Faculty of Medicine

 

Recent Submissions

  • Virtanen, Toni (Helsingin yliopisto, 2020)
    This dissertation describes the instruments available for image quality evaluation, develops new methods for subjective image quality evaluation and provides image and video databases for the assessment and development of image quality assessment (IQA) algorithms. The contributions of the thesis are based on six original publications. The first publication introduced the VQone toolbox for subjective image quality evaluation. It created a platform for free-form experimentation with standardized image quality methods and was the foundation for later studies. The second publication focused on the dilemma of reference in subjective experiments by proposing a new method for image quality evaluation: the absolute category rating with dynamic reference (ACR-DR). The third publication presented a database (CID2013) in which 480 images were evaluated by 188 observers using the ACR-DR method proposed in the prior publication. Providing databases of image files along with their quality ratings is essential in the field of IQA algorithm development. The fourth publication introduced a video database (CVD2014) based on having 210 observers rate 234 video clips. The temporal aspect of the stimuli creates peculiar artifacts and degradations, as well as challenges to experimental design and video quality assessment (VQA) algorithms. When the CID2013 and CVD2014 databases were published, most state-of-the-art I/VQAs had been trained on and tested against databases created by degrading an original image or video with a single distortion at a time. The novel aspect of CID2013 and CVD2014 was that they consisted of multiple concurrent distortions. To facilitate communication and understanding among professionals in various fields of image quality as well as among non-professionals, an attribute lexicon of image quality, the image quality wheel, was presented in the fifth publication of this thesis. Reference wheels and terminology lexicons have a long tradition in sensory evaluation contexts, such as taste experience studies, where they are used to facilitate communication among interested stakeholders; however, such an approach has not been common in visual experience domains, especially in studies on image quality. The sixth publication examined how the free descriptions given by the observers influenced the ratings of the images. Understanding how various elements, such as perceived sharpness and naturalness, affect subjective image quality can help to understand the decision-making processes behind image quality evaluation. Knowing the impact of each preferential attribute can then be used for I/VQA algorithm development; certain I/VQA algorithms already incorporate low-level human visual system (HVS) models in their algorithms.
  • Wuollet, Emma (Helsingin yliopisto, 2020)
    Molar-Incisor Hypomineralization (MIH) is a developmental enamel defect affecting 1-4 of the first permanent molars (FPM) and frequently also permanent incisors. Clinical appearance varies from small, opaque defects in enamel to extensive enamel breakdown. This doctoral thesis investigated the background and effects of MIH in groups of Finnish children, as well as Finnish dentists’ treatment practices concerning symptomatic, severely hypomineralized FPMs. The Study I population was a convenience sample of 818 children aged 7–13 years from different regions of Finland. Their teeth were examined for MIH. The possible associations with factors related to the family’s socio-economic status (SES) and the child’s living environment were assessed using the parent-filled questionnaire. Analyses did not show any significant association between MIH and the studied factors. However, the prevalence of MIH varied regionally, and the difference was greatest between Jalasjärvi (8.0%) and Lappeenranta (25.2%). Study II investigated the association between MIH and childhood illnesses and antibiotics. Patient records of 287 children from two locations, Lammi and Jalasjärvi, were obtained from the local health centers. Occurence of illnesses and exposure to antibiotics during the child’s first three years of life were investigated and the data was combined with the information of the dental examination. The children who were diagnosed with acute otitis media and the children who were prescribed penicillin, amoxicillin, or macrolide antibiotics had increased risk for hypomineralization in FPMs and permanent incisors. In a subset of the patients (Study III) whose caries experience had also been recorded (n = 636), MIH was found to be associated with the occurrence of caries in FPMs (DMFT > 0) as well as with the number of decayed or filled FPMs. MIH was a greater risk factor for caries than low SES. Study IV was a treatment practice survey among Finnish dentists (n = 765). The most common choice for symptomatic, severely affected FPM was restoration with composite resin (45.0%). Pediatric dentists preferred stainless-steel crowns. In addition, treatment practices varied from one area to another, and in the Helsinki-Uusimaa area it was more common than in other areas to refer an MIH patient forward. In summary, the prevalence of MIH seems to vary between regions for a reason that remains unknown. This thesis suggests a potential harmful effect of childhood illness or antibiotics on enamel development. This finding is waiting to be confirmed with further, prospective studies. In addition, MIH is a significant caries risk factor, especially in a low-caries population. However, unsolved issues related to the development and diagnosis of MIH need to be addressed in order to clarify the etiology.
  • Tiainen, Mikko (Helsingin yliopisto, 2020)
    The idea that hand gestures and speech are connected is quite old. Some of these theories even suggest that language is primarily based on a manual communication system. In this thesis, I present four studies in which we studied the connections between articulatory gestures and manual grasps. The work is based on an earlier finding showing systematic connections between specific articulatory gestures and grasp types. For example, uttering a syllable such as [kɑ] can facilitate power grip responses, whereas uttering a syllable such as [ti] can facilitate precision grip responses. I will refer to this phenomenon as the articulation-grip congruency effect. Similarly, to the original work, we used special power and precision grip devices that the participants held in their hand to perform responses. In Study I, we measured response times and accuracy of grip responses and vocalisations to investigate whether the effect can be also observed in vocal responses, and to which extent the effect operates in the action selection processes. In Study II, grip response times were measured to investigate whether the effect persists when the syllables are only heard or read silently. Study III investigated the influence of grasp planning and/or execution on categorizing perceived syllables. In Study IV, we measured electrical activity in the brain during listening of syllables that were either congruent or incongruent with the precision or power grip, and we investigated how performing different grips affected the auditory processing of the heard syllables. The results of Study I showed that besides manual facilitation, the effect is observed also in vocal responses, both when a simultaneous grip is executed and when it is only prepared, meaning that overt execution is not needed for the effect. This suggests that the effect operates in action planning. In addition, the effect was also observed when the participants knew beforehand which response they should execute, suggesting that the effect is not based on the action selection processes. Study II showed that the effect was also observed when the syllables were heard or read silently, supporting the view that articulatory simulation of a perceived syllable can activate the motor program of the grasp which is congruent with the syllable. Study III revealed that grip preparation can influence categorization of perceived syllables. The participants were biased to categorize noise-masked syllables as being [ke] rather than [te] when they were prepared to execute the power grip, and vice versa when they were prepared to execute the precision grip. Finally, Study IV showed that grip performance also modulates early auditory processing of heard syllables. These results support the view that articulatory and hand motor representations form a partly shared network, where activity from one domain can induce activity in the other. This is in line with earlier studies that have shown more general linkage between mouth and manual processes and expands this notion of hand-mouth interaction by showing that these connections can also operate between very specific hand and articulatory gestures.
