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  • Lampi, Jussi; Hyvärinen, Anne; Erhola, Marina; Haahtela, Tari; Haukipuro, Kyösti; Haverinen-Shaughnessy, Ulla; Jalkanen, Kaisa; Karvala, Kirsi; Lappalainen, Sanna; Reijula, Kari; Rämö, Hannele; Sainio, Markku; Salmela, Anniina; Salminen, Mika; Vasankari, Tuula; Pekkanen, Juha (BioMed Central, 2020)
    Abstract Clean and fresh indoor air supports health and well-being. However, indoor air can contain pollutants that can cause a variety of symptoms and reduce well-being. Individual exposure agents can also increase the risk of certain diseases. Finns have taken major steps to improve the quality of indoor air for several decades. The primary focus of these activities has been the prevention and reduction of exposure to poor indoor air quality through guidance and regulation directing remediation of damaged buildings. Nevertheless, reported symptoms related to poor indoor air quality are common in Finland. In addition to exposure to indoor air pollutants, this may be partly due to the lively public discussion on the health risks caused by poor indoor air quality, conflicting views between experts, and mistrust towards public authorities, building owners and builders. Because of the scale of the indoor air problems in Finland, people’s needs for reliable information and support, and the major costs involved, there is a call for new evidence-based methods, perspectives and solutions. Therefore, the Finnish Institute for Health and Welfare initiated the Finnish Indoor Air and Health Programme 2018–2028 together with a number of collaborators and stakeholders. The primary, long-term objective of the programme is to reduce hazards to health and well-being linked to indoor environments in Finland. To fulfill this objective, the programme will focus on the promotion of human health and well-being, the prevention of hazards, improved communication and engage the whole health-care sector to manage better patients´ symptoms and complaints. The 10-year Finnish Indoor Air and Health Programme consists of four areas that aim (1) to increase understanding of the effects of indoor environments on health and well-being; (2) to develop the management of problems linked to indoor environments; (3) to improve the treatment and working and functional capacity of people with symptoms and illnesses; and (4) to strengthen the competence in matters related to indoor environments. The progress of the programme and reaching the predefined, quantitative goals will be monitored throughout the programme.
  • Sihvonen, Raine; Kalske, Roope; Englund, Martin; Turkiewicz, Aleksandra; Toivonen, Pirjo; Taimela, Simo; Järvinen, Teppo L N (BioMed Central, 2020)
    Abstract Background The research objectives of the 5-year and 10-year assessments in the Finnish degenerative meniscal lesion study (FIDELITY) are twofold: (1) to assess the long-term efficacy of arthroscopic partial meniscectomy (APM) in adults (age 35 to 65 years) with a degenerative meniscus tear and (2) to determine the respective effects of APM and degenerative meniscus tear on the development of radiographic and clinical knee osteoarthritis (OA). Methods and design FIDELITY is an ongoing multi-center, randomized, participant and outcome assessor blinded, placebo-surgery-controlled trial in 146 patients. This statistical analysis plan (SAP) article describes the overall principles for analysis of long-term outcomes (5-year and 10-year follow up), including how participants will be included in each analysis, the primary and secondary outcomes and their respective analyses, adjustments for covariates, and the presentation of the results. In addition, we will present the planned sensitivity and subgroup analyses. Discussion To assess the long-term efficacy of APM on knee symptoms and function we are carrying out a long-term (5-year and 10-year) follow up of our placebo-surgery-controlled FIDELITY trial according to statistical principles outlined in detail in this document. As our second primary objective, whether APM (resection of torn meniscus tear) accelerates or delays the development of knee osteoarthritis in patients with an arthroscopically verified degenerative tear of the medial meniscus, a pre-registered follow-up is also carried out. Trial registration ClinicalTrials.gov, NCT00549172 (Arthroscopy in the Treatment of Degenerative Medial Meniscus Tear). Registered on 25 October 2007 (NCT00549172). ClinicalTrials.gov, NCT01052233 (Development of Knee Osteoarthritis After Arthroscopic Partial Resection of Degenerative Meniscus Tear). Registered on 20 January 2010.
  • Schmidt, Eeva-Kaisa; Mustonen, Tuuli; Kiuru-Enari, Sari; Kivelä, Tero T; Atula, Sari (BioMed Central, 2020)
    Abstract Background Hereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. Results The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70–74 years, for which it was 0.96. Conclusions AGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years.
