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  • Aaronson, Alexander (Helsingin yliopisto, 2021)
    The thesis studies uneventful cataract surgery and some of its most common complications. The data is based upon retrospective clinical trials performed in the Kymenlaakso Central Hospital, Kotka, Finland. In the first study learning curve of beginning surgeon´s is evaluated and advances in training and equipment analyzed. A common intra-operative complication, posterior capsule rupture with or without vitreous loss (PCR) was designated as the end-point. With appropriate training and equipment, incidence of complications can be reduced and training made safer. In the second study the incidence of late post operative complication pseudophakic cystoid macular edema (PCME) was analyzed and the current treatment protocol was compared with international publications. PCME can result in permanent visual deficiency, even if the surgical procedure was performed without complications. Ocular inflammation has been presumed to increase the risk for PCME development. In the third study the association between aqueous flare, a marker for ocular inflammation, and development with PCME was established by using a laser flare meter. The fourth study analyzes the cost-consequence in intraocular lense (IOL) selection with respect to development of common late complication called posterior Capsular Opacification (PCO) or secondary cataract. Different IOLs have different PCO incidence profiles. PCO requires laser therapy. By preferring IOLs with lower PCO incidence, the public sector can benefit considerably.
  • Martinez Majander, Nicolas (Helsingin yliopisto, 2021)
    Despite contemporary studies showing a high prevalence of cardiovascular risk factors in young adults (<50 years) with ischemic stroke, recent large hospital- and population-based studies also show high frequencies (33-50%) for cryptogenic strokes in this patient population. The proportion of patients without known vascular risk factors was even larger in younger (<30 years) age groups than in patients aged between 30 and 49 years. The risk for recurrence is high even in those with cryptogenic strokes, suggesting a still unknown active underlying pathology. The aim of this study was to explore the characteristics of early-onset cryptogenic ischemic stroke and associated less well-documented risk factors. In the first study, we explored baseline characteristics and long-term outcome of a carefully phenotyped subgroup of young individuals with early-onset cryptogenic ischemic stroke, embolic stroke of undetermined stroke (ESUS). These patients were identified from the retrospective Helsinki Young Stroke Registry (HYSR), which included all consecutive young patients aged 15-49 years with first-ever ischemic stroke treated at the Helsinki University Hospital between the years 1994 and 2007 and followed up for a median of 10.1 years. Of the 971 eligible patients in HYSR, 203 (20.9%) were classified as ESUS. These patients were more often female (43.3% vs. 35.7%), younger (median age 40 years, interquartile range 32-46 vs. 40 years, 39-47), and had lesser well-established cardiovascular risk factors for ischemic stroke than young patients with other defined stroke etiologies. Within the follow-up, ESUS patients had the lowest cumulative 15-year risk of mortality (9.5%, 95% confidence interval 4.0-15.1%) and the second lowest risk of any recurrent stroke (19.5%, 3.7-35.2%) and composite vascular events (23.9%, 14.1-33.6%) compared with other defined stroke etiologies. Small-vessel disease and large-artery atherosclerosis had a significantly higher risk for recurrent stroke than ESUS, whereas the risk was similar between high-risk cardioembolism and ESUS. In the second study, we designed and launched a multicenter, prospective case-control SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome; NCT01934725) study. This study includes equally young patients with first-ever cryptogenic ischemic stroke to explore more systematically the risk factors, triggers, and long-term outcome in this stroke subgroup. Patients were age- and sex-matched with stroke-free controls. By using data gathered in the SECRETO, we aimed to assess the association between migraine and endothelial dysfunction with early-onset cryptogenic ischemic stroke in the third and fourth studies. In the third study, we included 347 case-control pairs and showed that any migraine and migraine with aura (MA) were associated with early-onset cryptogenic ischemic stroke (odds ratio [OR] 2.48, 1.63-3.76 and OR 3.50, 2.19-5.61, respectively). Migraine without aura (MO) showed no association with stroke. Association for any migraine and MA with early-onset cryptogenic ischemic stroke was significant in both women (OR 2.97, 1.61-5.47 and 4.32, 2.16-8.65, respectively) and men (OR 2.47, 1.32-4.61 and 3.61, 1.75-7.45, respectively). MA was more frequent in patients with larger right-to-left shunts (29.2% for no shunt, 37.9% for small shunt, 46.7% for moderate shunt, and 49.4% for severe shunt; P=0.042). The association between MA and cryptogenic ischemic stroke remained significant irrespective of the shunt. In the fourth study, endothelial dysfunction was analyzed with a non-invasive device (EndoPAT 2000 device, Itamar Medical Inc., Caesarea, Israel) by measuring a natural logarithm of Reactive Hyperemia Index (LnRHI), with lower values reflecting dysfunction. An association between endothelial dysfunction and early-onset cryptogenic ischemic stroke was observed in men (OR 3.50, 1.22-10.07 for lowest vs. highest LnRHI tertile) and in patients ≥41 years (5.78, 1.52-21.95). There was no significant association in the entire cohort, in women, or in patients <41 years in 136 case-control pairs included in this sub-analysis. Patients in the lowest tertile of LnRHI were more often men and obese and had more frequently a history of dyslipidemia, lower high-density lipoprotein cholesterol, and lower diet score. In conclusion, ESUS patients in the retrospective HYSR cohort were younger and had a lower burden of cardiovascular risk factors than patients with well-established stroke etiology. They also had generally better long-term outcome, except for the risk of recurrent stroke between ESUS and high-risk cardioembolism. After designing and piloting the SECRETO study, we demonstrated a strong association between any migraine and MA and early-onset cryptogenic ischemic stroke irrespective of sex. We also showed an association between endothelial dysfunction and cryptogenic stroke in men and in slightly older individuals.
  • Hebbar, Prashantha (Helsingin yliopisto, 2021)
    BACKGROUND: The highly inbred Arab population of the Middle East region has been experiencing complex metabolic health catastrophe ever since adopting a change in lifestyle in the rich post-oil era. Characterization of genetic risk variants by genome-wide (GW) profiling of genetic variations and phenotypes of metabolic health in this population would help understand population specific disease etiology. AIM: This study employs single nucleotide variant association analysis to 1) discover variant association with 13 different quantitative metabolic traits using GW genotype data, 2) characterize runs of homozygous regions and examine the association of variants harbored in such regions with metabolic traits, 3) impute untyped variants and assess their association with quantitative metabolic traits of the Arab population. MATERIALS AND METHODS: The study is focused on two cohorts, namely the Kuwait Obesity Genetics Project (KOGP) and the Kuwait Diabetes Epidemiology Program (KDEP. The cohorts comprised 1965 (genotyped using Illumina HumanCardio-MetaboChip array or by TaqMan Assay) and 1350 Arab inhabitants of Kuwait (genotyped by Illumina HumanOmniExpress array) respectively. The respective GW variant data obtained were subjected to quality control measures and used to analyze variants association with 13 different quantitative traits. RESULTS: Examination of variant association using GW genotyping and/or imputing revealed several variants modulating metabolic traits. Upon using only the genotyped variants, risk variants from the following genes were revealed at GW significant p-values (P ≤ 5E-08): RPS6KA1, LAD1, Or5v1, [CTTNBP2-LSM8], PGAP3, [RP11-191L9.4-CERK], ST6GALNAC5, [SPP2-ARL4C], NPY1R, [LINC00911-FLRT2], [CDK12-NEUROD2], and STARD3 for serum triglycerides (TG); TCN2 for waist circumference; and RPS6KA1, CADPS, and [VARS and VWA7] for fasting plasma glucose (FPG). All these genes, except TCN2, were located in regions of runs of homozygosity. Furthermore, imputing untyped genotypes and combining GWA signals from both the study cohorts revealed 70 unique variants from 9 gene loci at GW significant p-values. Among these variants, 63 were associated with HDL-C, 1 with TG, 1 with LDL-C, 3 with SBP, and 2 with each of FPG and DBP. The gene loci included CETP, [INTS10, LPL], and [LOC105377613, LOC105377614] for HDL-C; CSMD1 for elevated FPG levels; [DYRK1A, LOC105372798] and RTN4 for SBP; RTN4 for DBP, BUD13 for TG, and [INTS10, LPL] for LDL-C. CONCLUSION: Many of the variant associations identified were not previously reported in global GWAS studies. Hence, these studies provide new insights into the Arab specific etiology of the metabolic syndrome and might help in devising more effective therapeutic approaches for Arab population.
