Browsing by Subject "Heterogeneity"

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  • Voutilainen, Mikko; Miettinen, Arttu; Sardini, Paul; Parkkonen, Joni; Sammaljärvi, Juuso; Gylling, Björn; Selroos, Jan-Olof; Yli-Kaila, Maarit; Koskinen, Lasse; Siitari-Kauppi, Marja (2019)
    The spatial porosity and mineral distribution of geological materials strongly affects transport processes in them. X-ray micro computed tomography (X-mu CT) has proven to be a powerful tool for characterizing the spatial mineral distribution of geological samples in 3-D. However, limitations in resolution prevent an accurate characterization of pore space especially for tight crystalline rock samples and 2-D methods such as C-14-polymethylmethacrylate (C-14-PMMA) autoradiography and scanning electron microscopy (SEM) are needed. The spatial porosity and mineral distributions of tight crystalline rock samples from Aspo, Sweden, and Olkiluoto, Finland, were studied here. The X-mu CT were used to characterize the spatial distribution of the main minerals in 3-D. Total porosities, fracture porosities, fracture densities and porosity distributions of the samples were determined using the C-14-PMMA autoradiography and characterization of mineral-specific porosities were assisted using chemical staining of rock surfaces. SEM and energy dispersive X-ray spectroscopy (EDS) were used to determine pore apertures and identify the minerals. It was shown that combination of the different imaging techniques creates a powerful tool for the structural characterization of crystalline rock samples. The combination of the results from different methods allowed the construction of spatial porosity, mineral and mineral grain distributions of the samples in 3-D. These spatial distributions enable reactive transport modeling using a more realistic representation of the heterogeneous structure of samples. Furthermore, the realism of the spatial distributions were increased by determinig the densities and porosities of fractures and by the virtual construction heterogeneous mineral distributions of minerals that cannot be separated by X-mu CT.
  • Jokela, Markus; García-Velázquez, Regina; Airaksinen, Jaakko; Gluschkoff, Kia; Kivimäki, Mika; Rosenström, Tom (2019)
    Background: Depression is a heterogeneous mental disorder with multiple symptoms, but only few studies have examined whether associations of risk factors with depression are symptom-specific. We examined whether chronic diseases and social risk factors (poverty, divorce, and perceived lack of emotional support) are differently associated with somatic and cognitive/affective symptoms of depression. Methods: Cross-sectional analyses were based on individual-level data from the 31,191 participants of six cross-sectional U.S. National Health and Nutrition Examination Surveys (NHANES) carried out between 2005 and 2016. Depressive symptoms were assessed using the 9-item Patient Health Questionnaire. Information on chronic diseases and social risk factors was self-reported by participants. Results: After adjustment for sex, age, race/ethnicity, and all the of other symptoms besides the outcome symptom, higher number of chronic diseases was independently related to fatigue, psychomotor retardation/agitation, and sleep problems in a dose-response pattern (range of odds ratios: 1.21 to 2.59). Except for concentration problems, social risk factors were associated with almost all of the cognitive/affective symptoms (range of odds ratios: 1.02 to 2.09) but only sporadically with somatic symptoms. Limitations: All measures were self-reported by the participants, which may have introduced bias to the associations. Cross-sectional data did not allow us to study temporal dynamics. Conclusions: Specific symptoms of depression may be useful in characterizing the heterogeneous etiology of depression with respect to somatic versus social risk factors.
