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Background: We investigated health consequences and genetic properties associated with serum IgG concentration in a young and working age general population. Methods: Northern Finland Birth Cohort 1966 (NFBC1966, n = 12,231) health data have been collected from birth to 52 years of age. Relationships between life-long health events, medications, chronic conditions, lifestyle, and serum IgG concentration measured at age 46 years (n = 5430) were analysed. Regulatory mechanisms of serum IgG concentration were considered. Findings: Smoking and genetic variation (FCGR2B and TNFRSF13B) were the most important determinants of serum IgG concentration. Laboratory findings suggestive of common variable immunodeficiency (CVID) were 10-fold higher compared to previous reports (73.7 per 100,000 vs 0.6–6.9 per 100,000). Low IgG was associated with antibiotic use (relative risk 1.285, 95% CI 1.001–1.648; p = 0.049) and sinus surgery (relative risk 2.257, 95% CI 1.163–4.379; p = 0.016). High serum IgG was associated with at least one pneumonia episode (relative risk 1.737, 95% CI 1.032–2.922; p = 0.038) and with total number of pneumonia episodes (relative risk 2.167, 95% CI 1.443–3.254; p < 0.001). Interpretation: CVID-like laboratory findings are surprisingly common in our unselected study population. Any deviation of serum IgG from normal values can be harmful; both low and high serum IgG may indicate immunological insufficiency. Critical evaluation of clinical presentation must accompany immunological laboratory parameters. Funding: Oulu University Hospital VTR, CSL Behring, Foundation for Pediatric Research.

Introduction: The European Association of Urology committee in 2020 suggested a new classification, intraoperative adverse incident classification (EAUiaiC), to grade intraoperative adverse events (IAE) in urology. Aims: We applied and validated EAUiaiC, for kidney tumor surgery. Patients and methods: A retrospective multicenter study was conducted based on chart review. The study group comprised 749 radical nephrectomies (RN) and 531 partial nephrectomies (PN) performed in 12 hospitals in Finland during 2016–2017. All IAEs were centrally graded for EAUiaiC. The classification was adapted to kidney tumor surgery by the inclusion of global bleeding as a transfusion of ≥3 units of blood (Grade 2) or as ≥5 units (Grade 3), and also by the exclusion of preemptive conversions. Results: A total of 110 IAEs were recorded in 13.8% of patients undergoing RN, and 40 IAEs in 6.4% of patients with PN. Overall, bleeding injuries in major vessels, unspecified origin and parenchymal organs accounted for 29.3, 24.0, and 16.0% of all IEAs, respectively. Bowel (n = 10) and ureter (n = 3) injuries were rare. There was no intraoperative mortality. IAEs were associated with increased tumor size, tumor extent, age, comorbidity scores, surgical approach and indication, postoperative Clavien–Dindo (CD) complications and longer stay in hospital. 48% of conversions were reactive with more CD-complications after reactive than preemptive conversion (43 vs. 25%). Conclusions: The associations between IAEs and preoperative variables and postoperative outcome indicate good construct validity for EAUiaiC. Bleeding is the most important IAE in kidney tumor surgery and the inclusion of transfusions could provide increased objectivity.

Summary Our existence on Earth is founded on a vital nature, which supports human physical and mental health. However, nature is often depicted only through biodiversity, whereas geodiversity—the diversity of non-living nature—has so far been neglected. Geodiversity consists of assemblages, structures, and systems of geological, geomorphological, soil, and hydrological components that fundamentally underlie biodiversity. Biodiversity can support overall human health only with the foundation of geodiversity. Landscape characteristics, such as varying topography or bodies of water, promote aesthetic and sensory experiences and are also a product of geodiversity. In this Personal View, we introduce the concept of geodiversity as a driver for planetary health, describe its functions and services, and outline the intricate relationships between geodiversity, biodiversity, and human health. We also propose an agenda for acknowledging the importance of geodiversity in health-related research and decision making. Geodiversity is an emerging topic with untapped potential for ensuring ecosystem functionality and good living conditions for people in a time of changing environments.