  • Štšepetova, Jelena; Baranova, Juliana; Simm, Jaak; Parm, Ülle; Rööp, Tiiu; Sokmann, Sandra; Korrovits, Paul; Jaagura, Madis; Rosenstein, Karin; Salumets, Andres; Mändar, Reet (BioMed Central, 2020)
    Abstract Background Only a few microbial studies have conducted in IVF (in vitro fertilization), showing the high-variety bacterial contamination of IVF culture media to cause damage to or even loss of cultured oocytes and embryos. We aimed to determine the prevalence and counts of bacteria in IVF samples, and to associate them with clinical outcome. Methods The studied samples from 50 infertile couples included: raw (n = 48), processed (n = 49) and incubated (n = 50) sperm samples, and IVF culture media (n = 50). The full microbiome was analyzed by 454 pyrosequencing and quantitative analysis by real-time quantitative PCR. Descriptive statistics, t-, Mann-Whitney tests and Spearman’s correlation were used for comparison of studied groups. Results The study involved normozoospermic men. Normal vaginal microbiota was present in 72.0% of female partners, while intermediate microbiota and bacterial vaginosis were diagnosed in 12.0 and 16.0%, respectively. The decreasing bacterial loads were found in raw (35.5%), processed (12.0%) and sperm samples used for oocyte insemination (4.0%), and in 8.0% of IVF culture media. The most abundant genera of bacteria in native semen and IVF culture media were Lactobacillus, while in other samples Alphaproteobacteria prevailed. Staphylococcus sp. was found only in semen from patients with inflammation. Phylum Bacteroidetes was in negative correlation with sperm motility and Alphaproteobacteria with high-quality IVF embryos. Conclusion Our study demonstrates that IVF does not occur in a sterile environment. The prevalent bacteria include classes Bacilli in raw semen and IVF culture media, Clostridia in processed and Bacteroidia in sperm samples used for insemination. The presence of Staphylococcus sp. and Alphaproteobacteria associated with clinical outcomes, like sperm and embryo quality.
  • Tuomisto, Jouni T; Asikainen, Arja; Meriläinen, Päivi; Haapasaari, Päivi (BioMed Central, 2020)
    Abstract Background Health risks linked with dioxin in fish remain a complex policy issue. Fatty Baltic fish contain persistent pollutants, but they are otherwise healthy food. We studied the health benefits and risks associated with Baltic herring and salmon in four countries to identify critical uncertainties and to facilitate an evidence-based discussion. Methods We performed an online survey investigating consumers’ fish consumption and its motivation in Denmark, Estonia, Finland, and Sweden. Dioxin and methylmercury concentrations were estimated based on Finnish studies. Exposure-response functions for several health endpoints were evaluated and quantified based on the scientific literature. We also quantified the infertility risk of men based on a recent European risk assessment estimating childhood dioxin exposure and its effect on sperm concentration later in life. Results Baltic herring and salmon contain omega-3 fatty acids and vitamin D, and the beneficial impact of these fishes on cardiovascular diseases, mortality, and the risk of depression and cancer clearly outweighs risks of dioxins and methylmercury in people older than 45 years of age and in young men. Young women may expose their children to pollutants during pregnancy and breast feeding. This study suggests that even in this critical subgroup, the risks are small and the health benefits are greater than or at least similar to the health risks. Value of information analysis demonstrated that the remaining scientific uncertainties are not large. In contrast, there are several critical uncertainties that are inherently value judgements, such as whether exceeding the tolerable weekly intake is an adverse outcome as such; and whether or not subgroup-specific restrictions are problematic. Conclusions The potential health risks attributable to dioxins in Baltic fish have more than halved in the past 10 years. The new risk assessment issued by the European Food Safety Authority clearly increases the fraction of the population exceeding the tolerable dioxin intake, but nonetheless, quantitative estimates of net health impacts change only marginally. Increased use of small herring (which have less pollutants) is a no-regret option. A more relevant value-based policy discussion rather than research is needed to clarify official recommendations related to dioxins in fish.
