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  • Tosetto, Alberto; Badiee, Zahra; Baghaipour, Mohammad-Reza; Baronciani, Luciano; Battle, Javier; Berntorp, Erik; Bodo, Imre; Budde, Ulrich; Castaman, Giancarlo; Eikenboom, Jeroen C. J.; Eshghi, Peyman; Ettorre, Cosimo; Goodeve, Anne; Goudemand, Jenny; Richard, Charles; Hay, Morris; Hoorfar, Hamid; Karimi, Mehran; Keikhaei, Bijan; Lassila, Riitta; Leebeek, Frank W. G.; Fernandez, Maria Fernanda Lopez; Mannucci, Pier Mannuccio; Mazzucconi, Maria Gabriella; Morfini, Massimo; Oldenburg, Johannes; Peake, Ian; Lopez, Rafael Parra; Peyvandi, Flora; Schneppenheim, Reinhard; Tiede, Andreas; Toogeh, Gholamreza; Trossaert, Marc; Zekavat, Omidreza; Zetterberg, Eva M. K.; Federici, Augusto B. (2020)
    Background Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. Aims To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. Methods We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. Results In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels <20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. Conclusions In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.
  • EPO-TBI Investigators; ANZICS Clinical Trials Grp; Knott, Rachel J.; Harris, Anthony; Higgins, Alisa; Pettilä, Ville; Skrifvars, Markus B. (2019)
    The EPO-TBI multi-national randomized controlled trial found that erythropoietin (EPO), when compared to placebo, did not affect 6-month neurological outcome, but reduced illness severity-adjusted mortality in patients with traumatic brain injury (TBI), making the cost-effectiveness of EPO in TBI uncertain. The current study uses patient-level data from the EPO-TBI trial to evaluate the cost-effectiveness of EPO in patients with moderate or severe TBI from the healthcare payers' perspective. We addressed the issue of transferability in multi-national trials by estimating costs and effects for specific geographical regions of the study (Australia/New Zealand, Europe, and Saudi Arabia). Unadjusted mean quality-adjusted life-years (QALYs; 95% confidence interval [CI]) at 6 months were 0.027 (0.020-0.034; p <0.001) higher in the EPO group, with an adjusted QALY increment of 0.014 (0.000-0.028; p = 0.04). Mean unadjusted costs (95% CI) were $US5668 (-9191 to -2144; p = 0.002) lower in the treatment group; controlling for baseline IMPACT-TBI score and regional heterogeneity reduced this difference to $2377 (-12,446 to 7693; p = 0.64). For a willingness-to-pay threshold of $US50,000 per QALY, 71.8% of replications were considered cost-effective. Therefore, we did not find evidence that EPO was significantly cost-effective in the treatment of moderate or severe TBI at 6-month follow-up.
  • Kahila, Hanna; Halmesmäki, Erja; Baldacchino, Alex; Graca, Luis; Kersmanc, Marjetka Hovnik; Kesmodel, Ulrik Schioler; Plant, Moira; Van Mieghem, Tim; EBCOG (2016)
  • Nikkola, Elina; Ko, Arthur; Alvarez, Marcus; Cantor, Rita M.; Garske, Kristina; Kim, Elliot; Gee, Stephanie; Rodriguez, Alejandra; Muxel, Reinhard; Matikainen, Niina; Soderlund, Sanni; Motazacker, Mahdi M.; Boren, Jan; Lamina, Claudia; Kronenberg, Florian; Schneider, Wolfgang J.; Palotie, Aarno; Laakso, Markku; Taskinen, Marja-Riitta; Pajukanta, Paivi (2017)
    Background and aims: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). Methods: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). Results: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. Conclusions: Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs. (c) 2017 Elsevier B.V. All rights reserved.
