Jeffrey P Krischer

University of South Florida, Tampa, Florida, United States

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Publications (240)1512.08 Total impact

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    ABSTRACT: Gut microbiome dysbiosis is associated with numerous diseases, including type 1 diabetes. This pilot study determines how geographical location affects the microbiome of infants at high risk for type 1 diabetes in a population of homogenous HLA class II genotypes. High-throughput 16S rRNA sequencing was performed on stool samples collected from 90 high-risk, nonautoimmune infants participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S., Germany, Sweden, and Finland. Study site-specific patterns of gut colonization share characteristics across continents. Finland and Colorado have a significantly lower bacterial diversity, while Sweden and Washington state are dominated by Bifidobacterium in early life. Bacterial community diversity over time is significantly different by geographical location. The microbiome of high-risk infants is associated with geographical location. Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes care. 12/2014;
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    ABSTRACT: We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive individuals. Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose <200 mg/dL (Ind60+Only) were compared with Index60 <2.00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P < 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range -22 to -34% in DPT-1 and -14 to -27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. An approach based on prediction and natural history appears to have utility for diagnosing T1D. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes care. 12/2014;
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    ABSTRACT: Rationale: The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined. Objectives: To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype. Methods and Measurements: 118 participants <19 years old with PCD were evaluated prospectively at 6 centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping. Main Results: Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone, n=54) and ODA plus inner dynein arm (IDA) defects (ODA+IDA; n=18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n=40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; p=0.003). Median BMI was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; p=0.003). For all 118 subjects, median number of lobes with bronchiectasis was 3 and alveolar consolidation was 2. However, the 5-11 year old IDA/CA/MTD group had more lobes of bronchiectasis (median= 5, p=0.0008) and consolidation (median=3, p=0.0001) compared to the ODA groups (median=3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations. Conclusions: Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.
    American Journal of Respiratory and Critical Care Medicine 12/2014; · 11.04 Impact Factor
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    ABSTRACT: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth, who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GADA, IA-2A or mIAA) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA SNPs that achieved genome-wide significance for association with T1D in the GWAS meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY-participants carrying high-risk HLA-genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (p<0.05), whereof four were significant after adjustment for multiple testing (p<0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]) and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA-region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 11/2014; · 7.90 Impact Factor
  • Maya Guglin, Kristian Lynch, Jeffrey Krischer
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    ABSTRACT: Background: Diabetes mellitus (DM) is a well-recognized risk factor for heart failure (HF). We hypothesized that HF also increases the risk for DM. Objective: We explored the hypothesis that HF is a risk factor for DM. Methods: The Cardiovascular Health Study was a prospective cohort study of cardiovascular risk in ambulatory older adults. We used a limited-access dataset provided by the National Heart, Lung and Blood Institute. The impact of HF at baseline on DM after 3 or 4 years was examined in a cohort of 3,748 nondiabetic participants aged ≥65 years. The magnitude and significance of the association were evaluated using logistic regression models. Analyses were performed with and without adjustment for confounders and separately among subjects with normal and impaired fasting glucose at baseline. Results: Among subjects with normal fasting glucose at baseline, HF significantly increased the odds of developing impaired fasting glucose after 3 or 4 years [odds ratio (OR) 2.18, 95% confidence interval (CI) 1.03-4.61, p = 0.043] or overt DM (OR 4.78, 95% CI 1.84-12.4, p < 0.001). After adjusting for demographic and biomedical factors, HF remained significantly associated with a worsening DM status (OR 2.43, 95% CI 1.38-4.29, p = 0.002). Conclusions: In the elderly population, the presence of HF more than doubles the incidence of DM within a few years. This association remains significant when adjusting for age, gender and cardiovascular comorbidities. © 2014 S. Karger AG, Basel.
    Cardiology 08/2014; 129(2):84-92. · 1.52 Impact Factor
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    ABSTRACT: Established in 2003 by the Office of Rare Diseases Research (ORDR), in collaboration with several National Institutes of Health (NIH) Institutes/Centers, the Rare Diseases Clinical Research Network (RDCRN) consists of multiple clinical consortia conducting research in more than 200 rare diseases. The RDCRN supports longitudinal or natural history, pilot, Phase I, II, and III, case-control, cross-sectional, chart review, physician survey, bio-repository, and RDCRN Contact Registry (CR) studies. To date, there have been 24,684 participants enrolled on 120 studies from 446 sites worldwide. An additional 11,533 individuals participate in the CR. Through a central data management and coordinating center (DMCC), the RDCRN's platform for the conduct of observational research encompasses electronic case report forms, federated databases, and an online CR for epidemiological and survey research. An ORDR-governed data repository (through dbGaP, a database for genotype and phenotype information from the National Library of Medicine) has been created. DMCC coordinates with ORDR to register and upload study data to dbGaP for data sharing with the scientific community. The platform provided by the RDCRN DMCC has supported 128 studies, six of which were successfully conducted through the online CR, with 2,352 individuals accrued and a median enrollment time of just 2 months. The RDCRN has built a powerful suite of web-based tools that provide for integration of federated and online database support that can accommodate a large number of rare diseases on a global scale. RDCRN studies have made important advances in the diagnosis and treatment of rare diseases.