  • Joki, Anu; Mäkelä, Johanna; Konttinen, Hanna; Fogelholm, Mikael (BioMed Central, 2020)
    Abstract Background Despite the current obesogenic environment creating challenges weight management, some people succeed in maintaining a normal weight. This study explored lifelong weight management from the life course perspective. We aimed to gain an insight into the issues related to the pathways of individuals of normal weight from childhood to adulthood, and how their experiences and social connections influence their weight management. Methods We approached the research topic using qualitative methods. Two age groups (30–45; 55–70 years, men and women), forming a total of 39 individuals, participated in theme interviews. Thematic analysis resulted in two main categories, namely (1) adoption of lifestyle and (2) maintenance of lifestyle. Results Childhood family played a central role in the formation of lifestyle: food-upbringing created the basis for the interviewees’ current diet, and their lives had always been characterized by an active lifestyle. High perceived self-efficacy was vital in weight management. The interviewees were confident about their routines and trusted their abilities to recognize and handle situations that threatened their lifestyles. They possessed skills for adjusting their lifestyle to altered environments, and showed a high level of coping self-efficacy. The interviewees also highlighted the importance of habits for weight management. They had improved their adopted lifestyle through constant learning. New routines had become more internalized through active repetition, finally turning into habitual practices, which simplified weight management. Conclusions Based on our interviews, we conclude that childhood was important in the development of the health-promoting lifestyle of our interviewees. However, weight management was described as a journey over the life course, and success also encouraged skills of identifying risks and adjusting actions to cope with challenging situations.
  • Kvist, Jouni; Athanàsio, Camila G; Pfrender, Michael E; Brown, James B; Colbourne, John K; Mirbahai, Leda (BioMed Central, 2020)
    Abstract Background Daphnia species reproduce by cyclic parthenogenesis involving both sexual and asexual reproduction. The sex of the offspring is environmentally determined and mediated via endocrine signalling by the mother. Interestingly, male and female Daphnia can be genetically identical, yet display large differences in behaviour, morphology, lifespan and metabolic activity. Our goal was to integrate multiple omics datasets, including gene expression, splicing, histone modification and DNA methylation data generated from genetically identical female and male Daphnia pulex under controlled laboratory settings with the aim of achieving a better understanding of the underlying epigenetic factors that may contribute to the phenotypic differences observed between the two genders. Results In this study we demonstrate that gene expression level is positively correlated with increased DNA methylation, and histone H3 trimethylation at lysine 4 (H3K4me3) at predicted promoter regions. Conversely, elevated histone H3 trimethylation at lysine 27 (H3K27me3), distributed across the entire transcript length, is negatively correlated with gene expression level. Interestingly, male Daphnia are dominated with epigenetic modifications that globally promote elevated gene expression, while female Daphnia are dominated with epigenetic modifications that reduce gene expression globally. For examples, CpG methylation (positively correlated with gene expression level) is significantly higher in almost all differentially methylated sites in male compared to female Daphnia. Furthermore, H3K4me3 modifications are higher in male compared to female Daphnia in more than 3/4 of the differentially regulated promoters. On the other hand, H3K27me3 is higher in female compared to male Daphnia in more than 5/6 of differentially modified sites. However, both sexes demonstrate roughly equal number of genes that are up-regulated in one gender compared to the other sex. Since, gene expression analyses typically assume that most genes are expressed at equal level among samples and different conditions, and thus cannot detect global changes affecting most genes. Conclusions The epigenetic differences between male and female in Daphnia pulex are vast and dominated by changes that promote elevated gene expression in male Daphnia. Furthermore, the differences observed in both gene expression changes and epigenetic modifications between the genders relate to pathways that are physiologically relevant to the observed phenotypic differences.
  • Skaga, Erlend; Kulesskiy, Evgeny; Brynjulvsen, Marit; Sandberg, Cecilie J; Potdar, Swapnil; Langmoen, Iver A; Laakso, Aki; Gaál-Paavola, Emília; Perola, Markus; Wennerberg, Krister; Vik-Mo, Einar O (Springer Berlin Heidelberg, 2019)
    Abstract Background Despite the well described heterogeneity in glioblastoma (GBM), treatment is standardized, and clinical trials investigate treatment effects at population level. Genomics-driven oncology for stratified treatments allow clinical decision making in only a small minority of screened patients. Addressing tumor heterogeneity, we aimed to establish a clinical translational protocol in recurrent GBM (recGBM) utilizing autologous glioblastoma stem cell (GSC) cultures and automated high-throughput drug sensitivity and resistance testing (DSRT) for individualized treatment within the time available for clinical application. Results From ten patients undergoing surgery for recGBM, we established individual cell cultures and characterized the GSCs by functional assays. 7/10 GSC cultures could be serially expanded. The individual GSCs displayed intertumoral differences in their proliferative capacity, expression of stem cell markers and variation in their in vitro and in vivo morphology. We defined a time frame of 10 weeks from surgery to complete the entire pre-clinical work-up; establish individualized GSC cultures, evaluate drug sensitivity patterns of 525 anticancer drugs, and identify options for individualized treatment. Within the time frame for clinical translation 5/7 cultures reached sufficient cell yield for complete drug screening. The DSRT revealed significant intertumoral heterogeneity to anticancer drugs (p < 0.0001). Using curated reference databases of drug sensitivity in GBM and healthy bone marrow cells, we identified individualized treatment options in all patients. Individualized treatment options could be selected from FDA-approved drugs from a variety of different drug classes in all cases. Conclusions In recGBM, GSC cultures could successfully be established in the majority of patients. The individual cultures displayed intertumoral heterogeneity in their in vitro and in vivo behavior. Within a time frame for clinical application, we could perform DSRT in 50% of recGBM patients. The DSRT revealed a remarkable intertumoral heterogeneity in sensitivity to anticancer drugs in recGBM that could allow tailored therapeutic options for functional precision medicine.