  • Korhonen, Emilia (Helsingin yliopisto, 2020)
    The vascular system consists of hierarchical networks of blood vessels and lymphatic vessels. The main function of the blood vasculature is to transport oxygen and nutrients to tissues, whereas the unidirectional lymphatic network is required mainly for maintenance of tissue fluid homeostasis and lipid absorption. Growth of new blood and lymphatic vessels, called angiogenesis and lymphangiogenesis, is required during embryonic development and in physiological processes in adults. Malfunction of the vascular systems is associated with various diseases such as cancer, inflammation and neovascular eye diseases. The functions of the vascular system are controlled by endothelial cells (ECs) lining the blood and lymphatic vessels. ECs are regulated by many growth factors including the endothelial angiopoietin (Ang) growth factor -Tie receptor signaling system. The two transmembrane tyrosine kinase receptors Tie1 and Tie2 form a receptor complex for angiopoietin growth factors, which regulate angiogenesis and lymphangiogenesis. Ang1 and Ang2 act as agonistic and context-dependent agonistic/antagonistic ligands of Tie2, respectively. However, Tie1 does not bind to angiopoietins. Instead, Tie1 participates in Ang-Tie2 signaling by forming a heterocomplex with Tie2. Ang-Tie signaling is important in vascular development and it controls pathological angiogenesis as well as vascular remodeling and integrity in inflammatory conditions. For example, increased Ang2 concentrations predict poor patient survival in severe diseases. Overall, the Ang-Tie pathway can be considered to be a potential therapeutic target. However, little is known about the function of Tie1 and the regulation of the context-dependency of Ang2. In this thesis, we investigated the function of Tie1 in embryonic lymphatic vascular development, postnatal sprouting angiogenesis and pathological angiogenesis. We also aimed to understand how Tie1 regulates angiopoietin signaling and the function of angiopoietins in inflammation. Furthermore, we studied the function of Ang2 in neuroinflammation. Constitutive Tie1-deletion results in embryonic lethality due to hemorrhage, edema and disruption of the microvasculature. Edema observed in Tie1-deleted embryos led us to hypothesize that Tie1 contributes to lymphatic vessel development. Indeed, we found that Tie1 was expressed in earliest lymphatic structures in developing embryos, called lymph sacs. The lymph sacs were fragmented in Tie1-deleted embryos. Analysis of different timepoints during development of Tie1-deleted embryos revealed that the edema and malformed lymph sacs precede the appearance of hemorrhages in these embryos. These results indicate that Tie1 is essential for normal lymphatic vessel development and that the lymphatic vessels are more sensitive to the loss of Tie1 than the blood vessels. We next investigated the function of Tie1 in tumor angiogenesis. EC-specific deletion of Tie1 reduced tumor angiogenesis and growth due to increased EC apoptosis. Tie1 deletion also reduced postnatal sprouting angiogenesis in the retina through activation of the Notch pathway. Importantly, Tie1 deletion did not affect healthy vasculature in adult mice. Tie1 deletion inhibited tumor growth as effectively as blockers targeting the vascular endothelial growth factor receptor (VEGFR) system, which are currently used in the clinic. However, no additive effects were observed when these two treatment strategies were combined, whereas additive inhibition of tumor growth was observed when Tie1 deletion was combined with angiopoietin inhibition. Combinatorial targeting of Tie1 and Ang2 also reduced angiogenesis in the retina, suggesting that targeting Tie1 in combination with Ang2 can improve anti-angiogenic therapy. We next analyzed the role of Tie1 in angiopoietin signaling and function in inflammation. We found that angiopoietin stimulation promoted Tie1-Tie2 interaction and Tie1 was required for normal Tie2 trafficking. Tie1 deletion in mice reduced Ang1- and Ang2-induced vascular remodeling. Furthermore, Tie1-deficiency reduced Ang1-induced activation of Tie2 and downstream signaling and inhibited the Tie2 agonistic activity of Ang2. In lipopolysaccharide (LPS)-induced inflammation, the extracellular domain of Tie1 was rapidly cleaved and this was associated with reduced Tie2 activation and loss of Ang2 agonistic activity. Our results thus indicated that Tie1 is an important regulator of Ang-Tie2 signaling and agonistic function of Ang2 is decreased in inflammation. Finally, we investigated the function of Ang2 in neuroinflammation. We found that Ang2 was induced in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). Ang2 overexpression exacerbated the severity of EAE whereas its blockade ameliorated EAE. Similarly, treatment of the mice with ABTAA (Ang2-binding and Tie2-activating antibody), increased Tie2 phosphorylation and this reduced EAE severity, indicating that Tie2 activation is beneficial in this model. Our study showed that in neuroinflammation, Ang2 regulates the expression of EC adhesion molecules, blood brain barrier (BBB) integrity and recruitment of leukocytes into the central nervous system (CNS), as well as the pro-inflammatory polarization of CNS myeloid cells. These data implicate a role for Ang2 in autoimmune neuroinflammation. Overall, this thesis provides insight into the function of Tie1 and Ang2. Our studies reveal previously unknown roles of Tie1 in lymphatic vessel development, postnatal sprouting angiogenesis as well as in pathological tumor angiogenesis. We found that Tie1 is a critical component of the angiopoietin-Tie2 signaling and in inflammation its cleavage is associated with reduced agonistic function of Ang2. Furthermore, our work provides novel possibilities for therapeutic targeting of Ang2 in neuroinflammation. A deeper understanding of the functions of Tie1 and Ang2 in disease pathogenesis should aid in the development of therapies targeting the Ang-Tie signaling system.
  • Turunen, Katri (Helsingin yliopisto, 2020)
    Strokes are one of the leading causes of loss of quality years of life. One-fourth of stroke patients are working aged. Incidence of stroke is increasing among the working-aged population, and more information is needed on post-stroke profiles in this patient group. In the present studies, executive functions and memory performance were examined in a well-defined working-aged stroke cohort. First, differences in neuropsychological profiles after cortical and subcortical strokes were examined. Second, associations between executive dysfunction and memory problems were studied. Finally, changes in domain-specific functioning during a 2-year follow-up period were examined. The studied cohort consisted of 230 first-ever stroke patients, aged 18–65 years, from two central hospitals in Finland. The patients were examined neuropsychologically, covering multiple cognitive domains, as well as neurologically. In different substudies, 132–179 patients were included. In this working-aged patient cohort, most cognitive improvement occurred between the baseline and 6 months, and little cognitive recovery was subsequently found. Cognitive impairments were common in thorough neuropsychological examination, even in patients demonstrating good recovery in neurological scales. Impairments in psychomotor speed and executive functions were the most common domain-specific impairments throughout the follow-up. Executive dysfunction was associated with impaired performance in memory tasks that required active use of memory strategies for up to 2 years post stroke. No differences were found in the frequency of executive dysfunction between subcortical and cortical strokes. More memory problems and loss of psychomotor speed arose after subcortical than cortical strokes. In terms of practical implications, the present studies demonstrated that long-lasting cognitive impairments are common post stroke, even in relatively well-recovered working-aged stroke patients. Early and detailed neuropsychological examinations are essential for finding cognitively impaired patients, as even small subcortical strokes can induce long-lasting impairments that may affect, for example, work performance. As cognitive recovery seems most prominent early post stroke, neuropsychological rehabilitation should also begin early to guide the recovery. Based on the present results, cognitive problems following stroke may be long lasting, and thus the need for rehabilitation should be evaluated throughout patient follow-up, and rehabilitation should be provided for a sufficiently long period.
