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 peerto- 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 alpha and cooperativity lambda. 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 alpha 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 lambda 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.
  • Elovainio, Marko; Lahti, Jari; Pirinen, Matti; Pulkki-Raback, Laura; Malmberg, Anni; Lipsanen, Jari; Virtanen, Marianna; Kivimaki, Mika; Hakulinen, Christian (2022)
    Background Social isolation and loneliness have been associated with increased risk of dementia, but it is not known whether this risk is modified or confounded by genetic risk of dementia. Methods We used the prospective UK Biobank study with 155 070 participants (mean age 64.1 years), including self-reported social isolation and loneliness. Genetic risk was indicated using the polygenic risk score for Alzheimer's disease and the incident dementia ascertained using electronic health records. Results Overall, 8.6% of participants reported that they were socially isolated and 5.5% were lonely. During a mean follow-up of 8.8 years (1.36 million person years), 1444 (0.9% of the total sample) were diagnosed with dementia. Social isolation, but not loneliness, was associated with increased risk of dementia (HR 1.62, 95% CI 1.38 to 1.90). There were no interaction effects between genetic risk and social isolation or between genetic risk and loneliness predicting incident dementia. Of the participants who were socially isolated and had high genetic risk, 4.4% (95% CI 3.4% to 5.5%) were estimated to developed dementia compared with 2.9% (95% CI 2.6% to 3.2%) of those who were not socially isolated but had high genetic risk. Comparable differences were also in those with intermediate and low genetic risk levels. Conclusions Socially isolated individuals are at increased risk of dementia at all levels of genetic risk.
  • Micai, Martina; Fulceri, Francesca; Salvitti, Tommaso; Romano, Giovanna; Poustka, Luise; Diehm, Robert; Iskrov, Georgi; Stefanov, Rumen; Guillon, Quentin; Roge, Bernadette; Staines, Anthony; Sweeney, Mary Rose; Boilson, Andrew Martin; Leosdottir, Thora; Saemundsen, Evald; Moilanen, Irma; Ebeling, Hanna; Yliherva, Anneli; Gissler, Mika; Parviainen, Tarja; Tani, Pekka; Kawa, Rafal; Pisula, Eva; Vicente, Astrid; Rasga, Celia; Budisteanu, Magdalena; Dale, Ian; Povey, Carol; Flores, Noelia; Jenaro, Cristina; Monroy, Maria Luisa; Primo, Patricia Garcia; Charman, Tony; Cramer, Susanne; Warberg, Christine Kloster; Canal-Bedia, Ricardo; Posada, Manuel; Schendel, Diana; Scattoni, Maria Luisa (2022)
    There is very little knowledge regarding autistic adult services, practices, and delivery. The study objective was to improve understanding of current services and practices for autistic adults and opportunities for improvement as part of the Autism Spectrum Disorder in the European Union (ASDEU) project. Separate survey versions were created for autistic adults, carers of autistic adults, and professionals in adult services. 2,009 persons responded to the survey and 1,085 (54%) of them completed at least one of the services sections: 469 autistic adults (65% female; 55% 50% responded "don't know"). Five of seven residential services features recommended for autistic adults were experienced by
  • 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.
  • Sotiropoulou Drosopoulou, Christina; Murray, Janice; Smith, Martine; Launonen, Kaisa; Neuvonen, Kirsi; Lynch, Yvonne; Stadskleiv, Kristine; von Tetzchner, Stephen (2022)
    Active engagement in interactions is crucial for the development of identity, social competence, and cognitive abilities. For children with severe speech impairment (SSI) who have little or no intelligible speech, active participation in conversations is challenging and can be critical for their social inclusion and participation. The present study investigated the conversational patterns emerging from interactions between children with SSI who use aided communication and typically speaking conversation partners (CPs) and explored whether active participation was different in interactions with different numbers of partners (dyadic versus multi-person interactions). An unusually large multilingual dataset was used (N= 85 conversations). This allowed us to systematically investigate discourse analysis measures indicating participation: the distribution of conversational control (initiations versus responses versus recodes) and summoning power (obliges versus comments). The findings suggest that (i) conversations were characterized by asymmetrical conversational patterns with CPs assuming most of the conversational control and (ii) multi-person interactions were noticeably more symmetric compared to dyadic, as children's active participation in multi-person interactions was significantly increased. Clinical implications and best practice recommendations are discussed.
  • 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
  • Brand, Randall E.; Persson, Jan; Bratlie, Svein Olav; Chung, Daniel C.; Katona, Bryson W.; Carrato, Alfredo; Castillo, Marien; Earl, Julie; Kokkola, Arto; Lucas, Aimee L.; Moser, A. James; DeCicco, Corinne; Mellby, Linda Dexlin; King, Thomas C. (2022)
    INTRODUCTION: The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9. METHODS: Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification. RESULTS: The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%. DISCUSSION: These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%).
