ABSTRACT
OBJECTIVE: To develop and externally validate prediction models for incident hand osteoarthritis (OA) in a large population-based cohort of middle aged and older men and women. DESIGN: We included 17,153 men and 18,682 women from a population-based cohort, aged 35-70 years at baseline (1995-1997). Incident hand OA were obtained from diagnostic codes in the Norwegian National Patient Register (1995-2018). We studied whether a range of self-reported and clinically measured predictors could predict hand OA, using the Area Under the receiver-operating Curve (AUC) from logistic regression. External validation of an existing prediction model for male hand OA was tested on discrimination in a sample of men. Bootstrapping was used to avoid overfitting. RESULTS: The model for men showed modest discriminatory ability (AUC = 0.67, 95% CI 0.62-0.71). Adding a genetic risk score did not improve prediction. Similar discrimination was observed in the model for women (AUC = 0.62, 95% CI 0.59-0.64). Prediction was not improved by adding a genetic risk score or hormonal and reproductive factors. Applying external validation, similar results were observed among men in HUNT (The Nord-Trøndelag Health Study) as in the developmental sample (AUC = 0.62, 95% CI 0.57-0.65). CONCLUSION: We developed prediction models for incident hand OA in men and women. For women, the model included body mass index (BMI), heavy physical work, high physical activity and perceived poor health. The model showed moderate discrimination. For men, we have shown that a prediction model including BMI, education and information on sleep can predict incident hand OA in several populations with moderate discriminative ability.
Subject(s)
Hand Joints , Osteoarthritis/epidemiology , Adult , Aged , Alcohol Drinking/epidemiology , Area Under Curve , Blood Pressure , Body Mass Index , Diabetes Mellitus/epidemiology , Educational Status , Estrogen Replacement Therapy/statistics & numerical data , Exercise , Female , Humans , Incidence , Logistic Models , Male , Menarche , Middle Aged , Norway/epidemiology , Occupations/statistics & numerical data , Parity , ROC Curve , Reproducibility of Results , Risk Assessment , Smoking/epidemiologyABSTRACT
BACKGROUND AND PURPOSE: Headache has been associated with various lifestyle and psychosocial factors, one of which is smoking. The aim of the present study was to investigate whether the association between smoking intensity and headache is likely to be causal. METHOD: A total of 58 316 participants from the Nord-Trøndelag Health (HUNT) study with information on headache status were genotyped for the rs1051730 C>T single-nucleotide polymorphism (SNP). The SNP was used as an instrument for smoking intensity in a Mendelian randomization analysis. The association between rs1051730 T alleles and headache was estimated by odds ratios with 95% confidence intervals. Additionally, the association between the SNP and migraine or non-migrainous headache versus no headache was investigated. All analyses were adjusted for age and sex. RESULTS: There was no strong evidence that the rs1051730 T allele was associated with headache in ever smokers (odds ratio 0.99, 95% confidence interval 0.95-1.02). Similarly, there was no association between the rs1051730 T allele and migraine or non-migrainous headache versus no headache. CONCLUSION: The findings from this study do not support that there is a strong causal relationship between smoking intensity and any type of headache. Larger Mendelian randomization studies are required to examine whether higher smoking quantity can lead to a moderate increase in the risk of headache subtypes.