  • Laakso, Teemu (Helsingin yliopisto, 2021)
    Aortic valve stenosis (AS) is the most prevalent valvular heart disease in the developing world and becomes more common due to ageing population and increased life expectancy. Severe symptomatic AS carries a dismal prognosis without operative treatment. Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of patients at high or prohibitive risk for surgical aortic valve replacement (SAVR). TAVR has been tested in randomized clinical trials which have shown superiority in comparison to medical treatment in inoperable patients, and comparable results in comparison to SAVR in intermediate- to high-risk patients. Recently, the ongoing clinical trials in low-risk patients have reported equivalent 2-year results after TAVR and SAVR. This thesis is based on five original articles from the FinnValve registry, which is is a nationwide registry including data on all patients who underwent TAVR or SAVR with a bioprosthesis for severe aortic stenosis from 2008 to 2017. The aim of this thesis was to investigate the efficacy of TAVR with a focus on important adverse effects. Study I examined the incidence of PVR and its impact on survival after TAVR and SAVR. In this study, both mild and moderate-to-severe PVR were associated with increased mortality in mid-term follow-up. Study II studied major vascular complications (MVC) after transfemoral TAVR. The rate of MVC declined significantly during the study period. Non-access-site related MVC increased mortality to threefold in 3-year follow-up. Access-site related MVC was associated with increased mortality if severe bleeding occurred. Study III investigated acute kidney injury (AKI) following TAVR and SAVR in patients without chronic kidney disease. In propensity score matched cohorts, the risk of AKI was significantly lower after TAVR. Mortality was significantly increased with increasing severity of AKI. Study IV examined the risk endocarditis after TAVR and SAVR. There was no difference in the risk of prosthetic valve endocarditis between TAVR and SAVR in mid-term follow-up. Study V assessed the efficacy of TAVR with newer generation prostheses in preventing 1-year mortality. The vast majority of patients underwent TAVR with acceptable risk in Finland. The accuracy of risk scores in estimating mortality risk were also investigated. In conclusion, TAVR has transformed the outlook for high-risk AS patients. Complication rates have decreased significantly with increased operator experience and better devices. Still, there are issues of concern and together with the lack of long-term valve durability data, TAVR is not yet the first choice in low-risk patients with longer life expectancy.
  • Hiltunen, Seppo (Helsingin yliopisto, 2021)
    Background. The present thesis combines studies on hypnosis, attention, and attention deficits from various perspectives to extend our understanding of hypnosis and its applications. This thesis includes experimental and clinical research of hypnosis from the perspectives of brain functions, behavioral performance, and clinical interventions. This thesis investigated whether brain oscillations, pre-attentive auditory information processing, auditory attentional performance, and deficits of attention can be influenced by hypnosis and hypnotic suggestions. Two studies focused on highly hypnotizable healthy participants, one study compared adults with attention deficit hyperactivity disorder (ADHD) to control participants, and one investigated solely adults with ADHD. Aims. The present thesis examined: 1) whether hypnosis differs from the wake state as measured with the spectral power density of electroencephalography (EEG); 2) whether hypnosis and hypnotic suggestions can be used to influence bottom-up and/or top-down auditory attention. The former was indexed by the pre-attentive mismatch negativity (MMN) component of the auditory event-related potential (ERP). The latter was measured as the performance on a Continuous Performance Test (CPT); 3) whether hypnotherapy and hypnotic suggestions can be applied to adults with ADHD to relieve their symptoms in a long-lasting way, and to improve their attentional performance in an auditory reaction time task requiring sustained voluntary attention. Methods. The present thesis applied various methods for investigating the research aims: EEG (Studies I–II), behavioral reaction time task (Study III) and self-report measures for evaluating the follow-up results of two individual psychological treatments, hypnotherapy and cognitive behavioral therapy (CBT) in ADHD adults (Study IV). The first three studies had a similar procedural structure including four experimental conditions: 1) pre-hypnosis, 2) after a hypnotic induction (i.e., neutral hypnosis), 3) hypnotic-suggestion condition with study-specific suggestions and 4) post-hypnosis. The first and second studies included a common EEG experiment with nine highly hypnotizable participants. In the first study, EEG spectral power was measured and analyzed at ten frontal, central, and posterior/occipital electrodes. In the second study, the MMN was recorded at three frontal electrodes using a passive oddball paradigm with sinusoidal standard (500 Hz) and deviant (520 Hz) tone stimuli. Both studies included in the hypnotic-suggestion condition suggestions aimed at altering the tone perception (“all tones sound similar in pitch”). The third study examined, in adults with ADHD and in healthy control participants, whether hypnotic suggestions can influence performance in a three-minute version of the auditory CPT. The suggestions aimed at improving speed and accuracy. The fourth study used a controlled, randomized design in investigating the effectiveness of hyp¬notherapy in treating adults with ADHD. It compared the six-month follow-up outcome of the hypnotherapy with the outcome of a short CBT in various self-report symptom scales. Repeated-measures analysis of variance and t-tests were used in the statistical analysis of the studies. Results. The results of Study I revealed no EEG power changes between pre-hypnosis and hypnosis conditions, challenging the current understanding that the increase of theta power is a marker of the hypnosis state. Contrary to the results of a few earlier studies, no statistically significant differences in the MMN amplitudes between the conditions were found in Study II, indicating that the auditory pre-attentive processing may not be influenced by hypnosis or hypnotic suggestions. Study III indicated that hypnotic suggestions have an effect on the reaction times in the CPT both in ADHD adults and healthy control participants. Study IV revealed that the treatment benefits remained during the six-month follow-up with both hypnotherapy and CBT groups when measured with self-report ADHD symptom scales. The benefits of hypnotherapy and CBT, however, differed in general psychological well-being, anxiety and depression, and approached significance in the ADHD symptoms scale, indicating a better long-term outcome for hypnothera¬py. Conclusion. Results of the present thesis indicate that: 1) the spectral power of EEG in the theta band cannot be used as a reliable marker of the hypnotic state in highly hypnotizable participants; 2) hypnotic suggestions can be used to influence performance in a sustained attention reaction time task, but they do not modulate the early pre-attentive auditory information processing, reflected by MMN; 3) hypnosis, hypnotic suggestions, and short hypnotherapy treatments can be successfully applied to adults with ADHD to improve their performance in a sustained attention reaction time task, and to reduce their ADHD and other symptoms in a long-lasting (at least half a year) way. Thus, hypnosis/hypnotherapy seems to be a usable treatment method for the ADHD adult population.
  • Ekström, Kaj (Helsingin yliopisto, 2021)
    The aim of this study was to study the role of sudden cardiac death (SCD) and life-threatening ventricular arrhythmias (VA) in cardiac sarcoidosis (CS) and giant cell myocarditis (GCM), and to investigate the clinicopathological relationship between these diseases. CS is the cardiac manifestation of sarcoidosis, a systemic disease of unknown etiology. The hallmark of sarcoidosis is the non-caseating granulomatous inflammation seen in affected organs. GCM is a rare myocardial inflammatory disease characterized by widespread myocardial destruction, eosinophilia, and giant cells in the absence of granulomas. Clinically significant VAs are common in both CS and GCM and sometimes SCD is their first manifestation. For this study, all CS and GCM patients detected both from the national research register and from the cause-of-death register from 1998 until the end of 2015 were included. Additionally, clinically manifest cases of GCM from 1991 to 1998 were included. Hospital charts, autopsy reports, and histological material were reviewed and cardiac magnetic resonance imaging (CMRI) studies for a subpopulation of 59 CS patients were analyzed. The study included 351 cases of CS and 29 cases of GCM. The detection rate of both diseases increased over the study period. Female predominance was seen in both CS and GCM. At the time of presentation, the mean age of CS and GCM patients was 52 and 57 years, respectively. The spectrum of manifestations was similar in both diseases. The most common clinical presentation was atrioventricular block in CS and heart failure in GCM. SCD was the first sign of myocardial disease in 14% of cases in both the CS and GCM cohorts. The role of SCD as the mode of death was substantial in both diseases: it accounted for four out of five fatalities in CS and nearly half in GCM. Over half of the cases originally diagnosed as GCM were converted to CS after reevaluation, most commonly due to missed myocardial granulomas or misclassification as GCM, despite recognition of cardiac or extra-cardiac granulomas. Lifetime symptomatic CS patients with an initial diagnosis of GCM had a better five-year (46%) transplant-free survival compared to “true” GCM patients (27%), but the groups did not differ with regard to cumulative incidence of SCD. The 10-year survival in lifetime-diagnosed CS patients was 87%. Several CMRI parameters were associated with worse transplant-free survival free of VAs. These included higher late gadolinium enhancement extent, lower right ventricular ejection fraction and thinning (< 4mm) of the basal interventricular septum. In GCM, the five-year overall and transplant-free survival rates were 67% and 26%. At least moderate necrosis or fibrosis on myocardial biopsy and elevated N-terminal pro b-type natriuretic peptide were predictive of worse transplant-free survival. The highest risk of life-threatening VAs was seen during the first year after symptom onset. The cumulative incidence of SCD or any life-threatening VA rose to 52% at 12 months after symptom onset and was associated with at least moderate fibrosis on myocardial biopsy and higher cardiac troponin at presentation. In conclusion, SCD and life-threatening VAs have a major role in the clinical course of many CS and GCM patients. Clinically and histopathologically, CS and GCM share many similarities and their differential diagnostics can be challenging.
