Hevosten "grass sickness" - tauti Suomessa : kirjallisuuskatsaus ja potilastapauksia

Tämän lisensiaatin työn tarkoituksena oli perehtyä kirjallisuuskatsauksella "grass sickness" – taudin esiintyvyyteen, etiologiaan, patogeneesiin, kliinisiin löydöksiin, diagnostiikkaan, hoitoon, ennusteeseen ja ennaltaehkäisyyn sekä tehdä tutkielmana yhteenveto Suomessa esiintyneistä tapauksista. "Grass sickness" on merkittävä hevosten kuolleisuutta aiheuttava tauti. Tautia on tavattu ensimmäisen kerran yli 100 vuotta sitten, vuonna 1909 Skotlannin itäosissa. Tällä hetkellä tautia tavataan Iso-Britannian lisäksi myös muualla Euroopassa sekä Etelä- ja Pohjois- Amerikassa. Laajasta levinneisyydestä huolimatta taudin esiintyvyys on suurinta Iso-Britanniassa ja sen läheisyydessä. "Grass sickness" – taudin aiheuttajaa ei edelleenkään tiedetä. Viimeaikaisten tutkimustulosten perusteella taudin oletetaan olevan C. botulinum tyyppi C:n aiheuttama toksikoinfektiivinen tauti. Itse taudin syntymisen epäillään olevan monen eri tekijän summa, jossa suoliston mikrobiflooran toiminnan häiriintyminen olisi tärkeässä roolissa. "Grass sickness" – taudille on ominaista neuronien rappeumamuutokset erityisesti suoliston hermokimpuissa sekä autonomisen hermoston ganglioissa. Tauti voidaan jakaa keston ja oireiden vakavuuden perusteella kolmeen eri muotoon: akuutti, subakuutti ja krooninen muoto. Akuutti ja subakuutti muoto johtavat hevosen kuolemaan tai lopettamiseen. Molempien muotojen oireet ovat melko epäspesifisiä ja ne voidaan helposti yhdistää ähkyyn. Tauti luokitellaan krooniseksi oireiden kestettyä yli 7 päivää. Krooniselle muodolle on ominaista hevosen huomattava laihtuminen sekä "vinttikoiramainen" ulkonäkö, eriasteiset nielemisvaikeudet, huonontunut tai puuttuva ruokahalu ja ähkyoireet. Krooniseen muotoon sairastuneista noin 49% selviää. Tautiin ei ole olemassa parantavaa hoitoa tai lääkettä, vaan hoito perustuu oireiden mukaiseen tukihoitoon. Tutkimuksen aineistona käytettiin Yliopistollisessa hevossairaalassa hoidettuja "grass sickness" – tautiin sairastuneita hevosia. Suomessa on todettu vuosien 1999-2012 aikana 8 tautitapausta. Tapauksia on esiintynyt kahdella eteläsuomalaisella tilalla. Sairastuneista suurin osa on ollut lämminverisiä ja sukupuoleltaan tammoja. Potilaiden ikä on vaihdellut välillä 1-13 vuotta. Tapauksia on esiintynyt eniten heinäkuussa. Potilaista 5 sairastui taudin krooniseen muotoon ja 3 subakuuttiin muotoon. Tyypillisimpiä oireita olivat lihasvärinä, kohonnut sydämen lyöntitiheys ja hiljaiset suolistoäänet. Kaikki tautiin sairastuneet jouduttiin lopettamaan. Diagnoosit varmistettiin post mortem tehdyllä hermosolmukkeiden histopatologisella tutkimuksella. Johtopäätelmänä "grass sickness" – tautia on myös Suomessa. Tautitapauksia esiintyy, mutta ei ole selvää, kuinka usein ja säännöllisesti tautia toistaiseksi maassamme ilmenee. "Grass sickness" – tautiin sairastunut hevonen voidaan kliinisten oireiden perusteella helposti sekoittaa ähkyyn. Tauti tulisi erityisesti pitää mielessä ähkyhevosten erotusdiagnostiikassa. Taudin esiintyvyydestä pidetään rekisteriä Iso-Britanniassa Animal Health Trustissa, jonne kaikki tautitapaukset olisi hyvä kirjata