  • Holmström, Oscar (Helsingin yliopisto, 2020)
    The lack of access to diagnostics is a global problem which causes underdiagnosis of various common and treatable diseases. In certain areas, the access to laboratory services and medical experts is extremely limited, such as in sub-Saharan Africa, with often less than one practising pathologist per one million inhabitants. Annually, hundreds of millions of microscopy samples are analysed to diagnose e.g. infectious diseases and cancers, but the need for more is significant. During the last decade, technological advancements and reduced prices of optical components have enabled the construction of inexpensive, portable devices for digitization of microscopy samples; a procedure traditionally limited to well-equipped laboratories with expensive high-end equipment. By allowing digitization of samples directly at the point of care (POC), advanced digital diagnostic techniques, such as the analysis of samples with medical ‘artificial intelligence’ (AI) algorithms, can be utilized also outside high-end laboratories – which is precisely where the need for improved diagnostics is often most significant. The aim of this thesis is to study how low-cost, POC digital microscopy, supported by automatized digital image analysis and AI can be applied for routine microscopy diagnostics with an emphasis on potential areas of application in low-resource settings. We describe, implement and evaluate various techniques for POC digitization and analysis of samples using both visual methods and digital algorithms. Specifically, we evaluate the technologies for the analysis of breast cancer tissue samples (assessment of hormone receptor expression), intraoperative samples from cancer surgeries (detection of metastases in lymph node frozen sections), cytological samples (digital Pap smear screening) and parasitological samples (diagnostics of neglected tropical diseases). Our results show how the digitization of a variety of routine microscopy samples is feasible using systems suitable POC usage with sufficient image quality for diagnostic applications. Furthermore, the findings demonstrate how digital methods, based on computer vision and AI, can be utilized to facilitate the sample analysis process to e.g. quantify tissue stains and detect atypical cells and infectious pathogens in the samples with levels of accuracy comparable to conventional methods. In conclusion, our findings show how technological advancements can be leveraged to create general-purpose digital microscopy diagnostic platforms, which are implementable and feasible to use for diagnostic purposes at the POC. This allows the utilization of modern digital algorithms and AI to aid in analysis of samples and facilitate the diagnostic process by automatically extracting information from the digital samples. These findings are important steps in the effort to develop novel diagnostic technologies which are usable also in areas without access to high-end laboratories, and the technologies described here are also likely to be applicable for diagnostics of other diseases which are currently diagnosed with light microscopy.
  • Manderoos, Sirpa (Helsingin yliopisto, 2020)
    The capacity of agility has been extensively studied in sport-specific contexts. Thus, there is a great need for understanding possible explanatory factors determining the capacity of agility and the meaning of agility in physical functioning in middle-aged and older people. The Agility Test for Adults (ATA) has been developed to assess the capacity of agility more comprehensively than previously used agility tests do. The main aims of this study were to evaluate 1) the test-retest reliability of the ATA and to quantify a clinically meaningful change (MDC95), 2) the determinants of agility, 3) the feasibility of the ATA, and 4) the effects of participation in competitive sports in young adulthood or life-long LTPA on the present level of physical functioning. The International Classification of Functioning, Disability and Health (ICF) was used as a framework to define the measures of physical functioning. The study includes three study cohorts. The first includes healthy untrained adults (n = 52, 25 women and 27 men) who participated in the reliability study. The second study cohort consists of 233 healthy participants (149 women and 84 men). The third includes 100 male former elite athletes (endurance n = 50, power n = 50) and 50 matched controls aged 66 to 91 years. Both objective measures and questionnaires-based data were used. The high reliability scores of the ATA showed that it is stable and reliable in untrained adults. The magnitudes of the values identifying clinically meaningful changes in the ATA were small in both women and men. Jumping length was the main determinant of agility in women and men, whereas jumping height and age were the main determinants of the results of the ATA in a cohort of men aged 66-91 years. Data including elderly men allowed the evaluation of the feasibility of the ATA for people over sixty years old and with a large age distribution. A former elite athletic career interrelated with greater explosive force production of the lower extremities at old age among former elite power athletes, which may partly be explained by participation in competitive power type sports from young age, and not by life-long LTPA. The thesis provides recommendations for a reliable, responsive, and clinically useful measurement method of the ATA suitable for evaluating the capacity of agility in middle-aged and older adults. The ATA seems to be a more sensitive test to reveal physical disorders of a participant than the other commonly used mobility tests. By using responsive measures, it is possible to identify early decline in agility. Our data set also showed that lower limb muscle function measured by a test demanding explosive power plays an important role in maintaining or enhancing the capacity of agility.
  • Rodionov, Andrei (Helsingin yliopisto, 2020)
    Spinal cord injury (SCI) is a devastating condition and consequent loss of motor control remains one of the main causes of disability. Motor recovery after SCI depends on the amount of spared and restored neural connections in the spinal cord. Most SCIs are incomplete and even neurologically complete injuries possess some spared neural connections. Damaged motor pathways can be reactivated by external stimulation. However, current treatment approaches are mainly palliative, such as assisting adaptation to impairments. Thus, there is a need for novel therapies to induce neuroplasticity in the spinal cord and strengthen weak and disrupted neural connections. In this thesis, paired associative stimulation (PAS) was applied as a long-term treatment for chronic incomplete SCI of traumatic origin. PAS is a non-invasive neuromodulation paradigm where descending volleys induced by transcranial magnetic stimulation (TMS) of the motor cortex are timed to coincide with antidromic volleys elicited by peripheral nerve electrical stimulation (PNS). The stimulation protocol was designed to coincide TMS- and PNS-induced volleys at the cortico-motoneuronal synapses in the spinal cord. Continuous pairing of TMS and PNS stimuli can change synaptic efficacy and produce long-term potentiation (LTP)-like plasticity in the corticospinal tract. Augmentation of synaptic strength at the spinal level has clear therapeutic value for SCI, as it can enhance motor control over paralyzed muscles. The aim of the thesis was to investigate the possible therapeutic effects of long-term PAS on hand and leg motor function in individuals with chronic incomplete SCI of traumatic origin. Study I explored long-term PAS therapeutic potential by providing long-term PAS until full recovery of hand muscle strength or until improvements ceased. The PAS protocol was designed to coincide TMS- and PNS-induced volleys in the cervical spinal cord, which is both the location of the stimulated lower motor neuron cell bodies and the site of the injury. Improvements up to normal values of hand muscle strength (Manual Muscle Test [MMT]) and increased amplitude of motor evoked potentials (MEPs) were obtained after more than 1-year stimulation in a participant with SCI. The participant regained almost complete self-care of the upper body. This was the first demonstration of restoring normal strength and range of movement of individual hand muscles by means of long-term PAS. The effect persisted over 6 months of follow up. Study II probed the effects of long-term PAS on leg muscle strength and walking in a group of five people with SCI. The PAS protocol was designed to coincide TMS- and PNS-induced volleys in the lumbar spinal cord but the site of the injury was in the cervical spinal cord. Long-term PAS delivered for 2 months significantly increased the total lower limb MMT score. This effect was stable over a 1-month follow up. Walking speed increased after 2 months of PAS in all participants. This study was the first demonstration that long-term PAS may significantly increase leg muscle strength and affect walking. The MMT score prior to the intervention was a good predictor of changes in walking speed. Study III developed a novel technique that enables probing neural excitability at the cervical spinal level by utilizing focal magnetic coil and anatomy-specific models for re-positioning of the coil. The technique enabled recording of highly reproducible MEPs and was suitable for accurate maintenance and retrieval of the focal coil position at the cervical level. In summary, this thesis contributes to the understanding of therapeutic efficacy of long-term PAS for restoration of motor control over hand and leg muscles after chronic SCI. This work challenges the view that chronic SCI is an irreversible pathologic condition and demonstrates the possibility of restoring neurological function many years postinjury when spontaneous recovery is extremely rare. The increased amplitude of MEPs, sustainable motor improvements, and the effects observed regardless of injury location indicate that PAS induces stable changes in the corticospinal pathways.
