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  • Tanhuanpää, Pirjo; Erkkilä, Maria; Kalendar, Ruslan; Schulman, Alan H; Manninen, Outi (BioMed Central, 2016)
    Abstract Background Timothy (Phleum pratense L.), a cool-season hexaploid perennial, is the most important forage grass species in Nordic countries. Earlier analyses of genetic diversity in a collection of 96 genebank accessions of timothy with SSR markers demonstrated high levels of diversity but could not resolve population structure. Therefore, we examined a subset of 51 accessions with REMAP markers, which are based on retrotransposons, and compared the diversity results with those obtained with SSR markers. Results Using four primer combinations, 533 REMAP markers were analyzed, compared with 464 polymorphic alleles in the 13 SSR loci previously. The average marker index, which describes information obtained per experiment (per primer combination or locus) was over six times higher with REMAPs. Most of the variation found was within accessions, with somewhat less, 89 %, for REMAPs, than for SSR, with 93 %. Conclusions SSRs revealed differences in the level of diversity slightly better than REMAPs but neither marker type could reveal any clear clustering of accessions based on countries, vegetation zones, or different cultivar types. In our study, reliable evaluation of SSR allele dosages was not possible, so each allele had to be handled as a dominant marker. SSR and REMAP, which report from different mechanisms of generating genetic diversity and from different genomic regions, together indicate a lack of population structure. Taken together, this likely reflects the outcrossing and hexaploid nature of timothy rather than failures of either marker system.
  • Pollesello, P.; Parissis, J.; Kivikko, M.; Harjola, V. -P. (ELSEVIER IRELAND LTD, 2016)
    Background: Levosimendan is an inodilator developed for treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. Levosimendan has been studied in different therapeutic settings including acutely decompensated chronic heart failure, advanced heart failure, right ventricular failure, cardiogenic shock, septic shock, and cardiac and non-cardiac surgery. This variety of data has been re-analysed in 25 meta-analyses from 15 different international research groups, based on different rationales to select the studies included. Methods: We here review all previously published meta-analyses on levosimendan to determine any common denominators for its effects on patient mortality. In addition, we also perform a comparative meta-analysis of the six phase II and III randomized double-blind trials which were taken into consideration by the regulatory authorities for the purpose of introducing levosimendan into the market. Results: Irrespective of clinical setting or comparator, all meta-analyses consistently show benefits for levosimendan, with lower relative risk (or odds ratio) for patient mortality. In 3/25 of the meta-analyses these beneficial trends did not reach statistical significance, while in 22/25 significance was reached. The relative risk is consistent overall, and very similar to that obtained in our own meta-analysis that considered only the 'regulatory' studies. Conclusion: The existing meta-analyses, now based on a population of over 6000 patients, provide the general message of significant benefits for levosimendan in terms of patient mortality. The weight of evidence is now clearly in favour of usefulness/efficacy of levosimendan, with data from multiple randomized trials and meta-analyses. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
  • Mäkeläinen, Sanna; de Knegt, Henrik J; Ovaskainen, Otso; Hanski, Ilpo K (BioMed Central, 2016)
  • Åberg, Fredrik (Baishideng Publishing Group Co, 2016)
    Return to active and productive life is a key goal of modern liver transplantation (LT). Despite marked improvements in quality of life and functional status, a substantial proportion of LT recipients are unable to resume gainful employment. Unemployment forms a threat to physical and psychosocial health, and impairs LT cost-utility through lost productivity. In studies published after year 2000, the average post-LT employment rate is 37%, ranging from 22% to 55% by study. Significant heterogeneity exists among studies. Nonetheless, these employment rates are lower than in the general population and kidney-transplant population. Most consistent employment predictors include pre-LT employment status, male gender, functional/health status, and subjective work ability. Work ability is impaired by physical fatigue and depression, but affected also by working conditions and society. Promotion of post-LT employment is hampered by a lack of interventional studies. Prevention of pre-LT disability by effective treatment of (minimal) hepatic encephalopathy, maintaining mobility, and planning work adjustments early in the course of chronic liver disease, as well as timely post-LT physical rehabilitation, continuous encouragement, self-efficacy improvements, and depression management are key elements of successful employment-promoting strategies. Prolonging LT recipients' working life would further strengthen the success of transplantation, and this is likely best achieved through multidisciplinary efforts ideally starting even before LT candidacy.