  • Saarinen, Tuure; Meriläinen, Sanna; Koivukangas, Vesa; Pietiläinen, Kirsi H; Juuti, Anne (BioMed Central, 2019)
    Abstract Introduction There is a lack of prospective studies comparing Roux-en-Y gastric bypass (RYGB) and one-anastomosis gastric bypass (OAGB). Also, the effects of bariatric surgery and weight loss need a deeper understanding through metabolic studies. We describe the trial protocol and interim analysis of a prospective randomized controlled study comparing RYGB and OAGB: the RYSA trial. Materials and methods In total, 120 bariatric patients will be randomized between RYGB and OAGB in two academic centers. All patients will be followed up for 10 years with analysis and measurements of weight, comorbidities, blood tests, body composition and questionnaires. Extensive metabolic analyses (mixed meal tests, energy expenditure, biopsies of muscle and subcutaneous fat, urine, saliva and fecal samples) will be carried out in the Obesity Research Unit, University of Helsinki, for all patients treated at the Helsinki University Hospital (80 patients) at baseline, 6 months and 12 months. Bile reflux will be studied for the OAGB group at the Helsinki University Hospital at 6 months with gastroscopy and scintigraphy. Results At an interim analysis at 3 months (half-way) through recruitment (30 RYGB and 30 OAGB patients) there have been no deaths and no intensive care unit admittances. One patient in both groups required additional gastroscopy, with anastomosis dilatation in the RYGB group but with no additional intervention in the OAGB group. Conclusion The trial can be safely carried out. Recruitment is estimated to be complete by the end of 2019. Trial registration Clinical Trials Identifier NCT02882685. Registered on August 30th 2016.
  • Mozhgani, Sayed-Hamidreza; Piran, Mehran; Zarei-Ghobadi, Mohadeseh; Jafari, Mohieddin; Jazayeri, Seyed-Mohammad; Mokhtari-Azad, Talat; Teymoori-Rad, Majid; Valizadeh, Narges; Farajifard, Hamid; Mirzaie, Mehdi; Khamseh, Azam; Rafatpanah, Houshang; Rezaee, Seyed-Abdolrahim; Norouzi, Mehdi (BioMed Central, 2019)
    Abstract Background Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP. Results High-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein–protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12). Conclusions High-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.
  • Rissanen, Annu-Riikka S; Jernman, Riina M; Gissler, Mika; Nupponen, Irmeli K; Nuutila, Mika E (BioMed Central, 2019)
    Abstract Background To establish the changes in perinatal morbidity and mortality in twin pregnancies in Finland, a retrospective register research was conducted. Our extensive data from a 28-year study period provide important information on the outcome of twin pregnancies in Finland that has previously not been reported to this extent. Methods All 23,498 twin pregnancies with 46,996 children born in Finland during 1987–2014 were included in the study. Data were gathered from the Medical Birth Register and the Hospital Discharge Register (Finnish Institute for Health and Welfare, Finland) regarding perinatal mortality (PNM) and morbidity. For statistical analysis, binomial regression analysis and crosstabs were performed. The results are expressed in means, percentages and ranges with comparison to singletons when appropriate. Odds ratios from binomial regression analysis are reported. A p-value <0.05 was considered statistically significant. Results There were 46,363 liveborn and 633 stillborn twins in Finland during 1987–2014. Perinatal mortality decreased markedly, from 45.1 to 6.5 per 1000 for twin A and from 54.1 to 11.9 per 1000 for twin B during the study period. Yet, the PNM difference between twin A and B remained. Early neonatal mortality did not differ between twins, but has decreased in both. Asphyxia, respiratory distress syndrome, need for antibiotics and Neonatal Intensive Care Unit (NICU) stay were markedly more common in twin B. Conclusions In Finland, PNM and early neonatal mortality in twins decreased significantly during 1987–2014 and are nowadays very low. However, twin B still faces more complications. The outline provided may be used to further improve the monitoring and thus perinatal outcome of twins, especially twin B.
