Browsing by Subject "ONSET"

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  • Haghighi, Mona; Johnson, Suzanne Bennett; Qian, Xiaoning; Lynch, Kristian F.; Vehik, Kendra; Huang, Shuai; TEDDY Study Grp; Knip, Mikael (2016)
    Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper demonstrates the value of using rule-based analysis methods that can identify subgroups with heterogeneous risk profiles in a population without imposing assumptions on the subgroups or method. The rules define the risk pattern of subsets of individuals by not only considering the interactions between the risk factors but also their ranges. We compared the rule-based analysis results with the results from a logistic regression model in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Both methods detected a similar suite of risk factors, but the rule-based analysis was superior at detecting multiple interactions between the risk factors that characterize the subgroups. A further investigation of the particular characteristics of each subgroup may detect the special health needs of the subgroup and lead to tailored interventions.
  • Marin-Gomez, Oscar H.; MacGregor-Fors, Ian (2021)
    Urbanization drives changes in acoustic communication systems in some animal species. Noise and light pollution are among the main urban factors known to disrupt the timing and structure of avian singing behaviour. Despite our understanding of the ways in which urbanization can drive variations in avian acoustic communication, our ability to generalize the underlying causes of such variation and its consequences is still limited. Here, we reviewed the literature focused on the study of avian dawn choruses in urban settings at a global scale. Our findings reveal that avian dawn chorus research has focused on the impact of anthropogenic noise on dawn chorus traits (i.e. timing, peak, song output, song frequencies); relationships between light pollution and chorus timing; the effects of temperature, cloudiness, moonlight and natural light on chorus timing; relationships between nocturnal noise and light, and dawn chorus timing; the effects of chemical pollution and supplementary feeding on dawn chorus activity; and ecological patterns of dawn choruses in soundscapes across urban-non-urban gradients. We identified important knowledge gaps in the study of avian dawn choruses in urban settings and thus suggest future research directions, including frameworks (e.g. the urbanization intensity gradient) and consideration of a wider array of urban conditions and variables. Given the complexity of urban settings, we encourage further studies to address the role that all sources of pollution can have on avian acoustic communication at dawn. Additionally, a central question to resolve is whether the function of avian dawn choruses in urban areas differs, and if so how, from non-urban counterparts. Given that most research has been performed across Holarctic cities and towns, studies from tropical and subtropical regions are needed if we aim to understand the phenomenon globally. Finally, studies at the community- and soundscape-level across cities could advance understanding of the way in which urban birds use the acoustic space during the most critical singing time period, dawn.
  • Kettunen, Jarno L. T.; Rantala, Elina; Dwivedi, Om P.; Isomaa, Bo; Sarelin, Leena; Kokko, Paula; Hakaste, Liisa; Miettinen, Päivi J.; Groop, Leif C.; Tuomi, Tiinamaija (2022)
    Aims/hypothesis Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. Methods We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. Results Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m(2) units of BMI, p=2.2 x 10(-4), using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 mu mol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 mu mol/l, p=3.1 x 10(-5)). Conclusions/interpretation The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.
  • Harjutsalo, Valma; Maric-Bilkan, Christine; Forsblom, Carol; Groop, Per-Henrik; FinnDiane Study Grp (2016)
    Aims/hypothesis The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. Methods Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. Results There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p <0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age+ 2 years) had a 2.30 (95% CI 1.27, 4.17; p <0.006) times higher risk of nephropathy compared with the women who underwent menarche at the mean age +/- 2 years. Delayed menarche also increased the risk of retinopathy (OR 2.34 [95% CI 1.36, 4.01]). After excluding patients with nephropathy, the OR for retinopathy was 2.11 (95% CI 1.15, 3.90). Earlier menarche (<mean age-2 years) did not have any effect on this risk. Conclusions/interpretation Delayed menarche was associated with an increased risk of diabetic nephropathy and retinopathy, whereas early menarche was not. Delayed menarche may be used as a new tool to identify women at risk of diabetic microvascular complications.
