Browsing by Subject "GRADE"

Sort by: Order: Results:

Now showing items 1-20 of 20
  • Sahlin, Ullrika; Helle, Inari; Perepolkin, Dmytro (2021)
    Failing to communicate current knowledge limitations, that is, epistemic uncertainty, in environmental risk assessment (ERA) may have severe consequences for decision making. Bayesian networks (BNs) have gained popularity in ERA, primarily because they can combine variables from different models and integrate data and expert judgment. This paper highlights potential gaps in the treatment of uncertainty when using BNs for ERA and proposes a consistent framework (and a set of methods) for treating epistemic uncertainty to help close these gaps. The proposed framework describes the treatment of epistemic uncertainty about the model structure, parameters, expert judgment, data, management scenarios, and the assessment's output. We identify issues related to the differentiation between aleatory and epistemic uncertainty and the importance of communicating both uncertainties associated with the assessment predictions (direct uncertainty) and the strength of knowledge supporting the assessment (indirect uncertainty). Probabilities, intervals, or scenarios are expressions of direct epistemic uncertainty. The type of BN determines the treatment of parameter uncertainty: epistemic, aleatory, or predictive. Epistemic BNs are useful for probabilistic reasoning about states of the world in light of evidence. Aleatory BNs are the most relevant for ERA, but they are not sufficient to treat epistemic uncertainty alone because they do not explicitly express parameter uncertainty. For uncertainty analysis, we recommend embedding an aleatory BN into a model for parameter uncertainty. Bayesian networks do not contain information about uncertainty in the model structure, which requires several models. Statistical models (e.g., hierarchical modeling outside the BNs) are required to consider uncertainties and variability associated with data. We highlight the importance of being open about things one does not know and carefully choosing a method to precisely communicate both direct and indirect uncertainty in ERA. Integr Environ Assess Manag 2020;00:1-12. (c) 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)
  • Jukonen, Joonas; Moyano-Galceran, Lidia; Höpfner, Katrin; Pietilä, Elina A.; Lehtinen, Laura; Huhtinen, Kaisa; Gucciardo, Erika; Hynninen, Johanna; Hietanen, Sakari; Grenman, Seija; Ojala, Päivi M.; Carpen, Olli; Lehti, Kaisa (2021)
    Erythropoietin producing hepatocellular (Eph) receptors and their membrane-bound ligands ephrins are variably expressed in epithelial cancers, with context-dependent implications to both tumor-promoting and-suppressive processes in ways that remain incompletely understood. Using ovarian cancer tissue microarrays and longitudinally collected patient cells, we show here that ephrinA5/EFNA5 is specifically overexpressed in the most aggressive high-grade serous carcinoma (HGSC) subtype, and increased in the HGSC cells upon disease progression. Among all the eight ephrin genes, high EFNA5 expression was most strongly associated with poor overall survival in HGSC patients from multiple independent datasets. In contrast, high EFNA3 predicted improved overall and progression-free survival in The Cancer Genome Atlas HGSC dataset, as expected for a canonical inducer of tumor-suppressive Eph receptor tyrosine kinase signaling. While depletion of either EFNA5 or the more extensively studied, canonically acting EFNA1 in HGSC cells increased the oncogenic EphA2-S897 phosphorylation, EFNA5 depletion left unaltered, or even increased the ligand-dependent EphA2-Y588 phosphorylation. Moreover, treatment with recombinant ephrinA5 led to limited EphA2 tyrosine phosphorylation, internalization and degradation compared to ephrinA1. Altogether, our results suggest a unique function for ephrinA5 in Eph-ephrin signaling and highlight the clinical potential of ephrinA5 as a cell surface biomarker in the most aggressive HGSCs.