  • Süvari, Liina (Helsingin yliopisto, 2020)
    At birth, the fluid-filled lung must be cleared to enable postnatal air breathing. Fluid clearance is mediated by the ion and water channels at the alveolar epithelium. The sodium-potassium pump—sodium potassium adenosine triphosphatase (NaKATPase)—generates the transepithelial ion gradient, a prerequisite for the functioning of the key players at the apical alveolar epithelium. These players include the epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR). Impaired ion and fluid transport leads to respiratory problems, the most common of which in late preterm and full-term infants is transient tachypnea of the newborn (TTN). In preterm infants, the leading cause of respiratory problems—respiratory distress syndrome—results from surfactant deficiency, but impaired lung-fluid clearance is also partly involved. This thesis investigated the earliest postnatal changes in the gene expression of the molecules involved in ion and fluid transport in the airway epithelium. In doing so, we attempted to identify associations between cord-blood hormones and gene expressions in preterm and term human infants. Thus, we gathered nasal epithelial samples at birth and on the first day postnatally to determine the gene expression of the molecules involved in the airway epithelial ion and fluid transport. Gene expression was detected through reverse transcription polymerase chain reaction (RT-PCR). We also collected cord blood at birth and measured the glucocorticoid (GC) and catecholamine concentrations using liquid-chromatography tandem-mass spectrometry. In addition, we used a static lung compliance measurement to estimate the fluid content in the lungs. National registries were used to study the associations between early pulmonary maladaptation and hospitalization due to respiratory syncytial virus (RSV) later in infancy. In term infants, we found associations between the gene expression of the molecules involved in the airway epithelial sodium transport and birth stress hormones—that is, cortisol and catecholamines. Vaginally delivered (VD) newborns exhibited higher stress hormone concentrations than infants born via elective cesarean section (CS). Higher stress hormone levels in the umbilical cord-blood correlated positively with the gene expressions of the sodium transporters. A lower gene expression of the chloride channel at birth associated with better static lung compliance during the initial postnatal hours. In preterm infants, we determined the betamethasone (BM) and cortisol levels in the cord blood following antenatal corticosteroid treatment. The BM levels in the cord blood decreased to low levels two days after the last dose. Preterm infants with respiratory distress syndrome (RDS) had lower cord-blood GC concentrations than those without RDS. Additionally, we found that the gene expressions of the airway epithelial sodium transporters associated with the GC concentrations in preterm human infants. These findings in term and preterm infants provide evidence of the promoting effect of stress hormones in the lung-fluid clearance and, thus, for enhanced pulmonary adaptation. Finally, we identified an association between early postnatal pulmonary maladaptation and hospitalization due to RSV, which may reveal the same pathogenetic background behind these two diseases, suggesting that TTN may not be related to the early postnatal phase alone.
  • Lagus, Heli (Helsingin yliopisto, 2020)
    Although the use of split thickness skin grafts (STSGs) is the gold standard to cover excised deep burns, relatively little is known about how regenerating dermal connective tissue underneath the STSGs affects wound healing and ultimately the outcome from grafting. We compared three ways to treat a wound bed of a deep burn after excision onto fascia. The recipient sites before transplanting the STSGs were: a plain excised wound as a control, a site treated with permanent artificial dermal template (Integra®), and a site with granulation tissue promoted by cellulose sponge (Cellonex™). In study I ten adult burn patients with deep burns covering 22-45 % of total body surface-area were included. Test areas were divided into three equal sections (5 x 10 cm each) that were covered in random order with one of the aforementioned materials. After two weeks, the artificial dermal template and the wound bed under the viscose cellulose sponge were also covered with STSGs. At each site the wound healing process was followed-up for up to one year. Histological analysis from punch biopsy samples and clinical scar assessments were performed using the Vancouver Scar Scale at 3 and 12 months. Study II concentrated on the healing process of STSGs one week and 3 months after grafting from the material retrieved from study I. Healing was assessed using immunohistochemistry of late inflammation, angiogenesis/vascularity, and proliferation . In study III, samples from study I were analysed using proteomics. The differentially expressed proteins (DEPs) were further analysed using Ingenuity Pathway Analysis. Based on the results of pathway analysis the potential role and function of DNAH10 (a motor protein usually found in cilia and flagella) was assessed in a group of patients with psoriasis as well as healthy controls. This thesis has five main findings: 1) A valuable experimental model was designed for objective comparative studies of different treatment modalities with-in a patient-controlled study protocol. 2) In study I, inflammation was more distinctive in the granulation tissue promoted by cellulose sponge. In contrast to expectations, more pronounced inflammation combined with granulation tissue formation did not jeopardize the outcome in terms of scarring problems when the wound bed was covered in a timely fashion. 3) After one year, the clinical outcome and the histological findings of the artificial template site did not differ from the two other test sites. 4) In study III, at one-year follow-up, approximately 12% of all proteins detected demonstrated differential expression across comparisons between the different wound bed treatments, and 5) the biggest differences were found in the expression of the axonemal heavy chain dynein DNAH10. STSGs on pre-treated wound beds demonstrated higher expression of DNAH10 than STSGs of control sites. The expression of DNAH10 was also higher in intra-lesional psoriasis skin samples than non-lesional or healthy control skin samples. The dermal composition of the wound bed has an impact on cellular behaviour during wound healing, and it affects functions such as proliferation and angiogenesis. Surprisingly by the end of the follow-up period, healthy granulation tissue resulted in as little scarring as dermal substitute in the STSGs. Despite the lack of clinical and histological differences with those assessment methods used, clear differences were found in protein levels at the long-term follow-up.