  • Wiersema, Renske; Eck, Ruben J; Haapio, Mikko; Koeze, Jacqueline; Poukkanen, Meri; Keus, Frederik; van der Horst, Iwan C C; Pettilä, Ville; Vaara, Suvi T (BioMed Central, 2019)
    Abstract Background Mortality rates associated with acute kidney injury (AKI) vary among critically ill patients. Outcomes are often not corrected for severity or duration of AKI. Our objective was to analyse whether a new variable, AKI burden, would outperform 1) presence of AKI, 2) highest AKI stage, or 3) AKI duration in predicting 90-day mortality. Methods Kidney Diseases: Improving Global Outcomes (KDIGO) criteria using creatinine, urine output and renal replacement therapy were used to diagnose AKI. AKI burden was defined as AKI stage multiplied with the number of days that each stage was present (maximum five), divided by the maximum possible score yielding a proportion. The AKI burden as a predictor of 90-day mortality was assessed in two independent cohorts (Finnish Acute Kidney Injury, FINNAKI and Simple Intensive Care Studies I, SICS-I) by comparing four multivariate logistic regression models that respectively incorporated either the presence of AKI, the highest AKI stage, the duration of AKI, or the AKI burden. Results In the FINNAKI cohort 1096 of 2809 patients (39%) had AKI and 90-day mortality of the cohort was 23%. Median AKI burden was 0.17 (IQR 0.07–0.50), 1.0 being the maximum. The model including AKI burden (area under the receiver operator curve (AUROC) 0.78, 0.76–0.80) outperformed the models using AKI presence (AUROC 0.77, 0.75–0.79, p = 0.026) or AKI severity (AUROC 0.77, 0.75–0.79, p = 0.012), but not AKI duration (AUROC 0.77, 0.75–0.79, p = 0.06). In the SICS-I, 603 of 1075 patients (56%) had AKI and 90-day mortality was 28%. Median AKI burden was 0.19 (IQR 0.08–0.46). The model using AKI burden performed better (AUROC 0.77, 0.74–0.80) than the models using AKI presence (AUROC 0.75, 0.71–0.78, p = 0.001), AKI severity (AUROC 0.76, 0.72–0.79. p = 0.008) or AKI duration (AUROC 0.76, 0.73–0.79, p = 0.009). Conclusion AKI burden, which appreciates both severity and duration of AKI, was superior to using only presence or the highest stage of AKI in predicting 90-day mortality. Using AKI burden or other more granular methods may be helpful in future epidemiological studies of AKI.
  • Majala, Susanna; Seppänen, Hanna; Kemppainen, Jukka; Sundström, Jari; Schalin-Jäntti, Camilla; Gullichsen, Risto; Schildt, Jukka; Mustonen, Harri; Vesterinen, Tiina; Arola, Johanna; Kauhanen, Saila (Springer Berlin Heidelberg, 2019)
    Abstract Background Predicting the aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PNET) remains controversial. We wanted to explore, in a prospective setting, whether the diagnostic accuracy can be improved by dual-tracer functional imaging 68Ga-DOTANOC and 18F-FDG-PET/CT in patients with NF-PNETs. Methods Thirty-one patients with NF-PNET (90% asymptomatic) underwent PET-imaging with 18F-FDG and 68Ga-DOTANOC, followed by surgery (n = 20), an endoscopic ultrasonography and fine-needle biopsy (n = 2) or follow-up (n = 9). A focal activity on PET/CT greater than the background that could not be identified as physiological activity was considered to indicate tumor tissue. The imaging results were compared to histopathology. The mean follow-up time was 31.3 months. Results Thirty-one patients presented a total of 53 lesions (40 histologically confirmed) on PET/CT. Thirty patients had a 68Ga-DOTANOC-positive tumor (sensitivity 97%) and 10 patients had an 18F-FDG-positive tumor. In addition, one 68Ga-DOTANOC-negative patient was 18F-FDG-positive. 18F-FDG-PET/CT was positive in 19% (3/16) of the G1 tumors, 63% (5/8) of the G2 tumors and 1/1 of the well-differentiated G3 tumor. 68Ga-DOTANOC-PET/CT was positive in 94% of the G1 tumors, 100% of the G2 tumors and 1/1 of the well-differentiated G3 tumor. Two out of six (33%) of the patients with lymph node metastases (LN+) were 18F-FDG-positive. The 18F-FDG-PET/CT correlated with tumor Ki-67 (P = 0.021). Further, the Krenning score correlated with tumor Ki-67 (P = 0.013). 18F-FDG-positive tumors were significantly larger than the 18F-FDG-negative tumors (P = 0.012). 18F-FDG-PET/CT showed a positive predictive value of 78% in the detection of potentially aggressive tumors (G2, G3, or LN + PNETs); the negative predictive value was 69%. Conclusions 18F-FDG-PET/CT is useful to predict tumor grade but not the LN+ of NF-PNETs. Patients with 18F-FDG-avid NF-PNETs should be referred for surgery. The 68Ga-DOTANOC-PET/CT also has prognostic value since the Krenning score predicts the histopathological tumor grade. Trial registration The study has been registered at ClinicalTrials.gov; Non-functional Pancreatic NET and PET imaging, NCT02621541.