Subject(s)
Headache/epidemiology , Mendelian Randomization Analysis , Smoking/adverse effects , Smoking/epidemiology , Adult , Aged , Aged, 80 and over , Causality , Female , Genotype , Headache/genetics , Humans , Male , Middle Aged , Migraine Disorders/epidemiology , Migraine Disorders/etiology , Norway/epidemiology , Polymorphism, Single Nucleotide/genetics , Sex Factors , Smoking/genetics , Young AdultSubject(s)
Agammaglobulinemia/diagnosis , B-Lymphocytes/pathology , Drug-Related Side Effects and Adverse Reactions/diagnosis , HIV Infections/diagnosis , HIV-1/immunology , Immunity, Maternally-Acquired , Immunoglobulin kappa-Chains/genetics , Rituximab/therapeutic use , Adult , Agammaglobulinemia/etiology , Agammaglobulinemia/genetics , Antigens, CD20/metabolism , Diagnostic Errors/prevention & control , Female , Fetomaternal Transfusion , HIV Infections/drug therapy , HIV Infections/genetics , Humans , Immunosuppression Therapy/adverse effects , Infant , Infant, Newborn , Lymphocyte Depletion , Lymphopenia , Male , Maternal Exposure/adverse effects , Neonatal Screening/methods , Pregnancy , Recombination, Genetic , Rituximab/adverse effectsABSTRACT
INTRODUCTION: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected infants/children. The measurement of T-cell receptor excision circles (TRECS) and kappa-deleting recombination excision circles (KRECS) can identify neonates with severe T or B-cell lymphopenia. OBJECTIVES: To determine TRECS and KRECS levels from prospectively collected dried blood spot samples (DBS) and to correctly identify severe T and B-cell lymphopenia. MATERIAL AND METHODS: Determination of TRECS and KRECS by multiplex PCR from neonates born in two tertiary hospitals in Seville between February 2014 and May 2014. PCR cut-off levels: TRECS<15 copies/µl, KRECS<10 copies/µl, ACTB (ß-actin)>1000 copies/µl. Internal (XLA, ataxia telangiectasia) and external (SCID) controls were included. RESULTS: A total of 1068 out of 1088 neonates (mean GA 39 weeks (38-40) and BW 3238g (2930-3520) were enrolled in the study. Mean (median, min/max) copies/µl, were as follows: TRECS 145 (132, 8/503), KRECS 82 (71, 7/381), and ACTB 2838 (2763, 284/7710). Twenty samples (1.87%) were insufficient. Resampling was needed in one neonate (0.09%), subsequently giving a normal result. When using lower cut-offs (TRECS<8 and KRECS<4 copies/µl), all the samples tested were normal and the internal and external controls were correctly identified. CONCLUSION: This is the first prospective pilot study in Spain using TRECS/KRECS/ACTB-assay, describing the experience and applicability of this method to identify severe lymphopenias. The ideal cut-off remains to be established in our population. Quality of sampling, storage and preparation need to be further improved.
Subject(s)
Agammaglobulinemia/diagnosis , Agammaglobulinemia/genetics , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Lymphopenia/diagnosis , Neonatal Screening/methods , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Agammaglobulinemia/blood , Algorithms , B-Lymphocytes , DNA, Circular/blood , Genetic Diseases, X-Linked/blood , Humans , Infant, Newborn , Longitudinal Studies , Pilot Projects , Prospective Studies , Severe Combined Immunodeficiency/blood , Severity of Illness Index , Spain , T-LymphocytesSubject(s)
Forkhead Transcription Factors/metabolism , Interleukin-7 Receptor alpha Subunit/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Diabetes Mellitus, Type 1/congenital , Diarrhea , Exons , Forkhead Transcription Factors/genetics , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Genetic Diseases, X-Linked/metabolism , Hemizygote , Humans , Immune System Diseases/congenital , Immunophenotyping , MutationABSTRACT
Severe combined immunodeficiency (SCID) is the most severe form of inherited primary immunodeficiency and is a paediatric emergency. Delay in recognising and detecting SCID can have fatal consequences and also reduces the chances of a successful haematopoietic stem cell transplant (HSCT). Screening for SCID at birth would prevent children from dying before HSCT can be attempted and would increase the success of HSCT. There is strong evidence to show that SCID fulfills the internationally-established criteria for a condition to be screened for at birth. There is also a test (the T-cell receptor excision circle (TREC) assay) that is now being successfully used in an increasing number of US states to screen for SCID in routine newborn Guthrie samples. Concerted lobbying efforts have highlighted the need for newborn screening (NBS) for SCID, and its implementation is being discussed in Europe both at EU and individual country level, but as yet there is no global mandate to screen for this rare and frequently lethal condition. This paper summarizes the current evidence for, and the success of SCID NBS, together with a review of the practical aspects of SCID testing and the arguments in favour of adding SCID to the conditions screened for at birth.
Subject(s)
Hematopoietic Stem Cell Transplantation , Neonatal Screening/statistics & numerical data , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/therapy , Enzyme Replacement Therapy , Europe/epidemiology , Female , Genetic Therapy , Humans , Infant, Newborn , Lymphocyte Count , Male , Neonatal Screening/methods , Severe Combined Immunodeficiency/epidemiology , Severe Combined Immunodeficiency/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , United States/epidemiologyABSTRACT
In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.
