Malnutrition requiring hospitalization, among children under 5 years of age, remains a major problem globally. Mortality is high and up to 2 out of 10 children die during hospitalisation. If this high mortality is to be lowered, it is necessary to find new treatment strategies to improve hospital management. The acute malnourished children can develop severe wounds and peeling of the skin, among other things. This is a symptom of malnutrition for which the cause is not yet known and for which the World Health Organization's (WHO) treatment guidelines do not yet provide an evidence-based management.

This PhD study is an investigation of skin changes in severe acute malnutrition. Published knowledge is reviewed, nomenclature is established and a scoring tool for clinical documentation of the skin changes is developed through a prospective observatory study. The prognostic effect of the skin changes is investigated and an exploratory study of the immune status of the patient group is included. Finally, a qualitative study of the challenges among health personnel illustrates the use of methods from health anthropology to identify the local agenda within the subject.

Coronavirus infections typically give rise to common cold symptoms. However, rare viral variants emerge, causing severe respiratory disease. At the outbreak of the SARS-CoV-2 pandemic in 2020, the lack of specific prophylactic and therapeutic treatment options was limiting for patient care. This PhD thesis explores the development of novel SARS-CoV-2 specific monoclonal antibodies for SARS-CoV-2 prophylaxis, through three stages: 1) Discovery of neutralizing monoclonal antibodies from convalescent individuals. 2)  In depth characterization of antibody potency, sensitivity to viral variants, and therapeutic potential of preventing infections in mice. 3) Investigation of the possibility of delivering antibody genetic sequences through Adeno Associated Virus for long-term expression and passive immune-prophylaxis.

Chronic cluster headache ranks among the most severe pain conditions known to man. Patients experience excruciatingly painful headache attacks, often described as a knife stabbing the eye. Sometimes, patients suffer from these headache attacks multiple times a day. For some patients, the conventional medical treatment options fail to provide sufficient relief. For this group of patients, a treatment modality called neuromodulation may be an option. Neuromodulation is a therapy where a nerve structure stimulated by weak electrical currents. Several smaller studies have shown that electrical stimulation of the so-called occipital nerves at the back of the head - occipital nerve stimulation (ONS), where a stimulation electrode in implanted under the scalp - can prevent the painful cluster headache attacks in patients where other treatment options seem exhausted.

A new Ph.D. project from Aarhus University, Health, systematically investigates the effect of ONS as a preventive treatment for patients with severe chronic cluster headache. The dissertation presents a database study of the clinical effect on patients already undergoing ONS treatment. It also includes an examination of the efficacy of a simpler, non-invasive stimulation, where the occipital nerves are stimulated through the skin of the scalp, and whether the effect of this transcutaneous stimulation can predict the effect of the implanted ONS electrode. 

Hip fracture is a devastating and common injury among older adults. The incidence rate of hip fracture in Denmark is among the highest globally and has increased in recent years. Despite infection being a potentially preventable and treatable condition, it remains one of the most frequent complications and causes of death following hip fracture surgery. Risk of infection after hip fracture has also increased.

What determines if the immune system can attack cancer cells? And how can we support it? This has been investigated in a new PhD project from Aarhus University, Health. 

The immune system plays an important role in cancer and represents a potential source of future treatments. One the constituents of the immune system, cells known as macrophages, are able to attack and kill cancer cells under the right conditions. This PhD project has investigated which factors regulate the ability of macrophages to destroy cancer cells, and how these factors can be medically influenced. The results of the project suggest that new techniques can potentially be used to support macrophage killing of cancer cells, and are based on laboratory experiments performed at the Department of Clinical Biochemistry at Aarhus University Hospital.