Tiivistelmä Musiikin opetuksessa soivat kaikissa oppilaitoksissa opiskelijoiden omat sävellykset ja improvisaatiot. Opetussuunnitelmien perusteet nostivat vuosina 2014–2018 säveltämisen, improvisoinnin ja luovan musiikin tekemisen kaikkien musiikin oppijoiden oikeudeksi kaikissa eri koulumuodoissa. Muutos haastoi kaikki opettajat: miten opettaa jotakin sellaista, mitä ei ehkä itse tunne osaavansa? Muutos haastoi paitsi opettajat uudistamaan opetustaan, myös musiikkialan opettajien koulutuksen. Olemme eri yliopistojen ja korkeakoulujen opettajankouluttajina koonneet Säveltämisen pedagogiikka eli Säpe-täydennyskoulutuksista suositukset säveltämisen ja luovan musiikin tuottamisen opettamiseen. Suositukset on kohdistettu erityisesti varhaiskasvattajien, luokan- ja musiikinopettajien sekä instrumenttipedagogien koulutukseen. Musiikkioppilaitoksissa voi olla myös säveltäminen omana oppiaineenaan. Sen opettaminen on rinnastettavissa muuhun erityistä ammatillista pätevyyttä edellyttävään opetukseen, esimerkiksi musiikkioppilaitosten tarjoamaan instrumenttiopetukseen. Suositukset on teemoiteltu oppijan oikeuksiksi, ja ne kattavat erilaiset musiikin opettamisen muodot ja musiikin genret. Oppijan oikeuksien toteutumista turvaa nämä suositukset huomioiva pedagoginen koulutus, jota musiikkikasvattajia ja musiikkipedagogeja kouluttavat korkeakoulut ja yliopistot tarjoavat. Julkaisu on tuotettu osana Säveltämisesen pedagogiikka eli Säpe-täydennyskoulutushanketta, jota rahoitti Opetushallitus. Koulutuksessa kehitettiin käytännön työkaluja säveltämisen ohjaamiseen digivälineillä. Hanketta toteutti Metropolia Ammattikorkeakoulu yhteistyössä Taideyliopiston Sibelius-Akatemian ja Helsingin yliopiston opettajankoulutusyksikön kanssa vuosina 2016–2021.

Background: The Beck Depression Inventory (BDI) and BDI-II (revised version) are some of the most widely used and comparable self-report scales for assessing the presence and severity of depressive symptoms in many countries. However, although the relative mean score of each symptom in different countries may vary, the cultural differences of BDI-II symptoms for each item have not been previously studied. Aims: To examine the overall picture of the magnitude of the symptoms in the Finnish population, and compare the relative mean score of each symptom between all published population-based samples from different countries fulfilling the search criteria. Method: We conducted a search for population-based studies reporting BDI-II item, using Scopus, PsycINFO and PubMed, and five population-based samples were identified. Relative average scores for each item of the scale were calculated for the Finnish population and five populations from other countries. Meta-regression methods were used to test the differences in the relative score of each symptom between each country separately, and results were then visually compared with spider charts. Results: We found significant differences in several BDI-II item scores between countries: lower indecisiveness, higher changes in sleep pattern and higher irritability in Finland; higher loss of pleasure in Norway; higher loss of interest in the Dominic Republic; higher self-criticalness and feelings of punishment in Mexico; and higher sadness in Japan. Conclusions: Based on the study fundings and including all currently published population-based samples with BDI-II scores, cultural differences in depressive symptoms should be considered when interpreting BDI-II item scores.

