Pronkjewail

The candidate will be supervised by excellent scientists from the autophagy (Reggiori) and the mosquito-borne viruses (Smit) research groups. Autophagy is an intracellular degradative process, which is part of our innate immunity, and several microbes have developed mechanisms to subvert it. The groups has explored the relevance autophagy proteins in the replication of various viruses and the candidate will focus on arboviruses including Dengue, West Nile, Zika and Chikungunya viruses. Using our siRNA library and virus strains expressing GFP, the candidate will determine in an automated manner which autophagy genes are relevant for the studied infections. The role of the hits in infections will be then studied in molecular detail using cell biological, biochemical, ultrastructural and microbiological methods. We expect to identify and characterise new factors involved in the life cycle of these human pathogens, with the ultimate goal of providing novel therapeutic targets for the treatment of their infections.

Influenza virus infections are associated with high morbidity and mortality rates, especially in immunocompromised and older individuals. Due to constant mutation of the influenza virus RNA genome, vaccines do not always match with the circulating virus strains and may fail to induce adequate protection. Recent evidence indicates that vaccination with a seasonal influenza vaccine not only induces antibodies to the virus strains included in the vaccine, but also to previously encountered virus strains, a phenomenon called ‘back-boost’. The question now is whether it would be generally beneficial to include the most recently isolated rather than the most frequently encountered influenza strains in the vaccine since that would lead to antibody responses to the new as well as to the older strains. The aim of this project is to get insight into the dynamics of influenza-specific antibody responses after vaccination using a combination of epidemiological methods, assessment of biobank samples and in vitro and in vivo experiments. This unique combined approach is expected to render novel leads for optimisation of future influenza vaccination strategies.

Prophylaxis is often prescribed to prevent infections in immuno-compromised patients. However, antimicrobial drugs used for prophylaxis are often prescribed in a one size fits all strategy, which may lead to break through infections or adverse drug effects. The PhD student will be supervised by the experts who successfully raised awareness of this problem. Training will address adequate dosing of the most important antimicrobial drugs used for prophylaxis in immuno-compromised patients: valganciclovir, co-trimoxazole and ciprofloxacin, fluconazole, posaconazole and voriconazole. You will evaluate current practice and develop a dosing algorithm for optimised administration of antimicrobial drugs for prophylaxis. Pharmacokinetic modeling to support the dose algorithm will be followed at the University of Liverpool under supervision of prof William Hope. In addition, cost effectiveness of different dosing strategies will be calculated. An internship at MSD on pharmaco-vigilance and medical information for healthcare professionals will be an integral part of the PhD training.

After esophageal surgery, bacterial pulmonary infection is one of the largest determinants of post-operative complications (40% of the patients). The supervisors proved Selective Decontamination of the Digestive tract (SDD) to be effective in intensive care patients. Further there seems to be a positive effect on anastomotic leakage when using SDD peri-operatively in major gastrointestinal surgery. Yet, SDD has not been applied peri-operatively in the field of esophagectomy and its impact on post-operative recovery and complications such as pneumonia, and anastomotic dehiscence. ESR 1.4 will set up a multicenter randomised clinical trial of SDD in patients undergoing esophagectomy in The Netherlands.

In cooperation with the University of Edinburgh (www.proteus.ac.uk), ESR 1.4 will introduce innovative optical imaging by microendoscopy and targeted optical tracers in patients with the suspicion of pneumonia for the early detection of bacterial and fungal infections. A novel multiwavelength clinical molecular fluorescence endoscopy system for lung imaging is introduced, tested and evaluated in an explanted lung model of discarded donor lungs unsuitable for in-human lung transplantation, in combination with Good Manufacturing Practice (GMP) produced optical tracer for the detection of neutrophils and bacteria in lungs. Subsequently, patients with the suspicion of a pulmonary infection will be imaged by this fiber-based system in combination with a cocktail of both a neutrophil and bacteria specific fluorescent tracer.

​Next generation sequencing is more and more used in routine clinical microbiology and infection prevention to determine the genetic relationship between pathogens (used to guide infection prevention measures) and for the molecular detection and further characterisation of (emerging) pathogens. This includes analyses for revealing (new) antibiotic resistance mechanisms and for determining the virulence of pathogens resulting in improved risk assessment and treatment of patients. In this project a (RNA)-metagenomic approach will be used and optimised to identify pathogens present in clinical samples. Furthermore, it will focus on studying interactions between pathogens and their host resulting in a method to differentiate between colonisation (presence of a pathogen) and infection of a patient with the pathogen. In addition, based on comparing whole genomes of pathogens, tailor-made diagnostic tests will be developed used for specific detection of outbreak and or virulent strains. The candidate will develop skills in Next Generation (deep) Sequencing and big data analyses.