  • Douillard, Francois P.; Rasinkangas, Pia; Bhattacharjee, Arnab; Palva, Airi; de Vos, Willem M. (PUBLIC LIBRARY OF SCIENCE, 2016)
    Predominantly identified in pathogenic Gram-positive bacteria, sortase-dependent pili are also found in commensal species, such as the probiotic-marketed strain Lactobacillus rhamnosus strain GG. Pili are typically associated with host colonization, immune signalling and biofilm formation. Comparative analysis of the N-terminal domains of pilin-specific sortases from various piliated Gram-positive bacteria identified a conserved motif, called GYPSY, within the signal sequence. We investigated the function and role of the GYPSY residues by directed mutagenesis in homologous (rod-shaped) and heterologous (coccoid-shaped) expression systems for pilus formation. Substitutions of some of the GYPSY residues, and more specifically the proline residue, were found to have a direct impact on the degree of piliation of Lb. rhamnosus GG. The present findings uncover a new signalling element involved in the functionality of pilin-specific sortases controlling the pilus biogenesis of Lb. rhamnosus GG and related piliated Gram-positive species.
  • Honeyborne, Isobella; McHugh, Timothy D; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; van Helden, Paul D; Gillespie, Stephen H; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D; Waddell, Simon J (BioMed Central, 2016)
    Abstract Background New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Methods and Results Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). Conclusions This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb mRNA profiles 0–2 weeks into chemotherapy predict the efficacy of treatment 6 weeks later. These observations advocate assaying dynamic bacterial phenotypes through drug therapy as biomarkers for treatment success.
  • Lehikoinen, Markku; Arffman, Martti; Manderbacka, Kristiina; Elovainio, Marko; Keskimäki, Ilmo (BioMed Central, 2016)
    Abstract Background Large cities are often claimed to display more distinct geographical and socioeconomic health inequalities than other areas due to increasing residential differentiation. Our aim was to assess whether geographical inequalities in mortality within the capital (City of Helsinki) both exceeded that in other types of geographical areas in Finland, and whether those differences were dependent on socioeconomic inequalities. Methods We analysed the inequality of distribution separately for overall, ischemic heart disease and alcohol-related mortality, and mortality amenable (AM) to health care interventions in 1992–2008 in three types of geographical areas in Finland: City of Helsinki, other large cities, and small towns and rural areas. Mortality data were acquired as secondary data from the Causes of Death statistics from Statistics Finland. The assessment of changing geographical differences over time, that is geographical inequalities, was performed using Gini coefficients. As some of these differences might arise from socioeconomic factors, we assessed socioeconomic differences with concentration indices in parallel to an analysis of geographical differences. To conclude the analysis, we compared the changes over time of these inequalities between the three geographical areas. Results While mortality rates mainly decreased, alcohol-related mortality in the lowest income quintile increased. Statistically significant differences over time were found in all mortality groups, varying between geographical areas. Socioeconomic differences existed in all mortality groups and geographical areas. In the study period, geographical differences in mortality remained relatively stable but income differences increased substantially. For instance, the values of concentration indices for AM changed by 54 % in men (p < 0.027) and by 62 % in women (p < 0.016). Only slight differences existed in the time trends of Gini or in the concentration indices between the geographical areas. Conclusions No geographical or income-related differences in the distribution of mortality existed between Helsinki and other urban or rural areas of Finland. This suggests that the effect of increasing residential differentiation in the capital may have been mitigated by the policies of positive discrimination and social mixing. One of the main reasons for the increase in health inequalities was growth of alcohol-related mortality, especially among those with the lowest incomes.