  • Savelieva, Kateryna; Marttila, Tero; Lampi, Jussi; Ung-Lanki, Sari; Elovainio, Marko; Pekkanen, Juha (BioMed Central, 2019)
    Abstract Background The associations between indoor environmental quality (IEQ) in homes and symptom reporting of children have been extensively studied, but only few large-scale studies have been done in schools. We examined associations between expert-assessed IEQ in schools and pupils’ reporting of different symptoms, and whether associations were stronger if participants relate symptoms to the school environment. Methods The questionnaire survey was done in all primary and secondary schools in two areas of Helsinki, Finland. Primary school pupils (grade 3–6, n = 8775, 99 school-buildings) and secondary school pupils (grade 7–9, n = 3410, 30 school-buildings) reported their symptoms. Symptoms were combined into respiratory, lower respiratory, eye, skin, and general symptom groups. Surveys were also done among the parents of the primary school pupils (grade 1–6, n = 3540, 88 school buildings), but results are reported only in the supplement due to the low response rate (20% in 2017 and 13% in 2018). The associations between IEQ and symptoms were analyzed using multilevel logistic regression analysis. Results Several of the IEQ indicators were highly correlated and indicators were therefore mainly analyzed by combining them into a summary score and into latent classes. Dose-response associations were found between IEQ problems and higher reporting of respiratory and general symptoms among both primary and secondary school pupils. Some associations were also observed with lower respiratory and skin symptoms, but not with eye symptoms. The associations were somewhat stronger with symptoms related to the school environment compared to symptoms reported without such relation: for a unit change in IEQ summary score and respiratory symptoms in primary schools, odds ratios were 1.07 (95% CI 1.02–1.06) and 1.04 (95% CI 1.04–1.10), and in secondary schools 1.09 (95% CI 1.01–1.09) and 1.05 (95% CI 1.02–1.17), respectively. Conclusions Expert-assessed IEQ problems in schools were associated with increased reporting of especially respiratory and general symptoms. The associations were only somewhat stronger in magnitude for symptoms reported in relation to the school environment compared to symptoms reported without such relation.
  • Bosqui, Tania; O’Reilly, Dermot; Väänänen, Ari; Patel, Kishan; Donnelly, Michael; Wright, David; Close, Ciara; Kouvonen, Anne (BioMed Central, 2019)
    Abstract Purpose There is a recent and growing migrant population in Northern Ireland. However, rigorous research is absent regarding access to mental health care by different migrant groups. In order to address this knowledge gap, this study aimed to identify the relative use of psychotropic medication between the largest first generation migrant groups in Northern Ireland and the majority population. Methods Census (2011) data was linked to psychotropic prescriptions for the entire enumerated population of Northern Ireland using data linkage methodology through the Administrative Data Research Centre Northern Ireland (ADRC-NI). Results Lower prescription dispensation for all psychotropic medication types, particularly antidepressants (OR = 0.35, CI 95% 0.33–0.36) and anxiolytics (OR = 0.42, CI 95% 0.40–0.44), was observed for all migrant groups with the exception of migrants from Germany. Conclusions It is likely that the results reflect poorer access to services and indicate a need to improve access and the match between resources, services and the health and social care needs of migrants. Further research is required to identify barriers to accessing primary care and mental health services.