Subject(s)
Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/epidemiology , Registries , Adolescent , Adult , Age Factors , Aged , Child , Child, Preschool , Databases, Factual , Female , Germany , Humans , Immunologic Deficiency Syndromes/genetics , Infant , Infant, Newborn , Male , Middle Aged , Prevalence , Young AdultABSTRACT
OBJECTIVES: Interleukin-21 (IL-21) has been shown to restore immunoglobulin production together with Interleukin-4 (IL-4) in common variable immunodeficiency syndrome (CVID). Here, we elucidate the functional and structural properties of the corresponding IL-21R : IL-4R system. PATIENTS AND METHODS: An in vitro cell culture system was established to study the molecular effects of IL-21 and IL-4 on B cell differentiation, class-switch recombination (CSR) and immunoglobulin (Ig) production in 32 paediatric patients with CVID. MHC haplotypes and the IL21 and IL21R gene were analysed by genotyping. Ternary complexes of the IL-21 respectively IL-4 receptor were set-up by homology modeling and ligand-interaction was examined by molecular dynamics (MD) simulation. RESULTS: Stimulation with IL-21, IL-4 and CD40L uniformly induced IgG and IgA production in B cells from all tested patients by initiation of both CSR and AID-independent Ig production. No mutations were found in the coding regions of the IL21 or IL21R genes and no distinct HLA allele or extended haplotype could be correlated with the amount of Ig production or the gene expression pattern induced by IL-21. MD simulations of the modelled receptor complexes showed that IL-4 and IL-21 are both able to bind to IL-4R and IL-21R complexes in an interchangeable manner. CONCLUSIONS: The function of the IL-21R : IL-4R system seems not to be related to the aetiology of CVID in paediatric patients and might be suitable for a regenerative therapy.
Subject(s)
B-Lymphocytes/immunology , Common Variable Immunodeficiency/immunology , Common Variable Immunodeficiency/therapy , Interleukin-21 Receptor alpha Subunit/drug effects , Interleukin-4 Receptor alpha Subunit/drug effects , Interleukin-4/pharmacology , Interleukins/pharmacology , Adolescent , B-Lymphocytes/drug effects , Cells, Cultured , Child , Child, Preschool , Common Variable Immunodeficiency/genetics , DNA Mutational Analysis , Female , Haplotypes/genetics , Humans , Immunoglobulin A/metabolism , Immunoglobulin Class Switching/genetics , Immunoglobulin G/metabolism , Interleukin-21 Receptor alpha Subunit/genetics , Interleukin-4/genetics , Interleukin-4 Receptor alpha Subunit/genetics , Interleukins/genetics , Male , Molecular Dynamics Simulation , Polymerase Chain Reaction , Recombinant Proteins/pharmacology , Sequence Analysis, DNAABSTRACT
OBJECTIVES: To evaluate the influence of low-dose MTX and etanercept treatment on efficacy of measles, mumps and rubella (MMR) revaccination in children with juvenile idiopathic arthritis. METHODS: A prospective nested case-control study was performed to investigate markers of MMR revaccination induced humoral and cell-mediated immunity in 15 patients with juvenile idiopathic arthritis (ages 6-17 yrs), treated with either low-dose MTX therapy alone or in combination with etanercept. The control group consisted of 22 healthy children. Production of IFN-gamma by T memory cells upon in vitro stimulation with measles, mumps and rubella antigens and seroprevalence of virus-specific IgG antibodies were assessed. Medication use, disease activity and patients' comments on side-effects were observed during the period of 6 months before and after revaccination. RESULTS: Low-dose MTX therapy following MMR vaccination proved not to hamper T-cell mediated immunity in vitro. Neither low-dose MTX nor etanercept treatment, given simultaneously with revaccination, markedly interfered with generation of long-lived virus-restricted T cells and protective levels of virus-specific IgG antibodies. No increase in disease activity or medication use was seen within 6 months after MMR revaccination, including JIA patients using etanercept. No overt measles, mumps, rubella or secondary severe infections were noted. CONCLUSIONS: Low-dose MTX and etanercept treatment do not seem to interfere with intended outcome of MMR revaccination in children with JIA.