Browsing by Subject "INDIVIDUALS"

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  • Kahila, Hanna; Marjonen, Heidi; Auvinen, Pauliina; Avela, Kristiina; Riikonen, Raili; Kaminen-Ahola, Nina (2020)
    Abstract Background A pair of dizygotic twins discordantly affected by heavy prenatal alcohol exposure (PAE) was reported previously by Riikonen, suggesting the role of genetic risk or protective factors in the etiology of alcohol-induced developmental disorders. Now, we have re-examined these 25-year-old twins and explored genetic origin of the phenotypic discordancy reminiscent with fetal alcohol syndrome (FAS). Furthermore, we explored alterations in DNA methylation profile of imprinting control region at growth-related insulin-like growth factor 2 (IGF2)/H19 locus in twins' white blood cells (WBC), which have been associated earlier with alcohol-induced genotype-specific changes in placental tissue. Methods Microarray-based comparative genomic hybridization (aCGH) was used to detect potential submicroscopic chromosomal abnormalities, and developmental as well as phenotypic information about twins were collected. Traditional bisulfite sequencing was used for DNA methylation analysis. Results Microarray-based comparative genomic hybridization revealed a microdeletion 18q12.3-q21.1. in affected twin, residing in a known 18q deletion syndrome region. This syndrome has been associated with growth restriction, developmental delay or intellectual deficiency, and abnormal facial features in previous studies, and thus likely explains the phenotypic discordancy between the twins. We did not observe association between WBCs? DNA methylation profile and PAE, but interestingly, a trend of decreased DNA methylation at the imprinting control region was seen in the twin with prenatal growth retardation at birth. Conclusions The microdeletion emphasizes the importance of adequate chromosomal testing in examining the etiology of complex alcohol-induced developmental disorders. Furthermore, the genotype-specific decreased DNA methylation at the IGF2/H19 locus cannot be considered as a biological mark for PAE in adult WBCs.
  • Acosta, Tania; Barengo, Noel C.; Arrieta, Astrid; Ricaurte, Carlos; Tuomilehto, Jaakko O. (2018)
    Type 2 diabetes (T2D) imposes a heavy public health burden in both developed and developing countries. It is necessary to understand the effect of T2D in different settings and population groups. This report aimed to present baseline characteristics of study participants in the demonstration area for the Type 2 Diabetes Prevention in Barranquilla and Juan Mina (DEMOJUAN) project after randomization and to compare their fasting and 2-hour glucose levels according to lifestyle and T2D risk factor levels. The DEMOJUAN project is a randomized controlled field trial. Study participants were recruited from study sites using population-wide screening using the Finnish Diabetes Risk Score (FINDRISC) questionnaire. All volunteers with FINDRISC of >= 13 points were invited to undergo an oral glucose tolerance test (OGTT). Participant inclusion criteria for the upcoming field trial were either FINDRISC of >= 13 points and 2-hour post-challenge glucose level of 7.0 to 11.0mmol/L or FINDRISC of >= 13 points and fasting plasma glucose level of 6.1 to 6.9mmol/L. Lifestyle habits and risk factors for T2D were assessed by trained interviewers using a validated questionnaire. Among the 14,193 participants who completed the FINDRISC questionnaire, 35% (n=4915) had a FINDRISC score of >= 13 points and 47% (n=2306) agreed to undergo the OGTT. Approximately, 33% (n=772) of participants underwent the OGTT and met the entry criteria; these participants were randomized into 3 groups. There were no statistically significant differences found in anthropometric or lifestyle risk factors, distribution of the glucose metabolism categories, or other diabetes risk factors between the 3 groups (P>.05). Women with a past history of hyperglycaemia had significantly higher fasting glucose levels than those without previous hyperglycaemia (103 vs 99mg/dL; P Lifestyle habits and risk factors were evenly distributed among the 3 study groups. No differences were found in fasting or 2-hour glucose levels among different lifestyle or risk factor categories with the exception of body mass index, past history of hyperglycaemia, and age of 64 years in women.
  • Levola, Jonna M.; Sailas, Eila S.; Saamanen, Timo S.; Turunen, Leena M.; Thomson, Annika C. (2019)
    Background: The focus of emergency room (ER) treatment is on acute medical crises, but frequent users of ER services often present with various needs. The objectives of this study were to obtain information on persistent frequent ER service users and to determine reasons for their ER service use. We also sought to determine whether psychiatric diagnoses or ongoing use of psychiatric or substance use disorder treatment services were associated with persistent frequent ER visits. Methods: A cohort (n = 138) of persistent frequent ER service users with a total of 2585 ER visits during a two-year-period was identified. A content analysis was performed for 10% of these visits. Register data including International Classification of Primary Care 2 (ICPC-2) -codes and diagnoses were analyzed and multivariable models were created in order to determine whether psychiatric diagnoses and psychosocial reasons for ER service use were associated with the number of ER visits after adjusting for covariates. Results: Patients who were younger, had a psychiatric diagnosis and engaged in ongoing psychiatric and other health services, had more ER visits than those who were not. Having a psychiatric diagnosis was associated with the frequency of ER visits in the multivariable models after adjusting for age, gender and ongoing use of psychiatric or substance use disorder treatment services. Reasons for ER-service use according to ICPC-2 -codes were inadequately documented. Conclusions: Patients with psychiatric diagnoses are overrepresented in this cohort of persistent frequent ER service users. More efficient treatments paths are needed for patients to have their medical needs met through regular appointments.