  • Karesvuo, Petteri (Helsingin yliopisto, 2021)
    Våt åldersrelaterad makuladegeneration är den vanligaste orsaken till synskada hos människor över 65 år i industrialiserade länder. Nya tillväxtfaktorhämmare har revolutionerat behandlingen av våt åldersrelaterad makuladegeneration. Problemet med dem är att deras verkningstid är kort och de måste ges varje månad – eller vart tredje månad i ögat. Gråstarr är den vanligaste orsaken till synskada och blindhet i utvecklingsländer. Starroperation är en vanlig dagkirurgisk åtgärd och den har konstaterats vara trygg och kostnadseffektiv. Starr och åldersrelaterad makuladegeneration uppträder hos äldre och de uppträder ofta samtidigt. Olika studier har gett olika resultat när det gäller huruvida en starroperation försämrar våt åldersrelaterad makuladegeneration. Vår studie ledde till att det inte spelar någon roll om man opererar våt åldersrelaterad makuladegeneration. Aflibercept är en ny tillväxtfaktorhämmare och den har längre verkningstid. Resultatet av vår studie är att aflibercept minskade förekomsten av synskada. Vid starroperation används lokala mediciner som minskar postoperativa komplikationer. I vår studie var kortisondroppar effektivare när det gäller att minska efterstarr jämfört med NSAID droppar. Vid starroperation använder man olika intraokulära linser, det finns blåljusfiltrerande och icke-blåljusfiltrerande linser. I djurstudier har man konstaterat att blåljus inte är bra för näthinnan, och i våra studier förekom det inte någon skillnad mellan dessa linser i frekvensen av ny våt åldersrelaterad makuladegeneration. Vi konstaterade att styrkan hos en intraokulär lins påverkar frekvensen av efterstarr. Hos personer som fått intraokulära linser förekom mer efterstarr än hos dem med normal och hög styrka. Riskfaktorerna för åldersrelaterad makuladegeneration är många, såsom hög ålder, ärftlighet och rökning. Vi fann att en ny riskfaktor, parodontit, infektion i tändernas stödvävnad, kunde ligga bakom åldersrelaterad makuladegeneration.
  • Virtanen, Suvi (Helsingin yliopisto, 2021)
    Internalizing disorders such as depression, anxiety disorders, and obsessive-compulsive disorder (OCD) frequently co-occur with substance use disorders (SUDs). Causes for the comorbidity remain unclear, and could be explained by several, not mutually exclusive general mechanisms. For instance, shared genetic and/or environmental factors may increase the risk of both internalizing disorders and SUDs, or the risk of SUDs might be causally increased by internalizing disorders via self-medication. The overarching aim of this dissertation was to describe the association of these internalizing disorders with substance misuse during the lifetime as well as during the important developmental period from childhood to early adulthood, and to clarify the mechanisms underlying the comorbidity using quasi-experimental research designs. Sub-studies of this dissertation included two sources of data: Swedish nationwide registers and the Child and Adolescent Twin Study in Sweden (CATSS), a longitudinal twin cohort study. Population-based samples linked to nationwide registers were used in Studies I (n=2,996,398), II (n=1,768,516), III (n=6,304,188), and IV (n=146,114). CATSS data were utilized in Studies II (n=12,408) and III (n=9,230). To account for familial effects, we used stratified analyses within sibling and twin pairs (Studies I and II), and conducted a within-individual analysis (Study IV). We also estimated the contribution of shared genetic and environmental factors to the associations with quantitative genetic structural equation modeling (Studies I and III). Both lifetime and childhood-onset anxiety and depressive disorders were associated with a substantially elevated risk of SUDs and substance use-related criminal offenses. OCD was also associated with an elevated risk of substance misuse, and self-reported OCD symptoms at age 18 were associated with increased alcohol and drug dependence symptoms among people who used alcohol or drugs. Shared familial liabilities contributed to the associations, but the associations were not entirely explained by familial factors. Further, we found an elevated risk of acute intoxications, accidental poisonings by alcohol or drugs, and substance use-related criminal offenses in patients with anxiety and depressive disorders during a 1-month period preceding SSRI medication treatment initiation, when compared to the reference period of more than 1 month before treatment start. On-treatment estimates were consistently lower than the 1 month pre-treatment estimate, but still elevated compared to the reference period. In conclusion, depression, anxiety, and OCD are important correlates of substance misuse across development. Genetic factors play a major role in explaining comorbidity, but the associations were not entirely explained by familial confounding. This pattern of results suggests that the relationship between internalizing disorders and substance misuse partially reflects shared etiology, but the findings were also consistent with (partially) direct effects between the disorders as proposed by the self-medication hypothesis. Thus, it appears that the comorbidity of internalizing disorders and substance misuse arises via several, not mutually exclusive mechanisms.
  • Satokangas, Markku (Helsingin yliopisto, 2021)
    Primary health care (PHC) has been shown to promote socioeconomic equity in health. However, geographic equity in health outcomes related to PHC performance remains little studied in Finland. This gap mirrors both the limited number of suitable indicators for comprehensive PHC performance evaluation and the complexity of measuring PHC performance at the population level. This thesis applied hospitalisations for ambulatory care sensitive conditions (ACSCs) and mortality potentially preventable by health policy and care (amenable mortality) to measure PHC as well as overall health care performance in Finland. These internationally utilized, population-level proxy health outcomes are suggested to be preventable by timely care. The aims of this thesis were to analyse what individual and area-level variables over time explained geographic variation in ACSCs in Finland – and what kind of over time developmental paths would emerge among areas providing public PHC in Finland when these areas were clustered by their age-standardised ACSC subgroup rates. Moreover, this thesis also aimed to analyse how geographic disparities in amenable mortality developed over time between three geographic areas in Finland – and whether this development disfavoured the capital City of Helsinki due to its increasing residential differentiation. ACSCs were obtained and identified from the Finnish Care Register for Health Care for the total Finnish adult population – and amenable mortality respectively from the Causes of Death statistics for all Finns aged 25-74. These outcomes were then linked to individual sociodemographic data and allocated into areas providing public PHC by individual area of residence. The associations between several selected variables and geographic variation in ACSCs were analysed with three-level nested Poisson regression models (individuals nested in areas providing PHC, nested in areas providing hospital care). The proportion of variance explained by each variable was quantified at three time points in 2011-2017 and in two separate datasets (all ACSCs and ACSC emergency admissions). In the null model, variances between areas providing hospital care were up to twice that between providers of PHC. While individual incomes and comorbidities explained up to third of the variances at both area-levels, area-level disease burden and arrangement and usage of hospital care explained an additional 14-16% and 32-33% of these variances in all ACSCs – and 7-15% and 28-33% in ACSC emergency admissions. After these adjustments the remaining variances in the two area-levels emerged to be nearly alike. To identify geographic disparities over time in the level and development of ACSCs in Finland, a group-based multi-trajectory model was applied. This model clustered areas providing PHC by their annual age-standardised acute, chronic and vaccine-preventable ACSC rates in 1996-2013. Moreover, it was tested which within-cluster values of area-level variables differed between the clusters over time. Three clusters emerged – each of them having a distinct level and development of ACSC rates. In these clusters, chronic ACSC rates over time halved, acute ACSC rates stagnated and vaccine-preventable ACSC rates increased slightly. The northern cluster had constantly the highest ACSC rates. While between-cluster absolute disparities in chronic ACSCs diminished over time, the respective relative disparities stagnated. Moreover, both of these disparities increased in acute and vaccine-preventable ACSC rates disfavouring the northern cluster. However, areas within the rural northern cluster shared the highest disease burden and usage of GP led inpatient wards – as well as the lowest education level and use of private health and dental care. Over time the development of amenable mortality was assessed both within and between three geographic areas in Finland: the city of Helsinki, the nine next most populated municipalities and the rest of Finland. Within these areas, development of geographic disparities in amenable mortality were quantified with Gini coefficients – and development of socioeconomic disparities with concentration indices. Finally, both the levels and over time changes of these disparities were compared between the three geographic areas. Over time geographic disparities in amenable mortality within the three geographic areas remained stable, but the socioeconomic ones slightly increased in the favour of the affluent population. The increase in socioeconomic disparities seemed to mirror both stagnating mortality rates in the lowest income quintile and otherwise consistent gradient in decreasing mortality rates among those with higher incomes. However, over time development in both of these within-area disparities were similar between the three geographic areas – and no hypothesised effect for increasing residential differentiation on mortality was found. To conclude, if age- and gender-adjusted ACSCs are applied to compare PHC performance between local providers in Finland, these values are not only confounded by individual socioeconomic position and health status but also by areas’ disease burden and variables related to hospital care. Indeed, when assessing over time geographic disparities in ACSCs, rural northern Finland seemed to be lagging behind the other parts of the country – possibly due to both high usage of GP led inpatient wards (low-threshold basic level hospital care) and excess disease burden in northern Finland. Either way, this finding emphasizes the need to strengthen health care in rural northern Finland. Finally, despite increasing residential differentiation in Helsinki, disparities in its health care performance did not diverge from those observed elsewhere in Finland – which might mirror the effects of policies of positive discrimination and social mixing applied in Helsinki.