Equine grass sickness in Finland II: Cases

Peer reviewe

Validation of a tail-mounted triaxial accelerometer for measuring foals' lying and motor behavior

Foals' locomotory and lying-down behavior can be an indicator of their health and development. However, measurement tools have not been well described with previously reported attachment sites used on limbs of adult horses unsafe for longer-term data collection in foals. In this study, a tail-mounted three-dimensional accelerometer was validated for monitoring foals lying, standing, and walking behavior. Eleven foals were recruited: four hospitalized and seven at private breeding stables. Accelerometers were attached to the dorsal aspect of the base of each foal's tail and their behavior was video recorded. Hospitalized foals had continuous video monitoring inside their stalls, and the breeding stable's foals were monitored outside at pasture for 1-5 periods (mean 42 minutes per period), depending how long they were at the facility. Acceleration was measured using 100 Hz frequency and mean, maximum, and minimum acceleration were recorded in 5 second epochs for x-, y-, and z-axes. Lying, standing, and walking behavior was monitored from videos of all foals, and the start and end time of each behavior was compared with the corresponding data from the accelerometer. Naive Bayes classifier was developed by using dynamic body acceleration and craniocaudal movement of the tail (tilt along z-axis), to predict a foal's lying behavior. The model was validated; the classifier achieved high accuracy in precision and in classifying foals' lying behavior (specificity, 0.92; sensitivity, 0.89; precision, 0.98; accuracy, 0.92). The overall accuracy for classifying walking and standing was also good, but the precision was poor (0.46 and 0.24, respectively). When standing and walking behavior was combined to a single "standing or walking" class, the precision improved (specificity, 0.62; sensitivity, 0.92; precision, 0.89; accuracy, 0.92). In conclusion, tail-mounted three-dimensional accelerometer can be used for monitoring foals' lying behavior. In addition, information regarding standing and walking can be gained with this method. (C) 2020 The Authors. Published by Elsevier Inc.Peer reviewe

Integration of questionnaire-based risk factors improves polygenic risk scores for human coronary heart disease and type 2 diabetes

Max Tamlander et al. combine polygenic risk scores and clinical assessments to improve prediction of coronary artery disease and type 2 diabetes in European cohorts. Taken together, their results provide a useful method for preliminary cardiometabolic risk assessment in patients. Large-scale biobank initiatives and commercial repositories store genomic data collected from millions of individuals, and tools to leverage the rapidly growing pool of health and genomic data in disease prevention are needed. Here, we describe the derivation and validation of genomics-enhanced risk tools for two common cardiometabolic diseases, coronary heart disease and type 2 diabetes. Data used for our analyses include the FinnGen study (N = 309,154) and the UK Biobank project (N = 343,672). The risk tools integrate contemporary genome-wide polygenic risk scores with simple questionnaire-based risk factors, including demographic, lifestyle, medication, and comorbidity data, enabling risk calculation across resources where genome data is available. Compared to routinely used clinical risk scores for coronary heart disease and type 2 diabetes prevention, the risk tools show at least equivalent risk discrimination, improved risk reclassification (overall net reclassification improvements ranging from 3.7 [95% CI 2.8-4.6] up to 6.2 [4.6-7.8]), and capacity to be improved even further with standard lipid and blood pressure measurements. Without the need for blood tests or evaluation by a health professional, the risk tools provide a powerful yet simple method for preliminary cardiometabolic risk assessment for individuals with genome data available.Peer reviewe

Cluster analysis identifies unmet healthcare needs among patients with rheumatoid arthritis