  • Lindgren, Maija; Jonninen, Minna; Jokela, Markus; Therman, Sebastian (2019)
    Background: We investigated whether psychosis risk symptoms predicted psychiatric service use using seven-year register follow-up data. Methods: Our sample included 715 adolescents aged 15-18, referred to psychiatric care for the first time. Psychosis risk symptoms were assessed with the Prodromal Questionnaire (PQ) at the beginning of the treatment. We assessed the power of the overall PQ as well as its positive, negative, general, and disorganized psychosis risk symptom factors in predicting prolonged service use. Baseline psychiatric diagnoses (grouped into 7 categories) were controlled for. Based on both inpatient and outpatient psychiatric treatment after baseline, adolescents were divided into three groups of brief, intermittent, and persistent service use. Results: Stronger symptoms on any PQ factor as well as the presence of a mood disorder predicted prolonged service use. All of the PQ factors remained significant predictors when adjusted for baseline mood disorder and multimorbidity. Conclusions: In a prospective follow-up of a large sample using comprehensive mental health records, our findings indicate that assessing psychosis risk symptoms in clinical adolescent settings at the beginning of treatment could predict long-term need for care beyond diagnostic information. Our findings replicate the previous findings that positive psychosis risk symptoms are unspecific markers of severity of psychopathology. Also psychosis risk symptoms of the negative, disorganization, and general clusters are approximately as strongly associated with prolonged psychiatric service use in the upcoming years.
  • Koponen, Ismo; Nousiainen, Maija (2018)
    Discourse patterns in a small group are assumed to form largely through the group's internal social dynamics when group members compete for floor in discourse. Here we approach such discourse pattern formation through the agent-based model (ABM). In the ABM introduced here the agents' interactions and participation in discussions are dependent on the agents' inherent potential activity to participate in discussion and on realised, externalised activity, discursivity. The discourse patterns are assumed to be outcomes of peer-to-peer comparison events, where agents competitively compare their activities and discursivities, and where activities also affect agents' cooperation in increasing the discursivity, i.e. floor for discourse. These two effects and their influence on discourse pattern formation are parameterised as comptetivity and cooperativity. The discourse patterns are here based on the agents' discursivity. The patterns in groups of four agents up to seven agents are characterised through triadic census (i.e. though counting triadic sub-patterns). The cases of low competitivity is shown to give rise to fully connected egalitarian, triadic patterns, which with increasing competitivity are transformed to strong dyadic patterns. An increase in cooperativity enhances the emergence of egalitarian triads and helps to maintain the formation of fully and partially connected triadic pattern also in cases of high competitivity. In larger groups of six and seven agents, isolation becomes common, in contrast to groups of four agents where isolation is relatively rare. These results are in concordance with known empirical findings of discourse and participation patterns in small groups.
  • Torniainen-Holm, Minna; Suvisaari, Jaana; Lindgren, Maija; Härkänen, Tommi; Dickerson, Faith; Yolken, Robert H. (2018)
    Background: Earlier studies have documented an association between cytomegalovirus and cognitive impairment, but results have been inconsistent. Few studies have investigated the association of cytomegalovirus and Epstein-Barr virus with cognitive decline longitudinally. Our aim was to examine whether cytomegalovirus and Epstein-Barr virus are associated with cognitive decline, in adults. Method: The study sample is from the Finnish Health 2000 Survey (BRIF8901, n = 7112), which is representative of the Finnish adult population. The sample was followed up after 11 years in the Health 2011 Survey. In addition, persons with dementia were identified from healthcare registers. Results: In the Finnish population aged 30 and over, the seroprevalence of cytomegalovirus was estimated to be 84% and the seroprevalence of Epstein-Barr virus 98%. Seropositivity of the viruses and antibody levels were mostly not associated with cognitive performance. In the middle-aged adult group, cytomegalovirus serointensity was associated with impaired performance in verbal learning. However, the association disappeared when corrected for multiple testing. No interactions between infection and time or between the two infections were significant when corrected for multiple testing. Seropositivity did not predict dementia diagnosis. Conclusions: The results suggest that adult levels of antibodies to cytomegalovirus and Epstein-Barr virus may not be associated with a significant decline in cognitive function or with dementia at population level. (C) 2018 Published by Elsevier Inc.
  • Markkula, Niina; Lindgren, Maija; Yolken, Robert H.; Suvisaari, Jaana (2020)
    Background Some prevalent infections have been associated with common mental disorders, but there are few longitudinal studies, and results are inconsistent. We aimed to assess whether serological evidence of exposure to Toxoplasma gondii (T. gondii), Epstein-Barr Virus (EBV), Herpes Simplex virus Type 1 (HSV-1) and Cytomegalovirus (CMV) predict development of new-onset depressive and anxiety disorders. Methods In a nationally representative sample of the Finnish adult population aged 30 and over (BRIF8901, n = 8028), IgG antibodies for T. gondii, EBV, HSV-1 and CMV were measured in plasma samples. The population was followed up for 11 years and new-onset depressive and anxiety disorders were diagnosed with the Composite International Diagnostic Interview. Associations were analysed controlling for sex, age, educational level, region of residence and marital status, and in separate analyses also for C-reactive protein level. Results Seropositivity and serointensity of the four infectious agents were not associated with an increased risk of new-onset depressive or anxiety disorders. Seropositivity for CMV at baseline was associated with a lower risk of new-onset generalized anxiety disorder (adjusted OR 0.43, 95% CI 0.22–0.86 for CMV positive persons). Conclusion The results of this large, nationally representative longitudinal study suggest that common viral infections are not significant risk factors for common mental disorders. The association of CMV with a lower risk of generalized anxiety disorder warrants further investigation.