Follicular lymphoma (FL) is a lymphoid malignancy derived from germinal center B cells. Despite advancements in treatment, the disease remains generally incurable with recurrent relapses. Furthermore, a subset of patients will experience treatment refractoriness, early disease progression, and histological transformation into a more aggressive lymphoma type, most often diffuse large B-cell lymphoma. This event is manifested by a rapid clinical course, often with unresponsiveness to treatment, and shortened survival. Thus, transformation marks a pivotal change in disease trajectory, yet reliable predictors for subsequent progression or transformation remain elusive.

This Ph.d. project describes the transformation of FL, with the aim to unravel pre-treatment biological differences underlying the diverse disease course for upfront personalized risk stratification and improved patient care.

The dissertation comprises eight original papers. These include several molecular biological investigations of proteins and gene expression thoroughly examined in relation to transformation of FL, revealing predictive potential of several proteins in the neoplastic cells as well as the tumor microenvironment.

Workplace intervention to reduce sick leave among pregnant hospital employees – a cluster randomized trial.

In a recently completed Ph.D. project from Occupational Medicine, Aarhus University Hospital and Aarhus University, Jane Lauridsen evaluated an intervention with occupational midwifery support on pregnant employees' sick leave and well-being.

Sick leave during pregnancy is common and 36% of all pregnant employees are absent for more than two weeks. Sick leave can be associated with individual and occupational factors. Occupational factors can be exposure to harmful agents or strenuous working conditions such as walking and standing, heavy lifting, or shift work. Work adjustment is associated with reduced sick leave.
This project evaluates an intervention aiming to reduce strenuous occupational exposures. The overall aim was to evaluate the effect of occupational midwifery support, where midwives facilitated risk assessment and work adjustment in meetings with pregnant employees and their managers.
The study was conducted at Aarhus Universityhospital as a cluster-randomised trial with hospital departments allocated to intervention or reference.
In addition to evaluating midwifery support, the projct also investigated managers´ perspectives and engagement in pregnancy policy.

The intricate interplay between inflammatory bowel disease (IBD), cancer, infections, and mortality is explored in a new PhD project at Aarhus University, Health.

IBD are chronic, immune-mediated inflammatory disorders encompassing Crohn’s disease and ulcerative colitis. Patients with IBD face an increased risk of developing colorectal cancer, as well as several other types of cancer.

When patients with IBD develop colorectal cancer, their prognosis is typically worse compared to those without IBD, which may be exacerbated by their inherent increased risk of infections. Serious infections are a leading cause of hospitalization and mortality among IBD patients. Moreover, infections account for more than half of all oncology-related hospital admissions, negatively affecting cancer-specific survival rates.

This PhD project provides novel insights into the association between IBD and post-cancer infection risk, as well as the link between IBD and post-colorectal cancer mortality, based on data from a Danish cancer cohort.

Broadly neutralizing antibodies (bNAbs) are being used in clinical studies which seeks to lower the viral reservoir in persons living with HIV-1. bNAbs have shown to be able to neutralize cell-free virusparticles and activate the immune system and thereby increase the pressure on HIV-1 infected cells. Due to a high mutation rate in HIV-1, the bNAbs do not have an effect in all persons living with HIV-1, which makes it important to screen virus from the participants prior to inclusion in a study using bNAbs. 

In this PhD project a published clinical study is presented, in which persons with HIV-1 were randomised to receive two bNAbs and a drug (Lefitolimod), which have shown to reactivate virus in HIV-1 infected cells. The participants stopped their normal antiviral treatment and the study showed that participants who received the bNAbs had longer time before virus was detectable in the blood, than participants who did not receive the bNAbs.  

Addtionally, a study in which methods to screen participant-specific HIV-1 for sensitivity toward the bNAbs were compared. The study showed that there can be differences in the methods which are being used for sensitivity assessment for the bNAbs.

Fluorescence Microscopy of the Living Kidney to Visualize and Understand Renal Physiology

The dissertation is centered around a cutting-edge microscopy technique that allows the real-time visualization and assessment of kidney function in living small rodents. The research introduces key advancements aimed at overcoming the challenges of data acquisition and processing in this complex field. In addition, the study highlights two practical applications of this technology, offering new insights into renal physiology and potential implications for future medical research.