  • Mikkola, Lea; Holopainen, Saila; Pessa-Morikawa, Tiina; Lappalainen, Anu K; Hytönen, Marjo K; Lohi, Hannes; Iivanainen, Antti (BioMed Central, 2019)
    Abstract Background Hip dysplasia and osteoarthritis continue to be prevalent problems in veterinary and human medicine. Canine hip dysplasia is particularly problematic as it massively affects several large-sized breeds and can cause a severe impairment of the quality of life. In Finland, the complex condition is categorized to five classes from normal to severe dysplasia, but the categorization includes several sub-traits: congruity of the joint, Norberg angle, subluxation degree of the joint, shape and depth of the acetabulum, and osteoarthritis. Hip dysplasia and osteoarthritis have been proposed to have separate genetic etiologies. Results Using Fédération Cynologique Internationale -standardized ventrodorsal radiographs, German shepherds were rigorously phenotyped for osteoarthritis, and for joint incongruity by Norberg angle and femoral head center position in relation to dorsal acetabular edge. The affected dogs were categorized into mild, moderate and severe dysplastic phenotypes using official hip scores. Three different genome-wide significant loci were uncovered. The strongest candidate genes for hip joint incongruity were noggin (NOG), a bone and joint developmental gene on chromosome 9, and nanos C2HC-type zinc finger 1 (NANOS1), a regulator of matrix metalloproteinase 14 (MMP14) on chromosome 28. Osteoarthritis mapped to a long intergenic region on chromosome 1, between genes encoding for NADPH oxidase 3 (NOX3), an intriguing candidate for articular cartilage degradation, and AT-rich interactive domain 1B (ARID1B) that has been previously linked to joint laxity. Conclusions Our findings highlight the complexity of canine hip dysplasia phenotypes. In particular, the results of this study point to the potential involvement of specific and partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderate-to-severe dysplasia and osteoarthritis of canine hip joints. Further studies should unravel the unique and common mechanisms for the various sub-traits.
  • Giardiello, Daniele; Steyerberg, Ewout W; Hauptmann, Michael; Adank, Muriel A; Akdeniz, Delal; Blomqvist, Carl; Bojesen, Stig E; Bolla, Manjeet K; Brinkhuis, Mariël; Chang-Claude, Jenny; Czene, Kamila; Devilee, Peter; Dunning, Alison M; Easton, Douglas F; Eccles, Diana M; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Haeberle, Lothar; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hopper, John L; Jager, Agnes; Jakubowska, Anna; Jung, Audrey; Keeman, Renske; Kramer, Iris; Lambrechts, Diether; Le Marchand, Loic; Lindblom, Annika; Lubiński, Jan; Manoochehri, Mehdi; Mariani, Luigi; Nevanlinna, Heli; Oldenburg, Hester S A; Pelders, Saskia; Pharoah, Paul D P; Shah, Mitul; Siesling, Sabine; Smit, Vincent T H B M; Southey, Melissa C; Tapper, William J; Tollenaar, Rob A E M; van den Broek, Alexandra J; van Deurzen, Carolien H M; van Leeuwen, Flora E; van Ongeval, Chantal; Van’t Veer, Laura J; Wang, Qin; Wendt, Camilla; Westenend, Pieter J; Hooning, Maartje J; Schmidt, Marjanka K (BioMed Central, 2019)
    Abstract Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.
  • Monat, Cécile; Padmarasu, Sudharsan; Lux, Thomas; Wicker, Thomas; Gundlach, Heidrun; Himmelbach, Axel; Ens, Jennifer; Li, Chengdao; Muehlbauer, Gary J; Schulman, Alan H; Waugh, Robbie; Braumann, Ilka; Pozniak, Curtis; Scholz, Uwe; Mayer, Klaus F X; Spannagl, Manuel; Stein, Nils; Mascher, Martin (BioMed Central, 2019)
    Abstract Chromosome-scale genome sequence assemblies underpin pan-genomic studies. Recent genome assembly efforts in the large-genome Triticeae crops wheat and barley have relied on the commercial closed-source assembly algorithm DeNovoMagic. We present TRITEX, an open-source computational workflow that combines paired-end, mate-pair, 10X Genomics linked-read with chromosome conformation capture sequencing data to construct sequence scaffolds with megabase-scale contiguity ordered into chromosomal pseudomolecules. We evaluate the performance of TRITEX on publicly available sequence data of tetraploid wild emmer and hexaploid bread wheat, and construct an improved annotated reference genome sequence assembly of the barley cultivar Morex as a community resource.