  • Savriama, Yoland; Valtonen, Mia; Kammonen, Juhana I.; Rastas, Pasi; Smolander, Olli-Pekka; Lyyski, Annina; Häkkinen, Teemu J.; Corfe, Ian J.; Gerber, Sylvain; Salazar-Ciudad, Isaac; Paulin, Lars; Holm, Liisa; Löytynoja, Ari; Auvinen, Petri; Jernvall, Jukka (2018)
    An increasing number of mammalian species have been shown to have a history of hybridization and introgression based on genetic analyses. Only relatively few fossils, however, preserve genetic material, and morphology must be used to identify the species and determine whether morphologically intermediate fossils could represent hybrids. Because dental and cranial fossils are typically the key body parts studied in mammalian palaeontology, here we bracket the potential for phenotypically extreme hybridizations by examining uniquely preserved cranio-dental material of a captive hybrid between grey and ringed seals. We analysed how distinct these species are genetically and morphologically, how easy it is to identify the hybrids using morphology and whether comparable hybridizations happen in the wild. We show that the genetic distance between these species is more than twice the modern human–Neanderthal distance, but still within that of morphologically similar species pairs known to hybridize. By contrast, morphological and developmental analyses show grey and ringed seals to be highly disparate, and that the hybrid is a predictable intermediate. Genetic analyses of the parent populations reveal introgression in the wild, suggesting that grey–ringed seal hybridization is not limited to captivity. Taken together, we postulate that there is considerable potential for mammalian hybridization between phenotypically disparate taxa.
  • Savolainen, Laura E.; Kantele, Anu; Knuuttila, Aija; Pusa, Liana; Karttunen, Riitta; Valleala, Heikki; Tuuminen, Tamara (2016)
    New biomarkers are needed for discriminating active tuberculosis (TB) from latent TB infection (LTBI), especially in vulnerable groups representing the major diagnostic challenge. This pilot study was carried out to explore the diagnostic potential of selected genes, IFN-gamma, IL-17, IL-4, and FoxP3, associated with TB immunity and immunopathology. IFN-gamma, IL-17, IL-4, and FoxP3 mRNA expression levels were measured by quantitative reverse transcription PCR (RT-qPCR) from antigen-stimulated peripheral blood mononuclear cells of patients with active TB (n = 25); patients with miscellaneous inflammatory disorders and concomitant LTBI (n = 20), rheumatoid arthritis (RA) being the most predominant in the group (n = 11); and in healthy Bacillus Calmette Guerin (BCG) vaccinees (n = 8). While the levels of FoxP3 mRNA did not differ between the tested groups, the cumulative expression levels of purified protein derivative -stimulated IFN-gamma, IL-17, and IL-4 mRNAs were found to distinguish active TB from the whole group of LTBI with 48% sensitivity and 85% specificity. When restricting the LTBI group to RA cases only, the sensitivity was 56% and specificity 100%. When interpreting the result as positive in at least one of the mRNAs IFN-gamma, IL-17, or IL-4, sensitivity of 64% and specificities of 75% (heterogeneous group of LTBI) or 100% (LTBI with RA) were achieved. Moderate discrimination of active TB from LTBI with miscellaneous inflammatory underlying conditions by using combined quantitative expression of IFN-gamma, IL-17, and IL-4 mRNA seems not to be of high diagnostic potential.
  • Lankinen, Kaisu; Saari, Jukka; Hlushchuk, Yevhen; Tikka, Pia; Parkkonen, Lauri; Hari, Riitta; Koskinen, Miika (2018)
    Movie viewing allows human perception and cognition to be studied in complex, real-life-like situations in a brain-imaging laboratory. Previous studies with functional magnetic resonance imaging (fMRI) and with magneto-and electroencephalography (MEG and EEG) have demonstrated consistent temporal dynamics of brain activity across movie viewers. However, little is known about the similarities and differences of fMRI and MEG or EEG dynamics during such naturalistic situations. We thus compared MEG and fMRI responses to the same 15-min black-and-white movie in the same eight subjects who watched the movie twice during both MEG and fMRI recordings. We analyzed intra-and intersubject voxel-wise correlations within each imaging modality as well as the correlation of the MEG envelopes and fMRI signals. The fMRI signals showed voxel-wise within-and between-subjects correlations up to r = 0.66 and r = 0.37, respectively, whereas these correlations were clearly weaker for the envelopes of band-pass filtered (7 frequency bands below 100 Hz) MEG signals (within-subjects correlation r <0.14 and between-subjects r <0.05). Direct MEG-fMRI voxel-wise correlations were unreliable. Notably, applying a spatial-filtering approach to the MEG data uncovered consistent canonical variates that showed considerably stronger (up to r = 0.25) between-subjects correlations than the univariate voxel-wise analysis. Furthermore, the envelopes of the time courses of these variates up to about 10 Hz showed association with fMRI signals in a general linear model. Similarities between envelopes of MEG canonical variates and fMRI voxel time-courses were seen mostly in occipital, but also in temporal and frontal brain regions, whereas intra-and intersubject correlations for MEG and fMRI separately were strongest only in the occipital areas. In contrast to the conventional univariate analysis, the spatial-filtering approach was able to uncover associations between the MEG envelopes and fMRI time courses, shedding light on the similarities of hemodynamic and electromagnetic brain activities during movie viewing.
