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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.

Background: Knowledge of pneumonia incidence and risk factors in adults is mainly based on clinical studies of selected patient data and registers with ageing populations. Prospective population-based investigations, such as birth cohort studies, are needed to understand pneumonia incidence and risk factors among young and working-age populations. Methods: Northern Finland Birth Cohort (NFBC) 1966 data (n=6750) were analysed for pneumonia incidence and risk factors. Incidence analysis was replicated using data from an independent NFBC 1986 cohort (n=9207). Pneumonia in relation to chronic conditions and lifestyle factors was analysed. Results: A peak with a maximum of 227 pneumonia episodes per 10 000 among men between the ages of 19 and 21 years was found in two independent cohorts. Pneumonia was associated with male sex (relative risk 1.72, 95% CI 1.45–2.04; p<0.001), low educational level (relative risk 2.30, 95% CI 1.72–3.09; p<0.001), smoking (relative risk 1.55, 95% CI 1.31–1.84; p<0.001), asthma (relative risk 2.19, 95% CI 1.73–2.75; p<0.001), cardiovascular diseases (relative risk 2.50, 95% CI 2.04–3.07; p=0.001), kidney diseases (relative risk 4.14, 95% CI 2.81–6.10; p<0.001), rheumatoid arthritis (relative risk 2.69, 95% CI 1.80–4.01; p<0.001), psoriasis (relative risk 2.91, 95% CI 1.92–4.41; p<0.001) and type II diabetes (relative risk 1.80, 95% CI 1.34–2.42; p<0.001). Men with excessive alcohol consumption at age 31 years were at risk of future pneumonia (relative risk 2.40, 95% CI 1.58–3.64; p<0.001). Conclusions: Birth cohort data can reveal novel high-risk subpopulations, such as young males. Our study provides understanding of pneumonia incidence and risk factors among young and working age populations.

Objectives: Ocular candidiasis (OC) can complicate Candida bloodstream infection (BSI). Antifungal treatment improves the prognosis of patients with BSI, but the effects of choice and timing of first-line medication on OC risk are incompletely understood. We explored the early treatments, risk factors and ocular presentations in Candida BSI. Methods and analysis: All patients (n=304) with Candida BSI during 2008–2017 at Oulu University Hospital were included. Those patients in whom clinical condition was appropriate for ocular examination (OE), including biomicroscopy (n=103), were carefully analysed by ophthalmologists. Criteria for patient selection were considered. Candida and yeast species, antifungal medications, echocardiography, underlying diseases and clinical properties of the patients with Candida BSI were analysed. Results: Clinical condition in 103 patients had been considered appropriate for OE. OC was diagnosed in 33 of the 103 patients. Candida albicans was the most common finding (88%) in OC. Patients in intensive care, alcohol-related conditions or poor prognosis were less frequently examined. Persistent candidemia increased the risk of OC. Chorioretinitis and endophthalmitis were diagnosed in 94% and 48% of the patients with OC, respectively. Any early antifungal treatment decreased the endophthalmitis risk. Echinocandin lowered the OC risk in those with central venous catheters (CVCs) or abdominal malignancy. Conclusion: Critical condition of patients with Candida BSI affects the selection and results of OE. OC was associated with C. albicans BSI especially among those with persistent candidemia, CVC or abdominal malignancy. Any early antifungal treatment reduced endophthalmitis risk. Early echinocandin treatment may reduce the risk of OC in selected patients.

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients’ immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in

Background: Cryptococcosis is one of the major causes of mortality among HIV patients worldwide. Though most often associated with late stage HIV infection/AIDS, a significant number of cases occur in other immunocompromised patients such as solid organ transplant recipients and patients with hematological malignancies. Immunocompromised patients are a heterogeneous group and their number increases constantly. Since little is known about the incidence and the clinical features of cryptococcosis in Northern Europe, our aim was to investigate the clinical characteristics of cryptococcosis patients in Finland. Methods: We retrospectively reviewed the laboratory confirmed cryptococcosis cases in Finland during 2004–2018. Only those who were treated for cryptococcosis were included in the study. Initial laboratory findings and medical records were also collected. Results: A total of 22 patients with cryptococcosis were included in our study. The annual incidence of cryptococcosis was 0.03 cases per 100,000 population. Ten patients were HIV-positive and 12 out of 22 were HIV-negative. Hematological malignancy was the most common underlying condition among HIV-negative patients. Conclusions: To our knowledge, this is the first study of the clinical presentation and incidence of cryptococcosis in Finland. We demonstrate that invasive cryptococcal infection occurs not only in HIV/AIDS patients or otherwise immunocompromised patients but also in immunocompetent individuals. Even though cryptococcosis is extremely rare in Finland, its recognition is important since the prognosis depends on rapid diagnostics and early antifungal therapy.

Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.

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.

Item does not contain fulltext, BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

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

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.

There are multiple factors simultaneously affecting speech perception in elderly people. These factors include hearing acuity, aging of the auditory system, and changes in both perception and cognitive processes, all of which can interfere with speech comprehension, especially in cognitively demanding situations. The aim of this study is to clarify which factors influence the use of an automatic phone service system designed for elderly (N = 36) people. More specifically, the aim is to investigate whether it is the factors connected to the system itself or the factors connected to the elderly users and their actions with the system that are the most crucial for using the system successfully. Both quantitative and qualitative methods are used in the study. There were four people who performed as speakers in the system. Analysis of the prosodic features of their speech was performed using acoustic analysis software. The variables connected to the elderly participants (n = 30) were investigated using interviews, pure-tone and speech audiometric tests, the Mini-Mental State Examination test (MMSE), and the Token Test for speech comprehension. Statistical analyses were used to explore whether there was a statistical connection between the acoustic measurements or the variables connected to participants themselves and their performance in usability test situation. In addition, the elderly participants’ actions in the test situation were observed using a material-based, qualitative video-analysis. The individuals who performed as speakers in the system were observed to use features of elderspeak in their speech. However, these speaker characteristics had little effect on the participants’ performance in the tasks. It was the voice-menu that contained the most semantically complex text structure that proved to be the most difficult for participants. Both low scores in the Token test and poor word recognition were connected to poor performance in the tasks. It was f, Tiivistelmä Ikääntyvien ihmisten puheen vastaanotossa vaikuttavat samanaikaisesti monet tekijät: kuulokyky, auditiivisen järjestelmän ikääntymismuutokset sekä havaintotoimintojen ja kognitiivisten toimintojen muutokset. Nämä voivat vaikeuttaa puheen ymmärtämistä erityisesti kognitiivisesti vaativassa tilanteessa. Tämän tutkimuksen tavoitteena on selvittää ikääntyneille osallistujille (N = 36) suunnitellun automaattisen puhelinpalvelujärjestelmän käyttöön liittyviä tekijöitä. Tavoitteena on selvittää se, missä määrin toisaalta kokeiltuun järjestelmään liittyvät tekijät ja toisaalta käyttäjien ominaisuudet sekä heidän toimintansa tutkimustilanteessa olivat yhteydessä järjestelmän menestykselliseen käyttöön. Tutkimuksessa käytetään kvantitatiivisia ja kvalitatiivisia menetelmiä. Järjestelmässä kokeiltiin neljän eri puhujan äänillä nauhoitettuja toimintaohjeita. Heidän puheensa prosodisia piirteitä analysoitiin äänen ja puheen analyysiohjelmilla. Ikääntyneisiin osallistujiin (n = 30) liittyviä muuttujia tutkittiin haastattelulla, kuulon tutkimuksilla (äänesaudiometria ja puheaudiometria), kognitiivisella seulontatestillä (Mini-mental state examination = MMSE) ja puheen ymmärtämistä mittaavalla Token-testillä. Mittaustulosten ja muuttujien yhteyttä tehtävistä suoriutumiseen tarkasteltiin tilastollisesti. Osallistujien toimintaa havainnoitiin järjestelmän käyttötilanteessa aineistolähtöisellä laadullisella videoanalyysillä. Järjestelmän puhujilla havaittiin ikääntyneille suunnatun puheen piirteitä. Tehtävistä suoriutuminen oli kuitenkin hyvin samanlaista puhujasta riippumatta. Semanttisesti monimutkaisin tekstivalikko oli osallistujille vaikein äänite. Matala Token-testin pistemäärä ja heikko puheen tunnistuskyky liittyivät heikkoon tehtävistä suoriutumiseen. Laadullisen analyysin perusteella puheen ymmärtämisen ohella keskeisiä kognitiivisia prosesseja tehtävissä menestymisen kannalta olivat seuraavat: ohjeiden muistaminen, huomion suuntaaminen, jakaminen ja ylläpito. He