Objective: To identify the patterns of healthcare resource utilization and unmet needs of persistent disease activity, pain, and physical disability in rheumatoid arthritis (RA) by cluster analysis. Method: Patients attending the Jyvaskyla Central Hospital rheumatology unit, Finland, were, from 2007, prospectively enrolled in a clinical database. We identified all RA patients in 2010-2014 and combined their individual-level data with well-recorded administrative data on all public healthcare contacts in fiscal year 2014. We ran agglomerative hierarchical clustering (Ward's method), with 28-joint Disease Activity Score with three variables, Health Assessment Questionnaire index, pain (visual analogue scale 0-100), and total annual health service-related direct costs (euro) as clustering variables. Results: Complete-case analysis of 939 patients derived four clusters. Cluster C1 (remission and low costs, 550 patients) comprised relatively young patients with low costs, low disease activity, and minimal disability. C2 (chronic pain, disability, and fatigue, 269 patients) included those with the highest pain and fatigue levels, and disability was fairly common. C3 (inflammation, 97 patients) had rather high mean costs and the highest average disease activity, but lower average levels of pain and less disability than C2, highlighting the impact of effective treatment. C4 (comorbidities and high costs, 23 patients) was characterized by exceptionally high costs incurred by comorbidities. Conclusions: The majority of RA patients had favourable outcomes and low costs. However, a large group of patients was distinguished by chronic pain, disability, and fatigue not unambiguously linked to disease activity. The highest healthcare costs were linked to high disease activity or comorbidities.Peer reviewe

Estimating Dementia Risk Using Multifactorial Prediction Models

IMPORTANCE: The clinical value of current multifactorial algorithms for individualized assessment of dementia risk remains unclear. OBJECTIVE: To evaluate the clinical value associated with 4 widely used dementia risk scores in estimating 10-year dementia risk. DESIGN, SETTING, AND PARTICIPANTS: This prospective population-based UK Biobank cohort study assessed 4 dementia risk scores at baseline (2006-2010) and ascertained incident dementia during the following 10 years. Replication with a 20-year follow-up was based on the British Whitehall II study. For both analyses, participants who had no dementia at baseline, had complete data on at least 1 dementia risk score, and were linked to electronic health records from hospitalizations or mortality were included. Data analysis was conducted from July 5, 2022, to April 20, 2023. EXPOSURES: Four existing dementia risk scores: the Cardiovascular Risk Factors, Aging and Dementia (CAIDE)-Clinical score, the CAIDE-APOE-supplemented score, the Brief Dementia Screening Indicator (BDSI), and the Australian National University Alzheimer Disease Risk Index (ANU-ADRI). MAIN OUTCOMES AND MEASURES: Dementia was ascertained from linked electronic health records. To evaluate how well each score predicted the 10-year risk of dementia, concordance (C) statistics, detection rate, false-positive rate, and the ratio of true to false positives were calculated for each risk score and for a model including age alone. RESULTS: Of 465 929 UK Biobank participants without dementia at baseline (mean [SD] age, 56.5 [8.1] years; range, 38-73 years; 252 778 [54.3%] female participants), 3421 were diagnosed with dementia at follow-up (7.5 per 10 000 person-years). If the threshold for a positive test result was calibrated to achieve a 5% false-positive rate, all 4 risk scores detected 9% to 16% of incident dementia and therefore missed 84% to 91% (failure rate). The corresponding failure rate was 84% for a model that included age only. For a positive test result calibrated to detect at least half of future incident dementia, the ratio of true to false positives ranged between 1 to 66 (for CAIDE-APOE-supplemented) and 1 to 116 (for ANU-ADRI). For age alone, the ratio was 1 to 43. The C statistic was 0.66 (95% CI, 0.65-0.67) for the CAIDE clinical version, 0.73 (95% CI, 0.72-0.73) for the CAIDE-APOE-supplemented, 0.68 (95% CI, 0.67-0.69) for BDSI, 0.59 (95% CI, 0.58-0.60) for ANU-ADRI, and 0.79 (95% CI, 0.79-0.80) for age alone. Similar C statistics were seen for 20-year dementia risk in the Whitehall II study cohort, which included 4865 participants (mean [SD] age, 54.9 [5.9] years; 1342 [27.6%] female participants). In a subgroup analysis of same-aged participants aged 65 (±1) years, discriminatory capacity of risk scores was low (C statistics between 0.52 and 0.60). CONCLUSIONS AND RELEVANCE: In these cohort studies, individualized assessments of dementia risk using existing risk prediction scores had high error rates. These findings suggest that the scores were of limited value in targeting people for dementia prevention. Further research is needed to develop more accurate algorithms for estimation of dementia risk