  • Finndiane Study Grp; Ahola, Aila J.; Harjutsalo, Valma; Forsblom, Carol; Pouwer, Francois; Groop, Per-Henrik (2021)
    OBJECTIVE To investigate the relationship between depression and diabetic nephropathy progression in type 1 diabetes. RESEARCH DESIGN AND METHODS Data from 3,730 participants without end-stage renal disease (ESRD) at baseline, participating in the Finnish Diabetic Nephropathy Study, were included. Depression was assessed in three ways. Depression diagnoses were obtained from the Finnish Care Register for Health Care. Antidepressant agent purchase data were obtained from the Drug Prescription Register. Symptoms of depression were assessed using the Beck Depression Inventory (BDI). Based on their urinary albumin excretion rate (AER), participants were classified as those with normal AER, microalbuminuria, and macroalbuminuria. Progression from normal AER to microalbuminuria, macroalbuminuria, or ESRD; from microalbuminuria to macroalbuminuria or ESRD; or from macroalbuminuria to ESRD, during the follow-up period, was investigated. RESULTS Over a mean follow-up period of 9.6 years, renal status deteriorated in 18.4% of the participants. Diagnosed depression and antidepressant purchases before baseline were associated with 53% and 32% increased risk of diabetic nephropathy progression, respectively. Diagnosed depression assessed during follow-up remained associated with increased risk of disease progression (32%). BDI-derived symptoms of depression showed no association with the progression, but the total number of antidepressant purchases modestly reduced the risk (hazard ratio 0.989 [95% CI 0.982-0.997]), P = 0.008). With the sample divided based on median age, the observations followed those seen in the whole group. However, symptoms of depression additionally predicted progression in those age
  • Mocroft, Amanda; Lundgren, Jens D.; Ross, Michael; Law, Matthew; Reiss, Peter; Kirk, Ole; Smith, Colette; Wentworth, Deborah; Neuhaus, Jacqueline; Fux, Christoph A.; Moranne, Olivier; Morlat, Phillipe; Johnson, Margaret A.; Ryom, Lene; DAD Study Grp; Royal Free Hosp Clin Cohort; INSIGHT Study Grp; SMART Study Grp; ESPRIT Study Grp; Ristola, M. (2015)
    Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score <0, 33 events), rising to 1: 47 and 1: 6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score >= 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.
  • Kamara, David A.; Ryom, Lene; Ross, Michael; Kirk, Ole; Reiss, Peter; Morlat, Philippe; Moranne, Olivier; Fux, Christoph A.; Mocroft, Amanda; Sabin, Caroline; Lundgren, Jens D.; Smith, Colette J.; DAD Study Grp; Ristola, Matti A (2014)
  • Xue, Yali; Mezzavilla, Massimo; Haber, Marc; McCarthy, Shane; Chen, Yuan; Narasimhan, Vagheesh; Gilly, Arthur; Ayub, Qasim; Colonna, Vincenza; Southam, Lorraine; Finan, Christopher; Massaia, Andrea; Chheda, Himanshu; Palta, Priit; Ritchie, Graham; Asimit, Jennifer; Dedoussis, George; Gasparini, Paolo; Palotie, Aarno; Ripatti, Samuli; Soranzo, Nicole; Toniolo, Daniela; Wilson, James F.; Durbin, Richard; Tyler-Smith, Chris; Zeggini, Eleftheria (2017)
    The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.
  • Lindgren, Maija; Holm, Minna; Markkula, Niina; Härkänen, Tommi; Dickerson, Faith; Yolken, Robert H.; Suvisaari, Jaana (2020)
    Common infectious agents, such as Toxoplasma gondii (T. gondii) and several human herpes viruses, have been linked to increased risk of self-harm. The aim of this study was to investigate the associations between self-harm and seropositivity to T. gondii, Epstein-Barr virus (EBV), Herpes Simplex virus Type 1 (HSV-1), and Cytomegalovirus (CMV). IgM and IgG antibodies to these infections were measured in the Health 2000 project nationally representative of the whole Finnish adult population, and 6250 participants, age 30 and over, were followed for 15 years via registers. In addition, lifetime suicidal ideation and suicide attempts based on medical records and interview were assessed within a subsample of 694 participants screened to a substudy for possible psychotic symptoms or as controls. Among the 6250 participants, 14 individuals died of suicide and an additional 4 individuals had a diagnosis of intentional self-harm during follow-up. Serological evidence of lifetime or acute infections was not found to be associated with these suicidal outcomes. However, in the subsample, those seropositive for CMV had fewer suicide attempts compared to those seronegative, adjusting for gender, age, educational level, childhood family size, regional residence, CRP, and screen status (OR for multiple attempts = 0.40, 95% confidence interval 0.20-0.83, p = 0.014). To conclude, common infections were not associated with risk of death by suicide or with self-harm diagnoses at a 15-year follow-up in the general population sample. Our finding of an increased number of suicide attempts among persons seronegative for CMV calls for further research.
  • Huovinen, Joel; Kastinen, Sami; Komulainen, Simo; Oinas, Minna; Avellan, Cecilia; Frantzen, Janek; Rinne, Jaakko; Ronkainen, Antti; Kauppinen, Mikko; Lonnrot, Kimmo; Perola, Markus; Pyykko, Okka T.; Koivisto, Anne M.; Remes, Anne M.; Soininen, Hilkka; Hiltunen, Mikko; Helisalmi, Seppo; Kurki, Mitja; Jaaskelainen, Juha E.; Leinonen, Ville (2016)
    Idiopathic normal pressure hydrocephalus (iNPH) is a late-onset surgically alleviated, progressive disease. We characterize a potential familial subgroup of iNPH in a nation-wide Finnish cohort of 375 shunt-operated iNPH-patients. The patients were questionnaired and phone-interviewed, whether they have relatives with either diagnosed iNPH or disease-related symptomatology. Then pedigrees of all families with more than one iNPH-case were drawn. Eighteen patients (4.8%) from 12 separate pedigrees had at least one shunt-operated relative whereas 42 patients (11%) had relatives with two or more triad symptoms. According to multivariate logistic regression analysis, familial iNPH-patients had up to 3-fold risk of clinical dementia compared to sporadic iNPH patients. This risk was independent from diagnosed Alzheimer's disease and APOE epsilon 4 genotype. This study describes a familial entity of iNPH offering a novel approach to discover the potential genetic characteristics of iNPH. Discovered pedigrees offer an intriguing opportunity to conduct longitudinal studies targeting potential preclinical signs of iNPH. (C) 2016 Elsevier B.V. All rights reserved.