The last few years, rapid molecular diagnostic technologies have, and still are, increasingly enabling clinicians to detect acute infections while the patient is still at the emergency room. Lessons learned and questions raised from these ameliorated techniques and procedures have resulted in the recognition of the significance of diagnostic stewardship. This concept together with the already prominent principle of antimicrobial stewardship has been studied and implemented to a large extent in the UMCG. Adding infection control stewardship to these two areas, the AID stewardship model has been introduced, which reflects the aim of the Medical Microbiology department of the UMCG to perform the correct diagnostic tests, in order to treat the patient optimally and to prevent the transmission of infections. The notion of €hour defines the relationship between costs and benefits of medical microbiological diagnostics within the AID principle. This notion provides an instrument for demonstrating that the costs and benefits of diagnostics may be disconnected within healthcare settings, but they are nevertheless benefiting the same patient through AID stewardship.

Furthermore, implementing improved rapid technologies, we have shown the added value of genotyping several viruses. This not only allowed us to expose transmission patterns, but also led to the identification of viruses which were not previously known to circulate in Europe. Main focus of this project is to develop techniques and strategies which will aid in the rapid characterisation of picornaviruses, including enteroviruses and rhinoviruses, and noroviruses. These viruses are highly contagious and capable of causing significant morbidity. Although both virus-groups can be transmitted in the community as well as in hospital settings, picornaviruses are first and foremost community pathogens, while noroviruses are principally nosocomial pathogens. By studying the genotypic epidemiology and the sequence variations of picornaviruses and noroviruses, we aim to achieve better understanding of how transmission can be reduced, but also to identify those viruses which are may become a threat to our patients’ health in the near future. Developing cost effective and rapid tests will be an aspect of this project. Collaborations will be with industries involved in the development of these rapid molecular diagnostic portfolios, which we call Point-of-Impact technologies, as well with software developers who will participate in the development of the economic models.

Infections are a leading cause of morbidity and mortality globally, and are a major challenge in clinical medicine. Rapid detection and identification of micro-organisms and resistance determinants is paramount for therapy and prevention of infections. Currently culture-based methods are often indispensable but relatively slow. The PhD candidate will develop automated methods and novel technical options, such as hyperspectral imaging combined with colorigenic/fluorogenic substrates and molecular methods, including next generation sequencing (metagenomics). The project aims at boosting diagnostic quality and speed up time to result while containing costs at a reasonable level. Combining the strengths of rapid culture-based, molecular, and novel diagnostic modalities offers novel options. Ultimately, an optimised, automated, multi-modal work flow should lead to early personalised treatment of patients. A training period with the collaboration partner in Italy to gain experience with diagnostic tools and automated high quality sample processing will be part of the project.

ProjectProcalcitonin (PCT) is an established biomarker that provides unique additional information on the severity of bacterial infection. Several smaller clinical trials have demonstrated that daily PCT-monitoring helps identify resolution of bacterial infection. Recently the largest study on PCT, the Dutch SAPS-I trial has been concluded. SAPS-I clearly demonstrated reduced antibiotic use with under PCT-guidance.
The next trial, SAPS-II, we plan to conduct in Dutch, German and Belgian ICU’s. The goal of SAPS-II is to verify with PCT-measurements if continuous antibiotic infusion is superior to conventional intermittent infusion. If continuous antibiotic administration leads to more rapid clearance of infection, this may constitute a next step in reducing antibiotic treatment duration. The key hypothesis to be tested in SAPS-II is that PCT will decrease earlier in patients with continuous antibiotic administration compared with intermittent administration.

Supervisors

• ​Maarten Nijsten (Dpt of Critical Care, UMC Groningen, Netherlands)
• Annemieke Oude Lansink (Dpt of Critical Care, UMC Groningen, Netherlands)

Antimicrobial resistance is emerging worldwide. The role of human migration in the transmission of infectious diseases is established but the role of one of the current, most significant influxes of migrants and refugees in Europe’s history is largely unknown. Carriage rates of MDRO in asylum seekers with no hospitalisations in their countries may be higher than in the Dutch population, but might actually be lower than in Greece, at least for Gram-negatives. The PhD student studies the carriage rate of migrants in different geographical settings and the change in carriage rate of antimicrobial resistant microorganisms and microbiomes over time.