  • Strausz, Satu (Helsingin yliopisto, 2021)
    Obstructive sleep apnoea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to reduced or absent breathing during sleep. The prevalence of OSA in adults is approximately 25% in developed countries. The main known risk factors for OSA are increasing age, male sex, menopause, obesity and certain craniofacial structures and anomalies. The role of OSA on the risk of adverse cardiovascular outcomes has been widely studied, and mechanisms linking OSA to its cardiometabolic correlates through intermittent hypoxia, oxidative stress and increasing sympathetic activity are also recognized. Despite the fact that the epidemiology of OSA has been under research for decades, the genetics behind OSA risk have remained mainly unstudied. However, family studies have shown that family members are at a 2–4-fold greater risk of having OSA if there are OSA patients in the family. It is estimated that 40% of the variation in the apnoea-hypopnoea-index (AHI) is genetically regulated. Previous genome-wide-association studies (GWASes) have addressed OSA severity based on AHI or respiratory event duration, but case-control studies have not been previously published. The World Health Organization (WHO) announced COVID-19 as a pandemic in March 2020. Patients with COVID-19 have a wide range of symptoms ranging from mild flu-like symptoms to severe illness. The first studies regarding COVID-19 revealed that male gender, higher age, obesity and diabetes are risk factors for the severe form of the disease, indicating that OSA and COVID-19 share numerous common risk factors and comorbidities. Furthermore, studies have suggested that OSA is a risk factor for the severe form of COVID-19. We estimated the role of OSA in major cardiometabolic disease by utilizing population-based cohorts, including FINRISK, Health 2000 and a subset of the Botnia Study, and registry information to longitudinally assess OSA risk in the Finnish population. Our data consisted of 36,963 individuals with over 500,000 person-years and up to twenty-five years of follow-up data, including 1,568 OSA patients. Using Cox-proportional hazards models, our results revealed that OSA is associated with a 1.36-fold increased risk for coronary heart disease (CHD), including a 2.01-fold increased risk in women independent of other potential confounding factors. Similarly, type 2 diabetes (T2D) correlated with OSA independent of obesity status and revealed a 1.48-fold increased risk. This association was also significant in women, showing a 1.63-fold increased risk. The risk of diabetic kidney disease (DKD) was increased by 1.75-fold in patients with OSA among the T2D study sample. All-cause mortality was increased in individuals with both OSA and T2D by 35%. To study the genetic burden for the risk of OSA we proceeded to identify genetic loci associated with OSA risk and aimed to test if OSA and its comorbidities share a common genetic basis. To elucidate these aims, data from the FinnGen project was used. The FinnGen project combines patient genotype data and nationwide registry information with anthropometric measurements, such as body mass index (BMI) and smoking. Using this information, we conducted the first large-scale case-control GWAS of OSA with 217,955 individuals including 16,761 OSA patients. We identified five genetic loci associated with OSA, highlighting the importance of genetic variation on OSA predisposition. This was further supported by our single nucleotide polymorphism (SNP)-based heritability estimates. We also showed the causal relationship between obesity and OSA by utilizing Mendelian randomization (MR). Although BMI is the major risk factor, we were also able to find a BMI-independent genetic locus for OSA that is associated with antidepressant purchases. However, we could not replicate this locus in independent cohorts. In addition, we found strong genetic correlations between OSA and its comorbidities including BMI, hypertension, T2D, CHD, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic diseases (IRD) in addition to other sleep traits such as sleepiness and sleep efficiency. These findings implicate OSA as a heterogenic disease with several distinct comorbidities, which would be beneficial to consider when treating patients with OSA. When COVID-19 emerged, it became apparent that the risk factors for the severe form of the disease showed similarities with OSA risk factors and comorbidities. Our aim was to study if OSA patients have a higher risk for hospitalisation due to COVID-19 disease in addition to other potential confounding factors, and if OSA associates with an increased risk of contracting COVID-19. We studied 445 individuals with COVID-19 including thirty-eight OSA patients extracted from the FinnGen project data (N=260,405). Of the OSA patients, nineteen required hospital treatment due to COVID-19 infection. OSA was associated with a 2.93-fold increased risk of COVID-19 hospitalisation independent of age, sex, BMI and other comorbidities. The results were further confirmed in a meta-analysis including 15,835 individuals. Importantly, treatment information regarding OSA was also collected and suggested that moderate and severe OSA is a risk factor for severe COVID-19 even if the OSA is well managed. This thesis concentrates on studying OSA as a risk factor for cardiometabolic comorbidities, the genetic variation between OSA and non-OSA individuals and whether OSA creates an elevated risk for severe COVID-19 disease. These studies were conducted by utilizing large and accurate data sets with an epidemiological and longitudinal ascertainment, and by applying modern genetic methods to show that OSA is a relevant topic during the exceptional times of the global COVID-19 pandemic.