  • Tikkinen, Kari A. O.; Craigie, Samantha; Schünemann, Holger J.; Guyatt, Gordon H. (2018)
    Objectives: The Grading of Recommendations Assessment, Development and Evaluation approach to rating certainty of evidence includes five domains of reasons for rating down certainty. Only one of these, precision, is easily amenable through the confidence interval to quantitation. The other four (risk of bias, inconsistency, indirectness, and publication bias) are not. Nevertheless, conceptually, one could consider a quantified "certainty range" within which the true effect lies. The certainty range would be at least as wide as the confidence interval and would expand with each additional reason for uncertainty. Study Design and Setting: We have applied this concept to rating the certainty of evidence in the baseline risk of venous thromboembolism (VTE) and bleeding in patients undergoing urological surgery. We considered rating up moderate or low quality evidence when the net benefit of VTE prophylaxis was unequivocally positive, that is, when the smallest plausible value of VTE reduction was greater than the largest plausible value of increased bleeding. To establish whether the net benefit was unequivocally positive, we expanded the range of plausible values by 20% for each of the four nonquantitative domains in which there were serious limitations. Results: We present how we applied these methods to examples of open radical cystectomy and laparoscopic partial nephrectomy. In high-VTE risk laparoscopic partial nephrectomy patients and high-and medium-VTE risk open radical cystectomy patients, results proved robust to expanded certainty intervals, justifying rating up quality of evidence. In low -risk patients, the results were not robust, and rating up was therefore not appropriate. Conclusion: This work represents the first empirical application in a decision -making context of the previously suggested concept of certainty ranges and should stimulate further exploration of the associated theoretical and practical issues. (C) 2018 Elsevier Inc. All rights reserved.
  • Riikonen, Jarno M.; Guyatt, Gordon H.; Kilpeläinen, Tuomas P.; Craigie, Samantha; Agarwal, Arnav; Agoritsas, Thomas; Couban, Rachel; Dahm, Philipp; Järvinen, Petrus; Montori, Victor; Power, Nicholas; Richard, Patrick O.; Rutanen, Jarno; Santti, Henrikki; Tailly, Thomas; Violette, Philippe D.; Zhou, Qi; Tikkinen, Kari A. O. (2019)
    Key PointsQuestionWhat is the association of decision aids vs usual care with shared decision-making in men deciding whether to undergo prostate cancer screening? FindingsThis systematic review and meta-analysis of 19 randomized clinical trials comparing decision aids for prostate cancer screening (12781 men) found that decision aids are probably associated with a small reduction in decisional conflict and are possibly associated with an increase in knowledge. Decision aids are possibly not associated with whether physicians and patients discuss prostate cancer screening and are possibly not associated with actual screening decisions. MeaningRandomized clinical trials have failed to provide compelling evidence for the use of decision aids for men contemplating prostate cancer screening that have, up to now, undergone rigorous testing to determine their outcome. ImportanceUS guidelines recommend that physicians engage in shared decision-making with men considering prostate cancer screening. ObjectiveTo estimate the association of decision aids with decisional outcomes in prostate cancer screening. Data SourcesMEDLINE, Embase, PsycINFO, CINAHL, and Cochrane CENTRAL were searched from inception through June 19, 2018. Study SelectionRandomized trials comparing decision aids for prostate cancer screening with usual care. Data Extraction and SynthesisIndependent duplicate assessment of eligibility and risk of bias, rating of quality of the decision aids, random-effects meta-analysis, and Grading of Recommendations, Assessment, Development and Evaluations rating of the quality of evidence. Main Outcomes and MeasuresKnowledge, decisional conflict, screening discussion, and screening choice. ResultsOf 19 eligible trials (12781 men), 9 adequately concealed allocation and 8 blinded outcome assessment. Of 12 decision aids with available information, only 4 reported the likelihood of a true-negative test result, and 3 presented the likelihood of false-negative test results or the next step if the screening test result was negative. Decision aids are possibly associated with improvement in knowledge (risk ratio, 1.38; 95% CI, 1.09-1.73; I-2=67%; risk difference, 12.1; low quality), are probably associated with a small decrease in decisional conflict (mean difference on a 100-point scale, -4.19; 95% CI, -7.06 to -1.33; I-2=75%; moderate quality), and are possibly not associated with whether physicians and patients discuss prostate cancer screening (risk ratio, 1.12; 95% CI, 0.90-1.39; I-2=60%; low quality) or with men's decision to undergo prostate cancer screening (risk ratio, 0.95; 95% CI, 0.88-1.03; I-2=36%; low quality). Conclusions and RelevanceThe results of this study provide moderate-quality evidence that decision aids compared with usual care are associated with a small decrease in decisional conflict and low-quality evidence that they are associated with an increase in knowledge but not with whether physicians and patients discussed prostate cancer screening or with screening choice. Results suggest that further progress in facilitating effective shared decision-making may require decision aids that not only provide education to patients but are specifically targeted to promote shared decision-making in the patient-physician encounter. This systematic review and meta-analysis of 19 randomized clinical trials estimates the association of decision aids with decisional outcomes in prostate cancer screening.