    Journal of general internal medicine. 07/2014;
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    ABSTRACT: Objective Type 1 diabetes (T1D) results from the inflammatory destruction of pancreatic β-cells. In this study, we investigated the effect of docosahexaenoic acid (DHA) supplementation on stimulated inflammatory cytokine production in white blood cells (WBC) from infants with a high genetic risk for T1D.Research design and methodsThis was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, beginning either in the last trimester of pregnancy (41 infants) or in the first 5 months after birth (57 infants). Levels of DHA in infant and maternal red blood cell (RBC) membranes and in breast milk were analyzed by gas chromatography/mass spectrometry. Inflammatory cytokines were assayed from whole blood culture supernatants using the Luminex multiplex assay after stimulation with high dose lipopolysaccharide (LPS), 1 µg/mL.ResultsThe levels of RBC DHA were increased by 61–100% in treated compared to control infants at ages 6–36 months. There were no statistically significant reductions in production of the inflammatory cytokines, IL-1β, TNFα, or IL-12p40 at any of the six timepoints measured. The inflammatory marker, high-sensitivity C-reactive protein (hsCRP), was significantly lower in breast-fed DHA-treated infants compared to all formula-fed infants at the age of 12 months. Three infants (two received DHA) were removed from the study as a result of developing ≥two persistently positive biochemical islet autoantibodies.Conclusions This pilot trial showed that supplementation of infant diets with DHA is safe and fulfilled the pre-study goal of increasing infant RBC DHA levels by at least 20%. Inflammatory cytokine production was not consistently reduced.
    Pediatric Diabetes 07/2014; · 2.08 Impact Factor
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    ABSTRACT: Importance: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. Design, Setting, and Participants: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows’ milk–based formula. The participants were observed to April 16, 2013. Interventions: The participants received either a casein hydrolysate or a conventional cows’ milk formula supplemented with 20% of the casein hydrolysate. Main Outcomes and Measures: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated–2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). Results: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. Conclusions and Relevance: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. Trial Registration: clinicaltrials.gov Identifier: NCT00179777
    JAMA The Journal of the American Medical Association 06/2014; 311(22):2279-2287. · 29.98 Impact Factor
  • Mark L Batshaw, Stephen C Groft, Jeffrey P Krischer
    JAMA The Journal of the American Medical Association 05/2014; 311(17):1729-30. · 29.98 Impact Factor
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    ABSTRACT: OBJECTIVE To determine basal and stimulated C-peptide percentiles in North American children and adolescents at risk for type 1 diabetes (T1D) and to examine factors associated with this distribution in the Diabetes Prevention Trial of Type 1 (DPT-1).RESEARCH DESIGN AND METHODS We included 582 subjects aged 4-18 years at randomization in the DPT-1 trials. A 2-h oral glucose tolerance test (OGTT) was performed at baseline and every 6 months during the 5-year follow-up period. The percentile values of C-peptide after baseline OGTT were estimated according to age, BMI Z score (BMIZ), and/or sex categories. Conditional quantile regression was used to examine the relationship between C-peptide percentiles and various independent variables.RESULTSThe basal and stimulated C-peptide levels increased significantly as age and BMIZ increased (P < 0.05). Both age and BMIZ had a stronger impact on the upper quartile of C-peptide distributions than the lower quartile. Sex was only significantly associated with stimulated C-peptide. Higher stimulated C-peptide levels were generally observed in girls compared with boys at the same age and BMIZ (P < 0.05). HLA type and number of positive antibodies and antibody titers (islet cell antibody [ICA], insulin autoantibody, GAD65A, and ICA512A) were not significantly associated with C-peptide distribution after adjustment for age, BMIZ, and sex.CONCLUSIONS Age-, sex-, and BMIZ-specific C-peptide percentiles can be estimated for North American children and adolescents at risk for T1D. They can be used as an assessment tool that could impact the recommendations in T1D prevention trials.
    Diabetes care 04/2014; · 7.74 Impact Factor
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    ABSTRACT: Objectives Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes.Methods Repeated measures of weight and height were collected from 5 969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index of 25 and 30 kg/m(2) at age 18.ResultsThe average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HLA, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (p for trend=0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age four (OR, 2.41; 95% CI, 1.21-4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes.Conclusions The HLA-DQ2/2 genotype may predispose to obesity among 2-4 year old children with genetic risk for type 1 diabetes.International Journal of Obesity accepted article peview online, 03 April 2014; doi:10.1038/ijo.2014.55.
    International journal of obesity (2005) 04/2014; · 5.22 Impact Factor
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    ABSTRACT: Osteogenesis Imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n=544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean LS aBMD was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answer questions that are relevant to patient care but also foster hypothesis-driven research, especially in the context of “phenotypic expansion” driven by next-generation sequencing.