  • Kontturi, Antti (Helsingin yliopisto, 2021)
    The World Health Organization declared tuberculosis (TB) a global emergency over 25 years ago, yet TB remains a significant public health concern and a leading infectious killer of our time. Young children are especially vulnerable to rapid and debilitating TB disease, and infected children should be identified and therapy initiated rapidly. Nontuberculous mycobacteria (NTM) infections have also emerged in Western countries. Childhood NTM infections predominantly manifest as prolonged cervical lymphadenitis, which is a diagnostic challenge for the clinician due to the limitations of NTM cultures. Bacille Calmette-Guérin (BCG) vaccine effectively prevents severe TB disease forms in young children. Some studies have further suggested that BCG might also offer protection against childhood NTM infections. In Finland, BCG coverage of infants was very high until the vaccination policy changed in 2006 to a risk group-based approach. Subsequently, for the first time since the 1940s, a generation of children has grown in Finland without the protection of BCG against mycobacterial diseases. Furthermore, the healthcare and national surveillance registries allowing retrospective evaluation of TB and NTM cases in Finland are exceptional and provide a rare look into paediatric TB and NTM epidemiology with or without universal BCG vaccinations. In addition, a novel in-house diagnostic test developed in the Hospital District of Helsinki and Uusimaa (HUS) laboratory has shown potential in childhood NTM lymphadenitis diagnostics but has not been evaluated. In the first study, we evaluated the performance of the novel modified T.SPOT.TB test in children under five years of age with culture-confirmed NTM lymphadenitis and compared the results to a control group of healthy children. The estimated sensitivity and specificity of the modified T-SPOT.TB test were 1.00 and 0.81, respectively. The modified T.SPOT. TB was a promising noninvasive diagnostic test for childhood NTM lymphadenitis. In the second study, we identified native-born children aged 0–4 years infected with NTM between 1995 and 2016 from the Finnish National Infectious Diseases Register (NIDR) and estimated the NTM incidence rate change between birth cohorts born during universal or selective BCG vaccination policy. We identified 97 native-born children infected with NTM under the age of five. The estimated incidence rates of NTM in universal-BCG and selective-BCG cohorts were 0.2 and 3.9 per 100,000 person-years, respectively. The incidence rate ratio (IRR) of selective-BCG cohorts compared to universal-BCG cohorts was 19.03 (95% confidence interval [CI], 8.82–41.07). Childhood NTM infections increased drastically after the infant BCG coverage decreased, suggesting that BCG offers protection against childhood NTM lymphadenitis. In the third study, we identified all newly diagnosed active TB cases under 15 years of age in Finland 1995–2015 by linking data from the NIDR, Finnish Care Register for Health Care, medical patient records, and Finnish Population Information System. We compared the under-five TB incidence rate ratio of birth cohorts with universal and selective BCG vaccinations. We identified a total of 139 paediatric TB cases. The under-five TB rate of birth cohorts with selective-BCG compared to birth cohorts with universal-BCG remained stable (IRR 1.3; 95% CI, 0.7–2.3). Paediatric TB in Finland was concentrated in families with an immigrant background from high TB incidence countries. The native under-five TB morbidity did not increase after the BCG vaccination policy change in Finland, suggesting that well-implemented selective vaccinations can prevent TB in the most vulnerable age group effectively in low-incidence settings. In the fourth study, we retrospectively reviewed paediatric TB contact tracing results from 2012 to 2016 in the HUS area. The yield for TB disease or infection was 4.6% and 12.8% for household contacts, 0.5% and 0% for contacts exposed in a congregate setting, and 1.4% and 5.0% for other contacts, respectively. Contact tracing in the HUS area identified exposed young children quickly: most of the TB infections among the children under five years of age were found before progression to disease, and none had severe disease forms. The maximum delay until the first contact investigation visit among the household contacts under five years of age with either TB disease or infection was seven days from the index case diagnosis. Contacts born in a TB endemic country (adjusted odds ratio [aOR] 3.07; 95% CI, 1.10–8.57), with household exposure (aOR 2.96; 95% CI, 1.33–6.58), or a sputum smear-positive index case (aOR 3.96; 95% CI, 1.20–13.03) were more likely to have TB disease or infection. The yield for TB disease or infection of large-scale investigations after exposure in a congregate setting was very low, and investigations in such events should be cautiously targeted. In summary, the epidemiological landscape of childhood mycobacterial infections in Finland has changed. The BCG vaccination policy change in 2006 resulted in an increase in childhood NTM infections, but childhood TB infections did not increase, and restarting universal BCG vaccinations seems unwarranted. Childhood TB, however, remains an essential public health issue, and future surveillance is vital. The focus of childhood TB prevention in Finland should be further targeted to those with an immigrant background from high TB burden countries.
  • Oulasvirta, Jelena (Helsingin yliopisto, 2021)
    Children form a small proportion of all emergency medical services (EMS) contacts. A Finnish study by Harve et al. (2016) discovered that young children aged one or less were overrepresented in children's contacts with EMS. Further, falls, respiratory problems, seizures, and poisonings accounted for half of all of their emergencies. Finally, an unexpected number of children were assessed by paramedics, but not transported to the hospital. Rooted in the Harve group findings, this study explored EMS contacts with children focusing on pediatric subpopulations such as children who had had seizures, infants, and children who after evaluation by EMS personnel were not transported to any health care facility. In addition, the study investigated whether and how the COVID-19 pandemic and restrictions intended to curb the pandemic impacted out-of-hospital (OOH) emergencies in children during the first wave. The thesis consists of four register-based retrospective cohort studies conducted in the Helsinki University Hospital area. Children under 16 years old formed the study population overall, except in the one study where the study population comprised 0- to 11-month-old infants. The data on EMS contacts were gathered from both OOH and in-hospital electronic patient record systems. The study periods lasted from three months to five years. EMS contacts with children comprised from 3.9% to 4.8% of all contacts. Infants constituted about 0.4% of all EMS contacts. EMS contacts with children who suffered seizures occurred in the 13% of pediatric missions. The non-transportation rate was high and ranged from 26.7% in pediatric seizure patients to 60.1% in infants. Hospitalization or pediatric intensive care unit (PICU) admissions were seldom necessary. On-scene mortality was low. Only a few patients died during follow-up periods, and none of these deaths were traceable to EMS contact. The study recognized several risk factors for secondary outcomes after EMS contact with children. Dispatch codes "dyspnea", "vomiting /diarrhea" and "mental illness" were associated with unintended visit after non-transportation. In infants, dispatch codes "dyspnea" and "urgent dispatch before symptom-specific code known", as well as problems in the neonatal period were associated with hospitalization and PICU admissions. In contrast, dispatch code "low-energy fall" was less associated with unintended visits after non-transportation, and hospitalizations and PICU admissions in infants. Fewer EMS contacts with children occurred during the first wave of the COVID-19 pandemic. However, the proportion of children in the most urgently dispatched and transported priority category A rose significantly. In addition, EMS personnel requested additional help more frequently to the scene. Thus, children appeared to be acutely more ill during the restriction period. COVID-19 infection among children with EMS contact was infrequent. In conclusion, EMS encounters with children were uncommon and around half of the children were not transported after evaluation by EMS personnel. The current practice appeared to be safe. The high non-transportation rate may reflect the changing role of EMS and possible non-medical needs of families with children. Taking into account the risk factors that were identified in this study could further improve patient safety among EMS contacts with children. Consideration that restrictions during the pandemic may have unexpected side effects on children's health may help to guide and direct curbing measures during future sudden pathogen outbreaks.