  • Ronkainen, Justiina; Lowry, Estelle; Heiskala, Anni; Uusitalo, Lida; Koivunen, Peppi; Kajantie, Eero; Vääräsmäki, Marja; Järvelin, Marjo-Riitta; Sebert, Sylvain (2019)
    Objective: To test whether maternal hemoglobin during pregnancy associates with offspring perinatal outcomes in a developed country. Changes in maternal hemoglobin concentration during pregnancy are partly physiological phenomena reflecting alterations of maternal blood volume. Especially hemoglobin measures outside the physiological range may influence maternal health and fetal growth with long-lasting consequences. Study design: We studied an unselected sample drawn from two regional birth cohorts born 20 years apart: The Northern Finland Birth Cohorts 1966 and 1986. These are two mother-and-child population-based birth cohorts together comprising 21,710 mothers and their children. After exclusions, the sample size of the current study was 20,554. Concentrations of maternal hemoglobin at first and last antenatal visits were categorized as low (lowest 10%), medium (reference) or high (highest 10%). Multinomial logistic regression analyses for categories of maternal hemoglobin and perinatal outcomes such as preterm delivery and full-term small and large for gestational age were conducted with adjustments for maternal cofactors. Results: Low maternal hemoglobin at early pregnancy associated with decreased risk of full-term small for gestational age (adjusted OR 0.73, 95% CI [0.58, 0.93], p = 0.010). At late pregnancy, low maternal hemoglobin associated with increased risk of preterm delivery (adjusted OR 1.60, 95% CI [1.26, 2.02], p <0.0005) whereas high maternal hemoglobin associated with increased risk of full-term small for gestational age (adjusted OR 1.29, 95% CI [1.07, 1.56], p=0.009). Maternal hemoglobin did not show constant association with risk of large for gestational age. Conclusion: The results from this study support evidence that both low and high maternal hemoglobin associate with adverse perinatal outcomes. Low maternal hemoglobin associated with preterm delivery and high with full-term small for gestational age. Association was mainly present when maternal hemoglobin was measured during the third trimester. These results indicate that it is important to monitor both extremes of maternal hemoglobin throughout the pregnancy. (C) 2019 Elsevier B.V. All rights reserved.
  • CTR-TBI Participants Investigators; Jacob, Louis; Cogne, Melanie; Tenovuo, Olli; Azouvi, Philippe; Palotie, Aarno; Piippo-Karjalainen, Anna; Pirinen, Matti; Raj, Rahul; Ripatti, Samuli (2020)
    Background Although rehabilitation is beneficial for individuals with traumatic brain injury (TBI), a significant proportion of them do not receive adequate rehabilitation after acute care. Objective Therefore, the goal of this prospective and multicenter study was to investigate predictors of access to rehabilitation in the year following injury in patients with TBI. Methods Data from a large European study (CENTER-TBI), including TBIs of all severities between December 2014 and December 2017 were used (N = 4498 patients). Participants were dichotomized into those who had and those who did not have access to rehabilitation in the year following TBI. Potential predictors included sociodemographic factors, psychoactive substance use, preinjury medical history, injury-related factors, and factors related to medical care, complications, and discharge. Results In the year following traumatic injury, 31.4% of patients received rehabilitation services. Access to rehabilitation was positively and significantly predicted by female sex (odds ratio [OR] = 1.50), increased number of years of education completed (OR = 1.05), living in Northern (OR = 1.62; reference: Western Europe) or Southern Europe (OR = 1.74), lower prehospital Glasgow Coma Scale score (OR = 1.03), higher Injury Severity Score (OR = 1.01), intracranial (OR = 1.33) and extracranial (OR = 1.99) surgery, and extracranial complication (OR = 1.75). On contrast, significant negative predictors were lack of preinjury employment (OR = 0.80), living in Central and Eastern Europe (OR = 0.42), and admission to hospital ward (OR = 0.47; reference: admission to intensive care unit) or direct discharge from emergency room (OR = 0.24). Conclusions Based on these findings, there is an urgent need to implement national and international guidelines and strategies for access to rehabilitation after TBI.
  • CENTER-TBI High Resolution; Zeiler, Frederick A.; Ercole, Ari; Piippo-Karjalainen, Anna; Raj, Rahul; Younsi, Alexander (2019)
    BackgroundMonitoring cerebrovascular reactivity in adult traumatic brain injury (TBI) has been linked to global patient outcome. Three intra-cranial pressure (ICP)-derived indices have been described. It is unknown which index is superior for outcome association in TBI outside previous single-center evaluations. The goal of this study is to evaluate indices for 6- to 12-month outcome association using uniform data harvested in multiple centers.MethodsUsing the prospectively collected data from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, the following indices of cerebrovascular reactivity were derived: PRx (correlation between ICP and mean arterial pressure (MAP)), PAx (correlation between pulse amplitude of ICP (AMP) and MAP), and RAC (correlation between AMP and cerebral perfusion pressure (CPP)). Univariate logistic regression models were created to assess the association between vascular reactivity indices with global dichotomized outcome at 6 to 12months, as assessed by Glasgow Outcome Score-Extended (GOSE). Models were compared via area under the receiver operating curve (AUC) and Delong's test.ResultsTwo separate patient groups from this cohort were assessed: the total population with available data (n=204) and only those without decompressive craniectomy (n=159), with identical results. PRx, PAx, and RAC perform similar in outcome association for both dichotomized outcomes, alive/dead and favorable/unfavorable, with RAC trending towards higher AUC values. There were statistically higher mean values for the index, % time above threshold, and hourly dose above threshold for each of PRx, PAx, and RAC in those patients with poor outcomes.ConclusionsPRx, PAx, and RAC appear similar in their associations with 6- to 12-month outcome in moderate/severe adult TBI, with RAC showing tendency to achieve stronger associations. Further work is required to determine the role for each of these cerebrovascular indices in monitoring of TBI patients.