  • Rauma, Ville (Helsingin yliopisto, 2020)
    Lung cancer is a nefarious disease causing more deaths than any other cancer worldwide. It is also among the most common cancers in Finland and the leading cause of cancer-related deaths, with 5-year survival rates of only 10-15%. However, more cases are being diagnosed at an earlier, possibly curable stage – radical surgery being the main curative treatment. As more patients survive the disease, long-term results, including quality of life, have attained more weight as treatment outcome measures. Thus, less invasive video-assisted thoracoscopic surgery (VATS) has largely replaced the more invasive thoracotomy as the standard treatment for operable local non-small cell lung cancer (NSCLC) patients. This study assessed the long-term health-related quality of life (HRQoL) among surgically treated NSCLC survivors, determining possible patient and treatment factors affecting the long-term HRQoL and survival among these patients, and comparing the effects of VATS and thoracotomy on the long-term HRQoL. For Studies I and II, we gathered patient and operational characteristics on 579 patients operated on for NSCLC in our clinic at Helsinki University Central Hospital between January 2000 and June 2009. The 276 survivors received two HRQoL questionnaires, the generic 15D and the cancer-specific EORTC QLQ-C30, in 2011. The HRQoL of our 230 respondents was compared with that of the age- and gender-standardized general population. Study II utilized the same data to determine factors predicting survival and long-term HRQoL among NSCLC survivors via regression analyses. Study III compared long-term HRQoL between 88 thoracotomy and 92 VATS patients undergoing lobectomy for local NSCLC in our clinic from January 2006 to January 2013. All of the studies were retrospective in nature. The NSCLC survivors reported significantly lower long-term HRQoL than the general population, with the most severe deterioration observed on the dimensions of mobility and breathing. Long-term survival proved to be moderately predictable by objective patient, disease, and treatment features, such as age, disease stage, and perioperative complications, but the regression models failed to notably predict long-term HRQoL. VATS patients reported significantly lower long-term HRQoL than thoracotomy patients, although the groups had comparable pre- and perioperative characteristics, and particularly no differences favouring the thoracotomy group were observed. The apparent long-term reduction in HRQoL should be considered in patient counselling, and more resources directed to the pre- and postoperative rehabilitation of the most severely affected functions. Long-term postoperative HRQoL seems poorly predictable, or at least the commonly measured clinical features fail to have a marked effect on HRQoL.
  • Heinänen, Mikko (Helsingin yliopisto, 2020)
    Severely injured trauma patients and trauma deaths due to severe injury are a burden to the world as these patients are often young, treatment is costly, and outcomes can be unsatisfactory. Trauma registries around the world collect valuable information about these patients, injury mechanisms, sustained injuries, treatment methods, and outcomes. With this information, research can be performed to better understand how to prevent these injuries and how to provide better care for these patients. New treatment modalities can be tested and analyzed with the data. Trauma registry data are also used for resource allocations and administrative decision making in hospitals, hospital districts, and nationally within countries. International comparisons and collaborations are also possible with this data. Therefore, the data must be valid; it must be reliable, complete, and correct. Otherwise, the conclusions made with the data can be misleading or even completely wrong. The Helsinki Trauma Registry (HTR) is a local trauma registry of the Helsinki University Hospital Trauma Unit. Since 2006, data of severely injured patients has been recorded to the registry. Thus far, there are more than 5000 patients in the registry. This study focused on evaluating the quality of the HTR by assessing the case completeness, data completeness, data accuracy, and data correctness. We compared the HTR data to patient files and Finnish Hospital Discharge Registry (FHDR) data. We also compared a patient group with severe chest injury to a similar group of patients from the German trauma registry (TR-DGU) to verify the comparability of the HTR data with international data and to identify possible differences in treatment, outcomes, and resource use with these patients. This was also an external validation of the HTR. Finally, we used the HTR data on road traffic injury patients as a reference to test the accuracy and reliability of an international, EU-recommended, ICD-AIS mapping tool in Finnish patient material. This tool generates injury severity classification scores from commonly used ICD-10 injury diagnosis codes automatically instead of the AIS (Abbreviated Injury Scale) coding performed by an expert coder. We discovered that the HTR yields quality data of seriously injured patients. Case completeness (97%), data completeness (93-99%), data accuracy (90-95%), and data correctness (97%) were excellent and therefore can reliably be used for research, administrative decision making, and national or international comparisons. Comparisons with the TR-DGU could be performed without problems. The treatment results (main outcome was survival) of patients with severe chest injury were similar in Finland and Germany; however, this was managed in Finland with fewer resources. We observed that the ICD-AIS mapping tool is not reliable in Finnish patient material. In the future, we should establish a high-class nationwide Finnish trauma registry that includes the trauma units of the five Finnish University Hospitals and the largest Central Hospitals that treat multiple severely injured trauma patients per year. In this way, we could more effectively unify treatment protocols, learn from each trauma unit, and improve the already good treatment of severely injured trauma patients in Finland. As treating severely injured patients is costly and resource consuming, we must also know the treatment results to ensure that our work among trauma patients is cost effective. This way we can ensure that limited health care resources are prioritized correctly. This is only possible with an effective nationwide Finnish trauma registry.
  • Hemiö, Katri (Helsingin yliopisto, 2020)
    Work conditions can have a substantial impact on workers’ lifestyles and thus, on the development of chronic diseases. One important determinant of the risk of chronic disease is diet. The aim of this thesis was to examine the role that perceived work stress and work schedule may play in workers’ dietary habits in a shift-work intensive workplace. In order to facilitate reliable evaluation of workers’ dietary habits, a brief food intake questionnaire (FIQ) was also validated. This thesis is based on data from a screening and prevention programme for chronic diseases implemented in a Finnish airline company between 2006 and 2008. The programme consisted of a health assessment of the participants and a discussion on the health assessment results with an occupational health physician or nurse. The assessment involved measurements of height, weight, waist circumference and blood pressure; blood tests; comprehensive questionnaires covering work, work schedule, sleep, perceived stress, stress symptoms, diseases, medication, lifestyle habits; the type 2 diabetes risk score FINDRISC; and a fasting glucose measurement. An FIQ was filled in by the participants whose risk of type 2 diabetes was elevated and by the participants who took part in the FIQ validation study. The follow-up study was carried out in 2009 to 2010. The health assessment was similar to that at baseline except that the study questionnaire was extended to include the FIQ and more detailed work-related questions. Cross-sectional data were used for the FIQ validation study (n=77); the shift schedules and dietary habits study (n=1478); and the recovery from work, sleep and dietary habits study (n=1342). The effect of work stress changes on dietary habits was evaluated in a prospective design, with a 2.4-year follow-up (n=366). The relative validity of the FIQ, using a seven-day food diary as a reference method, was shown to be acceptable for estimating participants’ food intake. Based on the FIQ answers, nutrient intake models were created separately for men and women; for proportions of energy from fat, saturated fat and sucrose; as well as for amount of fibre, vitamin C, iron, and vitamin D. These models were used to calculate the estimated nutrient intakes of the workers in the study cohort. The dietary habits of the work schedule groups differed and were better among the day workers. Male shift workers’ fruit and vegetable consumption was lower than that of male day and in-flight workers. Older age was associated with higher vegetable and fruit consumption among both men and women. The quality of fat in the day workers’ diets was better than that in the shift or in-flight workers’ diets. Poor recovery from work and sleep problems were associated with many unhealthy dietary habits, including more eating occasions, higher fast food and sweet consumption, and lower fruit and vegetable consumption among men; and more eating occasions, higher fast food, desserts, and sweet consumption among women. During over two years of follow-up, an increase in stress and decrease in work ability were associated with an increase in fat and saturated fat intake among men, as well as an increase in night shifts was associated with increased fat and saturated fat intake among women. In conclusion, shift schedule, higher perceived stress, poor recovery from work, sleep problems, and reduced work ability were associated with worse dietary habits, especially among men. The effects were seen as reduced consumption of fruit and vegetables as well as a higher fat and saturated fat intake. Shift workers’ risk of coronary heart diseases has already been proven, and this effect may be partly mediated by poor diet. The increase in saturated fat in parallel with increased work stress observed in this study may increase this risk among shift workers. Therefore, occupational health services should incorporate diet quality assessment into routine health examinations, together with dietary counselling targeted especially towards workers with high levels of stress.