  • Agache, Ioana; Song, Yang; Rocha, Claudio; Beltran, Jessica; Posso, Margarita; Steiner, Corinna; Alonso-Coello, Pablo; Akdis, Cezmi; Akdis, Mubeccel; Canonica, Giorgio Walter; Casale, Thomas; Chivato, Tomas; Corren, Jonathan; del Giacco, Stefano; Eiwegger, Thomas; Firinu, Davide; Gern, James E.; Hamelmann, Eckard; Hanania, Nicola; Mäkelä, Mika; Martin, Irene Hernandez; Nair, Parameswaran; O'Mahony, Liam; Papadopoulos, Nikolaos G.; Papi, Alberto; Park, Hae-Sim; de Llano, Luis Perez; Quirce, Santiago; Sastre, Joaquin; Shamji, Mohamed; Schwarze, Jurgen; Canelo-Aybar, Carlos; Palomares, Oscar; Jutel, Marek (2020)
    Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor alpha, is approved as add-on maintenance treatment for inadequately controlled type 2 severe asthma. This systematic review evaluated the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled severe asthma. PubMed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. Three RCTs including 2735 subjects >12 years old and 24-52 weeks of follow-up were included. Dupilumab reduced with high certainty severe asthma exacerbations (Incidence rate ratio 0.51; 95% CI 0.45-0.59) and the percentage use of oral corticosteroid use (mean difference (MD) -28.2 mg/d; 95% CI -40.7 to -15.7). Asthma control (ACQ-5), quality of life (AQLQ) and rescue medication use [puffs/d] improved, without reaching the minimal important clinical difference: ACQ-5 MD -0.28 (95% CI -0.39 to -0.17); AQLQ MD +0.28 (95% CI 0.20-0.37); and rescue medication MD -0.35 (95% CI -0.73 to +0.02). FEV1 increased (MD +0.15; 95% CI +0.11 to +0.18) (moderate certainty). There was an increased rate of dupilumab-related adverse events (AEs) (moderate certainty) and of drug-related serious AEs (low certainty). The incremental cost-effectiveness ratio of dupilumab versus standard therapy was 464 000$/QALY (moderate certainty). More data on long-term safety are needed both for children and for adults, together with more efficacy data in the paediatric population.
  • European Stroke Org; Fuentes, Blanca; Ntaios, George; Putaala, Jukka; Thomas, Brenda; Turc, Guillaume; Diez-Tejedor, Exuperio (2018)
    Background Hyperglycaemia is a frequent complication in acute stroke that has been shown to be independently associated with larger infarct size, haematoma growth, poor clinical outcome and mortality. This Guideline Document presents the European Stroke Organisation (ESO) Guidelines for the management of blood glucose levels in patients with acute ischemic or haemorrhagic stroke. Methods The working group identified related questions and developed its recommendations based on evidence from randomised controlled trials following the standard operating procedure of the ESO. This Guideline Document was reviewed and approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. Results We found low-quality evidence from clinical trials in ischemic or haemorrhagic stroke exploring the use of intravenous insulin aimed to achieve a tight glycaemic control with different glucose level targets and several other sources of heterogeneity. None of these trials neither the meta-analysis of them have demonstrated any significant benefit of tight glycaemic control with intravenous insulin in acute ischemic or haemorrhagic stroke patients on functional outcome or in survival and they have shown an increased risk for hypoglycaemia. Conclusions We suggest against the routine use of tight glycaemic control with intravenous insulin as a means to improve outcomes. The currently available data about the management of glycaemia in patients with acute stroke are limited and the strengths of the recommendations are therefore weak. Nevertheless, this does not prevent that hyperglycaemia in acute stroke patients could be treated as any other hospitalised patient.