  • Kuronen, Marja; Koponen, Hannu; Nykanen, Irma; Karppi, Pertti; Hartikainen, Sirpa (2015)
    Background: The number of people with dementia is increasing alongside the aging population, and most of these patients manifest with neuropsychiatric symptoms (NPS). The objective of this study was to investigate anti-dementia drug use and its associations with NPS. Methods: Questionnaires on demographic information, current drug use, activities of daily living and NPS were sent to all municipal home care producers and to all institutions providing long-term residential care in the South Savo Hospital District, Finland. Results: The study population comprised 2821 persons. Their mean age was 81 years and 68 % were female. Dementia had been diagnosed in 31 % (n = 410) in home care and in 56 % (n = 774) in residential care. Anti-dementia drugs were used by 69 % of patients with dementia. Hyperactivity symptoms were common in residential care patients (n = 456, 33 %), while problems with mood and apathy dominated in home care patients (n = 486, 54 %). In multivariate regression analysis, the mood symptoms and apathy subgroup was associated with use of an acetylcholinesterase inhibitor (AChEI) (OR 1.44; 95 % Cl 1.03-2.02), memantine (OR 1.77, 95 % Cl 1.15-2.72) or their combinations (OR 1.56, 95 % Cl 1.03-2.34). Hyperactivity symptoms were associated with combination therapy of this type (OR 2.03, 95 % Cl 1.36-2.34). Conclusions: The use of anti-dementia drugs was common in both care settings. The use of any anti-dementia drug or combination was associated with the mood and apathy subgroup. The hyperactivity subgroup was associated with combination use of memantine and AChEI.
  • CTR-TBI Investigators Participants; Huijben, Jilske A.; Volovici, Victor; Cnossen, Maryse C.; Haitsma, Iain K.; Stocchetti, Nino; Maas, Andrew I. R.; Menon, David K.; Ercole, Ari; Citerio, Giuseppe; Nelson, David; Polinder, Suzanne; Steyerberg, Ewout W.; Lingsma, Hester F.; van der Jagt, Mathieu; Raj, Rahul (2018)
    Background: General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. Methods: We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. Results: The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36-40 mmHg (4.8-5.3 kPa) in case of controlled intracranial pressure (ICP) <20 mmHg (n = 45, 69%) and PaCO2 target of 30-35 mmHg (4-4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%). Conclusions: Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome.
  • Cnossen, Maryse C.; Huijben, Jilske A.; van der Jagt, Mathieu; Volovici, Victor; van Essen, Thomas; Polinder, Suzanne; Nelson, David; Ercole, Ari; Stocchetti, Nino; Citerio, Giuseppe; Peul, Wilco C.; Maas, Andrew I. R.; Menon, David; Steyerberg, Ewout W.; Lingsma, Hester F.; CENTER-TBI Investigators; Palotie, Aarno; Pirinen, Matti; Raj, Rahul; Ripatti, Samuli (2017)
    Background: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management strategies, resulting in practice variation. The aim of this study was to examine variation in monitoring and treatment policies for intracranial hypertension in patients with TBI. Methods: A 29-item survey on ICP monitoring and treatment was developed on the basis of literature and expert opinion, and it was pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Results: The survey was completed by 66 centers (97% response rate). Centers were mainly academic hospitals (n = 60, 91%) and designated level I trauma centers (n = 44, 67%). The Brain Trauma Foundation guidelines were used in 49 (74%) centers. Approximately 90% of the participants (n = 58) indicated placing an ICP monitor in patients with severe TBI and computed tomographic abnormalities. There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first-and second-tier treatments for elevated ICP. Approximately half of the centers were classified as using a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas the others were considered more conservative (n = 34, 52%). Conclusions: Substantial variation was found regarding monitoring and treatment policies in patients with TBI and intracranial hypertension. The results of this survey indicate a lack of consensus between European neurotrauma centers and provide an opportunity and necessity for comparative effectiveness research.