  • Nettleton, Jennifer A.; Follis, Jack L.; Ngwa, Julius S.; Smith, Caren E.; Ahmad, Shafqat; Tanaka, Toshiko; Wojczynski, Mary K.; Voortman, Trudy; Lemaitre, Rozenn N.; Kristiansson, Kati; Nuotio, Marja-Liisa; Houston, Denise K.; Perala, Mia-Maria; Qi, Qibin; Sonestedt, Emily; Manichaikul, Ani; Kanoni, Stavroula; Ganna, Andrea; Mikkila, Vera; North, Kari E.; Siscovick, David S.; Harald, Kennet; Mckeown, Nicola M.; Johansson, Ingegerd; Rissanen, Harri; Liu, Yongmei; Lahti, Jari; Hu, Frank B.; Bandinelli, Stefania; Rukh, Gull; Rich, Stephen; Booij, Lisanne; Dmitriou, Maria; Ax, Erika; Raitakari, Olli; Mukamal, Kenneth; Mannisto, Satu; Hallmans, Goran; Jula, Antti; Ericson, Ulrika; Jacobs, David R.; Van Rooij, Frank J. A.; Deloukas, Panos; Sjogren, Per; Kahonen, Mika; Djousse, Luc; Perola, Markus; Barroso, Ines; Hofman, Albert; Stirrups, Kathleen; Viikari, Jorma; Uitterlinden, Andre G.; Kalafati, Ioanna P.; Franco, Oscar H.; Mozaffarian, Dariush; Salomaa, Veikko; Borecki, Ingrid B.; Knekt, Paul; Kritchevsky, Stephen B.; Eriksson, Johan G.; Dedoussis, George V.; Qi, Lu; Ferrucci, Luigi; Orho-Melander, Marju; Zillikens, M. Carola; Ingelsson, Erik; Lehtimaki, Terho; Renstrom, Frida; Cupples, L. Adrienne; Loos, Ruth J. F.; Franks, Paul W. (2015)
    Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.
  • Mateos, Marion K.; Tulstrup, Morten; Quinn, Michael C. J.; Tuckuviene, Ruta; Marshall, Glenn M.; Gupta, Ramneek; Mayoh, Chelsea; Wolthers, Benjamin O.; Barbaro, Pasquale M.; Ruud, Ellen; Sutton, Rosemary; Huttunen, Pasi; Revesz, Tamas; Trakymiene, Sonata S.; Barbaric, Draga; Tedgard, Ulf; Giles, Jodie E.; Alvaro, Frank; Jonsson, Olafur G.; Mechinaud, Francoise; Saks, Kadri; Catchpoole, Daniel; Kotecha, Rishi S.; Dalla-Pozza, Luciano; Chenevix-Trench, Georgia; Trahair, Toby N.; MacGregor, Stuart; Schmiegelow, Kjeld (2020)
    Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p <5 x 10(-8)) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p <1 x 10(-6)), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 x 10(-7)) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 x 10(-7)) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
  • Roth, Gregory A.; Collaborotors, G. B. D.Causes Death; Abate, Degu; Abate, Kalkidan Hassen; Abay, Solomon M.; Abbafati, Cristiana; Abbasi, Nooshin; Abbastabar, Hedayat; Abd-Allah, Load; Abdela, Jemal; Abdelalim, Ahmed; Abdollahpour, Ibrahim; Abdulkader, Rizwan Suliankatchi; Abebe, Haftom Temesgen; Abebe, Molla; Abebe, Zegeye; Abejie, Ayenew Negesse; Abera, Semaw F.; Abil, Olifan Zewdie; Abraha, Haftom Niguse; Abrham, Aklilu Roba; Abu-Raddad, Laith Jamal; Accrombessi, Manfred Mario Kokou; Acharya, Dilaram; Adamu, Abdu A.; Adebayo, Oladimeji; Adedoyin, Rufus Adesoji; Adekanmbi, Victor; Adookunboh, Olatunii; Adhena, Beyene Meressa; Adib, Mina G.; Admasie, Aniha; Afshin, Ashkan; Agarwal, Gina; Agesa, Karelia M.; Agrawal, Anurag; Agrawal, Sutapa; Ahmadi, Alireza; Ahmadi, Melidi; Ahmed, Muktar Beshir; Ahmed, Sayent; Aichour, Amani Nidhal; Aichour, Ibtihel; Aichour, Miloud Taki Fddine; Akbari, Mohammad Esmaeil; Akinyeniti, Rufus Olusola; Akseer, Nadia; Al-Aly, Ziyad; Al-Eyadhy, Ayman; Al-Raddadi, Rajaa M.; Alandab, Fares; Alam, Khurshid; Alam, Tahiya; Alebel, Animut; Alene, Kefyalew Addis; Alijanzadeh, Mehran; Alizadeh-Navaei, Reza; Aljunid, Syed Mohamed; Alkerwi, Ala'a; Alla, Francois; Allebeck, Peter; Alonso, Jordi; Altirkawi, Khalid; Alvis-Guzman, Nelson; Amare, Azmeraw T.; Aminde, Leopold N.; Amini, Erfan; Ammar, Walid; Amoako, Yaw Ampern; Anber, Nahla Hamed; Andrei, Catalina Liliana; Androudi, Sofia; Animut, Megbaru Debalkie; Anjomshoa, Mina; Ansari, Hossein; Aniha, Mustafa Geleto; Antonio, Carl Abelardo T.; Anwari, Palwasha; Aremu, Olatunde; Arnlov, Johan; Arora, Amit; Arora, Monika; Artaman, Al; Aryal, Krishna K.; Asayesh, Hamid; Asfaw, Ephremi Tsegay; Ataro, Zerihun; Atique, Suleman; Atre, Sachin R.; Ausloos, Marcel; Avokpaho, Euripide F. G. 