  • Petridis, Christos; Brook, Mark N.; Shah, Vandna; Kohut, Kelly; Gorman, Patricia; Caneppele, Michele; Levi, Dina; Papouli, Efterpi; Orr, Nick; Cox, Angela; Cross, Simon S.; dos-Santos-Silva, Isabel; Peto, Julian; Swerdlow, Anthony; Schoemaker, Minouk J.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Benitez, Javier; Gonzalez-Neira, Anna; Tessier, Daniel C.; Vincent, Daniel; Li, Jingmei; Figueroa, Jonine; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Soucy, Penny; Simard, Jacques; Milne, Roger L.; Giles, Graham G.; Margolin, Sara; Lindblom, Annika; Bruening, Thomas; Brauch, Hiltrud; Southey, Melissa C.; Hopper, John L.; Doerk, Thilo; Bogdanova, Natalia V.; Kabisch, Maria; Hamann, Ute; Schmutzler, Rita K.; Meindl, Alfons; Brenner, Hermann; Arndt, Volker; Winqvist, Robert; Pylkas, Katri; Fasching, Peter A.; Beckmann, Matthias W.; Lubinski, Jan; Jakubowska, Anna; Mulligan, Anna Marie; Andrulis, Irene L.; Tollenaar, Rob A. E. M.; Devilee, Peter; Le Marchand, Loic; Haiman, Christopher A.; Mannermaa, Arto; Kosma, Veli-Matti; Radice, Paolo; Peterlongo, Paolo; Marme, Frederik; Burwinkel, Barbara; van Deurzen, Carolien H. M.; Hollestelle, Antoinette; Miller, Nicola; Kerin, Michael J.; Lambrechts, Diether; Floris, Giuseppe; Wesseling, Jelle; Flyger, Henrik; Bojesen, Stig E.; Yao, Song; Ambrosone, Christine B.; Chenevix-Trench, Georgia; Truong, Therese; Guenel, Pascal; Rudolph, Anja; Chang-Claude, Jenny; Nevanlinna, Heli; Blomqvist, Carl; Czene, Kamila; Brand, Judith S.; Olson, Janet E.; Couch, Fergus J.; Dunning, Alison M.; Hall, Per; Easton, Douglas F.; Pharoah, Paul D. P.; Pinder, Sarah E.; Schmidt, Marjanka K.; Tomlinson, Ian; Roylance, Rebecca; Garcia-Closas, Montserrat; Sawyer, Elinor J. (2016)
    Background: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. Methods: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Results: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P <5.0x10(-8). Conclusion: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
  • Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie; Neuhausen, Susan L.; Fox, Stephen; Karlan, Beth Y.; Mitchell, Gillian; James, Paul; Thull, Darcy L.; Zorn, Kristin K.; Carter, Natalie J.; Nathanson, Katherine L.; Dornchek, Susan M.; Rebbeck, Timothy R.; Ramus, Susan J.; Nussbaum, Robert L.; Olopade, Olufunrnilayo I.; Rantala, Johanna; Yoon, Sook-Yee; Caligo, Maria A.; Spugnesi, Laura; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Muds; Jensen, Uffe Birk; Toland, Amanda Ewart; Senter, Leigha; Andrulis, Irene L.; Glendon, Gord; Hulick, Peter J.; Irnyanitov, Evgeny N.; Greene, Mark H.; Mai, Phuong L.; Singer, Christian F.; Rappaport-Fuerhauser, Christine; Kramer, Gero; Vijai, Joseph; Offit, Kenneth; Robson, Mark; Lincoln, Anne; Jacobs, Lauren; Machackova, Eva; Foretova, Lenka; Navratilova, Marie; Vasickova, Petra; Couch, Fergus J.; Hallberg, Emily; Ruddy, Kathryn J.; Sharma, Priyanka; Kim, Sung-Won; Teixeira, Manuel R.; Pinte, Pedro; Montagna, Marco; Matricardi, Laura; Arason, Adalgeir; Johannsson, Oskar Th; Barkardottir, Rosa B.; Jakubowska, Anna; Lubinski, Jan; Izquierdo, Angel; Angel Pujana, Miguel; Balmana, Judith; Diez, Orland; Ivady, Gabriella; Papp, Janos; Olah, Edith; Kwong, Ava; Nevanlinna, Heli; Aittomaki, Kristiina; Perez Segura, Pedro; Caldes, Trinidad; Van Maerken, Tom; Poppe, Bruce; Claes, Kathleen B. M.; Isaacs, Claudine; Elan, Camille; Lasset, Christine; Stoppa-Lyonnet, Dominique; Barjhoux, Laure; Belotti, Muriel; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Enger, Christoph; Niederacher, Dieter; Steinemann, Doris; Hahnen, Eric; Kast, Karin; Arnold, Norbert; Varon-Mateeva, Raymonda; Wand, Dorothea; Godwin, Andrew K.; Evans, D. Gareth; Frost, Debra; Perkins, Jo; Adlard, Julian; Izatt, Louise; Platte, Radka; Eeles, Ros; Ellis, Steve; Hamann, Ute; Garber, Judy; Fostira, Florentia; Fountzilas, George; Pasini, Barbara; Giannini, Giuseppe; Rizzolo, Piera; Russo, Antonio; Cortesi, Laura; Papi, Laura; Varesco, Liliana; Palli, Domenico; Zanna, Ines; Savarese, Antonella; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Bonanni, Bernardo; Viel, Alessandra; Pensotti, Valeria; Tommasi, Stefania; Peterlongo, Paolo; Weitzel, Jeffrey N.; Osorio, Ana; Benitez, Javier; McGuffog, Lesley; Healey, Sue; Gerdes, Anne-Marie; Ejlertsen, Bent; Hansen, Thomas V. O.; Steele, Linda; Ding, Yuan Chun; Tung, Nadine; Janavicius, Ramunas; Goldgar, David E.; Buys, Saundra S.; Daly, Mary B.; Bane, Anita; Terry, Mary Beth; John, Esther M.; Southey, Melissa; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Ottini, Laura; kConFab Investigators; Hereditary Breast Ovarian Canc Res; EMBRACE (2016)
    Background: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 x 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 x 10(-12)). Conclusions: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