  • Halmesmäki, Esa; Pasternack, Iris; Roine, Risto Paavo Antero (BIOMED CENTRAL LTD, 2016)
    Background: This study examines, as a part of the European Union funded Adopting Hospital Based Health Technology Assessment (AdHopHTA) project, the results and barriers of collaboration between Finnish hospitals and the national health technology assessment (HTA) agency, Finohta. A joint collaborative HTA program has existed since 2006 between the Finnish hospitals and the national agency. Methods: A case study method was used. Information about the collaboration between Finnish hospitals and Finohta was retrieved from interviews and publications, and categorised per theme. Hypotheses and indicators of successful collaboration were determined beforehand and reflected on the observations from the interviews and literature. Results: Overall, 48 collaborative HTA reports have been performed during 7 years of collaboration. However, there were no clear indications that the use of HTA information or the transparency of decision-making regarding new technologies would have increased in hospitals. The managerial commitment to incorporate HTAs into the decision-making processes in hospitals was still low. The quality of the collaborative HTA reports was considered good, but their applicability in the hospital setting limited. There were differing expectations about the timing and relevance of the content. Signs of role conflict and mistrust were observed. Conclusions: Despite collaborative efforts to produce HTAs for hospitals, the impact of HTA information on hospital decision-making appears to remain low. The difficulties identified in this case study, such as lack of managerial commitment in hospitals, can hopefully be better addressed in the future with the guidance and tools having been developed in the AdHopHTA project. Collaboration between hospitals and national HTA agencies remains important for the efficient sharing of skills and resources.
  • Koskinen, Jyri-Pekka; Kiviranta, Hannu; Vartiainen, Erkki; Jousilahti, Pekka; Vlasoff, Tiina; von Hertzen, Leena; Mäkelä, Mika; Laatikainen, Tiina; Haahtela, Tari (BioMed Central, 2016)
    Abstract Background Atopic allergy is much more common in Finnish compared with Russian Karelia, although these areas are geographically and genetically close. To explore the role of environmental chemicals on the atopy difference a random sample of 200 individuals, 25 atopic and 25 non-atopic school-aged children and their mothers, were studied. Atopy was defined as having at least one positive skin prick test response to 14 common inhalant and food allergens tested. Concentrations of 11 common environmental pollutants were measured in blood samples. Results Overall, the chemical levels were much higher in Russia than in Finland, except for 2,2′,4,4′-tetra-bromodiphenyl ether (BDE47). In Finland but not in Russia, the atopic children had higher concentrations of polychlorinated biphenyls and 1,1-Dichloro-2,2-bis-(p-chlorophenyl)-ethylene (DDE) than the non-atopic children. In Russia but not in Finland, the atopic mothers had higher DDE concentrations than the non-atopic mothers. Conclusions Higher concentrations of common environmental chemicals were measured in Russian compared with Finnish Karelian children and mothers. The chemicals did not explain the higher prevalence of atopy on the Finnish side.