  • Amudhala Hemanthakumar, Karthik (Helsingin yliopisto, 2021)
    Cardiovascular diseases (CVD) rank as a number one cause for mortality and accounts for one third of the deaths in several OECD countries (OECD, 2015). According to WHO, CVD pathology is characterised by impaired coronary vasculature associated with cardiac dysfunction, which often results in heart failure (Mendis S, 2011). Although the outlook for prevention and management of CVD risk factors is advancing, the extent of CVD mortality and morbidity remains relatively high (Mendis S, 2011) and the clinical prognosis of heart failure remains poorer than most of the cancers (Braunwald, 2015). Better understanding of the cellular and molecular links between the coronary vasculature and cardiac function under physiological and pathological conditions would enhance the development of personalized targeted therapies for CVD. In this thesis, my main objective is to define mechanistic insights how proangiogenic cues like VEGF-B or PlGF promote coronary angiogenesis -mediated physiological cardiac hypertrophy and to characterise the effect of CVD risk factors (aging, obesity, physical inactivity, and pressure overload) on cardiac endothelial cells (ECs) and cardiac function. We have applied molecular, biochemical, imaging and gene delivery methods to elucidate the phenotypes and molecular mechanisms in in vivo and in vitro model systems. In the study I, we showed that AAV9-VEGF-B overexpression or endothelial deletion of VEGFR1 increased the bioavailability of the endogenous VEGF to activate VEGFR2 in ECs promoting coronary angiogenesis. Importantly, this indirect activation of VEGFR2 is limited by endogenous levels of VEGF, and it did not promote vascular leakage. VEGFR2 activation induced expression of e.g., Dll4, Notch, Apln, Apj, Klk8 and Adam12, indicating activation of Notch and apelin signalling. Adam12 and Klk8, in turn, have been shown to induce shredding of Hb-egf and Nrg1 on the cell surface, leading to activation of ErbB receptors present in cardiomyocytes (CMCs). The findings of this study demonstrate a bidirectional crosstalk between ECs and CMCs via VEGFR2, NOTCH and ErbB signalling pathways. In the study II, overexpression of VEGF-B promoted cardiac EC activation throughout the heart, detected by lineage tracing using AplnCreERT2;Tdtomato reporter mice. However, the VEGF-B -induced EC proliferation was mainly concentrated to the subendocardial myocardium, which was detected by EdU labelling of proliferating cells and staining for a proliferation marker Ki67. In the Study II, my main contribution was the development and optimization of cardiac EC isolation for single-cell RNA sequencing. In this study, the main novel finding was that VEGF-B can promote coronary vessel formation from the endocardium during development and after myocardial infarction, which was accompanied by protection from the ischemic insult. In conclusion, the Studies I and II demonstrated the coronary angiogenesis -mediated physiological cardiomyocyte growth is mediated via VEGFR2-NOTCH-ErbB pathways and involves delicate bidirectional crosstalk between ECs and CMC. In the study III, the effects of CVD risk factors aging, obesity and pressure overload, and exercise training as a physiological stimulus, was studied on cardiac endothelial cells of C57Bl/6J mice. Pure and viable cardiac ECs were isolated and analysed by RNA sequencing and various bioinformatics tools. The data demonstrated that CVD risk factors significantly decreased the number of ECs in the heart as well as the coronary vascular density and cardiac function. Importantly, exercise training improved all of these parameters compared to the sedentary control mice. The next generation RNA sequencing revealed that CVD risk factors significantly remodelled the cardiac EC transcriptome and upregulated several genes and pathways related to inflammation, oxidative stress, TGF-b signalling, vascular permeability, endothelial to mesenchymal transition (EndMT) and cellular senescence, whereas exercise training inhibited most of the same pathways, demonstrating the beneficial role of exercise training on ECs and vasculature. Exercise training also promoted blood vessel development, vascular stability and homeostasis and cell-cell junctions. The gene overlap analysis of the differentially expressed genes in the different data sets revealed SerpinH1 as one of the commonly regulated gene. SerpinH1 was significantly induced by aging and obesity and repressed by exercise training. In vitro studies in human coronary arterial endothelial cells (HCAEC) showed that overexpression of SERPINH1 increased the cell size, induced the expression of EndMT and senescence related transcripts, repressed EC genes and enhanced migration in a wound healing assay. Silencing of SERPINH1 in HCAECs, in turn, completely blocked cell proliferation and decreased collagen deposition and wound healing. As SERPINH1 has previously been linked to fibrosis in other tissues and cell types, and here we found it in all ECs throughout the human and mouse heart, it might be a potential target for the treatment of CVD. The ECs are not often considered as therapeutic targets, even though in many cases heart problems arise secondary to vascular defects (Heusch et al., 2014). The results from this thesis suggest that cardiac ECs are highly adaptive to physiological stimuli and maladaptive to pathological stressors. These findings would help to develop innovative and new therapeutic opportunities to treat heart diseases.
  • Kettunen, Jarno (Helsingin yliopisto, 2021)
    The most common form of monogenic diabetes is called Maturity-onset Diabetes of the Young (MODY), which accounts for 1–3% of all cases of diabetes. Initially, MODY was a diagnosis for a familial form of diabetes that occurred in the lean and the young, demonstrated no dependence on exogenous insulin, and followed a dominant pattern of inheritance. Today, the clinical manifestation is more heterogeneous, and MODY has increasingly become a genetic diagnosis. More than 90% of the pathogenic gene variants responsible for MODY reside in GCK, HNF1A, HNF4A, or HNF1B. Although classical Mendelian diseases involve fully penetrant and distinctive phenotypes, heterogeneity in patients with MODY is pronounced. Even those with the same gene variant manifest with diverse clinical presentations. The characterization of gene–disease associations and heterogeneity in patients with MODY have inspired the three studies included in this thesis. In Study I, our aim was to systematically assess hepatobiliary and pancreatic manifestations in 14 Finnish patients affected by pathogenic gene variants of HNF1B. The patients underwent magnetic resonance imaging and magnetic resonance cholangiopancreatography. In conclusion, half of the patients (7 of 14) had an anomalous finding of the biliary system, and 6 of them had bile duct cysts (BDCs). Although untreated BDCs have generally been associated with a substantial risk of malignant transformation, it is not known whether the BDCs of genetic origin are similarly premalignant. In Study II, the aim of the international effort was to establish whether heterozygous protein-truncating variants (PTVs) in RFX6 are a novel genetic aetiology for MODY. Comparing between independent patient and control cohorts, we found that the RFX6 PTVs were enriched among the patients, whose clinical presentation was strongly suggestive of MODY, and among those routinely referred to genetic testing for MODY. In addition, the individuals heterozygous for the RFX6 PTVs demonstrated dysglycaemia and lower levels of serum glucose–dependent insulinotropic polypeptide (a.k.a. gastric inhibitory polypeptide, GIP). Study III was a multigenerational, longitudinal and cross-sectional family-based characterization study with a specific focus on the clinical and metabolic presentation of HNF1A p.(Gly292fs), the most common pathogenic variant responsible for HNF1A-MODY. The 12 families studied included 145 heterozygous carriers of the variant and their 139 first-degree relatives without the variant. Three of the 12 families were large multigenerational families who have continued their extensive follow-up ever since they were first identified and reported by our group in the 1990s. In conclusion, the carriers were leaner than the non-carriers, and they demonstrated enhanced lipolytic activity. Plasma glucose levels were higher in carriers than in non-carriers throughout the OGTT, and suggestive of insulin deficiency, serum insulin levels were lower in carriers than in noncarriers during the OGTT response. Although most carriers developed diabetes at a young age, one-third remained free of diabetes at 33 years. The polygenic risk score for type 2 diabetes also modified the age at onset of diabetes in patients with HNF1A-MODY. Studies I–III and numerous previous studies have indicated that patients with MODY are vastly heterogeneous. National efforts, including the studies conducted in Finland, might play a major role due to possible population differences. Personalized tailoring of medical therapy (e.g. a switch from insulin treatment to oral agents) is often possible regardless of the clinical presentation and origin of a patient, but further research is essential to explore individual predictors of the treatment response. Although the response has only rarely been assessed in engineered human cell line models, in vitro studies could provide novel mechanistic insights concerning MODY and other monogenic forms of diabetes. To summarize, systematic studies on individuals with a pathogenic gene variant can uncover profound heterogeneity associated with monogenic diabetes. These studies provide a valuable source for genetic laboratories to produce high-quality gene reports. Precision medicine in monogenic diabetes is progressively becoming a reality.
  • Brinck, Elina (Helsingin yliopisto, 2021)
    Suboptimal postoperative pain management increases complication rates and health care costs, and is a risk factor for chronic postoperative pain. Opioids have been the pharmacological cornerstone in postoperative pain management but adverse effects may limit their use. Multimodal analgesia combines different pain treatment modalities, aiming to reduce pain intensity, decrease opioid consumption and opioid-related adverse effects. Low-dose ketamine modulates molecular and cellular mechanisms behind pain and mitigates the development of opioid tolerance. The optimal dosing regimen of ketamine, and timing of dosing have not been established. The aim of the research was to evaluate the efficacy and tolerability of perioperative intravenous (IV) ketamine in adult patients when used for adjunct analgesia. The thesis constitutes of a Cochrane review (130 RCTs, 8341 patients) and two prospective, randomized, placebo-controlled and double- blinded clinical trials on adult patients undergoing spinal fusion surgery (198 patients and 100 patients, respectively). The RCTs compared two different intraperative IV infusions of S- ketamine with placebo and three different doses of S-ketamine added to an IV oxycodone patient-controlled analgesia (PCA). Perioperative IV ketamine reduced postoperative opioid consumption over 24 h and 48 h by 19%. With two different doses of intraoperative IV S-ketamine in lumbar fusion surgery, differences with placebo in 48 h oxycodone consumption were not significant. S-ketamine added to oxycodone IV-PCA in a ratio 0.75:1 reduced oxycodone need by 25% 24 h postoperatively. Postoperative pain intensity after perioperative IV ketamine administration was approximately 20% lower bot at rest and during movement. The degree of pain relief was greater following thoracic, major orthopedic, and major abdominal surgery. Both intraoperative S-ketamine infusions decreased pain scores significantly only at 4th postoperative hour after lumbar fusion surgery. A significant beneficial effect in mean change in pain intensity during the first 24 h after lumbar fusion surgery was achieved when the S-ketamine:oxycodone ratio in an IV-PCA was 0.75:1. All studies showed that perioperative IV ketamine and S-ketamine did not induce significant CNS adverse events. Approximately 5% of patients receiving perioperative IV ketamine experienced CNS adverse events, compared to 4% of controls. Perioperative IV ketamine reduced PONV from 27% with placebo to 23% with ketamine. Differences in the occurrence of PONV were nonsignificant in patients undergoing lumbar fusion surgery when S-ketamine was administered either as intraoperative infusions or as an adjunct with oxycodone IV-PCA. Conclusions: Ketamine and S-ketamine reduce postoperative pain intensity and opioid consumption especially in operations that are likely to induce more intense pain. Administration via IV-PCA in the postoperative period should be favoured over infusions after lumbar fusion surgery. Ketamine and S-ketamine cause negligible adverse events.