  • Xu, Haifeng; Lien, Tonje; Bergholtz, Helga; Fleischer, Thomas; Djerroudi, Lounes; Vincent-Salomon, Anne; Sorlie, Therese; Aittokallio, Tero (2021)
    Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer with a highly variable potential of becoming invasive and affecting mortality of the patients. Due to the lack of accurate markers of disease progression, many women with detected DCIS are currently overtreated. To distinguish those DCIS cases who are likely to require therapy from those who should be left untreated, there is a need for robust and predictive biomarkers extracted from molecular or genetic profiles. We developed a supervised machine learning approach that implements multi-omics feature selection and model regularization for the identification of biomarker combinations that could be used to distinguish low-risk DCIS lesions from those with a higher likelihood of progression. To investigate the genetic heterogeneity of disease progression, we applied this approach to 40 pure DCIS and 259 invasive breast cancer (IBC) samples profiled with genome-wide transcriptomics, DNA methylation, and DNA copy number variation. Feature selection using the multi-omics Lasso-regularized algorithm identified both known genes involved in breast cancer development, as well as novel markers for early detection. Even though the gene expression-based model features led to the highest classification accuracy alone, methylation data provided a complementary source of features and improved especially the sensitivity of correctly classifying DCIS cases. We also identified a number of repeatedly misclassified DCIS cases when using either the expression or methylation markers. A small panel of 10 gene markers was able to distinguish DCIS and IBC cases with high accuracy in nested cross-validation (AU-ROC = 0.99). The marker panel was not specific to any of the established breast cancer subtypes, suggesting that the 10-gene signature may provide a subtype-agnostic and cost-effective approach for breast cancer detection and patient stratification. We further confirmed high accuracy of the 10-gene signature in an external validation cohort (AU-ROC = 0.95), profiled using distinct transcriptomic assay, hence demonstrating robustness of the risk signature.
  • Saarinen, Lilli; Nummela, Pirjo; Thiel, Alexandra; Lehtonen, Rainer; Järvinen, Petrus; Järvinen, Heikki; Aaltonen, Lauri A.; Lepisto, Anna; Hautaniemi, Sampsa; Ristimaki, Ari (2017)
    Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma mainly restricted to the peritoneal cavity and most commonly originating from the appendix. The genetic background of PMP is poorly understood and no targeted treatments are currently available for this fatal disease. While RAS signaling pathway is affected in most if not all PMP cases and over half of them also have a mutation in the GNAS gene, other genetic alterations and affected pathways are, to a large degree, poorly known. In this study, we sequenced whole coding genome of nine PMP tumors and paired normal tissues in order to identify additional, commonly mutated genes and signaling pathways affected in PMP. These exome sequencing results were validated with an ultra-deep amplicon sequencing method, leading to 14 validated variants. The validated results contain seven genes that contribute to the protein kinase A (PKA) pathway. PKA pathway, which also contains GNAS, is a major player of overproduction of mucin, which is the characteristic feature of PMP. In addition to PKA pathway, we identified mutations in six genes that belong to the transforming growth factor beta (TGF-beta) pathway, which is a key regulator of cell proliferation. Since either GNAS mutation or an alternative mutation in the PKA pathway was identified in 8/9 patients, inhibition of the PKA pathway might reduce mucin production in most of the PMP patients and potentially suppress disease progression.
  • Lappi, Pauli Antero; Ollikainen, Markku Martti Olavi (2019)
    This study analyzes socially optimal environmental policy for a mine with a model that takes into account waste or waste rock production and abatement possibilities of the mine. We develop a model, in which the mine produces an externality related to the waste rocks, such as acid mine drainage. We find that the extraction rate tends to be lower in a mine with higher waste rock production, and that the optimal tax on the waste rock production is strictly increasing in time. We extend the model to incorporate an additional externality in the form of a stock pollutant. We analyze the optimal taxes and show that the typical result that the time path of the tax on the stock pollutant is inverted U-shaped may be lost in a mine model with abatement possibility and fixed operation period.