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Dean; Hosseini, Seyed Mostafa; Hosseinzadeh, Mehdi; Hostiuc, Mihaela; Hostiuc, Sorin; Hotez, Peter J.; Hoy, Damian C.; Hsiao, Thomas; Hu, Guoqing; Huang, John J.; Husseini, Abdullatif; Hussen, Mohammedaman Mama; Hutfless, Susan; Idrisov, Bulat; Ilesanmi, Olayinka Stephen; Iqbal, Usman; Irvani, Seyed Sina Naghibi; Irvine, Caleb Mackay Salpeter; Islam, Nazrul; Islam, Sheikh Mohammed Shariful; Islami, Farhad; Jacobsen, Kathryn H.; Jahangiry, Leila; Jahanmehr, Nader; Jain, Sudhir Kumar; Jakovlievic, Mihajlo; Jalu, Moti Tolera; James, Spencer L.; Javanbakht, Mehdi; Jayatilleke, Achala Upendra; Jeemon, Panniyammakal; Jenkins, Kathy J.; Jha, Ravi Prakash; Jha, Vivekanand; Johnson, Catherine O.; Johnson, Sarah C.; Jonas, Jost B.; Joshi, Ankur; Jozwiak, Jacek Jerzy; Jungari, Suresh Banayya; Jurisson, Mikk; Kabir, Zubair; Kadel, Rajendra; Kahsay, Amaha; Kalani, Rizwan; Karami, Manoochehr; Matin, Behzad Karami; Karch, Andre; Karema, Corine; Karimi-Sari, Hamidreza; Kasaeian, Amir; Kassa, Dessalegn H.; Kassa, Getachew Mullu; Kassa, Tesfaye Dessale; Kassebaum, Nicholas J.; Katikireddi, Srinivasa Vittal; Kaul, Anil; Kazemi, Zhila; Karyani, Ali Kazemi; Kazi, Dhruv Satish; Kefale, Adane Teshome; Keiyoro, Peter Njenga; Kemp, Grant Rodgers; Kengne, Andre Pascal; Keren, Andre; Kesavachandran, Chandrasekharan Nair; Khader, Yousef Saleh; Khafaei, Behzad; Khafaie, Morteza Abdullatif; Khajavi, Alireza; Khalid, Nauman; Khalil, Ibrahim A.; Khan, Ejaz Ahmad; Khan, Muhammad Shahzeb; Khan, Muhammad Ali; Khang, Young-Ho; Khater, Mona M.; Khoja, Abdullah T.; Khosravi, Ardeshir; Khosravi, Mohammad Hossein; Khubchandani, Jagdish; Kiadaliri, Aliasghar A.; Kibret, Getiye D.; Kidanemariam, Zelalem Teklemariam; Kiirithio, Daniel N.; Kim, Daniel; Kim, Young-Eun; Kim, Yun Jin; Kimokoti, Ruth W.; Kinfu, Yohannes; Kisa, Adnan; Kissimova-Skarbek, Katarzyna; Kivimäki, Mika; Knudsen, Ann Kristin Skrindo; Kocarnik, Jonathan M.; Kochhar, Sonali; Kokubo, Yoshihiro; Kolola, Tufa; Kopec, Jacek A.; Koul, Parvaiz A.; Koyanagi, Ai; Kravchenko, Michael A.; Krishan, Kewal; Defo, Barthelemy Kuate; Bicer, Burcu Kinuk; Kumar, G. Anil; Kumar, Manasi; Kumar, Pushpendra; Kutz, Michael J.; Kuzin, Igor; Kyu, Hmwe Hmwe; Lad, Deepesh P.; Lad, Sheetal D.; Lafranconi, Alessandra; Lal, Dharmesh Kumar; Lalloo, Ratilal; Lallukka, Tea; Lam, Jennifer O.; Lami, Faris Hasan; Lansingh, Van C.; Lansky, Sonia; Larson, Heidi J.; Latifi, Amman; Lau, Kathryn Mei-Ming; Lazarus, Jeffrey V.; Lebedev, Georgy; Lee, Paul H.; Leigh, James; Leili, Mostafa; Leshargie, Cheru Tesema; Li, Shanshan; Li, Yichong; Liang, Juan; Lim, Lee-Ling; Lim, Stephen S.; Limenih, Miteku Andualem; Linn, Shai; Liu, Shiwei; Liu, Yang; Lodha, Rakesh; Lansdale, Chris; Lopez, Alan D.; Lorkowski, Stefan; Lotufo, Paulo A.; Lozano, Rafael; Lunevicius, Raimundas; Ma, Stefan; Macarayan, Erlyn Rachelle King; Mackay, Mark T.; MacLachlan, Jennifer H.; Maddison, Emilie R.; Nadotto, Fabiana; Abd El Razek, Hassan Magdy; Abd El Razek, Muhammed Magdy; Maghavani, Dhaval P.; Majdan, Marek; Majdzadeh, Reza; Majeed, Azeem; Malekzadeh, Reza; Malta, Deborah Carvalho; Manda, Ana-Laura; Mandarano-Filho, Luiz Garcia; Manguerra, Helena; Mansournia, Mohammad Ali; Mapoma, Chabila Christopher; Marami, Dadi; Maravilla, Joemer C.; Marcenes, Wagner; Marczak, Laurie; Marks, Ashley; Marks, Guy B.; Martinez, Gabriel; Martins-Melo, Francisco Rogerlandio; Martopullo, Ira; Marz, Winfried; Marron, Melvin B.; Masci, Joseph R.; Lylassenburg, Benjamin Ballard; Mathur, Manu Raj; Mathur, Prashant; Matzopoulos, Richard; Maulik, Pallab K.; Mazidi, Mohsen; McAlinden, Cohn; McGrath, John J.; McKee, Martin; McMahon, Brian J.; Mehata, Suiiesh; Mehndiratta, Man Mohan; Mehrotra, Ravi; Mehta, Kala M.; Mehta, Varshil; Mekonnen, Tefera C.; Melese, Addisu; Melku, Mulugeta; Memiah, Peter T. 