  • Jääskeläinen, Tiina; Heinonen, Seppo; Hämäläinen, Esa; Pulkki, Kari; Romppanen, Jarkko; Laivuori, Hannele (2018)
    Objectives: To study first and second/third trimester levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) in FINNPEC case-control cohort. The participants were further divided into subgroups based on parity and onset of the disease. Recommended cut-off values in aid of pre-eclampsia (PE) prediction and diagnosis were also tested. Methods: First trimester serum samples were available from 221 women who later developed PE and 239 women who did not develop PE. Second/third trimester serum samples were available from 175 PE and 55 non-PE women. sFl1-1 and PlGF were measured electro-chemiluminescence immunoassays and sEng by ELISA. Results: In all timepoints PlGF, endoglin and the sFlt-1/PlGF ratio were increased in the PE group compared to the non-PE group. The serum concentrations of sFlt-1 were increased only a second/third trimester in PE women. Higher concentrations of s-Flt1, endoglin and higher sFlt/PlGF ratio were found a the third trimester in primiparous women compared to multiparous women. Primiparous PE women also had lower concentrations of PlGF a the third trimester. The proportion of women exceeding all cut-offs of the sFlt-1/PlGF ratio (>= 33, >= 38, >= 85 and >= 110) was greater in the PE group, but there were also pre-eclamptic women who met rule-out cut-off or did no meet rule-in cut-off. Conclusions: Primiparous pregnancies have more anti-angiogenic profile during second/third trimester compared with multiparous pregnancies. Our findings also suggest that certain maternal characteristics, e.g. BMI, smoking and pre-existing diseases, should be taken into account when different sFlt-1/PlGF ratio cut-offs are utilized.
  • Vaarala, Outi; Vuorela, Arja; Partinen, Markku; Baumann, Marc; Freitag, Tobias L.; Meri, Seppo; Saavalainen, Paivi; Jauhiainen, Matti; Soliymani, Rabah; Kirjavainen, Turkka; Olsen, Paivi; Saarenpaa-Heikkila, Outi; Rouvinen, Juha; Roivainen, Merja; Nohynek, Hanna; Jokinen, Jukka; Julkunen, Ilkka; Kilpi, Terhi (2014)
  • Nohynek, Hanna; Jokinen, Jukka; Partinen, Markku; Vaarala, Outi; Kirjavainen, Turkka; Sundman, Jonas; Himanen, Sari-Leena; Hublin, Christer; Julkunen, Ilkka; Olsen, Paivi; Saarenpaa-Heikkila, Outi; Kilpi, Terhi (2012)
  • Finnish Pediat Diabet Register; Ilonen, Jorma; Laine, Antti-Pekka; Kiviniemi, Minna; Härkönen, Taina; Lempainen, Johanna; Knip, Mikael (2022)
    Objectives We aimed to further characterize demography and genetic associations of type 1 diabetes "endotypes" defined by the first appearing islet specific autoantibodies. Research Design and Methods We analyzed 3277 children diagnosed before the age of 10 years from the Finnish Pediatric Diabetes Register. The most likely first autoantibody could be deduced in 1636 cases (49.9%) based on autoantibody combinations at diagnosis. Distribution of age, sex, HLA genotypes and allele frequencies of 18 single nucleotide polymorphisms (SNPs) in non-HLA risk genes were compared between the endotypes. Results Two major groups with either glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the deduced first autoantibody showed significant differences in their demographic and genetic features. Boys and children diagnosed at young age had more often IAA-initiated autoimmunity whereas GADA-initiated autoimmunity was observed more frequently in girls and in subjects diagnosed at an older age. IAA as the first autoantibody was also most common in HLA genotype groups conferring high-disease risk while GADA first was seen more evenly and frequently in HLA groups associated with lower type 1 diabetes risk. The risk alleles in IKZF4 and ERBB3 genes were associated with GADA-initiated whereas those in PTPN22, INS and PTPN2 genes were associated with IAA-initiated autoimmunity. Conclusions The results support the assumption that in around half of the young children the first autoantibody can be deduced based on islet autoantibody combinations at disease diagnosis. Strong differences in sex and age distributions as well as in genetic associations could be observed between GADA- and IAA-initiated autoimmunity.