  • Tikkinen, Kari A. O.; Craigie, Samantha; Agarwal, Arnav; Siemieniuk, Reed A. C.; Cartwright, Rufus; Violette, Philippe D.; Novara, Giacomo; Naspro, Richard; Agbassi, Chika; Ali, Bassel; Imam, Maha; Ismaila, Nofisat; Kam, Denise; Gould, Michael K.; Sandset, Per Morten; Guyatt, Gordon H. (2018)
    Context: Pharmacological thromboprophylaxis involves a trade-off between a reduction in venous thromboembolism (VTE) and increased bleeding. No guidance specific for procedure and patient factors exists in urology. Objective: To inform estimates of absolute risk of symptomatic VTE and bleeding requiring reoperation in urological non-cancer surgery. Evidence acquisition: We searched for contemporary observational studies and estimated the risk of symptomatic VTE or bleeding requiring reoperation in the 4 wk after urological surgery. We used the GRADE approach to assess the quality of the evidence. Evidence synthesis: The 37 eligible studies reported on 11 urological non-cancer procedures. The duration of prophylaxis varied widely both within and between procedures; for example, the median was 12.3 d (interquartile range [IQR] 3.1-55) for open recipient nephrectomy (kidney transplantation) studies and 1 d (IQR 0-1.3) for percutaneous nephrolithotomy, open prolapse surgery, and reconstructive pelvic surgery studies. Studies of open recipient nephrectomy reported the highest risks of VTE and bleeding (1.8-7.4% depending on patient characteristics and 2.4% for bleeding). The risk of VTE was low for 8/11 procedures (0.2-0.7% for patients with low/medium risk; 0.8-1.4% for high risk) and the risk of bleeding was low for 6/7 procedures ( Conclusions: Although inferences are limited owing to low-quality evidence, our results suggest that extended prophylaxis is warranted for some procedures (eg, kidney transplantation procedures in high-risk patients) but not others (transurethral resection of the prostate and reconstructive female pelvic surgery in low-risk patients). Patient summary: The best evidence suggests that the benefits of blood-thinning drugs to prevent clots after surgery outweigh the risks of bleeding in some procedures ( such as kidney transplantation procedures in patients at high risk of clots) but not others ( such as prostate surgery in patients at low risk of clots). (C) 2017 European Association of Urology. Published by Elsevier B.V.
  • Kinnunen, Pete T. T.; Murtola, Teemu J.; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo L. J.; Auvinen, Anssi (2017)
    Background: Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease. Methods: The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. Results: In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant nonusers, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1. 13-1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death. Conclusions: We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.
  • Int PCOS Network; Teede, Helena J.; Misso, Marie L.; Costello, Michael F.; Dokras, Anuja; Laven, Joop; Moran, Lisa; Piltonen, Terhi; Norman, Robert J.; Tapanainen, Juha (2018)
    STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.
  • Int PCOS Network; Teede, Helena J.; Misso, Marie L.; Costello, Michael F.; Dokras, Anuja; Laven, Joop; Moran, Lisa; Piltonen, Terhi; Norman, Robert J.; Tapanainen, Juha (2018)
    Study QuestionWhat is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary AnswerInternational evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. What is Known AlreadyPrevious guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. Study Design, Size, DurationInternational evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Participants/Materials, Setting, MethodsGovernance included a six continent international advisory and a project board, five guideline development groups (GDGs), and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. Main Results and the Role of ChanceThe evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (a) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (b) reducing unnecessary testing; (c) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (d) emphasizing evidence based medical therapy and cheaper and safer fertility management. Limitations, Reasons for CautionOverall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. Wider Implications of the FindingsThe international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.