Tiivistelmä Hemofagosyyttinen lymfohistiosytoosi (HLH) on henkeä uhkaava tulehdusreaktio, jonka syntymekanismina on T-imusolujen ja makrofagien keskinäinen sytokiinivälitteinen aktivaatio. Taudin tunnusmerkkejä ovat epäselvä ja pitkittynyt kuume, maksan ja pernan suurentuminen sekä verenkuvan solupuutokset. Perinnöllinen HLH (FHL) on ryhmä geneettisiä sairauksia, joissa tauti kehittyy ensimmäisten elinkuukausien aikana muutoin terveelle lapselle. FHL johtuu sytotoksisten imusolujen kyvyttömyydestä tuhota tulehdusvasteen herättäneet antigeeniä esittelevät solut, mistä seuraa sytokiinivälitteinen itseään voimistava tulehdusreaktio. FHL:n hoito perustuu T-solujen tukahduttamiseen ja allogeeniseen kantasolusiirtoon. FHL on harvinainen mutta merkittävä erotusdiagnostinen vaihtoehto, kun kuumeisen imeväisen verenkuvassa havaitaan solupuutoksia. Taudin nopea tunnistaminen on tärkeää, jotta tehokas hoito päästään aloittamaan ennen monielinvauriota.

Aim: To evaluate the regional variation in restorative treatment need among Finnish young people based on the socioeconomic factors. Materials and methods: This cross-sectional study was conducted in 20 garrisons of the Finnish Defence Forces in January and July 2011. The study population comprised 13,819 Finnish conscripts born in the beginning of 1990s, including females. A computer-based survey was done together with clinical oral examination to gather background information, e.g., educational status. Furthermore, average annual income of the conscript’s residence municipality was achieved from the Statistics of Finland. The zip code of the place of residence of each conscript was later extracted from the Mildoc® system. Georeferenced place of residence and income status were merged as information on provinces’ level in a dataset. The association between the outcome variable and explanatory variables was determined by using the generalized linear mixed model, and geomaps were constructed. Results: Mean D value was 1.41 ranging from 0.89 (Kymenlaakso) to 2.33 (Kainuu). Higher education and high-income level were protective factors for restorative treatment need. Restorative treatment need was also low in those areas with high (OR: 0.70, 95% CI: 0.56–0.87) and medium (OR: 0.79, 95% CI: 0.70–0.89) yearly income compared to low yearly income. The high odds for the need of restorative treatment were discovered in Northern Ostrobothnia (OR: 2.26, 95% CI: 1.53–3.33) followed by Central Ostrobothnia (OR: 2.08, 95% CI: 1.17–3.70), Uusimaa (OR: 1.55, 95% CI: 1.16–2.08), and Central Finland (OR: 1.54, 95% CI: 1.10–2.16) compared to Varsinais-Suomi. Conclusion: In conclusion, there is a significant regional variation in restorative treatment need among Finnish young people in their twenties based on the socioeconomic factors.

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

Background: Tumor necrosis factor α–induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation. Methods: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings. Results: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis. Conclusions: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.

Background: Rare tonsillar granulomas may be caused for example by infections, malignancies or sarcoidosis. Granulomas also occur in inborn errors of immunity (IEI) such as common variable immunodeficiency (CVID) with B cell maturation defects and hypogammaglobulinemia. CVID shares various features with sarcoidosis and drug-induced secondary hypogammaglobulinemia; careful consideration of differential diagnosis between these conditions is warranted. Case presentation: A 29-year-old female with epilepsy developed dysphagia, dyspnea and impaired exercise tolerance. Obstruction caused by swollen lingual tonsil and edema in the epiglottis and arytenoid mucosa were found. Lingual tonsil and epiglottis biopsies displayed non-necrotizing granulomas. There was no evidence of viral, bacterial, mycobacterial or fungal infections. Chest X-ray, computerized tomography of chest and ultrasound of neck and abdomen remained unremarkable. Positron emission tomography/computed tomography (PET/CT) showed laryngeal enhancement. Empiric antimicrobials combined with prednisolone were insufficient to control her disease. In immunological evaluation, the patient had normal counts of B and T cells. Proportions of CD27+ memory B cells (30.3%) and IgD−IgM−CD27+ switched memory B cells (7.2%; normal range 6.5–29.2%) were normal. Percentage of activated CD21low B cells was high (6.6%; normal range 0.6–3.5%). IgG (3.5 g/L; normal range 6.77–15.0 g/l) and all IgG subclass concentrations were low. Anti-polysaccharide responses were impaired, with 3/10 serotypes reaching a level of 0.35 µg/ml after immunization with Pneumovax®. The findings were consistent with hypogammaglobulinemia resembling CVID, possibly secondary to antiepileptic medication. Her dyspnea and dysphagia responded favorably to subcutaneous IgG and rituximab. Conclusions: Tonsillar granulomas can be the presenting and only clinical feature of B cell deficiency, highlighting the diversity of symptoms and findings in primary

