induce protection against malaria infection, as shown by Plasmodium fakiparum (Pf) sporozoites attenuated by radiation in multiple clinical trials. As alternative attenuation strategy with a more homogeneous population of Pf sporozoites (PfSPZ), genetically engineered Plasmodium berghei sporozoites (SPZ) lacking the genes b9 and slarp induced sterile protection against malaria in mice. Consequently, PfSPZ-GA1 Vaccine, a Pf identical double knockout (Pf Delta b9 Delta s/arp), was generated as a genetically attenuated malaria parasite vaccine and tested for safety, immunogenicity, and preliminary efficacy in malaria-naive Dutch volunteers. Dose-escalation immunizations up to 9.0 x 10(5) PfSPZ of PfSPZ-GA1 Vaccine were well tolerated without break-through blood-stage infection. Subsequently, groups of volunteers were immunized three times by direct venous inoculation with cryopreserved PfSPZ-GA1 Vaccine (9.0 x 10(5) or 4.5 x 10(5) PfSPZ, N = 13 each), PfSPZ Vaccine (radiation-attenuated PfSPZ, 4.5 x 10(5) PfSPZ, N= 13), or normal saline placebo at 8-week intervals, followed by exposure to mosquito bite controlled human malaria infection (CHMI). After CHMI, 3 of 25 volunteers from both PfSPZ-GA1 groups were sterilely protected, and the remaining 17 of 22 showed a patency >= 9 days (median patency in controls, 7 days; range, 7 to 9). All volunteers in the PfSPZ Vaccine control group developed parasitemia (median patency, 9 days; range, 7 to 12). Immunized groups exhibited a significant, dose-related increase in anti-Pf circumsporozoite protein (CSP) antibodies and Pf-specific interferon-gamma (IFN-gamma)-producing T cells. Although no definite conclusion can be drawn on the potential strength of protective efficacy of PfSPZ-GA1 Vaccine, the favorable safety profile and induced immune responses by PfSPZ-GA1 Vaccine warrant further clinical evaluation. Show less
Lambregts, M.M.C.; Wijnakker, R.; Bernards, A.T.; Visser, L.G.; Cessie, S. le; Boer, M.G.J. de 2020
Background: Timely empiric antimicrobial therapy is one of the cornerstones of the management of suspected bloodstream infection (BSI). However, studies about the effects of empiric therapy on... Show moreBackground: Timely empiric antimicrobial therapy is one of the cornerstones of the management of suspected bloodstream infection (BSI). However, studies about the effects of empiric therapy on mortality have reported inconsistent results. The objective of this study was to estimate the effect of delay of appropriate empiric therapy on early mortality in patients with BSI. Methods: Data for the propensity score matching (PSM) study were obtained from a cohort of patients with BSI. Inadequate empiric treatment was defined as in vitro resistance to the antimicrobial regimen administered < 6 h after blood cultures were taken. The primary outcome measure was 14-day mortality. Thirty-day mortality and median length of stay (LOS) were secondary outcomes. PSM was applied to control for confounding. Results: Of a total of 893 included patients with BSI, 35.7% received inadequate initial empiric treatment. In the PSM cohort (n = 334), 14-day mortality was 9.6% for inadequate antibiotic treatment, compared to. 10.2% in adequate empiric treatment (p = 0.85). No prolonged median LOS was observed in patients who initially received inadequate therapy (10.5 vs. 10.7 days, p = 0.89). Conclusions: In this study, we found no clear effect of inadequate empirical treatment on mortality in a low-risk BSI population. The importance of early empiric therapy compared to other determinants, may be limited. This may not apply for specific subpopulations, e.g., patients with sepsis. Show less
Burkhard, J.; Ciurea, A.; Gabay, C.; Hasler, P.; Muller, R.; Niedrig, M.; ... ; Buhler, S. 2020
Background: The live-attenuated yellow fever vaccine (YFV) is generally contraindicated in immunosuppressed patients. Our aim was to investigate if immunosuppressive therapy impairs the long-term... Show moreBackground: The live-attenuated yellow fever vaccine (YFV) is generally contraindicated in immunosuppressed patients. Our aim was to investigate if immunosuppressive therapy impairs the long-term protection against yellow fever virus in patients who had received YFV prior to the start of their immunosuppressive therapy.Methods: Our study examined 35 healthy individuals and 40 immunosuppressed patients with autoimmune diseases or organ transplants. All individuals had received YFV prior to the onset of their immunosuppression. We analysed the long-term influence of the immunosuppressive therapy on the YFV protective immunity by measuring neutralising antibodies (NA) with the Plaque Reduction Neutralisation Test (PRNT). We assessed risk factors for a negative PRNT result (titre below 1: 10) and their influence on the magnitude of the NA.Results: A median time interval of 21.1 years (interquartile range 14.4-31.3 years) after the YFV in all patients, a total of 35 immunosuppressed patients (88%) were seropositive (PRNT >= 1:10) compared to 31 patients (89%) in the control group. The geometric mean titres of NA did not differ between the groups. The duration of an underlying rheumatic disease was the only risk factor found for a lower magnitude of NA. An insufficient level of NA was found in nine subjects (12%) who had received a single dose of YFV (in one subject, the number of YFV doses was unknown).Conclusion: The use of an immunosuppressive drug started after the administration of the YFV did not affect long-term persistence of NA. A second dose of YFV may be necessary to secure long-term immunity. (C) 2019 Elsevier Ltd. All rights reserved. Show less
Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas(1). Novel medicines and vaccines are urgently... Show moreSchistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas(1). Novel medicines and vaccines are urgently needed(2,3). An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov ), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4(+) T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis.A new human challenge model of schistosomiasis, which affects more than 290 million people globally, will aid development of novel therapies and vaccines for this neglected tropical disease. Show less
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... Show moreBackground 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 immunityMethods 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 mu g or Engerix-B 20 mu g) as the control, or to Twinrix 20 mu g, Fendrix 20 mu g, or HBVaxPro 40 mu g. 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 (71.346.5) 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]; 1:0 .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. Copyright (C) 2019 Elsevier Ltd. All right reserved. Show less
Purpose of review Climate change, deforestation, urbanization, and increased population mobility have made the risk of large outbreaks of yellow fever more likely than ever. Yellow fever vaccine... Show morePurpose of review Climate change, deforestation, urbanization, and increased population mobility have made the risk of large outbreaks of yellow fever more likely than ever. Yellow fever vaccine production barely meets demands. In this review, we address the causes of the recent yellow fever outbreaks, why fractional dose yellow fever vaccination works, the role of virus neutralizing antibodies in the protection against yellow fever, and the need for revaccination. Recent findings Human activities have profoundly changed the epidemiology of yellow fever. The excess of infectious viral particles in routine yellow fever vaccine batches allows for off-label use of fractional dose yellow fever vaccination in response to emergency situations. Two studies have confirmed long-term protection after fractional dose yellow fever vaccination. The need for the presence of virus neutralizing antibodies (VNA) to protect an individual against yellow fever depends on the epidemiological setting. In case of sylvatic transmission, population immunity is irrelevant for individual protection, as mosquitoes are transmitting the virus from infected nonhuman primates to human. With the growing connectivity through air travel, countries with high densities of nonimmune populations and of the urban mosquito vector, Aedes aegypti, should ensure that their citizens are properly vaccinated against yellow fever before traveling to a yellow fever endemic country. In the situation of sylvatic transmission, the presence of protective levels of VNA will determine the outcome and may require revaccination at some point in time. Show less
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... Show moreBackground: 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. Show less