Diabetic polyneuropathy is a common and debilitating complication to diabetes that affects up to 50% of all patients with diabetes. It affects the long nerves of the body, causing loss of sensation as well as unpleasant sensory disturbances in the feet and legs. Between 10-35 % of patients with diabetic polyneuropathy suffer from pain. It is currently unknown what causes pain to develop. This condition, especially with concurrent pain, impacts the quality of life of patients in various negative ways, and no satisfactory treatment exists. Despite this, diabetic polyneuropathy has often been considered an overlooked complication to diabetes, which may be the reason that there are few detailed studies on its development over time.

This PhD project followed patients with diabetic polyneuropathy and type 2 diabetes over five years using state-of-the-art diagnostic methods to determine how both diabetic polyneuropathy and pain develops over time, which patients develop pain, what impacts this development, and how these changes affect patient quality of life and mental health.

Autoimmune diseases are rising in society and a huge burden to patients. The main characteristic shared by all of them is the patient’s own immune system attacking the body and damaging organs, up to the point of failure. However, current treatment options are limited and come with severe side effects such as infections and even cancer.

The development and progression of autoimmune diseases is complex, long-lasting and not fully understood – including the emergence and shutdown of autoreactive germinal centers, which are presumably contributing to disease progression, especially the germinal centers in the spleen.

The emergence and shutdown of germinal centers are week-long dynamic processes and therefore difficult to capture and understand. Thus the development of novel techniques is necessary to study germinal center dynamics to help understand the development and progression of autoimmunity to one day hopefully being able to develop better treatment.

In my PhD defense, I will present a newly developed and validated approach to study autoreactive germinal center dynamics over two weeks in a living organism by using serial intravital microscopy of the spleen. I will furthermore present how we are exploiting this technique to shed more light on the development of autoimmunity.

A positive screening test for colorectal cancer, but no cancer - What now?

In a recently completed Ph.D. project from Aarhus University and Randers Regional Hospital, Pernille Thordal Larsen investigated how many people are diagnosed with colorectal cancer after initially being screened without any findings of cancer. 

The evidence supporting the Danish recommendations for follow-up after a screening-derived colonoscopy is limited, despite the fact that since 2014, these recommendations for colonoscopy follow-ups have led to a significant increase in the number of colonoscopies performed in Denmark. This Ph.D. project utilized Danish health registers and databases to investigate how many people are diagnosed with cancer after initially undergoing a screening process that did not result in a cancer diagnosis. The project found that, in general, there were few cases of cancer, but the number of polyps found during the colonoscopy was a poor indicator of the risk at the next screening or follow-up examination. Therefore, it is concluded that screening recommendations should be based on risk factors that consider more than just the results of the colonoscopy, and further efforts should be made to ensure high-quality colonoscopies for all screening participants in Denmark.

Towards more accurate and gentle surgery for women with endometrial cancer - The SENTIREC-endo study

In endometrial cancer, the presence of lymph node metastasis is the most significant negative prognostic factor. Surgical staging is performed to identify women with lymph node metastasis to allocate them to adjuvant therapy, with the overall purpose to improve survival. Sentinel lymph node (SLN) mapping represents an accurate and minimally invasive staging technique, with the potential to increase the identification of lymph node metastases. This PhD thesis is based on two national prospective studies, SENTIREC-endo I and II, that investigated aspects of SLN mapping implementation in women with endometrial cancer. SENTIREC-endo I presents the result of a national protocolled implementation of SLN mapping in women with low- and intermediate-risk endometrial cancer. We conclude that SLN mapping, in a centralized setting, carries a very low risk of peri- and postoperative complications and that women benefit from the procedure in terms of increased detection of lymph node metastases compared to previous standards. Despite more comprehensive surgery for a large proportion of women, SLN mapping was not associated with an increased risk of clinically significant lymphoedema. SENTIREC-endo II, investigated diagnostically safe SLN mapping algorithms to replace the standard of pelvic and paraaortic lymphadenectomy in women with high-risk endometrial cancer. We identified two safe surgical algorithms. The SENTIREC-endo studies have changed clinical guidelines towards more gentle and accurate surgery for women with endometrial cancer and lead to new international evidence.