  • Wiersema, Renske; Jukarainen, Sakari; Eck, Ruben J.; Kaufmann, Thomas; Koeze, Jacqueline; Keus, Frederik; Pettilä, Ville; van der Horst, Iwan C. C.; Vaara, Suvi T. (2020)
    Background Acute kidney injury (AKI) is a frequent and clinically relevant problem in critically ill patients. Various randomized controlled trials (RCT) have attempted to assess potentially beneficial treatments for AKI. Different approaches to applying the Kidney Disease Improving Global Outcomes (KDIGO) criteria for AKI make a comparison of studies difficult. The objective of this study was to assess how different approaches may impact estimates of AKI incidence and whether the association between AKI and 90-day mortality varied by the approach used. Methods Consecutive acutely admitted adult intensive care patients were included in a prospective observational study. AKI was determined following the KDIGO criteria during the first 7 days of ICU admission. In this post hoc analysis, we assessed whether AKI incidence differed when applying the KDIGO criteria in 30 different possible methods, varying in (A) serum creatinine (sCr), (B) urine output (UO), and (C) the method of combining these two into an outcome, e.g., severe AKI. We assessed point estimates and 95% confidence intervals for each incidence. Univariable regression was used to assess the associations between AKI and 90-day mortality. Results A total of 1010 patients were included. Baseline creatinine was available in 449 (44%) patients. The incidence of any AKI ranged from 28% (95%CI 25-31%) to 75% (95%CI 72-77%) depending on the approach used. Methods to estimate missing baseline sCr caused a variation in AKI incidence up to 15%. Different methods of handling UO caused a variation of up to 35%. At 90 days, 263 patients (26%) had died, and all 30 variations were associated with 90-day mortality. Conclusions In this cohort of critically ill patients, AKI incidence varied from 28 to 75%, depending on the method used of applying the KDIGO criteria. A tighter adherence to KDIGO definitions is warranted to decrease the heterogeneity of AKI and increase the comparability of future studies.
  • Wiersema, Renske; Jukarainen, Sakari; Eck, Ruben J; Kaufmann, Thomas; Koeze, Jacqueline; Keus, Frederik; Pettilä, Ville; van der Horst, Iwan C C; Vaara, Suvi T (BioMed Central, 2020)
    Abstract Background Acute kidney injury (AKI) is a frequent and clinically relevant problem in critically ill patients. Various randomized controlled trials (RCT) have attempted to assess potentially beneficial treatments for AKI. Different approaches to applying the Kidney Disease Improving Global Outcomes (KDIGO) criteria for AKI make a comparison of studies difficult. The objective of this study was to assess how different approaches may impact estimates of AKI incidence and whether the association between AKI and 90-day mortality varied by the approach used. Methods Consecutive acutely admitted adult intensive care patients were included in a prospective observational study. AKI was determined following the KDIGO criteria during the first 7 days of ICU admission. In this post hoc analysis, we assessed whether AKI incidence differed when applying the KDIGO criteria in 30 different possible methods, varying in (A) serum creatinine (sCr), (B) urine output (UO), and (C) the method of combining these two into an outcome, e.g., severe AKI. We assessed point estimates and 95% confidence intervals for each incidence. Univariable regression was used to assess the associations between AKI and 90-day mortality. Results A total of 1010 patients were included. Baseline creatinine was available in 449 (44%) patients. The incidence of any AKI ranged from 28% (95%CI 25–31%) to 75% (95%CI 72–77%) depending on the approach used. Methods to estimate missing baseline sCr caused a variation in AKI incidence up to 15%. Different methods of handling UO caused a variation of up to 35%. At 90 days, 263 patients (26%) had died, and all 30 variations were associated with 90-day mortality. Conclusions In this cohort of critically ill patients, AKI incidence varied from 28 to 75%, depending on the method used of applying the KDIGO criteria. A tighter adherence to KDIGO definitions is warranted to decrease the heterogeneity of AKI and increase the comparability of future studies.
  • Murphy, Neil; Ward, Heather A.; Jenab, Mazda; Rothwell, Joseph A.; Boutron-Ruault, Marie-Christine; Carbonnel, Franck; Kvaskoff, Marina; Kaaks, Rudolf; Kuehn, Tilman; Boeing, Heiner; Aleksandrova, Krasimira; Weiderpass, Elisabete; Skeie, Guri; Borch, Kristin Benjaminsen; Tjonneland, Anne; Kyro, Cecilie; Overvad, Kim; Dahm, Christina C.; Jakszyn, Paula; Sanchez, Maria-Jose; Gil, Leire; Huerta, Jose M.; Barricarte, Aurelio; Ramon Quiros, J.; Khaw, Kay-Tee; Wareham, Nick; Bradbury, Kathryn E.; Trichopoulou, Antonia; La Vecchia, Carlo; Karakatsani, Anna; Palli, Domenico; Grioni, Sara; Tumino, Rosario; Fasanelli, Francesca; Panico, Salvatore; Bueno-de-Mesquita, Bas; Peeters, Petra H.; Gylling, Bjorn; Myte, Robin; Jirstrom, Karin; Berntsson, Jonna; Xue, Xiaonan; Riboli, Elio; Cross, Amanda J.; Gunter, Marc J. (2019)
    BACKGROUND & AIMS: Colorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most studies have been of insufficient size to identify heterogeneous associations with precision. METHODS: In the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumors at different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests. RESULTS: After a median of 14.9 years of follow-up of 521,330 men and women, 6291 colorectal cancer cases occurred. Physical activity was related inversely to proximal colon and distal colon cancer, but not to rectal cancer (P heterogeneity = .03). Height was associated positively with proximal and distal colon cancer only, but not rectal cancer (P heterogeneity = .0001). For men, but not women, heterogeneous relationships were observed for body mass index (P heterogeneity = .008) and waist circumference (P heterogeneity = .03), with weaker positive associations found for rectal cancer, compared with proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P heterogeneity = .05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors. CONCLUSIONS: The relationships between physical activity, anthropometry, and smoking with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.