  • van Essen, Thomas A.; den Boogert, Hugo F.; Cnossen, Maryse C.; CENTER-TBI Investigators Partici; Kaukonen, Maija; Kivisaari, Riku; Piippo-Karjalainen, Anna; Raj, Rahul; Tanskanen, Päivi; Palotie, Aarno; Pirinen, Matti; Ripatti, Samuli (2019)
    BackgroundNeurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe.MethodsA survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP).ResultsThe survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25mmHg, 18% 30mmHg, and 17% 20mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions.ConclusionDespite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care.
  • Determinants Diet Phys Act Knowle; Int Children's Accelerometry Datab; IDEFICS Consortium; HELENA Consortium; Steene-Johannessen, Jostein; Hansen, Bjorge Herman; Dalene, Knut Eirik; Kolle, Elin; Northstone, Kate; Moller, Niels Christian; Grontved, Anders; Wedderkopp, Niels; Kriemler, Susi; Page, Angie S.; Puder, Jardena J.; Reilly, John J.; Sardinha, Luis B.; van Sluijs, Esther M. F.; Andersen, Lars Bo; van der Ploeg, Hidde; Ahrens, Wolfgang; Flexeder, Claudia; Standl, Marie; Shculz, Holger; Moreno, Luis A.; De Henauw, Stefaan; Michels, Nathalie; Cardon, Greet; Ortega, Francisco B.; Ruiz, Jonatan; Aznar, Susana; Fogelholm, Mikael; Decelis, Andrew; Olesen, Line Gronholt; Hjorth, Mads Fiil; Santos, Rute; Vale, Susana; Christiansen, Lars Breum; Jago, Russ; Basterfield, Laura; Owen, Christopher G.; Nightingale, Claire M.; Eiben, Gabriele; Polito, Angela; Lauria, Fabio; Vanhelst, Jeremy; Hadjigeorgiou, Charalambos; Konstabel, Kenn; Molnar, Denes; Sprengeler, Ole; Manios, Yannis; Harro, Jaanus; Kafatos, Anthony; Anderssen, Sigmund Alfred (2020)
    Background Levels of physical activity and variation in physical activity and sedentary time by place and person in European children and adolescents are largely unknown. The objective of the study was to assess the variations in objectively measured physical activity and sedentary time in children and adolescents across Europe. Methods Six databases were systematically searched to identify pan-European and national data sets on physical activity and sedentary time assessed by the same accelerometer in children (2 to 9.9 years) and adolescents (>= 10 to 18 years). We harmonized individual-level data by reprocessing hip-worn raw accelerometer data files from 30 different studies conducted between 1997 and 2014, representing 47,497 individuals (2-18 years) from 18 different European countries. Results Overall, a maximum of 29% (95% CI: 25, 33) of children and 29% (95% CI: 25, 32) of adolescents were categorized as sufficiently physically active. We observed substantial country- and region-specific differences in physical activity and sedentary time, with lower physical activity levels and prevalence estimates in Southern European countries. Boys were more active and less sedentary in all age-categories. The onset of age-related lowering or leveling-off of physical activity and increase in sedentary time seems to become apparent at around 6 to 7 years of age. Conclusions Two third of European children and adolescents are not sufficiently active. Our findings suggest substantial gender-, country- and region-specific differences in physical activity. These results should encourage policymakers, governments, and local and national stakeholders to take action to facilitate an increase in the physical activity levels of young people across Europe.
  • Vuorjoki-Ranta, Tiina-Riitta; Aarab, Ghizlane; Lobbezoo, Frank; Tuomilehto, Henri; Ahlberg, Jari (2019)
    Purpose The aim was to analyze whether or not weight gain influences the treatment outcome of patients with obstructive sleep apnea (OSA) treated with mandibular advancement devices (MAD). Methods As a part of a follow-up study among OSA patients treated with MAD in primary oral health care, a group of 28 patients reporting worsening of daytime or nighttime symptoms of OSA was given closer examination. Altogether, 21 subjects had a complete set of recordings and were enrolled into the study. Results Only three subjects had lost weight during the study period. The mean weight gain of 3.6kg7.1kg was significant (p=0.035). According to linear regression, weight gain was independently significantly associated with lower mean peripheral oxygen saturation 92.4 (SD 1.8 (% per hour) (p=0.019)) and lowest oxygen saturation 80.1 (SD 7.2 (%) (p=0.024)) scores. Conclusions Weight gain is detrimentally associated with MAD treatment in patients with OSA. These findings suggest that regular follow-up by an experienced dentist is advisable to assess for possible worsening of OSA. Patient support to encourage weight control may be an important adjunct to MAD treatment for OSA.