Lifetime risk of rheumatoid arthritis-associated interstitial lung disease in MUC5B mutation carriers

ObjectivesTo estimate lifetime risk of developing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with respect to the strongest known risk factor for pulmonary fibrosis, a MUC5B promoter variant.MethodsFinnGen is a collection of epidemiological cohorts and hospital biobank samples, integrating genetic data with up to 50 years of follow-up within nationwide registries in Finland. Patients with RA and ILD were identified from the Finnish national hospital discharge, medication reimbursement and cause-of-death registries. We estimated lifetime risks of ILD by age 80 with respect to the common variant rs35705950, a MUC5B promoter variant.ResultsOut of 293 972 individuals, 1965 (0.7%) developed ILD by age 80. Among all individuals in the dataset, MUC5B increased the risk of ILD with a HR of 2.44 (95% CI: 2.22 to 2.68). Out of 6869 patients diagnosed with RA, 247 (3.6%) developed ILD. In patients with RA, MUC5B was a strong risk factor of ILD with a HR similar to the full dataset (HR: 2.27, 95% CI: 1.75 to 2.95). In patients with RA, lifetime risks of ILD were 16.8% (95% CI: 13.1% to 20.2%) for MUC5B carriers and 6.1% (95% CI: 5.0% to 7.2%) for MUC5B non-carriers. The difference between risks started to emerge at age 65, with a higher risk among men.ConclusionOur findings provide estimates of lifetime risk of RA-ILD based on MUC5B mutation carrier status, demonstrating the potential of genomics for risk stratification of RA-ILD.Data availability statementThe Finnish biobank data can be accessed through the Fingenious® services (https://site.fingenious.fi/en/) managed by FINBB. The remaining data are available within the article, supplemental information or available from the authors upon request.</p

Genetic risk factors have a substantial impact on healthy life years

The impact of genetic variation on overall disease burden has not been comprehensively evaluated. We introduce an approach to estimate the effect of genetic risk factors on disability-adjusted life years (DALYs; 'lost healthy life years'). We use genetic information from 735,748 individuals and consider 80 diseases. Rare variants had the highest effect on DALYs at the individual level. Among common variants, rs3798220 (LPA) had the strongest individual-level effect, with 1.18 DALYs from carrying 1 versus 0 copies. Being in the top 10% versus the bottom 90% of a polygenic score for multisite chronic pain had an effect of 3.63 DALYs. Some common variants had a population-level effect comparable to modifiable risk factors such as high sodium intake and low physical activity. Attributable DALYs vary between males and females for some genetic exposures. Genetic risk factors can explain a sizable number of healthy life years lost both at the individual and population level.Peer reviewe

The role of polygenic risk and susceptibility genes in breast cancer over the course of life

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10-90(th) percentile) have a lifetime risk of breast cancer at 55% (95% CI 49-61%), which increases to 84% (71-97%) with a high PRS (>90(th) percentile), and decreases to 49% (30-68%) with a low PRS (Peer reviewe

Genetic analyses implicate complex links between adult testosterone levels and health and disease

BackgroundTestosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of genetically determined testosterone on complex diseases in both sexes.MethodsLeveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality.ResultsWe show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes.ConclusionsOverall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences.Plain language summaryHormones, such as testosterone, travel around the body communicating between the different parts. Testosterone is present at higher levels in men, but also present in women. Variable testosterone levels explain some differences in human traits and disease prevalence. Here, we study how adult testosterone levels relate to health and disease. Genetic, i.e. inherited, differences in testosterone levels contribute to many traits specific to men or women, such as women's reproductive health, hormonal cancers, and hair growth typical in males. However, testosterone levels do not appear as a major cause of most traits studied, including psychiatric diseases and metabolic health. Normal variation in baseline testosterone levels thus seems to have a relatively minor impact on health and disease.Leinonen et al. investigate correlations between testosterone levels and disease using genetic and health registry data from the UK Biobank and FinnGen. There is a lack of evidence for normal variation in testosterone levels having a causal contribution to most non-sex-specific traits.Peer reviewe