  • Pöllänen, Petra M.; Härkönen, Taina; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Siljander, Heli; Knip, Mikael (2022)
    Objective To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD(65)(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies. Design In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD(65) (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. Results T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2-61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P < 0.001). Conclusions Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.
  • Luo, Guo; Ambati, Aditya; Lin, Ling; Bonvalet, Melodie; Partinen, Markku; Ji, Xuhuai; Maecker, Holden Terry; Mignot, Emmanuel Jean-Marie (2018)
    Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4(+) T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA(273-287) (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3 beta TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA(273-287)-tetramers, suggesting molecular mimicry. This public CDR3 beta uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-alpha/beta CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3 alpha, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-alpha/beta CDR3 sequences found in pHA(273-287), NP17-31, and HCRTNH2 tetramer-positive CD4(+) cells were also retrieved in single INF-gamma-secreting CD4(+) sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
  • Lietzen, Raija; Virtanen, Pekka; Kivimaki, Mika; Korkeila, Jyrki; Suominen, Sakari; Sillanmaki, Lauri; Koskenvuo, Markku; Vahtera, Jussi (2017)
    Objective: This prospective, population-based cohort study of 1102 Finnish adults with asthma, examined whether exposure to stressful life events is associated with the intensity of usage of inhaled short-acting beta(2)-agonists. Methods: Survey data was collected by two postal questionnaires. Baseline characteristics were obtained in 1998 and data on 19 specific stressful events (e.g. death of a child or spouse or divorce) within the six preceding months in 2003. Exposure to life events was indicated by a sum score weighted by mean severity of the events. Participants were linked to records of filled prescriptions for inhaled short-acting beta(2)-agonists from national registers from 2000 through 2006. The rates of purchases of short-acting beta(2)-agonists before (2000 2001), during (2002 2003) and after (2004-2006) the event exposure were estimated using repeated-measures Poisson regression analyses with the generalized estimating equation. Results: Of the 1102 participants, 162 (15%) were exposed to highly stressful events, 205 (19%) to less stressful events. During the 7-year observation period, 5955 purchases of filled prescription for inhaled short-acting beta(2)-agonists were recorded. After exposure to highly stressful events, the rate of purchases of beta(2)-agonists was 1.50 times higher (95% confidence interval (CI): 1.05, 2.13) than before the stressful event occurred. Among those with low or no exposure to life events, the corresponding rate ratios were not elevated (rate ratio 0.81, 95% CI: 0.66, 0.99 and 0.95, 95% CI: 0.83, 1.09 respectively). Conclusion: An increase in beta(2)-agonist usage after severe life events suggests that stressful experiences may worsen asthma symptoms.
  • Kröger, Björn (2018)
    Near-equatorial peak diversities are a prominent first-order feature of today's latitudinal diversity gradient (LDG), but were not a persistent pattern throughout geological time. In an analysis of Ordovician (485-444 Ma) fossil occurrences, an equatorward shift of the latitudinal diversity peak can be detected. A modern-type LDG and out-of-the-tropics range shift pattern were synchronously established during emerging icehouse conditions at the climax of the Great Ordovician Biodiversity Event. The changes in the LDG pattern and range shift trends can be best explained as a consequence of global cooling during the Middle Ordovician and of diversification in the tropical realm following a greenhouse period with temperatures too hot to support diverse tropical marine life. These results substantiate a fundamental role of temperature changes in establishing global first-order diversity patterns.