  • Haapanen, Aleksi (Helsingin yliopisto, 2020)
    Background and purpose: Glucocorticoids (GCs) are used in various medical indications. One generally accepted and well-known indication is perioperative administration to reduce postoperative nausea and vomiting. GCs are also used with mixed results in promoting nerve recovery after an injury. However, these two potential indications have not been extensively investigated in facial trauma populations. The aim of this study was to determine whether dexamethasone could reduce the incidence of postoperative nausea and vomiting (PONV) and promote nerve recovery in the trigeminal nerve area after a facial trauma. Patients and methods: The study was based on a randomized controlled trial where patients were randomized to either receive dexamethasone or serve as a control. Study I included patients with different types of facial fractures (n=119), Study II patients with isolated zygomatic complex (ZC) fractures (n=64), Study III patients with isolated orbital fractures (n=18), and Study IV patients with one or two fractures in the dentate part of the mandible (n=27). In Study I, the outcome variable was PONV and the primary predictor variable was the administration of perioperative dexamethasone. In Studies II-IV, the outcome variable was neurosensory disturbance (NSD) at 6 months and the primary predictor variable was the use of perioperative dexamethasone. Results: The overall PONV incidence (Study I) was 16.8%. Dexamethasone did not reduce PONV incidence. In Studies II-IV, dexamethasone did not reduce long-term NSD. PONV was significantly more common in patients who received postoperative opioids. In Study III, a significant predictor for prolonged NSD was treatment delay. Conclusions: The role of short-term dexamethasone in the indications studied remained insignificant. The findings therefore do not support the use of perioperative dexamethasone in reducing PONV or postoperative NSD in facial fracture patients. The low number of study subjects excluded the possibility for subgroup analysis.
  • Ripatti, Pietari (Helsingin yliopisto, 2020)
    Lähetin abstraktin erikseen sähköpostitse.
  • Gyllenberg, Frida (Helsingin yliopisto, 2020)
    Long-acting reversible contraception (LARC) methods are the most effective methods in preventing unintended pregnancy. LARC methods include intrauterine devices, contraceptive implants, and injectables, and do not require any daily tasks from the user. Hence, these methods are as effective in practical use as at their theoretical best. Expert organizations advocate the use of LARC methods as a first-line choice for all women, as these methods are not only effective but also safe and cost-effective. However, on the global scale, there are many barriers to LARC use. These include lack of patient and provider awareness, high up-front costs, and misconceptions about safety. For this this reason, in most Western countries, these methods are not as widely used as short-acting methods. Programs addressing these barriers and promoting LARC have been evaluated, but little is known of the effects of a public program providing LARC methods free of charge on the population level. This thesis evaluates the effects and characteristics of a public LARC program in the City of Vantaa in the Helsinki Metropolitan Area of Finland. In Vantaa, rates of induced abortion were for a long time higher than both national and regional levels. In January 2013, a public program was launched aiming at preventing unintended pregnancies and thus reducing rates of induced abortions. This program offered all women their first LARC method free of charge at public family planning clinics. These clinics have been in place since the 1970s, with well-established services, and they are frequently used by the local population. When the LARC program started, the only new benefit was the provision of free-of-charge LARC methods, while all other services, legislation, and access regarding induced abortion remained unchanged. For this thesis, a new population cohort was established. The complete study population comprised all women living in Vantaa in 2013–2014 aged 15–44 years who were eligible for free-of-charge LARC, almost 50,000 women in total. Eligibility was defined as not having a LARC initiation or removal at public clinics since 2000. All women using public contraceptive services during the first two years since the beginning of the public LARC program were identified (9,669 women), as were all women who initiated a LARC method free of charge (2,035 women). The cohort participants were monitored by means of national registers to identify all the pregnancies that had started before February 28th, 2016. This dissertation consists of three articles. The first article describes factors predicting the initiation of a free-of-charge LARC method among those eligible. A history of delivery increased the odds for initiating a free-of-charge LARC method in all age groups (odds ratio [OR] 5.39, 95% confidence interval [CI] 4.69–6.19). A history of induced abortion was also associated with initiation (OR 1.39, 95% CI 1.21–1.56), but in age-stratified models, this association was only present among women younger than 25 years of age. Other factors significantly associated with LARC initiation were being 20–24 years old (OR 1.25, 95% CI 1.07–1.47), being married (OR 1.23, 95% CI 1.08–1.40), and not having used public family planning clinic services within two years before this study (OR 1.31, 95% CI 1.17–1.46). The second article assesses the need for induced abortion during follow-up among women eligible for a free-of-charge LARC method. Altogether, 78,500 person-years were monitored, and the mean follow-up time was two years. Women initiating and those not initiating LARC methods at public family planning clinics were compared. In addition, both groups were compared with age-matched population controls from the complete study population not using public family planning services. The rate of induced abortions was 80% lower among women who initiated free-of-charge LARC compared to women not initiating a LARC method, despite being eligible for one free of charge (adjusted rate ratio [aRR] 0.20, 95% CI 0.11–0.32). Furthermore, the rate of induced abortions was more than 70% lower among women initiating LARC methods than among their population controls (aRR 0.26, 95% CI 0.14–0.43). However, there was no difference in the rate of induced abortions among women using public family planning services but not initiating a free-of-charge LARC as compared to their population controls (aRR 1.01, 95% CI 0.87–1.18). In the third study, times series methods were used to investigate the effects of the public program on the population level. The step change in monthly mean rates of LARC initiations was assessed, adjusting for confounders on the aggregated level. A significant increase in the rate of LARC initiations was identified in all age groups: almost four-fold among 15–19-year-olds and approximately two-fold among 20–44-year-olds. The time series of induced abortions in the neighboring municipality of Espoo was included when evaluating the change in monthly mean rates of induced abortions to control for possible concurrent events affecting the local rates of induced abortions. These analyses revealed a reduction in the rates of induced abortions of 36% among 15–19-year-old women (aRR 0.64, 95% CI 0.54–0.74) and of 14% among 20–24-year-old women (aRR 0.85, 95% CI 0.74–0.96). The modest reduction in rates of induced abortions seen among 25–44-year-olds was not statistically significant (aRR 0.94, 95% CI 0.84–1.03). To conclude, the public program in Vantaa reached women with a history of induced abortion and delivery well. The program was associated with a reduced need for induced abortion assessed by both survival analysis on the individual level and with time series analysis on the aggregated level. Thus, the free-of-charge program addressed an unmet need for family planning services in the population. In addition, the program was cost-effective among women under 25 years of age.