  • Moller, M. H.; Granholm, A.; Junttila, E.; Haney, M.; Oscarsson-Tibblin, A.; Haavind, A.; Laake, J. H.; Wilkman, E.; Sverrisson, K. O.; Perner, A. (2018)
    BackgroundAdult critically ill patients often suffer from acute circulatory failure and those with low cardiac output may be treated with inotropic agents. The aim of this Scandinavian Society of Anaesthesiology and Intensive Care Medicine guideline was to present patient-important treatment recommendations on this topic. MethodsThis guideline was developed according to GRADE. We assessed the following subpopulations of patients with shock: (1) shock in general, (2) septic shock, (3) cardiogenic shock, (4) hypovolemic shock, (5) shock after cardiac surgery, and (6) other types of shock, including vasodilatory shock. We assessed patient-important outcome measures, including mortality and serious adverse reactions. ResultsFor all patients, we suggest against the routine use of any inotropic agent, including dobutamine, as compared to placebo/no treatment (very low quality of evidence). For patients with shock in general, and in those with septic and other types of shock, we suggest using dobutamine rather than levosimendan or epinephrine (very low quality of evidence). For patients with cardiogenic shock and in those with shock after cardiac surgery, we suggest using dobutamine rather than milrinone (very low quality of evidence). For the other clinical questions, we refrained from giving any recommendations or suggestions. ConclusionsWe suggest against the routine use of any inotropic agent in adult patients with shock. If used, we suggest using dobutamine rather than other inotropic agents for the majority of patients, however, the quality of evidence was very low, implying high uncertainty on the balance between the benefits and harms of inotropic agents.
  • Alonso-Coello, Pablo; Carrasco-Labra, Alonso; Brignardello-Petersen, Romina; Neumann, Ignacio; Akl, Elie A.; Vernooij, Robin W. M.; Johnston, Brad C.; Sun, Xin; Briel, Matthias; Busse, Jason W.; Ebrahim, Shanil; Granados, Carlos E.; Iorio, Alfonso; Irfan, Affan; Martinez Garcia, Laura; Mustafa, Reem A.; Ramirez-Morera, Anggie; Selva, Anna; Sola, Ivan; Juliana Sanabria, Andrea; Tikkinen, Kari A. O.; Vandvik, Per Olav; Zazueta, Oscar E.; Zhang, Yuqing; Zhou, Qi; Schuenemann, Holger; Guyatt, Gordon H. (2016)
    Objectives: Expressing treatment effects in relative terms yields larger numbers than expressions in absolute terms, affecting the judgment of the clinicians and patients regarding the treatment options. It is uncertain how authors of systematic reviews (SRs) absolute effect estimates are reported in. We therefore undertook a systematic survey to identify and describe the reporting and methods for calculating absolute effect estimates in SRs. Study Design and Setting: Two reviewers independently screened title, abstract, and full text and extracted data from a sample of Cochrane and non-Cochrane SRs. We used regression analyses to examine the association between study characteristics and the reporting of absolute estimates for the most patient-important outcome. Results: We included 202 SRs (98 Cochrane and 104 non-Cochrane), most of which (92.1%) included standard meta-analyses including relative estimates of effect. Of the 202 SRs, 73 (36.1%) reported absolute effect estimates for the most patient-important outcome. SRs with statistically significant effects were more likely to report absolute estimates (odds ratio, 2.26; 95% confidence interval: 1.08, 4.74). The most commonly reported absolute estimates were: for each intervention, risk of adverse outcomes expressed as a percentage (41.1%); number needed to treat (26.0%); and risk for each intervention expressed as natural units or natural frequencies (24.7%). In 12.3% of the SRs that reported absolute effect estimates for both benefit and harm outcomes, harm outcomes were reported exclusively as absolute estimates. Exclusively reporting of beneficial outcomes as absolute estimates occurred in 6.8% of the SRs. Conclusions: Most SRs do not report absolute effects. Those that do often report them inadequately, thus requiring users of SRs to generate their own estimates of absolute effects. For any apparently effective or harmful intervention, SR authors should report both absolute and relative estimates to optimize the interpretation of their findings. (C) 2016 Elsevier Inc. All rights reserved.