  • Huvinen, Emilia; Eriksson, Johan G.; Stach-Lempinen, Beata; Tiitinen, Aila; Koivusalo, Saila B. (2018)
    AimsGestational diabetes (GDM) affects a growing number of women and identification of individuals at risk, e.g., with risk prediction models, would be important. However, the performance of GDM risk scores has not been optimal. Here, we assess the impact of GDM heterogeneity on the performance of two top-rated GDM risk scores.MethodsThis is a substudy of the RADIEL triala lifestyle intervention study including women at high GDM risk. We assessed the GDM risk score by Teede and that developed by Van Leeuwen in our high-risk cohort of 510 women. To investigate the heterogeneity of GDM, we further divided the women according to GDM history, BMI, and parity. With the goal of identifying novel predictors of GDM, we further analyzed 319 women with normal glucose tolerance in the first trimester.ResultsBoth risk scores underestimated GDM incidence in our high-risk cohort. Among women with a BMI30kg/m(2) and/or previous GDM, 49.4% developed GDM and 37.4% received the diagnosis already in the first trimester. Van Leeuwen score estimated a 19% probability of GDM and Teede succeeded in risk identification in 61%. The lowest performance of the risk scores was seen among the non-obese women. Fasting plasma glucose, HbA(1c), and family history of diabetes were predictors of GDM in the total study population. Analysis of subgroups did not provide any further information.ConclusionsOur findings suggest that the marked heterogeneity of GDM challenges the development of risk scores for detection of GDM.
  • Huvinen, Emilia; Eriksson, Johan G.; Koivusalo, Saila B.; Grotenfelt, Nora; Tiitinen, Aila; Stach-Lempinen, Beata; Rono, Kristiina (2018)
    To assess the metabolic health of obese and non-obese women at high GDM risk 5 years postpartum. This is a secondary analysis of the 5-year follow-up of the RADIEL GDM prevention study including 333 women at high GDM risk (BMI ae 30 kg/m(2) and/or previous GDM). Five years postpartum metabolic health was assessed including anthropometric measurements, oral glucose tolerance test, lipid metabolism, and body composition as well as medical history questionnaires. For the analysis, we divided the women into four groups based on parity, BMI, and previous history of GDM. Five years postpartum impaired glucose regulation (IFG, IGT, or diabetes) was diagnosed in 15% of the women; 3.6% had type 2 diabetes. The highest prevalence was observed among obese women with a history of GDM (26%), and the lowest prevalence (8%) among primiparous obese women (p = 0.021). At follow-up 25-39% of the obese women fulfilled the diagnostic criteria for the metabolic syndrome, in the non-obese group 11% (p <0.001). This was associated with body fat percentage. The non-obese group, however, faced metabolic disturbances (IFG, IGT, diabetes, or metabolic syndrome) at a significantly lower BMI (p <0.001). Among women who were non-obese before pregnancy, 5 years postpartum, the obesity prevalence based on BMI was 14% and based on body fat percentage 58%. The prevalence of impaired glucose regulation and metabolic syndrome is high 5 years postpartum among women at high risk of GDM. There are high-risk women also among the non-obese, who develop metabolic derangements already at a lower BMI.