  • Luukkainen, Veera (Helsingin yliopisto, 2020)
    Normal middle ear function is based on the air-filled middle ear (ME) cleft. The air in the ME is derived from the nasopharynx through the Eustachian tube (ET) and from the mastoid air cell system through transmucosal gas exchange. In chronic ear diseases, aeration is usually impaired because of ET dysfunction (ETD) or because the aeration routes from the mastoid are blocked or both. Balloon Eustachian tuboplasty (BET) aims at improving the function of the ET, thereby facilitating the prevention and treatment of chronic ear diseases. Only individual reports mention performing BET under local anesthesia (LA). However, BET under LA can offer several advantages, including reduced anesthesia-related risks and decreased time needed in the operation room. Although short-term outcomes of BET are promising, more studies focusing on the long-term outcomes of BET, subjective and objective, are warranted. Establishing accepted indications for BET is also necessary. In Study I, we investigated the feasibility of BET under LA by comparing it with endoscopic sinus surgery (ESS) that is routinely performed under LA. The study focused on safety of the procedure and the patients’ experience. The balloon dilation device was Acclarent Aera (Acclarent Inc., Menlo Park, CA, USA) but its import to the EU ceased and, therefore, in Study II, we decided to examine if BET was feasible under LA with other BET devices (TubaVent and TubaVent Short, Spiggle & Theis Medizintechnik GmbH, Overath, Germany). In Study II, we also compared lidocaine-prilocaine cream and cocaine-adrenaline solution in anesthetizing the ET. No adverse effects occurred among the patients treated with BET under LA. Intraoperatively, those treated with Acclarent Aera and TubaVent Short had similar visual analog scale (VAS) scores for pain to those of the ESS group. Compared with ESS patients, TubaVent patients reported significantly more pain and discomfort during BET. No differences emerged between the effects of lidocaine-prilocaine cream and cocaine-adrenaline solution. In Study III, we examined the long-term outcomes of BET in our institution, focusing on the patients’ perspective. The questionnaire study showed that pain in the ears, feeling of pressure in the ears, and feeling that ears are clogged reduced the most, in 75% or more of the patients who had suffered from these symptoms preoperatively. Of all patients, 77% had milder overall ear symptoms after the mean follow-up of 3.1 years. In Study IV, a systematic literature review revealed that the studies on the long-term outcomes of BET were heterogeneous in definition of ETD, selection of patients, duration of follow-up, additional treatments, and chosen outcome measures. Together, data from the studies suggested that BET has a positive long-term effect on chronic ETD symptoms and objective findings. Study IV also presented national indications for BET in adults as proposed by the Finnish Otosurgical Society: chronic bothersome symptoms referring to ETD, ETD symptoms when atmospheric pressure changes rapidly, or recurring serous otitis media. We conclude that BET is safe and feasible under local anesthesia. In addition to regular nasal nerve block anesthesia, both lidocaine-prilocaine cream and cocaine-adrenaline solution are suitable for local anesthesia although room for improvement regarding the anesthesia method still exists. Pain and discomfort scores were similar between the three different BET devices. However, patients treated with TubaVent experienced significantly more pain and discomfort during the operation than patients undergoing ESS. With the knowledge of which symptoms of chronic ETD respond best to BET and with the national consensus on indications for BET, patient counseling and selection can be enhanced. However, more long-term studies – with uniform criteria – on the effect of BET are still needed.  
  • Furu, Heidi M (Helsingin yliopisto, 2020)
    The global burden of occupational diseases (ODs) is heavy, and a notable part of work-related ill health remains unrecognised. The methods of reporting ODs and of conducting workers’ health surveillance around the world vary, and many parts of the world, have no surveillance or reporting at all. In Finland, health examinations are mandatory if workers are exposed to hazardous substances or factors. Occupational health (OH) conducts nearly 200 000 exposure-based health-examinations every year which requires a great deal of resources. However, little has their effectiveness studied before. The goal of the research was to study exposure-based occupational health examinations using one OD, chronic solvent encephalopathy (CSE) as a proxy. We assessed their effectiveness and costs, limitations to detect ODs, and solvent-exposed workers work ability. Organic solvents present a ubiquitous occupational exposure, and in Finland, 20 000 workers are regularly exposed to them, and are thus obliged to attend exposure-based health examinations. Long-term solvent exposure may cause permanent central nervous system disturbances, i.e. CSE, which is characterised by cognitive memory and concentration problems. In Finland, five to seven CSE cases are diagnosed annually, and most common occupations among which they are found are painting, printing, floor-layering, metal degreasing, and boat building. A questionnaire inquiring about exposure, CSE-compatible symptoms and health was sent to 3 600 workers. Symptomatic respondents were invited to OD physician’s clinical examinations. As a result, 18 new occupational CSE cases were diagnosed. The study showed that new CSE cases can still be detected in Finland and that CSE is under-detected despite the mandatory OHS health examination system. The economic evaluation revealed that the SPC screening identified a new CSE case at 1/30 of the cost of the OHS health examinations. In addition, the CSE cases detected were younger and their retirement rate was lower than that of those detected by OHS (6.7% vs. 74%), which indicates that SPC screening was able to detect milder cases or those at an earlier phase, preserving work ability. However, the study showed that solvent exposure is an independent risk factor of poor work ability in elderly workers; it is comparable to a high level of alcohol consumption. We retrospectively studied the OHS patient records of the 18 CSE cases detected through SPC screening. The study revealed that although mandatory the exposure-based OHS health examinations were conducted, they did not always follow the guidelines. Common health counselling seems to overrule exposure-based issues in health examinations. This study was conducted in an industrialised country with a unique mandatory OHS system, good occupational hygiene, and declining solvent exposure levels. However, other countries and exposures probably also face the same kinds of challenges in OD detection. The global burden of occupational diseases (ODs) is heavy, and a notable part of work-related ill health remains unrecognised. The methods of reporting ODs and of conducting workers’ health surveillance around the world vary, and many parts of the world, have no surveillance or reporting at all. In Finland, health examinations are mandatory if workers are exposed to hazardous substances or factors. Occupational health (OH) conducts nearly 200 000 exposure-based health-examinations every year which requires a great deal of resources. However, little has their effectiveness studied before. The goal of the research was to study exposure-based occupational health examinations using one OD, chronic solvent encephalopathy (CSE) as a proxy. We assessed their effectiveness and costs, limitations to detect ODs, and solvent-exposed workers work ability. Organic solvents present a ubiquitous occupational exposure, and in Finland, 20 000 workers are regularly exposed to them, and are thus obliged to attend exposure-based health examinations. Long-term solvent exposure may cause permanent central nervous system disturbances, i.e. CSE, which is characterised by cognitive memory and concentration problems. In Finland, five to seven CSE cases are diagnosed annually, and most common occupations among which they are found are painting, printing, floor-layering, metal degreasing, and boat building. A questionnaire inquiring about exposure, CSE-compatible symptoms and health was sent to 3 600 workers. Symptomatic respondents were invited to OD physician’s clinical examinations. As a result, 18 new occupational CSE cases were diagnosed. The study showed that new CSE cases can still be detected in Finland and that CSE is under-detected despite the mandatory OHS health examination system. The economic evaluation revealed that the SPC screening identified a new CSE case at 1/30 of the cost of the OHS health examinations. In addition, the CSE cases detected were younger and their retirement rate was lower than that of those detected by OHS (6.7% vs. 74%), which indicates that SPC screening was able to detect milder cases or those at an earlier phase, preserving work ability. However, the study showed that solvent exposure is an independent risk factor of poor work ability in elderly workers; it is comparable to a high level of alcohol consumption. We retrospectively studied the OHS patient records of the 18 CSE cases detected through SPC screening. The study revealed that although mandatory the exposure-based OHS health examinations were conducted, they did not always follow the guidelines. Common health counselling seems to overrule exposure-based issues in health examinations. This study was conducted in an industrialised country with a unique mandatory OHS system, good occupational hygiene, and declining solvent exposure levels. However, other countries and exposures probably also face the same kinds of challenges in OD detection.
