The modern landscape of managing effects for the working programmer

The management of side effects is a crucial aspect of modern programming, especially in concurrent and distributed systems. This thesis analyses different approaches for managing side effects in programming languages, specifically focusing on unrestricted side effects, monads, and algebraic effects and handlers. Unrestricted side effects, used in mainstream imperative programming languages, can make programs difficult to reason about. Monads offer a solution to this problem by describing side effects in a composable and referentially transparent way but many find them cumbersome to use. Algebraic effects and handlers can address some of the shortcomings of monads by providing a way to model effects in more modular and flexible way. The thesis discusses the advantages and disadvantages of each of these approaches and compares them based on factors such as expressiveness, safety, and constraints they place on how programs must be implemented. The thesis focuses on ZIO, a Scala library for concurrent and asynchronous programming, which revolves around a ZIO monad with three type parameters. With those three parameters ZIO can encode the majority of practically useful effects in a single monad. ZIO takes inspiration from algebraic effects, combining them with monadic effects. The library provides a range of features, such as declarative concurrency, error handling, and resource management. The thesis presents examples of using ZIO to manage side effects in practical scenarios, highlighting its strengths over other approaches. The applicability of ZIO is evaluated by implementing a server side application using ZIO, and analyzing observations from the development process

Elevated serum chemokine CCL22 levels in first-episode psychosis: associations with symptoms, peripheral immune state and in vivo brain glial cell function

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p < 0.0001; Cohen's d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (rho = 0.20) and disorganization (rho = 0.23), and with worse verbal performance (rho = -0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [C-11]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (V-T) of [C-11]PBR28 was lower in patients compared to controls (p = 0.026; Cohen's d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells

Systemic metabolic signatures of oral diseases

Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 (n = 6,229) and Parogene (n = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants (n = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B-containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders.Peer reviewe

Shotgun metagenomic analysis of the oral microbiome in gingivitis: a nested case-control study

Background: Gingivitis, i.e. inflammation of the gums, is often induced by dental plaque. However, its exact link to the oral microbiota remains unclear. Methods: In a case-control study involving 120 participants, comprising 60 cases and 60 controls (mean age (SD) 36.6 (7.6) years; 50% males), nested within a prospective multicentre cohort study, we examined the oral microbiome composition of gingivitis patients and their controls using shotgun metagenomic sequencing of saliva samples. Participants underwent clinical and radiographic oral health examinations, including bleeding on probing (BOP), at six tooth sites. BOP ≥33% was considered ‘generalized gingivitis/initial periodontitis’(GG/IP), and BOP<33% as ‘healthy and localized gingivitis’(H/LG). Results: GG/IP exhibited an increase in the abundance of Actinomyces, Porphyromonas, Aggregatibacter, Corynebacterium, Olsenella, and Treponema, whereas H/LG exhibited an increased abundance of Candidatus Nanosynbacter. Nineteen bacterial species and four microbial functional profiles, including L-methionine, glycogen, and inosine-5’-phosphate biosynthesis, were associated with GG/IP. Constructing models with multiple markers resulted in a strong predictive value for GG/IP, with an area under the curve (ROC) of 0.907 (95%CI: 0.848-0.966). Conclusion: We observed distinct differences in the oral microbiome between the GG/IP and H/LG groups, indicating similar yet unique microbial profiles and emphasizing their potential role in progression of periodontal diseases.Peer reviewe

Subgingival microbiome at different levels of cognition

Oral health and declining cognition may have a bi-directional association. We characterized the subgingival microbiota composition of subjects from normal cognition to severe cognitive decline in two cohorts. Memory and Periodontitis (MINOPAR) include 202 home-living participants (50-80 years) in Sweden. Finnish Oral Health Studies in Older Adults (FINORAL) include 174 participants (>= 65 years) living in long-term care in Finland. We performed oral examination and assessed the cognitive level with Mini Mental State Examination (MMSE). We sequenced the 16S-rRNA gene (V3-V4 regions) to analyse the subgingival bacterial compositions. The microbial diversities only tended to differ between the MMSE categories, and the strongest determinants were increased probing pocket depth (PPD) and presence of caries. However, abundances of 101 taxa were associated with the MMSE score. After adjusting for age, sex, medications, PPD, and caries, only eight taxa retained the significance in the meta-analyses of the two cohorts. Especially Lachnospiraceae [XIV] at the family, genus, and species level increased with decreasing MMSE. Cognitive decline is associated with obvious changes in the composition of the oral microbiota. Impaired cognition is accompanied with poor oral health status and the appearance of major taxa of the gut microbiota in the oral cavity. Good oral health-care practices require special deliberations among older adults.Peer reviewe

Elevated serum chemokine CCL22 levels in first-episode psychosis : associations with symptoms, peripheral immune state and in vivo brain glial cell function

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p <0.0001; Cohen's d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (rho = 0.20) and disorganization (rho = 0.23), and with worse verbal performance (rho = -0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [C-11]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (V-T) of [C-11]PBR28 was lower in patients compared to controls (p = 0.026; Cohen's d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells.Peer reviewe