  • Tirkkonen, Joonas; Karlsson, Sari; Skrifvars, Markus B (BioMed Central, 2019)
    Abstract Background The national early warning score (NEWS) enables early detection of in-hospital patient deterioration and timely activation of hospital’s rapid response team (RRT). NEWS was updated in 2017 to include a separate SpO2 scale for those patients with type II respiratory failure (T2RF). In this study we investigated whether NEWS with and without the new SpO2 scale for the T2RF patients is associated with immediate and in-hospital patient outcomes among the patients actually attended by the RRT. Methods We conducted a two-year prospective observational study including all adult RRT patients without limitations of medical treatment (LOMT) in a large Finnish university associated tertiary level hospital. According to the first vital signs measured by the RRT, we calculated NEWSs for the RRT patients and further utilized the new SpO2 scale for the patients with confirmed T2RF. We used multivariate logistic regression and area under the receiver operating characteristic analyses to test NEWS’s accuracy to predict two distinct outcomes: RRT patient’s I) immediate need for intensive care and/or new LOMT and 2) in-hospital death or discharge with cerebral performance category >2 and/or LOMT. Results The final cohort consisted of 886 RRT patients attended for the first time during their hospitalization. Most common reasons for RRT activation were respiratory (343, 39%) and circulatory (226, 26%) problems. Cohort’s median (Q1, Q3) NEWS at RRT arrival was 8 (5, 10) and remained unchanged if the new SpO2 scale was applied for the 104 patients with confirmed T2RF. Higher NEWS was independently associated with both immediate (OR 1.28; 95% CI 1.22–1.35) and in-hospital (1.15; 1.10–1.21) adverse outcomes. Further, NEWS had fair discrimination for both the immediate (AUROC 0.73; 0.69–0.77) and in-hospital (0.68; 0.64–0.72) outcomes. Utilizing the new SpO2 scale for the patients with confirmed T2RF did not improve the discrimination capability (0.73; 0.69–0.76 and 0.68; 0.64–0.71) for these outcomes, respectively. Conclusions We found that in patients attended by a RRT, the NEWS predicts patient’s hospital outcome with moderate accuracy. We did not find any improvement using the new SpO2 scale in T2RF patients.
  • Tarkiainen, Maarit; Tynjälä, Pirjo; Vähäsalo, Paula; Kröger, Liisa; Aalto, Kristiina; Lahdenne, Pekka (BioMed Central, 2019)
    Abstract Background Juvenile Idiopathic Arthritis (JIA) may cause significant impairment in health-related quality of life (HrQoL), despite effective therapies. The aim of this study was to assess HrQoL during first-year treatment in patients with new-onset polyarticular JIA, and to compare treatment strategies. Methods In ACUTE-JIA Study, 60 patients with new-onset JIA were randomized to receive either infliximab with methotrexate (IFX+MTX); a triple therapy of methotrexate, hydroxychloroquine, and sulfasalazine (Triple); or methotrexate monotherapy (MTX). Efficacy was measured with American College of Rheumatology pediatric (ACRp) score, and juvenile arthritis disease activity score (JADAS). HrQoL was evaluated with Child Health Questionnaire (CHQ), which includes physical and psychosocial summary scores (PhS and PsS). Linear mixed models were utilized to compare groups over time. Results In the whole group of 60 patients, mean physical summary score (PhS) improved from 26.2 (SD 8.7) at week 0 to 49.7 (SD 13.2) at week 54 (p=0.046). Mean improvement of PhS was 20.3 (95% CI -15.5 to 56.2); 22.6 (-19.5 to 64.7); and 26.6 (-12.1 to 65.3) in IFX+MTX, Triple, and MTX, respectively. Changes in psychosocial summary score (PsS) were smaller: from 51.0 (SD 8.5) to 54.7 (6.3) (p=0.019) in all patients. No differences between the three treatment groups were detected in either of the measures. In multivariate analyses, Child Health Assessment Questionnaire (CHAQ), pain VAS, and time spent in inactive disease contributed to improvement in PhS; gender and CHAQ to PsS. Conclusions HrQol improved during the first year on therapy for JIA irrespective of the treatment strategy. The timing of change in the different dimensions of HrQoL varied; improvement occurred earlier in physical than psychosocial domains of HrQol. Trial registration This study was registered within the Hospital District of Helsinki and Uusimaa (http://www.hus.fi) clinical trials, number 211864 in October 2002, and later on with ClinicalTrials.gov, number NCT01015547.

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