The goal of this project is to study the influence of the presence of antibiotic, chlorine, disinfectants and heavy metals in environmental water streams on the gut microbiome, possibly leading to an increased presence of antibiotic resistant bacteria (ARB) in the gut. The results will be used to support prevention and improve diagnostics of ARB in patients. The PhD student will analyse the effect of colonisation with ARB, as community-acquired ARB, and correlate incidence of ARB infection with length of hospital stay, treatment success and healthcare costs.
The PhD student will be trained in the Molecular Bacteriology and Genomics for Infection Prevention groups at the Department of Medical Microbiology of the University Medical Center Groningen in Groningen, which are highly experienced in cross-border network studies addressing the molecular epidemiology of ARB and infection control, the Centre of Excellence for Water in Leeuwarden for a secondment for one year and six months, and and the Nanobiophotonics Department of the Institute of Photonic Technology in Jena, Germany for a six-month internship.

Hospitalisation and treatment to cure patients, will also have an effect on the normal functioning of the body and its relationship with microbes. The development of infectious complications in patients may be associated with a dysbiosis caused by these iatrogenic effects. To study these effects, the composition of the oral and fecal microbiota will be analysed in relation to disease outcome, such as infections, length of stay and number of comorbidities. Patient samples and data will be collected and analysed in the microbiota research lab. The goal for this is to design clinical interventions, where infections and antibiotics use can be minimised, using strategies such as selective digestive tract decontamination (SDD) or enforcement of the normal microbiota by clinical nutrition with pre- and probiotics. To learn more about the aspects used in the interventions such as the effect of enteral feeding on microbiota and in the safety of probiotics, stays at international expert labs are planned.

​​​​​​Mucositis is an inflammatory condition of the gastric tract in oncological patients that is induced by chemotherapy. This condition makes the patients vulnerable to malnutrition and infections. The microbiota in the gastric tract plays an essential role in this, although the mechanisms are yet poorly understood. Recent studies show that the anaerobic microbiota is strongly reduced during mucositis, which may be caused by the increased oxidative stress during the inflammation. We want to study in an already established mucositis rat model, if mucositis can be ameliorated and infection rates can be improved by supportive care with prebiotics and vitamins aimed at the microbiome. The level of oxidative stress during chemotherapy will be related to clinical parameters and microbiota. Nutritional intervention studies will be done with treatment success and infection rates as outcome. To learn more about the immunological and nutritional aspects of such interventions, two 6 months visits at international expert labs are planned.

Invasive and biomaterial-associated staphylococcal infections in humans are often difficult to diagnose and treat. The objective of this project is to explore the application potential of several recently developed human monoclonal antibodies against pathogenic staphylococci to detect or fight infections precipitated by implanted materials. Antibodies will be labelled with near-infrared fluorophores, isotopes suitable for PET imaging, or photosensitive molecules suitable for photodynamic therapy and, subsequently, tested in animal infection models. The results will be applied to develop new generation diagnostics and immune-therapeutics. Specific requirements: background in biochemistry or molecular microbiology, and willingness to perform research with small laboratory animals.

Recent proof-of-principle studies have shown that fluorescently labeled antibiotics, such as vancomycin, can be applied to specifically target and detect bacterial infections. The objective of this project is to perform translational studies towards the clinical use of fluorescently or radioactively labeled antibiotics, metabolisable compounds, or other ligands as targeting molecules to specifically detect infections using ex vivo or in vivo model systems. The results will be applied to develop new generation diagnostics and immune-therapeutics. Specific requirements: background in biochemistry or molecular microbiology, and willingness to perform research with small laboratory animals.

Drug level guided dosing has been introduced to increase efficacy and to reduce toxicity. Dry blood spot (DBS) analysis is a tool to easily obtain the necessary drug levels and the UMCG has an international leading position in this field. You will focus on implementation of e-health combined with DBS spot analysis to support personalised dosing. You will determine risk factors for suboptimal patient care in current practice. Coached by MAD multimedia, you will then develop a smart phone application to exchange relevant informationbetween patient, physician and pharmacist. In the next step you will evaluate the cost effectiveness of the DBS/e-health program. Finally, you will work on the implementation of the developed tools in tuberculosis patients in a high burden setting in Romania. Gilead offers an internship on pharmacovigilance and medical information for healthcare professionals

Optimising early diagnosis and therapy of infections in patients admitted to an ICU is crucial to improving outcome. Positive clinical effects should be reflected partially in a reduced length of stay, reduced use of antimicrobials, and fewer complications. In order to optimise the work flow and support high quality of care, the candidate will further develop and use computerised tools (clinical decision support systems) to facilitate the early recognition of patients at the ICU who require intensified and directed diagnostic efforts. Furthermore, these tools will be used to early and dynamically adjust antimicrobial therapy, including stopping. One aspect of this project will be the clinical and financial analysis of the obtained results, with a focus on medical impact.

During a training period with the collaboration partner (IDMC) the candidate will receive training on the use of sophisticated electronic tools, such as highly condensed and integrated synoptic visualisation of patient data and dynamically prioritised patient lists.