  • Finne, Patrik; Groop, Per-Henrik; Arffman, Martti; Kervinen, Marjo; Helve, Jaakko; Gronhagen-Riska, Carola; Sund, Reijo (2019)
    OBJECTIVE To estimate long-term cumulative risk of end-stage renal disease (ESRD) after diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS This nationwide population-based inception cohort study included 421,429 patients with type 2 diabetes diagnosed in 1990-2011; patients were followed until the end of 2013. Data linkage between several national health care registers in Finland, covering 100% of the population, enabled the inclusion of almost all inhabitants who started taking diabetes medication or were hospitalized for diabetes. Cumulative risk of ESRD and hazard ratios [HR] for ESRD and death were estimated according to age, sex, and time period of diabetes diagnosis. RESULTS Among 421,429 patients with type 2 diabetes, 1,516 developed ESRD and 150,524 died during 3,458,797 patient-years of follow-up. Cumulative risk of ESRD was 0.29% at 10 years and 0.74% at 20 years from diagnosis of diabetes. Risk was higher among men than among women (HR 1.93 [95% CI 1.72-2.16]), decreased with older age at diagnosis (HR 0.70 [95% CI 0.60-0.81] for age 60-69 vs. 40-49 years), and was lower for those diagnosed in 2000-2011 than in 1990-1994 (HR 0.72 [95% CI 0.63-0.81]). Patients diagnosed with diabetes in 2000-2011 had lower risk of death during follow-up than those diagnosed in 1990-1994 (HR 0.64 [95% CI 0.63-0.65]). CONCLUSIONS Cumulative risk of ESRD is minimal among patients with type 2 diabetes compared with their risk of death. Patients diagnosed with diabetes at an older age have a lower risk of ESRD due to higher competing mortality.
  • Sandell, Satu; Huovinen, Sanna; Palmio, Johanna; Raheem, Olayinka; Lindfors, Mikaela; Zhao, Fang; Haapasalo, Hannu; Udd, Bjarne (2016)
    Introduction: Limb girdle muscular dystrophies are a large group of both dominantly and recessively inherited muscle diseases. LGMD1D is caused by mutated DNAJB6 and the molecular pathogenesis is mediated by defective chaperonal function leading to impaired handling of misfolded proteins which normally would be degraded. Here we aim to clarify muscle pathology of LGMD1D in order to facilitate diagnostic accuracy. After following six Finnish LGMD1D families, we analysed 21 muscle biopsies obtained from 15 patients at different time points after the onset of symptoms. All biopsies were obtained from the lower limb muscles and processed for routine histochemistry, extensive immunohistochemistry and electron microscopy. Results: Histopathological findings were myopathic or dystrophic combined with rimmed vacuolar pathology, and small myofibrillar aggregates. These myofibrillar inclusions contained abnormal accumulation of a number of proteins such as myotilin, aB-crystallin and desmin on immunohistochemistry, and showed extensive myofibrillar disorganization with excess of Z-disk material on ultrastructure. Later in the disease process the rimmed vacuolar pathology dominated with rare cases of pronounced larger pleomorphic myofibrillar aggregates. The rimmed vacuoles were reactive for several markers of defect autophagy such as ubiquitin, TDP-43, p62 and SMI-31. Conclusions: Since DNAJB6 is known to interact with members of the chaperone assisted selective autophagy complex (CASA), including BAG3 - a known myofibrillar myopathy causing gene, the molecular muscle pathology is apparently mediated through impaired functions of CASA and possibly other complexes needed for the maintenance of the Z-disk and sarcomeric structures. The corresponding findings on histopathology offer clues for the diagnosis.
  • Lindqvist, U.; Gudbjornsson, B.; Iversen, L.; Laasonen, L.; Ejstrup, L.; Ternowitz, T.; Stahle, M. (2017)
    Objective: To describe the social status and health-related quality of life of patients with psoriatic arthritis mutilans (PAM) in the Nordic countries.Method: Patients with at least one mutilated joint confirmed by radiology were studied. Disease activity involving joints and skin, physician-assessed disease activity, and patient's education and work status were recorded. Data from the 36-item Short Form Health Survey, Health Assessment Questionnaire and Dermatology Life Quality Index questionnaire were gathered and correlated with disease duration, pain, and general well-being (visual analogue scale). The controls were 58 Swedish patients with long-standing psoriatic arthritis sine PAM.Results: Sixty-seven patients were included. Patients with PAM had a protracted disease history (3314years) and disease onset at a relatively early age (30 +/- 12years). Overall inflammatory activity at inclusion was mild to moderate. The mean number of mutilated joints was 8.2 and gross deformity was found in 16% of patients. Forty per cent were treated with biological and 32% with conventional synthetic disease-modifying anti-rheumatic drugs. Forty-two per cent had retired early or were on sick leave. Impaired functional capacity with little or no ability to perform self-care or everyday tasks was reported by 21% of the patients. Patients between 45 and 60years of age reported the most impaired quality of life in comparison to the control group.Conclusion: PAM seriously affects social functioning. Whether early recognition of PAM and new forms of therapy can improve disease outcome and quality of life remains to be studied.