  • 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)
  • Manca, Maria Laura; Solini, Anna; Haukka, Jani K.; Sandholm, Niina; Forsblom, Carol; Groop, Per Henrik; Ferrannini, Ele (2021)
    Background: Chronic kidney disease (CKD) shows different clinical features in Types1 (T1D) and 2 diabetes (T2D). Metabolomics have recently provided useful contribution to the identification of biomarkers of CKD progression in either form of the disease. However, no studies have so far compared plasma metabolomics between T1D and T2D in order to identify differential signatures of progression of estimated glomerular filtration rate (eGFR) decline. Methods: We used two large cohorts of T1D (from Finland) and T2D (from Italy) patients followed up to 7 and 3 years, respectively. In both groups, progression was defined as the top quartile of yearly decline in eGFR. Pooled data from the two groups were analysed by univariate and bivariate random forest (RF), and confirmed by bivariate partial least squares (PLS) analysis, the response variables being type of diabetes and eGFR progression. Results: In progressors, yearly eGFR loss was significantly larger in T2D [-5.3 (3.0), median (interquartile range)mL/min/1.73 m2/year] than T1D [-3.7 (3.1) mL/min/1.73 m2/year; P = 0.018]. Out of several hundreds, bivariate RF extracted 22 metabolites associated with diabetes type (all higher in T1D than T2D except for 5-methylthioadenosine, pyruvate and β-hydroxypyruvate) and 13 molecules associated with eGFR progression (all higher in progressors than non-progressors except for sphyngomyelin). Three of the selected metabolites (histidylphenylalanine, leucylphenylalanine, tryptophylasparagine) showed a significant interaction between disease type and progression. Only eight metabolites were common to both bivariate RF and PLS. Conclusions: Identification of metabolomic signatures of CKD progression is partially dependent on the statistical model. Dual analysis identified molecules specifically associated with progressive renal impairment in both T1D and T2D.
  • Luukkonen, Panu K.; Qadri, Sami; Ahlholm, Noora; Porthan, Kimmo; Mannisto, Ville; Sammalkorpi, Henna; Penttilä, Anne K.; Hakkarainen, Antti; Lehtimäki, Tiina E.; Gaggini, Melania; Gastaldelli, Amalia; Ala-Korpela, Mika; Orho-Melander, Marju; Arola, Johanna; Juuti, Anne; Pihlajamäki, Jussi; Hodson, Leanne; Yki-Järvinen, Hannele (2022)
    Background & Aims: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. Methods: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D-5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). Results: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepaticmitochondrial redox state, as determined by serum beta-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum beta-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. Conclusions: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. Lay summary: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
  • Tougaard, Ninna H.; Frimodt-Moller, Marie; Salmenkari, Hanne; Stougaard, Elisabeth B.; Zawadzki, Andressa D.; Mattila, Ismo M.; Hansen, Tine W.; Legido-Quigley, Cristina; Horkko, Sohvi; Forsblom, Carol; Groop, Per-Henrik; Lehto, Markku; Rossing, Peter (2022)
    Type 1 diabetes is associated with increased intestinal inflammation and decreased abundance of butyrate-producing bacteria. We investigated the effect of butyrate on inflammation, kidney parameters, HbA1c, serum metabolites and gastrointestinal symptoms in persons with type 1 diabetes, albuminuria and intestinal inflammation. We conducted a randomized placebo-controlled, double-blind, parallel clinical study involving 53 participants randomized to 3.6 g sodium butyrate daily or placebo for 12 weeks. The primary endpoint was the change in fecal calprotectin. Additional endpoints were the change in fecal short chain fatty acids, intestinal alkaline phosphatase activity and immunoglobulins, serum lipopolysaccharide, CRP, albuminuria, kidney function, HbA1c, metabolites and gastrointestinal symptoms. The mean age was 54 +/- 13 years, and the median [Q1:Q3] urinary albumin excretion was 46 [14:121] mg/g. The median fecal calprotectin in the butyrate group was 48 [26:100] mu g/g at baseline, and the change was -1.0 [-20:10] mu g/g; the median in the placebo group was 61 [25:139] mu g/g at baseline, and the change was -12 [-95:1] mu g/g. The difference between the groups was not significant (p = 0.24); neither did we find an effect of butyrate compared to placebo on the other inflammatory markers, kidney parameters, HbA1c, metabolites nor gastrointestinal symptoms. Twelve weeks of butyrate supplementation did not reduce intestinal inflammation in persons with type 1 diabetes, albuminuria and intestinal inflammation.