  • Brück, Oscar (Helsingin yliopisto, 2021)
    Histopathology is used in the diagnosis of hematologic malignancies to identify and immunophenotype leukemic cells. However, the surrounding immunologic microenvironment is not characterized in routine clinical practice. This thesis aims to profile immune populations of the chronic (CML) and acute myeloid leukemia (AML) bone marrow (BM) from a T cell perspective. Moreover, we evaluate the potential of machine learning for characterizing molecular genetics and prognosis using H&E stained BM samples of myelodysplastic syndrome (MDS) patients. In study I, we collected diagnostic BM biopsies of 56 chronic-phase CML (CP-CML) patients and 14 control subjects. These were profiled with multiplex immunohistochemistry (mIHC) and image analysis. Compared to control subjects, T cells expressed higher levels of immune checkpoint receptors PD-1, TIM-3 and CTLA-4. PD-1 expression was elevated in the BM compared to PB emphasizing the priority to study BM samples in hemato-oncological research. Moreover, PD-1 expression decreased in T cells during tyrosine kinase (TKI) therapy indicating restoration of the normal immune phenotype. In study II, we collected diagnostic BM biopsies of 52 B-cell acute lymphoblastic leukemia (B-ALL) and 69 AML patients. These were studied with mIHC and image analysis, and the results were combined with data from study I. We could accurately classify AML, B-ALL, CML, and control subjects based on their immunologic profiles. We identified two AML clusters, which contrasted by patient age, T-cell receptor clonality, and prognosis suggesting that patient age could be associated with a distinct clinical phenotype. In study III, we collected BM biopsies of 236 MDS, 87 myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), and 11 control subjects. We applied convolutional neural networks to examine the spectrum of morphological features. Moreover, we used multivariate regression models to predict the occurrence of genetic aberrations, patient demographics and prognosis. We found that morphological features predict reliably the occurrence of TET2 mutations, spliceosome mutations and chromosome 7 monosomy. The prediction accuracy correlated both with the variant allele frequency and the number of affected genes per pathway. Finally, we identified morphological patterns associated with individual gene and cytogenetic aberrations, patient age, gender, and survival. The thesis shows that leukemic patients form distinct subgroups based on their BM immune microenvironments and their detailed immunoprofiling can help to identify novel prognostic biomarkers. Morever, deep learning -based mining of the BM texture could help to understand the cellular composition and morphology related to molecular genetics profiles.
  • Whipp, Alyce (Helsingin yliopisto, 2021)
    Problems of aggressive behavior affect as many as one in every six children and are associated with negative outcomes for not only the individual themselves, but also their family, friends, and community. Aggressive behavior includes a variety of different behaviors (e.g., yelling, hitting, bullying) and has been notoriously difficult to treat. In assessing aggression, researchers and clinicians have repeatedly been recommended to utilize reports from multiple informants (e.g., parents, teachers, the child him/herself) in order to obtain the most complete picture of the problem. In studying aggressive behavior, early research was initially focused on males only and severe outcomes, but now investigates gender similarities and differences and a broad range of behaviors related to aggression. While much has been learned from research thus far, new biological mechanisms and detailed phenotypic information are still important to continue clarifying the heterogenous nature of aggression and to improve ideas for personalized treatment. Thus, this thesis aimed to contribute to those efforts. Study I and II showed that aggressive behavior (as rated by all raters) often co-occurred with other externalizing behaviors and low prosocial behavior, and also co-occurred with internalizing problems but not as often. Patterns were similar across cohorts and genders, however, parents indicated more co-occurrence with internalizing problems and less co-occurrence with other externalizing behaviors than teachers did. Study III showed teacher and self ratings were able to predict ASPD, both in separate models and when both ratings were in the same model. Additionally, the direct aggression subtype (e.g., hitting, yelling) was able to predict ASPD well, for both genders. Furthermore, when the co-occurring influence of hyperactivity was removed from the aggression ratings (using a residual aggression variable with hyperactivity co-occurrence removed), aggressive behavior was still able to predict ASPD. Study IV showed the ketone body 3-hydroxybutyrate to be negatively associated with aggressive behavior in initial analyses. In more detailed modeling, nearly all raters of aggression showed the same trend with 3-hydroxybutyrate, including in fully adjusted models. In a model including both teacher and self ratings, 3-hydroxybutyrate was significantly associated with both aggressive behavior ratings. A replication dataset of young adult Dutch twins (N=960) showed support for the association found in FinnTwin12, however, the issue of whether there are gender differences of the association of 3-hydroxybutyrate with aggressive behavior remains to be clarified by future research. These findings help to clarify the co-occurrence of aggressive behavior with other behaviors across raters and countries, to show how common the co-occurrence is and that it should be taken into consideration when studying aggressive behavior, including from (epi)genetic or biological perspectives. Additionally, aggressive behavior, in particular direct aggression, can inform future ASPD risk, and obtaining behavior data from teachers and the child are of high importance. Furthermore, the new association of 3-hydroxybutyrate with aggressive behavior suggests new biological pathways to investigate to improve our understanding of aggressive behavior, including potential treatments. This thesis provides refinements to the aggressive behavior phenotype, new avenues for aggression biology investigations, and ideas for where to improve or personalize treatment options.
  • Danni, Reeta (Helsingin yliopisto, 2021)
    Syftet med vår avhandling var att fördjupa kunskaperna om förebyggande av komplikationer efter kataraktoperationer hos patienter med diabetes. Makulaödem efter kataraktoperation (PCME; pseudophakic cystoid macular edema) är en av de vanligaste komplikationerna efter kataraktoperationer, och risken för denna komplikation har tidigare påvisats vara förhöjd hos diabetiker. Diabetespatienters synprognos efter kataraktoperation är sämre än för icke-diabetiker, och de behöver i genomsnitt mer frekvent postoperativ lokalbehandling och uppföljning. Det första delarbetet i vår avhandling belyser betydelsen av systemisk läkemedelsbehandling med avseende på prevalensen av PCME. Vi upptäckte att betablockerare, kalciumantagonister och statiner ledde till en minskning av retinal tjocklek (CRT; central retinal thickness) i kortisongruppen, trots en högre diabetesprevalens. I en multivariat analys visade sig systemisk användning av kalciumantagonister vara en självständig skyddande faktor mot PCME hos diabetespatienter. Beträffande betablockerare och statiner upptäckte vi en stark korrelation med diabetesprevalensen. Vi kunde dock inte bedöma orsakssambandets riktning, eftersom det är fråga om en retrospektiv studie. Med beaktande av den kliniska och biokemiska aspekten är det dock mera sannolikt att den skyddande effekt av diabetes mot PCME som framträtt i vår forskning i verkligheten förmedlas via systemiska läkemedel såsom beta¬blockerare och statiner. Våra fynd tyder på att förekomsten av PCME hos diabetiker kan minska om god sjukdomskontroll uppnåtts i fråga om patienternas systemiska sjukdomar. Det andra delarbetet i doktorsavhandlingen stöder de fynd som beskrivits i det första delarbetet, beträffande vikten av att patienternas systemiska sjukdomar är kliniskt stabila med tanke på förebyggande av komplikationer efter kataraktoperationer hos diabetespatienter. I avhandlingen jämfördes icke-diabetiker med patienter med diabetes typ I respektive typ II som inte hade utvecklat skador i retina (makulopati eller retinopati) orsakade av diabetes. Den genomsnittliga blodsockerbalansen hos diabetespatienterna var god, och den övriga systemiska läkemedelsbehandlingen var adekvat. I strid med den tidigare uppfattningen upptäckte vi att diabetes som självständig faktor i frånvaro av retinopatiförändringar inte ökade risken för uppkomst av PCME, om sjukdomskontrollen var god och sjukdomen kliniskt stabil. Även den postoperativa synskärpan var jämförbar mellan grupperna. Baserat på våra fynd drog vi slutsatsen att om den glykemiska kontrollen hos diabetespatienterna har optimerats kan den, i kombination med att andra kardiovaskulära riskfaktorer är välkontrollerade, skydda även mot komplikationer i retina efter kataraktoperation. Det tredje, prospektiva delarbetet behandlade betydelsen av preoperativ antiinflammatorisk läkemedelsbehandling i eftervården av diabetespatienter som genomgått kataraktoperation. Diabetespatienterna som kom in för kataraktoperation randomiserades till två grupper; i den första gruppen sattes läkemedelsbehandling in tre dygn före kataraktoperationen och i den andra gruppen efter operationen. Vi upptäckte att förekomsten av intraokulär inflammation var lägre vid 28 dagar efter operationen i patientgruppen som fått preoperativ läkemedelsbehandling, men skillnaden mellan grupperna hade jämnats ut vid 3 månader efter operationen. Cystiskt makulaödem efter kataraktoperation observerades inte i någondera gruppen. Preoperativ läkemedelsbehandling minskade alltså inte uppkomsten av PCME om den postoperativa läkemedelsbehandlingen var adekvat.