  • Ellonen, Noora; Pitkanen, Joonas; Miller, Bryan L.; Remes, Hanna; Aaltonen, Mikko; Oksanen, Atte; Martikainen, Pekka (2022)
    Introduction The aim was to analyse whether age at first drug offense predicts premature mortality and morbidity due to substance use and violence among adolescents and young adults. Methods A prospective longitudinal register-linkage study based on a total population sample from Finland including individuals born between 1987 and 1992 and aged 15-25 years during follow-up in 2002-2017 (n = 386 435). Age-specific rates of deaths and health-care admissions (morbidity) during a 5-year follow-up were calculated from the first drug offense. Cox regression models were used to estimate differences in mortality and morbidity at ages 21-25. Results Of all 15- to 20-year-olds, 1.4% (n = 5540) have had a police contact. The 5-year mortality rates (per 1000 person-years) among those with first drug offense at ages 15-16 was 2.92 [95% confidence interval (CI) 1.56-6.18], and 5.26 (CI 4.00-7.07) and 5.05 (CI 4.06-6.38) at ages 17-18, and 19-20, respectively. The rates of morbidity varied between 61.20 (CI 52.43-71.76) and 87.51 (CI 82.11-93.33). Both mortality and morbidity rates were over 10 times higher than among the general population. In models adjusted for family background, first police contact at an early age (15-16) did not increase the risk of mortality at ages 21-25 compared with first police contact at ages 17-18 (hazard ratio 1.55, CI 0.77-3.09) or 19-20 (hazard ratio 1.52, CI 0.78-2.98). The results were similar for morbidity. Discussion and Conclusions Adolescents with drug-related police contacts have high risk of mortality and morbidity due to substance use and violence regardless of age of first contact.
  • Siljander, Heli; Jason, Eeva; Ruohtula, Terhi; Selvenius, Jenni; Koivusaari, Katariina; Salonen, Marja; Ahonen, Suvi; Honkanen, Jarno; Ilonen, Jorma; Vaarala, Outi; Virtanen, Suvi M.; Lähdeaho, Marja-Leena; Knip, Mikael (2021)
    Objectives To assess whether weaning to an extensively hydrolyzed formula (EHF) decreases gut permeability and/or markers of intestinal inflammation in infants with HLA-conferred diabetes susceptibility, when compared with conventional formula. Study design By analyzing 1468 expecting biological parent pairs for HLA-conferred susceptibility for type 1 diabetes, 465 couples (32 %) potentially eligible for the study were identified. After further parental consent, 332 babies to be born were randomized at 35th gestational week. HLA genotyping was performed at birth in 309 infants. Out of 87 eligible children, 73 infants participated in the intervention study: 33 in the EHF group and 40 in the control group. Clinical visits took place at 3, 6, 9, and 12 months of age. The infants were provided either EHF or conventional formula whenever breastfeeding was not available or additional feeding was required over the first 9 months of life. The main outcome was the lactulose to mannitol ratio (L/M ratio) at 9months. The secondary outcomes were L/M ratio at 3, 6, and 12 months of age, and fecal calprotectin and human beta-defensin 2 (HBD-2) levels at each visit. Results Compared with controls, the median L/M ratio was lower in the EHF group at 9 months (.006 vs.028; P = .005). Otherwise, the levels of intestinal permeability, fecal calprotectin, and HBD-2 were comparable between the two groups, although slight differences in the age-related dynamics of these markers were observed. Conclusions It is possible to decrease intestinal permeability in infancy through weaning to an extensively hydrolyzed formula. This may reduce the early exposure to dietary antigens.