  • Granberg, Fredric Gustaf; Nordlund, Kai Henrik; Ullah, Mohammad Wali; Jin, K; Lu, C; Bei, H; Wang, L; Djurabekova, Flyura Gatifovna; Weber, WJ; Zhang, Y (American Institute of Physics, 2016)
  • Riddle, Matthew C.; Bolli, Geremia B.; Home, Philip D.; Bergenstal, Richard M.; Ziemen, Monika; Muehlen-Bartmer, Isabel; Wardecki, Marek; Vinet, Laetitia; Jeandidier, Nathalie; Yki-Jarvinen, Hannele (Mary Ann Liebert, Inc, 2016)
    Background: Insulin glargine 300 U/mL (Gla-300) has a more constant and prolonged action profile than insulin glargine 100 U/mL and in clinical studies is associated with similar glycemic control but less hypoglycemia. Whether its effects are altered by variability of injection time was examined in two 3-month substudies. Materials and Methods: Eligible participants completing 6 months of optimized treatment with Gla-300 in EDITION 1 (n = 109) and EDITION 2 (n = 89), having a mean hemoglobin A1c (HbA(1c)) level of 7.3 % (SD 1.0 %), were randomized (1:1) to groups advised to increase variability of between-injection intervals to 24 +/- up to 3 h or to maintain fixed 24-h intervals for 3 months. Changes of HbA(1c) level and other efficacy and safety measures were assessed. Results: In the fixed-dosing group, 64% of participants reported all intervals within the 23-25-h range, compared with 15% of those advised flexible dosing. In the fixed- and flexible-dosing groups, 12% and 41%, respectively, of between-injection intervals were outside the 23-25-h range, and 2% and 16%, respectively, were outside the 21-27-h range. Least squares mean between-group difference in HbA(1c) change from baseline was 0.05 % (95% confidence interval [CI], -0.13 to 0.23); for fasting plasma glucose, 2.7 mg/dL (95% CI, -9.0 to 14.4); and for daily basal insulin dose, 0.00 U/kg (95% CI, -0.02 to 0.03). Frequencies of hypoglycemia and adverse events did not differ between groups. Conclusions: The efficacy and safety of Gla-300 demonstrated in EDITION 1 and EDITION 2 are maintained in substudies when the insulin was injected up to 3 h before or after the usual time of administration.
  • Määttä, Jussi; Roos, Teemu (PUBLIC LIBRARY OF SCIENCE, 2016)
  • Schuijt, Tim J.; Lankelma, Jacqueline M.; Scicluna, Brendon P.; e Melo, Felipe de Sousa; Roelofs, Joris J. T. H.; de Boer, J. Daan; Hoogendijk, Arjan J.; de Beer, Regina; de Vos, Alex; Belzer, Clara; de Vos, Willem M.; van der Poll, Tom; Wiersinga, W. Joost (BMJ GROUP, 2016)
    Objective Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against Streptococcus pneumoniae infections. Design We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumoniae. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses. Results We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-alpha and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose S. pneumoniae. Conclusions This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut-lung axis in bacterial infections.
  • Pulkkinen, Lea; Latvala, Antti; Rose, Richard J. (Cambridge University Press, 2016)
  • Nevalainen, Terttu; Vartiainen, Turo; Säily, Tanja; Kesäniemi, Joonas; Dominowska, Agata; Öhman, Emily (NORWEGIAN COMPUTING CENTRE FOR THE HUMANITIES, 2016)
    We introduce the Language Change Database (LCD), which provides access to the results of previous corpus-based research dealing with change in the English language. The LCD will be published on an open-access linked data platform that will allow users to enter information about their own publications into the database and to conduct searches based on linguistic and extralinguistic parameters. Both metadata and numerical data from the original publications will be available for download, enabling systematic reviews, meta-analyses, replication studies and statistical modelling of language change. The LCD will be of interest to scholars, teachers and students of English.