  • Laukkanen, Kirsi (Helsingin yliopisto, 2021)
    Cutaneous T-cell lymphomas (CTCLs) constitute an incurable, chronic, heterogeneous group of non-Hodgkin lymphomas, characterized by a malignant population of mature T-lymphocytes that infiltrate the skin. The incidence of CTCLs has increased worldwide. Symptoms vary from indolent skin patches to aggressive skin tumors. In addition to the skin, lymph nodes, blood, and other body organs are affected depending on the stage and subtype of the disease. Difficulties in differentiating early symptoms from other skin conditions and complex diagnostic criteria make CTCLs challenging to diagnose, often delaying the diagnosis for years. Despite intensive research, the pathogenesis of CTCLs remains mostly unknown. This study emphasizes the impact of the tumor microenvironment (TME) and the tumor cell-released extracellular vesicles (EVs) on the pathogenesis of CTCLs. Particularly, this study examines the role of the tryptophan pathway-associated enzymes indoleamine 2,3-deoxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). IDO induces immune tolerance in the TME by inflammation and T-cell activation. While TDO catabolizes the same metabolic pathway as IDO1, its role in tumors is poorly characterized. We showed that both IDO1 and TDO are expressed in CTCL tissues and cell lines. Interestingly, different CTCL subtypes show unique patterns of expression. In addition, elevated serum kynurenine/ tryptophan ratios observable in plasma samples of mycosis fungoides (the most common subtype of CTCL) patients correlated with advanced disease. Furthermore, four tryptophan catabolic route metabolites were upregulated, and two were downregulated. These observations could be exploited in clinical tests, and therapeutic potential for CTCLs may result from blocking IDO activity. EVs are small membranous vesicles released into the extracellular milieu by most cell types – also by cancer cells. The EVs released from cancer cells contain various proteins, lipids, amino acids, and metabolites and have proven to be an essential form of intercellular communication. Malignant cells can release EVs into TME and the circulation to reprogram target cells or prepare a pre-metastatic niche. Such transfer could occur at a very early stage in tumor progression because the small size of EVs allows them to cross barriers that cells cannot. Consequently, the molecular cargo of EVs reflects the cell of origin, which is also detectable in the circulation by the non-invasive liquid biopsy method. This study shows that human endogenous retrovirus, type W (HERV-W)-coded syncytin-1 in CTCL cells and CTCL cell-derived EVs is upregulated. Functionally, upregulated syncytin-1 can promote cell-to-cell fusion. Cell-to-cell fusion in cancers can induce genomic instability and aneuploidy and contribute to tumor heterogeneity, drug resistance, and metastasis. Although the molecular mechanisms of EVs are not fully characterized, syncytin-1 could be involved in binding EVs to target cells to facilitate the progressing fusion. Our functional study suggested that EV-harbored syncytin-1 promoted giant plasma membrane-surrounding fusion cells in the recipient T-cell leukemia cells. In addition, we studied alterations of EV-derived metabolite cargo in CTCL, prostate carcinoma, and colon carcinoma cell lines and compared these with the cargo of their healthy counterparts. In cancers, the expression of metabolites is commonly reregulated due to oncogenes or tumor suppressor mutations. The enhanced metabolism supports cancer cell proliferation and survival. Previously, numerous cancer-associated metabolites have been detected, but little is known of their role in cancer-derived EVs. This study shows that despite the differences among the studied cancer types, all cell line-derived EVs shared a common metabolomic feature: upregulation of proline and succinate. In addition, in CTCL- and prostate cancer-derived EVs, folate and creatinine were upregulated. This doctoral thesis explores the role of EVs and the kynurenine pathway in the pathogenesis of CTCLs. These observations could impact diagnosis and have therapeutic value for currently incurable, complex CTCLs. In addition, our results from three different cancer cell line-derived EVs show that metabolomic reprogramming of cancer cells influences the EV metabolome. In particular, this finding suggests that proline, succinate, folate, and creatinine could constitute a metabolomic fingerprint of cancer, which could serve as a peripherally detectable cancer marker. Thus, exploring the function of EVs in cancer progression will prove valuable in next-generation cancer diagnosis and treatment.
  • Salmela, Jatta (Helsingin yliopisto, 2021)
    Obesity is a major and growing public health problem in Finland and worldwide. The burden of obesity is unequally distributed between socioeconomic groups, however. In Finland, socioeconomic differences in obesity have persisted over decades. To reduce socioeconomic inequalities in obesity, understanding the trajectories behind these differences is crucial. This study aimed to examine the associations of childhood disadvantage (Sub-study I), changes in adult economic circumstances (Sub-study II), and intergenerational social mobility (Sub-study III) with body mass index (BMI) trajectories in a Finnish occupational cohort. I derived the data from the Helsinki Health Study cohort, which consists of four questionnaire surveys. In Phase 1 (2000–2002), the participants were 40–60-year-old employees of the City of Helsinki, Finland (n=8,960, response rate 67%). The follow-up surveys were conducted in 2007 (n=7,332), 2012 (n=6,809), and 2017 (n=6,832) (response rates 83%, 79%, and 82%, correspondingly). Childhood disadvantage comprised the retrospective measures of parental education and seven types of childhood adversity. I measured changes in adult economic circumstances by household income and experienced economic difficulties (Phases 1–4). Intergenerational social mobility was based on parental and participant’s own education. I calculated BMI from self-reported height and weight (Phases 1–4 and at the age of 25) and analysed the BMI trajectories using group-based trajectory modelling and mixed-effects linear regression. I examined changes in economic circumstances within the BMI trajectory groups using sequence analysis. Other statistical methods included multinomial logistic regression and chi-squared tests. For both genders, low parental education increased the odds of belonging to the trajectory groups of developing overweight and obesity. Experiencing peer bullying and accumulation of adversities in childhood among women, and parental alcohol problems among men, increased the odds of belonging to the trajectory groups of developing obesity. Economic disadvantage was constantly more common in the higher BMI trajectory groups (i.e., groups of overweight and obesity) during Phases 1–4. Differences in household income increased over time between the BMI trajectory groups, and changes in experienced economic difficulties were more common in the higher BMI trajectory groups. Intergenerationally stable low socioeconomic position, but also downward social mobility among men, were associated with the highest BMI trajectory levels. However, birth cohort impacted how upward and downward social mobility were associated with the BMI trajectories. The lowest BMI trajectory levels were found for the groups of stable high socioeconomic position among both genders and birth cohorts. The findings of this study indicate that socioeconomic disadvantage both in childhood and adulthood may predispose an individual to unhealthy weight gain over adulthood. Since socioeconomic disadvantage remains intergenerationally inherited in Finland, obesity prevention should be enhanced among people with unfavourable socioeconomic backgrounds. Additionally, targeted workplace interventions might reduce the existing socioeconomic gradient in obesity among employees, given that substantial increases in BMI were observed during working age. Nevertheless, to tackle socioeconomic inequalities in weight gain more broadly, several societal-level and multidisciplinary policies and actions are highly needed.