  • EXTEND Investigator; ECASS-4 Investigator; EPITHET Investigator; Campbell, Bruce C.; Ma, Henry; Curtze, Sami; Donnan, Geoffrey A.; Kaste, Markku (2019)
    Background Stroke thrombolysis with alteplase is currently recommended 0-4.5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4.5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. Methods In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials. gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged =18 years) with ischaemic stroke treated more than 4.5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. Findings We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1.86, 95% CI 1.15-2.99, p=0.011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9.7, 95% CI 1.23-76.55, p=0.031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1.55, 0.81-2.96, p=0.66). Interpretation Patients with ischaemic stroke 4.5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis. Copyright (c) 2019 Elsevier Ltd. All rights reserved.
  • Seppälä, Severi; Rajala, Kaisa; Lehto, Juho Tuomas; Sutinen, Eva; Mäkitalo, Laura; Kautiainen, Hannu; Kankaanranta, Hannu; Ainola, Mari; Saarto, Tiina; Myllärniemi, Marjukka (2020)
    Background: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with a poor prognosis. Patients with IPF suffer from a high symptom burden, which impairs their health-related quality of life (HRQoL). Lack of research on IPF symptoms and their clustering, however, makes symptom-centred care challenging. Methods: We sent two questionnaires, RAND 36-Item Health Survey and Edmonton Symptom Assessment System, to 300 patients from the FinnishIPF registry. Of the 300 patients, 245 (82%) responded. We performed an exploratory factor analysis on the results to search for potential clustering of symptoms into factors. Results: We found three distinct symptom factors: the emotional factor (including depression, anxiety, insomnia, loss of appetite and nausea), the pain factor (pain at rest or in movement) and the respiratory symptoms factor (shortness of breath, cough, tiredness and loss of wellbeing). Correlation was strong within the factors (rho(tau) 0.78-0.85) and also evident between them. The factors correlated with the different dimensions of HRQoL: the emotional factor with mental health (correlation coefficient=-0.69) and vitality (-0.63), the pain factor with bodily pain (-0.72) and the respiratory symptoms factor with vitality (-0.69), general health (-0.64) and physical functioning (-0.62). Conclusion: We found three distinct symptom factors in IPF, of which respiratory and emotional factors showed the strongest association with decreasing HRQoL. Routine assessment of IPF patients' respiratory symptoms, mental health and pain are important as these may be linked with other symptoms and significantly impair the patient's HRQoL.
  • Winther, Signe Abitz; Maininki Mannerla, Miia; Frimodt-Moller, Marie; Persson, Frederik; Hansen, Tine Willum; Lehto, Markku; Hoerkkoe, Sohvi; Blaut, Michael; Forsblom, Carol; Groop, Per-Henrik; Rossing, Peter (2021)
    Gastrointestinal dysbiosis is common among persons with type 1 diabetes (T1D), but its potential impact on diabetic nephropathy (DN) remains obscure. We examined whether faecal biomarkers, previously associated with low-grade gastrointestinal inflammation, differ between healthy controls and T1D subjects with and without DN. Faecal samples were analyzed for levels of calprotectin, intestinal alkaline phosphatase (IAP), short-chain fatty acids (SCFA) and immunoglobulins in subjects with T1D (n=159) and healthy controls (NDC; n=50). The subjects with T1D were stratified based on albuminuria: normoalbuminuria (300 mg/g; n=60). aecal calprotectin, IAP and immunoglobulin levels did not differ between the T1D albuminuria groups. However, when subjects were stratified based on faecal calprotectin cut-off level (50 mu g/g), macroalbuminuric T1D subjects exceeded the threshold more frequently than NDC (p=0.02). Concentrations of faecal propionate and butyrate were lower in T1D subjects compared with NDC (p=0.04 and p=0.03, respectively). Among T1D subjects, levels of branched SCFA (BCFA) correlated positively with current albuminuria level (isobutyrate, p=0.03; isovalerate, p=0.005). In our study cohort, fatty acid metabolism seemed to be altered among T1D subjects and those with albuminuria compared to NDC. This may reflect gastrointestinal imbalances associated with T1D and renal complications.