  • Biancari, Fausto; Mariscalco, Giovanni; Mariani, Silvia; Saari, Petri; Satta, Jari; Juvonen, Tatu (SAGE, 2016)
    Purpose: To determine the efficacy of thoracic endovascular aortic repair (TEVAR) for degenerative aneurysm involving only the descending thoracic aorta (DTAA). Methods: An English-language literature review was performed through PubMed, Scopus, and Google Scholar to identify any study evaluating the outcomes of TEVAR for DTAA. The main endpoints of this analysis were all-cause 30-day and late postoperative mortality. Secondary outcome measures were procedure success, vascular access complications, paraplegia, stroke, early endoleaks during the index hospitalization, aneurysm-related death, reinterventions, and conversion to open repair. To control for the anticipated heterogeneity among small observational studies, absolute values and means were pooled using random effects models; the results are expressed as pooled proportions, means, or risk ratio (RR) with 95% confidence intervals (CIs). Results: Eleven studies reporting on 673 patients (mean age 72.6 years, mean aneurysm diameter 62.9 cm) with DTAA were selected for the analysis. Technical success was reported in 91.0% of patients, and vascular access complications requiring repair were encountered in 9.7% of cases. Pooled overall 30-day, 1-year, 2-year, and 3-year survival rates were 96.0%, 80.3%, 77.3%, and 74.0%, respectively. Five studies compared the results of TEVAR after elective (n=151) and urgent/emergent procedure (n=77); the latter was a predictor of 30-day mortality (17.1% vs 1.8%, RR 3.83, 95% CI 1.18 to 12.40, p=0.025). Paraplegia occurred in 3.2% of patients and was permanent in 1.4% of patients. The stroke rate was 2.7%. Early type I endoleak was observed in 7.3%, type II endoleak in 2.0%, and type III in 1.2% of patients. The mean follow-up of 9 studies was 22.3 months. At 3 years, freedom from reintervention was 90.3%. Death secondary to aneurysm rupture and/or fistula was reported in 3.2% of patients. Conclusion: Current results indicate that TEVAR for DTAA can be performed with rather high technical success, low postoperative morbidity, and good 3-year survival.
  • Palmio, Johanna; Evilä, Anni; Bashir, Ayat; Norwood, Fiona; Viitaniemi, Kati; Vihola, Anna; Huovinen, Sanna; Straub, Volker; Hackman, Peter; Hirano, Michio; Bushby, Kate; Udd, Bjarne (BMJ GROUP, 2016)
  • Eising, Else; Huisman, Sjoerd M. H.; Mahfouz, Ahmed; Vijfhuizen, Lisanne S.; Anttila, Verneri; Winsvold, Bendik S.; Kurth, Tobias; Ikram, M. Arfan; Freilinger, Tobias; Kaprio, Jaakko; Boomsma, Dorret I.; van Duijn, Cornelia M.; Jarvelin, Marjo-Riitta R.; Zwart, John-Anker; Quaye, Lydia; Strachan, David P.; Kubisch, Christian; Dichgans, Martin; Smith, George Davey; Stefansson, Kari; Palotie, Aarno; Chasman, Daniel I.; Ferrari, Michel D.; Terwindt, Gisela M.; de Vries, Boukje; Nyholt, Dale R.; Lelieveldt, Boudewijn P. F.; van den Maagdenberg, Arn M. J. M.; Reinders, Marcel J. T. (Springer, 2016)
    Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.
  • Lee, Laura M.; Wallace, Roberta S.; Clyde, Victoria L.; Gendron-Fitzpatrick, Annette; Sibley, Samuel D.; Stuchin, Margot; Lauck, Michael; O'Connor, David H.; Nakao, Minoru; Lavikainen, Antti; Hoberg, Eric P.; Goldberg, Tony L. (National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), 2016)
    We previously reported fatal infection of a captive Bornean orangutan with metacestodes of a novel taeniid tapeworm, Versteria sp. New data implicate mustelids as definitive hosts of these tapeworms in North America. At least 2 parasite genetic lineages circulate in North America, representing separate introductions from Eurasia.
  • Kuhle, J.; Hardmeier, M.; Disanto, G.; Gugleta, K.; Ecsedi, M.; Lienert, C.; Amato, M. P.; Baum, K.; Buttmann, M.; Bayas, A.; Brassat, D.; Brochet, B.; Confavreux, C.; Edan, G.; Färkkilä, Markus; Fredrikson, S.; Frontoni, M.; D'Hooghe, M.; Hutchinson, M.; De Keyser, J.; Kieseier, B. C.; Kuempfel, T.; Rio, J.; Polman, C.; Roullet, E.; Stolz, C.; Vass, K.; Wandinger, K. P.; Kappos, L.; European Long Term Follow Up Study (SAGE, 2016)
    Objectives: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). Methods: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. Results: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R-2: 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R-2: 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained <5% of the variability. Conclusions: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.