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Mohammed; Mohammed, Shafiu; Mohan, Viswanathan; Mokdad, Ali H.; Molokhia, Mariam; Monasta, Lorenzo; Moradi, Ghobad; Moradi-Lakeh, Maziar; Moradinazar, Mehdi; Moraga, Paula; Morawska, Lidia; Velasquez, Ilais Moreno; Morgado-Da-Costa, Joana; Morrison, Shane Douglas; Moschos, Marilita M.; Mouodi, Simin; Mousavi, Seyyed Meysam; Muchie, Kindie Eentahun; Mueller, Ulrich Otto; Mukhopadhyay, Satinath; Muller, Kate; Mumford, John Everett; Musa, Jonah; Musa, Kamand Imran; Mustafa, Ghulam; Muthupandian, Saravanan; Nachega, Jean B.; Nagel, Gabriele; Naheed, Aliya; Nahvijou, Azin; Naik, Gunidatta; Nair, Sanjeev; Najafi, Farid; Naldi, Luigi; Nam, Hae Sung; Nangia, Vinay; Nansseu, Jobert Richie; Nascirnento, Bruno Ramos; Natarajan, Gopalakrishnan; Nearnati, Nahid; Negoi, Ionut; Negoi, Ruxcandra Irina; Nettpane, Subas; Newton, Charles R. J.; Ngalesoni, Frida N.; Ngunjiri, Josephine W.; Anh Quynh Nguyen,; Nguyen, Grant; Ha Thu Nguyen,; Luong Thanh Nguyen,; Long Hoang Nguyen,; Minh Nguyen,; Trang Huyen Nguyen,; Nichols, Emma; Ningnun, Dina Nur Anggraini; Nirayo, Yirga Legesse; Nixon, Molly R.; Nolutshungu, Nomonde; Nomura, Shhhei; Norhelin, Ole F.; Noroozi, Mehdi; Norrving, Bo; Noubiap, Jean Jacques; Nouri, Hamid Reza; Shiadeh, Malihe Nourollahpour; Nowroozi, Mohammad Reza; Nyasulu, Peter S.; Odell, Christopher M.; Ofori-Asenso, Richard; Ogbo, Felix Akpojene; Oh, In-Hwan; Oladimeji, Olanrewaju; Olagunju, Andrew T.; Olivares, Pedro R.; Olsen, Helen Elizabeth; Olusanya, Bolajoko Olubukunola; Olusanya, Jacob Olusegun; Ong, Kanyin L.; Ong, Sok King Sk; Oren, Eyal; Orpana, Heather M.; Ortiz, Alberto; Ortiz, Justin R.; Otstavnov, Stanislav S.; Overland, Simon; Owolabi, Mayowa Ojo; Ozdemir, Raziye; Mahesh, P. 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I.; Tabares-Seisdedos, Rafael; Tabuchi, Takahiro; Tadakamadla, Santosh Kumar; Takahashi, Ken; Tandon, Nikhil; Tassew, Segen Gebremeskel; Taveira, Nuno; Tehrani-Banihashemi, Arash; Tekalign, Tigist Gashaw; Tekle, Merhawi Gebremedhin; Temsah, Mohamad-Hani; Temsah, Omar; Terkawi, Abdullah Sulieman; Teshale, Manaye Yihune; Tesserna, Belay; Tessema, Gizachew Assefa; Thankappan, Kavumpurathu Raman; Thirinavukkarasu, Sathish; Thomas, Nihal; Thrift, Amanda G.; Thurston, George D.; Tilahun, Binyam; To, Quyen G.; Tobe-Gai, Ruoyan; Tonellli, Marcello; Topor-Madry, Roman; Torre, Anna E.; Tortajada-Cirbes, Miguel; Touvier, Mathilde; Tovani-Palone, Marcos Roberto; Bach Xuan Tran, [No Value]; Khah Bao Tran,; Tripathi, Suryakant; Troeger, Christopher E.; Truelsen, Thomas Clement; Nu Thi Truong,; Tsadik, Afewerki Gebremeskel; Tsoi, Derrick; Car, Lorainne Tudor; Tuzcu, E. Murat; Tyrovolas, Stefanos; Ukwaja, Kingsley N.; Whiff, Irfan; Undurraga, Eduardo A.; Updike, Rachel L.; Usman, Muhammad Shariq; Uthman, Olalekan A.; Uzun, Selen Begum; Vaduganathan, Muthiah; Vaezi, Afsane; Vaidya, Gaurang; Valdez, Pascual R.; Varavikova, Elena; Vasankari, Tommi Juhani; Venketasubramanian, Narayanaswamy; Villafaina, Santos; Violante, Francesco S.; Vladimirov, Sergey Konstantinovitch; Vlassov, Vasily; Vollset, Stein Email; Vos, Theo; Wagner, Gregory R.; Wagnew, Fasil Shiferaw; Waheed, Yasir; Wallin, Mitchell Taylor; Watson, Judd L.; Wang, Yanping; Wang, Yuan-Pang; Wassie, Molla Mesele; Weiderpass, Elisabete; Weintraub, Robert G.; Weldegebreal, Eitsum; Weldegwergs, Kidu Gidey; Werdecker, Andrea; Werkneh, Adhena Ayaliew; West, T. Eoin; Westerman, Ronny; Whiteford, Harvey A.; Widecka, Justyna; Wilner, Lauren