  • Lee, Yung; Yu, James; Tikkinen, Kari A.O.; Pędziwiatr, Michał; Major, Piotr; Aditya, Ishan; Krakowsky, Yonah; Doumouras, Aristithes G.; Gmora, Scott; Anvari, Mehran; Hong, Dennis (2019)
    Abstract Objectives To systematically review and meta-analyze the impact of bariatric surgery on obese patients with urinary incontinence (UI). Methods A search of Medline, EMBASE, CENTRAL, and PubMed to June 2018 was performed using methods pre-published on PROSPERO. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Studies comparing UI status in obese patients before and after bariatric surgery were included. Primary outcomes were the improvement or complete resolution of any UI, stress urinary incontinence (SUI), and urgency urinary incontinence (UUI). Secondary outcomes were validated UI questionnaire scores. The GRADE approach assessed overall quality of evidence. Results 33 cohort studies (2,910 patients) were included (median follow-up 12 months). Bariatric surgery resulted in improvement or resolution of any UI in 56% (95% confidence interval [CI] 48?63%), SUI in 47% (95% CI 34?60%), and UUI in 53% (95% CI 32?73%) of patients. Moreover, bariatric surgery significantly decreased (P
  • Pesonen, Jori S.; Vernooij, Robin W. M.; Cartwright, Rufus; Aoki, Yoshitaka; Agarwal, Arnav; Mangera, Altaf; Markland, Alayne D.; Tsui, Johnson F.; Santti, Henrikki; Griebling, Tomas L.; Pryalukhin, Alexey E.; Riikonen, Jarno; Tähtinen, Riikka M.; Vaughan, Camille P.; Johnson, Theodore M.; Heels-Ansdell, Diane; Guyatt, Gordon H.; Tikkinen, Kari A. O. (2020)
    Purpose: Although nocturia is associated with various comorbidities, its impact on falls and fractures remains unclear. We performed a systematic review and meta-analysis to evaluate the association between nocturia and falls and fractures as a prognostic and as a causal risk factor. Materials and Methods: We searched PubMed (R), Scopus (R), CINAHL (Cumulative Index to Nursing and Allied Health Literature) and abstracts of major urological meetings up to December 31, 2018. We conducted random effects meta-analyses of adjusted relative risks of falls and fractures. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for nocturia as a prognostic and causal factor of falls and fractures. Results: Among 5,230 potential reports 9 observational longitudinal studies provided data on the association between nocturia and falls or fractures (1 for both, 4 for falls, 4 for fractures). Pooled estimates demonstrated a risk ratio of 1.20 (95% CI 1.05-1.37, I-2 = 51.7%, annual risk difference 7.5% among the elderly) for association between nocturia and falls and 1.32 (95% CI 0.99-1.76, I-2 = 57.5%, annual risk difference 1.2%) for association between nocturia and fractures. Subgroup analyses showed no significant effect modification by age, gender, followup time, nocturia case definition or risk of bias. We rated the quality of evidence for nocturia as a prognostic factor as moderate for falls and low for fractures, and as very low as a cause of falls/fractures. Conclusions: Nocturia is probably associated with an approximately 1.2-fold increased risk of falls and possibly an approximately 1.3-fold increased risk of fractures.
  • Pesonen, Jori S.; Cartwright, Rufus; Vernooij, Robin W. M.; Aoki, Yoshitaka; Agarwal, Arnav; Mangera, Altaf; Markland, Alayne D.; Tsui, Johnson F.; Santti, Henrikki; Griebling, Tomas L.; Pryalukhin, Alexey E.; Riikonen, Jarno; Tähtinen, Riikka M.; Vaughan, Camille P.; Johnson, Theodore M.; Auvinen, Anssi; Heels-Ansdell, Diane; Guyatt, Gordon H.; Tikkinen, Kari A. O. (2020)
    Purpose: Nocturia (waking from sleep at night to void) is a common cause of sleep disruption associated with increased comorbidity and impaired quality of life. However, its impact on mortality remains unclear. We performed a systematic review and meta-analysis to evaluate the association of nocturia with mortality as a prognostic factor and a causal risk factor. Materials and Methods: We searched PubMed (R), Scopus (R), CINAHL (R) (Cumulative Index of Nursing and Allied Health Literature) and major conference abstracts up to December 31, 2018. Random effects meta-analyses were done to address the adjusted RR of mortality in people with nocturia. Metaregression was performed to explore potential determinants of heterogeneity, including the risk of bias. We applied the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) framework to rate the quality of evidence for nocturia as a prognostic risk factor for mortality and separately as a cause of mortality. Results: Of the 5,230 identified reports 11 observational studies proved eligible for inclusion. To assess nocturia 10 studies used symptom questionnaires and 1 used frequency-volume charts. Nocturia was defined as 2 or more episodes per night in 6 studies (55%) and as 3 or more episodes per night in 5 (45%). Pooled estimates demonstrated a RR of 1.27 (95% CI 1.16-1.40, I-2=48%) with an absolute 1.6% and 4.0% 5-year mortality difference in individuals 60 and 75 years old, respectively. The pooled estimates of relative risk did not differ significantly across varying age, gender, followup, nocturia case definition, risk of bias or study region. We rated the quality of evidence for nocturia as a prognostic factor as moderate and as a cause of mortality as very low. Conclusions: Nocturia is probably associated with an approximately 1.3-fold increased risk of death.