  • Gautam, Prson; Karhinen, Leena; Szwajda, Agnieszka; Jha, Sawan Kumar; Yadav, Bhagwan; Aittokallio, Tero; Wennerberg, Krister (2016)
    Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method: The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results: Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions: Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
  • Huvinen, Emilia; Engberg, Elina; Meinilä, Jelena; Tammelin, Tuija; Kulmala, Janne; Heinonen, Kati; Bergman, Paula; Stach-Lempinen, Beata; Koivusalo, Saila (2020)
    Aim Women with prior gestational diabetes (GDM) are at increased diabetes risk. This study aimed to assess whether lifestyle is associated with glycemic health of high-risk women 5 years postpartum, taking into account the pre-pregnancy BMI. Methods The RADIEL study enrolled before or in early pregnancy 720 women with pre-pregnancy BMI >= 30 kg/m(2)and/or prior GDM. The follow-up visit 5 years postpartum included questionnaires and measurements of anthropometrics, blood pressure, and physical activity (PA) as well as analyses of glucose metabolism, lipids, and inflammatory markers. We measured body composition (Inbody) and calculated a Healthy Food Intake Index (HFII) from Food Frequency Questionnaires (FFQ). ArmBand measured PA, sedentary time, and sleep. To take into account the diverse risk groups of GDM, we divided the women based on pre-pregnancy BMI over/under 30 kg/m(2). Results Altogether 348 women attended the follow-up. The obese and non-obese women showed similar prevalence of glycemic abnormalities, 13% and 19% (p = 0.139). PA levels were higher among the non-obese women (p <0.05), except for step count, and their HFII was higher compared to the obese women (p = 0.033). After adjusting for age, education, and GDM history, PA and HFII were associated with glycemic health only among obese women. When both lifestyle factors were in the same model, only PA remained significant. PA associated with other markers of metabolic health also among the non-obese women, excluding HbA1c. Conclusion Lifestyle 5 years postpartum was associated with better glycemic health only among the obese high-risk women. PA, however, is essential for the metabolic health of all high-risk women.
  • Kentta, Tuomas V.; Nearing, Bruce D.; Porthan, Kimmo; Tikkanen, Jani T.; Viitasalo, Matti; Nieminen, Markku S.; Salomaa, Veikko; Oikarinen, Lasse; Jula, Antti; Kontula, Kimmo; Newton-Cheh, Chris; Huikuri, Heikki V.; Verrier, Richard L. (2016)
    BACKGROUND Heterogeneity of depolarization and repolarization underlies the development of lethal arrhythmias. OBJECTIVE We investigated whether quantification of spatial depolarization and repolarization heterogeneity identifies individuals at risk for sudden cardiac death (SCD). METHODS Spatial R-, J-, and T-wave heterogeneity (RWH, JWH, and TWH, respectively) was analyzed using automated second central moment analysis of standard digital 12-lead electrocardiograms in 5618 adults (2588, 46% men; mean +/- SEM age 50.9 +/- 0.2 years), who took part in the epidemiological Health 2000 Survey as representative of the entire Finnish adult population. RESULTS During the follow-up period of 7.7 +/- 0.2 years, a total of 72 SCDs occurred (1.3%), with an average yearly incidence rate of 0.17% per year. Increased RWH, JWH, and TWH in left precordial leads (V-4-V-6) were univariately associated with SCD (P <.001 for each). When adjusted with standard clinical risk markers, JWH and TWH remained independent predictors of SCD. Increased TWH (>= 102 mu V) was associated with a 1.7-fold adjusted relative risk for SCD (95% confidence interval [CI] 1.0-2.9; P = .048) and increased JWH (>= 123 mu V) with a 2.0-fold adjusted relative risk for SCD (95% CI 1.2-3.3; P = .006). When both TWH and JWH were above the threshold, the adjusted relative risk for SCD was 2.9-fold (95% CI 1.5-5.7; P = .002). When RWH (>= 470 mu V), JWH, and TWH were all above the threshold, the adjusted relative risk for SCD was 3.2-fold (95% CI 1.4-7.1; P = .009). CONCLUSION Second central moment analysis of standard resting 12-lead electrocardiographic morphology provides an ultrarapid means for the automated measurement of spatial RWH, JWH, and TWH, enabling analysis of high subject volumes and screening for SCD risk in the general population.