B.; Wilson, Shadrach; Winkler, Andrea Sylvia; Wiysonge, Charles Shey; Wolfe, Charles D. A.; Wu, Shouling; Wu, Yun-Chun; Wyper, Grant M. A.; Xavier, Denis; Xu, Gelin; Yadgir, Simon; Yadollahpour, Ali; Jabbari, Seyed Hossein Yahyazadeh; Yakob, Bereket; Yan, Lijing L.; Yano, Yuichiro; Yaseri, Mehdi; Yasin, Yasin Jemal; Yentur, Gokalp Kadri; Yeshaneh, Alex; Yimer, Ebrahim M.; Yip, Paul; Yirsaw, Biruck Desalegn; Yisma, Engida; Yonemoto, Naohiro; Yonga, Gerald; Yoon, Seok-Jun; Yotebieng, Marcel; Younis, Mustafa Z.; Yousefifard, Mahmoud; Yu, Chuanhua; Zadnik, Vesna; Zaidi, Zoubida; Bin Zaman, Sojib; Zamani, Mohammad; Zare, Zohreh; Zeleke, Ayalew Jejaw; Zenebe, Zerihun Menlkalew; Zhang, Anthony Lin; Zhang, Kai; Zhou, Maigeng; Zodpey, Sanjay; Zuhlke, Liesl Joanna; Naghavi, Ntishsen; Murray, Christopher J. L. (2018)
    Background Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. Methods The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODErn), to generate cause fractions and cause specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised. Findings At the broadest grouping of causes of death (Level 1), non-communicable diseases (NC Ds) comprised the greatest fraction of deaths, contributing to 73.4% (95% uncertainty interval [UI] 72.5-74.1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 186% (17.9-19.6), and injuries 8.0% (7.7-8.2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22.7% (21.5-23.9), representing an additional 7.61 million (7. 20-8.01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7.9% (7.08.8). The number of deaths for CMNN causes decreased by 222% (20.0-24.0) and the death rate by 31.8% (30.1-33.3). Total deaths from injuries increased by 2.3% (0-5-4-0) between 2007 and 2017, and the death rate from injuries decreased by 13.7% (12.2-15.1) to 57.9 deaths (55.9-59.2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118.0% (88.8-148.6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36.4% (32.2-40.6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33.6% (31.2-36.1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respirator}, infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990 neonatal disorders, lower respiratory infections, and diarrhoeal diseases were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases. Interpretation Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.
  • Platzer, Konrad; Yuan, Hongjie; Schuetz, Hannah; Winschel, Alexander; Chen, Wenjuan; Hu, Chun; Kusumoto, Hirofumi; Heyne, Henrike O.; Helbig, Katherine L.; Tang, Sha; Willing, Marcia C.; Tinkle, Brad T.; Adams, Darius J.; Depienne, Christel; Keren, Boris; Mignot, Cyril; Frengen, Eirik; Stromme, Petter; Biskup, Saskia; Doecker, Dennis; Strom, Tim M.; Mefford, Heather C.; Myers, Candace T.; Muir, Alison M.; LaCroix, Amy; Sadleir, Lynette; Scheffer, Ingrid E.; Brilstra, Eva; van Haelst, Mieke M.; van der Smagt, Jasper J.; Bok, Levinus A.; Moller, Rikke S.; Jensen, Uffe B.; Millichap, John J.; Berg, Anne T.; Goldberg, Ethan M.; De Bie, Isabelle; Fox, Stephanie; Major, Philippe; Jones, Julie R.; Zackai, Elaine H.; Abou Jamra, Rami; Rolfs, Arndt; Leventer, Richard J.; Lawson, John A.; Roscioli, Tony; Jansen, Floor E.; Ranza, Emmanuelle; Korff, Christian M.; Lehesjoki, Anna-Elina; Courage, Carolina; Linnankivi, Tarja; Smith, Douglas R.; Stanley, Christine; Mintz, Mark; McKnight, Dianalee; Decker, Amy; Tan, Wen-Hann; Tarnopolsky, Mark A.; Brady, Lauren I.; Wolff, Markus; Dondit, Lutz; Pedro, Helio F.; Parisotto, Sarah E.; Jones, Kelly L.; Patel, Anup D.; Franz, David N.; Vanzo, Rena; Marco, Elysa; Ranells, Judith D.; Di Donato, Nataliya; Dobyns, William B.; Laube, Bodo; Traynelis, Stephen F.; Lemke, Johannes R. (2017)
    Background We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.