Tuberculosis is an infectious disease that is especially prevalent in low-income countries, where poverty and crowded living conditions contribute to disease transmission. Although tuberculosis can be cured with antibiotics, it is estimated that over 10 million people develop tuberculosis, and over 1 million people die from tuberculosis every year worldwide.

Malnutrition, especially undernutrition, is a well-known risk factor for developing tuberculosis. An insufficient intake of energy, protein, and micronutrients, weakens the immune system and thereby increases the risk of developing tuberculosis. Malnutrition may be a result of food insecurity in low-income countries. Furthermore, tuberculosis disease causes malnutrition through various disease-specific effects on the body. It is often difficult to ascertain which comes first - malnutrition or tuberculosis - and which makes the other worse.

The West African country Guinea-Bissau is one of the poorest countries in the world. It has a high prevalence of both food insecurity and tuberculosis. The Ph.d. project explores the relationships between malnutrition and tuberculosis in Guinea-Bissau, and examines if a combined treatment of both malnutrition and tuberculosis is beneficial to patients.

Fernando Valentim Bitencourt, Department of Dentistry

The prevalence of periodontitis, an inflammatory condition that affects the tissues supporting teeth, is three times greater in individuals with Type 2 Diabetes Mellitus (T2DM) than in those without T2DM. Despite this prevalence, the relationship between periodontitis and diabetes-related complications has remained unclear until now. The PhD studies, conducted through population-based studies, analyzed data from participants across US and Denmark: the National Health and Nutrition Examination Survey (NHANES) and the Health in Central Denmark (HICD) study. The findings reveal that periodontitis co-occurs with other diabetes-related complications, influenced by factors such as age, sex, obesity, physical activity, diet, socioeconomic status, smoking, HbA1c levels, and dyslipidaemia. The study also demonstrated that higher HbA1c levels and obesity had a significant indirect effect on periodontitis through dyslipidaemia. In addition, diabetic retinopathy, neuropathy, and both complications increase the likelihood of developing periodontitis by 1.2 to 1.5 times. Furthermore, dyslipidaemia was shown to significantly modify the odds of 'moderate/severe' periodontitis, particularly when multiple diabetic microvascular complications are present.

Faecal microbiota transplantation (FMT) involves the transfer of intestinal microbiota from a healthy donor to a patient. The choice of donor is crucial to ensure a safe and possible also effective treatment. Despite this, faeces donation criteria are not based on evidence.

The aim of this project was to produce knowledge that will contribute to establishing evidence-based criteria for faeces donation. A wide range of donor criteria are addressed, including gastrointestinal symptoms and bowel habits, asymptomatic Helicobacter pylori carriage, and an assessment of whether donor factors affect the clinical effect of FMT in patients with Clostridioides difficile infection.

Screening for breast, colorectal, and cervical cancer can reduce morbidity and mortality from these three types of cancer, but participation in the three national screening programmes varies.

The aim of the PhD project was to investigate cross-programme synergies and correlations across the three cancer screening programmes in Denmark.

In a clinical intervention study, women attending breast cancer screening in the Central denmark Region were offered an administrative check-up on their screening status for cervical and colorectal cancer. Women who were not up-to-date with their screenings were subsequently offered the opportunity to perfom self-collected screening for cervical and colorectal cancer.

In two register-based studies, the relationship between screening participation and both sociodemographic data and level of health literacy was examioned to better understand the characteristics of those who do not participate in all three screening programmes.