  • Heikkilä, Kauko (Helsingin yliopisto, 2020)
    The known bias in human hand usage is fascinating, but the origins of handedness remain largely unknown, with about 10% of people being left-handed. Studies however point to early development in handedness formation. As a developmental approach, we asked whether perinatal covariates have an association with left-handedness. Such associations have been reported, although not without controversies: Prenatal ultrasound associated with increased proportion of left-handedness or twins having an increased proportion of left-handedness. Study I of the thesis addressed the ultrasound hypothesis. Studies II and III investigated twins and triplets with perinatal correlates other than ultrasound: twin status, birthweight, gestational age, Apgar scores, birth order and some others. Among triplets, we tested the motor control development of the left- vs right-handed. A dataset of singletons (N=4150) was used for showing that ultrasound was not associated with left-handedness. Twins (N=8786) and singletons (N=5892) were compared in study II. Based on earlier findings on very-low-birthweight singletons we expected birthweight to be a correlate. Many of our correlates were twin-specific (birthweight smaller than in singletons etc). Using them we tried to address risks of multiple births. Twins eventually were slightly more often left-handed than singletons in Study II, and the difference was explained by twin-specific correlates. After Study II we proceeded to investigate triplets in Study III. We had two datasets: Dutch (N=947 triplet individuals) and Japanese (N=1305 triplet individuals). These were used exclusively, without comparing to singletons and birthweight was used as continuous (in kg). The two triplet datasets consistently showed that left-handedness was associated with lower birthweight (Japanese OR = 0.50, 95% CI 0.31 to 0.78, p < 0.01; Dutch OR = 0.62, 95% CI 0.43 to 0.90, p = 0.01). The left-handed triplets showed delayed motoric development in comparison to the right-handed, with this delay being totally explained in models by the lower birthweight of the left-handed. Some handedness theories have tried to explain excess left-handedness by perinatal mechanisms so far unconfirmed. Future research of mechanisms will thus be challenging with the small associations found herein. The mystery of handedness formation mostly remains, but we could demonstrate an involvement of developmental factors in handedness formation.
  • Jäämaa-Holmberg, Salla (Helsingin yliopisto, 2020)
    Heart failure (HF) is a significant cause of morbidity and mortality globally. Most common cause of HF is ischemic heart disease. Other etiologies include hypertension, valvular heart diseases, arrhythmias, cardiomyopathies, inflammatory heart diseases, and structural heart diseases. Cardiogenic shock (CS) is the most severe form of HF, with in-hospital mortality of approximately 40%. CS or cardiac arrest (CA) refractory to pharmacological therapy can be treated with mechanical circulatory support using venoarterial extracorporeal membrane oxygenation (VA ECMO). It provides full temporary circulatory support, and can be used as a bridge to recovery, heart transplantation or long-term ventricular assist device (VAD) implantation. However, ECMO is a treatment modality requiring substantial resources and carrying a risk of complications, and thus not suitable for all patients. Heart transplantation (HTx) is the treatment of choice for patients with severe HF, meeting the criteria for transplantation. Prognosis after HTx is good; more than 90% of the patients survive to one year, and of these patients 80% to ten years. The main challenges affecting long-term survival are cardiac allograft vasculopathy (CAV) and cancers. In CAV, coronary arteries of the allograft get occluded due to immune-mediated intimal proliferation. Cancer risk after transplantation is elevated due to the immunosuppression required to prevent rejection and CAV. Most common cancers after transplantation are non-melanoma skin cancers and lymphomas. This thesis aimed to study the prognosis of adult patients with severe HF treated with VA ECMO or HTx. Studies I and II assessed patient survival, health-related quality of life (HRQoL) and costs and cost-utility and after VA ECMO. Study III assessed Finnish heart transplant recipients’ cancer risk in comparison to the population. The patient cohorts consisted of HF patients treated in Helsinki University Hospital: in studies I and II, of 157 patients treated in 2007-2017 with VA ECMO due to refractory CS or CA (in study I 133 patients, and in study II 102 patients; 78 patients were included in both studies), and in study III of 479 consequent patients who had undergone HTx in 1985-2015. In study I, focusing on the survival and HRQoL after VA ECMO, the survival to discharge in the whole cohort was 63.9%, and to one year 60.9%. Survival of patients treated with extracorporeal cardiopulmonary resuscitation (ECPR) was 31.8%. VA ECMO was used as a bridge to HTx for 12% of the patients, and to VAD for 11%. One patient received a total artificial heart. In multivariate regression analysis, low arterial HCO3 concentration before VA ECMO implantation, and high need of red blood cell transfusions (RBCs) during the ICU care predicted in-hospital mortality (odds ratio (OR) 1.2/ 1 mmol/l for HCO3, 95% confidence interval (CI) 1.09-1.33; OR 1.9/ unit of RBCs/day, 95% CI 1.39 - 2.57). The HRQoL, measured by EuroQol -5 Dimensions - 3 Levels survey at a minimum of one year after VA ECMO, was equal to validated Finnish population’s HRQoL. In a more detailed survey, the Short Form-36, patients reported better emotional wellbeing than reference population, while the general health perception and social dimensions were equal. Limitations were reported in the physical dimensions of the survey. Patients who had underwent HTx reported better HRQoL than other patients. In study II focusing on the costs and cost-utility of VA ECMO in CS and CA, the survival to discharge in the whole cohort was 65.7%, and to one year 64.7%. Survival of ECPR treated patients was 20.8%. The effective costs per one-year survivor were 245 974€. Median in-hospital costs per patient were 129 967€. Mean predicted number of quality-adjusted life years (QALYs) gained by the treatment was 21 and the median cost per QALY were 7 474€ without discount. The costs were significantly higher for patients who underwent HTx or received a VAD compared to other patients. In study III, cancer risk after HTx was found to be six-fold (standardized incidence ratio (SIR) 6.0, 95% CI 5.3-6.7), and the risk of cancer death three-fold (standardized mortality ratio (SMR) 3.1, 95% CI 2.4-4.1) compared to general population’s risk. Cancer risk was substantially more elevated for men than for women. Most frequent cancers detected in the cohort were non-melanoma skin cancers (83 cases of basal cell carcinoma; 56 cases of squamous cell carcinoma), non-Hodgkin lymphoma (NHL; 36 cases), lung cancer (17 cases) and prostate cancer (16 cases). SIR was highest for squamous cell skin cancer (51.9; 95% CI 39.2-67.4), lip and tongue cancers (47.4; 19.1-97.7 and 26.3; 7.2-67.4), and for NHL (25.9; 18.0-35.6).  

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