Mutations in several proteins functioning as endolysosomal components cause monogenic autoimmune diseases, of which pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and defective recycling of immune receptors. We report here a heterozygous TOM1 p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency. Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris. Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells. In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells. The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology. In sum, we report here an identification of a novel gene, TOM1, associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype.

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.

Objectives: TNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating inflammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and, recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease ‘haploinsufficiency of A20’ (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related inflammasome pathway. Methods: NF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein–protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analysed using mass spectrometry. NF-κB -dependent transcription, cytokine secretion and inflammasome activation were compared in immune cells of the HA20 patients and control subjects. Results: The protein–protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-κB activation, DNA repair responses and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signalling, which led to increased NF-κB -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients’ immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1β and interleukin-18. Conclusions: The current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.

Objectives: The aim of this study was to investigate the oral health of Nepalese schoolchildren relative to their sociodemographic characteristics. Methods: This school‐based, cross‐sectional study was conducted among 5–6‐, 12‐ and 15‐year‐old Nepalese children in 18 randomly selected districts of the 75 in Nepal. Clinical parameters were recorded according to the World Health Organization (WHO) guidelines. Results were presented as mean (SD) and proportions; the chi‐square test, t‐test and one way‐ANOVA were also performed. The risk of dental caries in association with the place of residence was presented according to the outcome of a binary logistic regression analysis. Results: The mean d‐value for the 5–6‐year‐old children was 5.0 (4.22), which was higher than the mean D‐values for the 12‐ and 15‐year‐old subjects, of 1.3 (1.77) and 1.9 (2.28), respectively. The youngest children, as well as children from the Kathmandu Valley, were likely to have more untreated caries lesions than children in the other age groups. The mean number of teeth with severe consequences of dental caries (pulpitis/ulceration/fistula/abscess or pufa/PUFA) was 1.3 (1.91) for the 5–6‐year‐old children, 0.1 (0.35) for the 12‐year‐old children and 0.3 (0.75) for the 15‐year‐old children. All age groups had gingival bleeding on probing in more than 15% of teeth. Children from rural locations had significantly more gingival bleeding than urban children. The same was true for 15‐year‐old girls compared with boys of the same age. Conclusions: Among Nepalese children, oral diseases are common, and geographical variation is prevalent. The health policy should address the alarming oral health situation and need for urgent treatment and population‐based preventive programmes that is evident in Nepal.

Work life relevance is emphasized these days in higher education. In addition to domain-specific knowledge and skills, students should learn general work life competencies, such as team work, networking, project work and digital skills. At the University of Helsinki, agricultural science students’ work life skills are promoted in a project course. The 5 ETCS course has been held for B.Sc. and M.Sc. students in 2016 and 2017. The course in 2016 had eight students and three supervisors in two project teams; the course in 2017 had 15 students in four teams, and six supervisors (university teachers). Each team had its own external client from businesses and national government departments. The course implementation was examined from a design-based research approach. The aim of the study was to evaluate the summative evaluations made by all groups participating in the course, receive research-based knowledge about improving the course design further, and to try out instruments and methods that can be used in educational practice to assess participant satisfaction and competence development during courses about work life. An online questionnaire was used to examine the evaluations of the supervisors and students about the success of the course and the competencies gained by the students (Collaborative Knowledge Practices Questionnaire, CKP). Interviews were used to examine the views of the clients concerning the realization and development of the course. The data were analysed using quantitative and qualitative methods. The project process was mostly graded the same by the evaluators (students, supervisors and clients), but most student groups gave the report a higher grade than the other evaluators did. Students’ evaluations were that they had acquired knowledge work competencies well, particularly the development of shared objects, the integration of individual and collaborative working and persistent development of knowledge objects. The students particularly