    Clinical Genetics 04/2014; · 4.25 Impact Factor
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    ABSTRACT: Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic etiology is not defined for all PCD patients. Objectives: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in PCD patients. Measurements and Main Results: We performed exome sequencing on affected sib-pair with normal ultrastructure in >85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in 9 additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in PCD patients with other gene mutations (98.3 versus 20.7 nl/min; p<0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8/16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared to 75 age- and gender-matched PCD cases (73.0 versus 61.8, FEV1 % Pred.; p=0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 +/- Hz at 25°C), but an abnormal, circular beat pattern. Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function. Abstract has 250 words. Keywords: cilia, Kartagener, sequencing, mutation, RSPH1.
    American Journal of Respiratory and Critical Care Medicine 02/2014; · 11.04 Impact Factor
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    ABSTRACT: OBJECTIVE We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants.RESEARCH DESIGN AND METHODS The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values >7.00 and dysglycemic individuals in the TNNHS (n = 991). The cumulative incidence was compared between individuals with DPTRS values <7.00 and >7.00 among those with dysglycemia and those with multiple autoantibodies in the TNNHS. DPTRS values >7.00 were compared with dysglycemia for characterizing risk in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 670) and TNNHS participants. The reliability of DPTRS values >7.00 was compared with dysglycemia in the TNNHS.RESULTSThe cumulative incidence of T1D for normoglycemic TNNHS participants with DPTRS values >7.00 was comparable to those with dysglycemia. Among those with dysglycemia, the cumulative incidence was much higher (P < 0.001) for those with DPTRS values >7.00 than for those with values <7.00 (3-year risks: 0.16 for <7.00 and 0.46 for >7.00). Dysglycemic individuals in DPT-1 were at much higher risk for T1D than those with dysglycemia in the TNNHS (P < 0.001); there was no significant difference in risk between the studies among those with DPTRS values >7.00. The proportion in the TNNHS reverting from dysglycemia to normoglycemia at the next visit was higher than the proportion reverting from DPTRS values >7.00 to values <7.00 (36 vs. 23%).CONCLUSIONSDPTRS thresholds can improve T1D risk classification accuracy by identifying high-risk normoglycemic and low-risk dysglycemic individuals. The 7.00 DPTRS threshold characterizes risk more consistently between populations and has greater reliability than dysglycemia.
    Diabetes care 02/2014; · 7.74 Impact Factor
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    ABSTRACT: Broad consensus assigns T lymphocytes fundamental roles in inflammatory, infectious, and autoimmune diseases. However, clinical investigations have lacked fully characterized and validated procedures, equivalent to those of widely practiced biochemical tests with established clinical roles, for measuring core T cell functions. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) type 1 diabetes prevention trial used consecutive measurements of T cell proliferative responses in prospectively collected fresh heparinized blood samples shipped by courier within North America. In this article, we report on the quality control implications of this simple and pragmatic shipping practice and the interpretation of positive- and negative-control analytes in our assay. We used polyclonal and postvaccination responses in 4,919 samples to analyze the development of T cell immunocompetence. We have found that the vast majority of the samples were viable up to 3 days from the blood draw, yet meaningful responses were found in a proportion of those with longer travel times. Furthermore, the shipping time of uncooled samples significantly decreased both the viabilities of the samples and the unstimulated cell counts in the viable samples. Also, subject age was significantly associated with the number of unstimulated cells and T cell proliferation to positive activators. Finally, we observed a pattern of statistically significant increases in T cell responses to tetanus toxin around the timing of infant vaccinations. This assay platform and shipping protocol satisfy the criteria for robust and reproducible long-term measurements of human T cell function, comparable to those of established blood biochemical tests. We present a stable technology for prospective disease-relevant T cell analysis in immunological diseases, vaccination medicine, and measurement of herd immunity.
    Clinical and vaccine Immunology: CVI 02/2014; 21(2):203-11. · 2.60 Impact Factor
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    ABSTRACT: To identify the risk-predictive baseline profile patterns of demographic, genetic, immunologic, and metabolic markers and synthesize these patterns for risk prediction.
    PLoS ONE 01/2014; 9(6):e91095. · 3.53 Impact Factor
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    ABSTRACT: The Environmental Determinants of Diabetes in the Young (TEDDY) planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes (T1D) using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. This paper describes the details of planning the TEDDY biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples, and reduction of batch effects along with proper sample allocation. Our design is to reduce potential bias and retain study power while reduce the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of T1D). The resulting list of case-control matched samples for each laboratory was augmented with external quality control (QC) samples. This article is protected by copyright. All rights reserved.
    Diabetes/Metabolism Research and Reviews 12/2013; · 2.97 Impact Factor
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    ABSTRACT: To determine the safety and efficacy of abatacept in non-severe relapsing granulomatosis with polyangiitis (Wegener's)(GPA). An open-label trial of intravenous abatacept was conducted in 20 patients with non-severe relapsing GPA. Prednisone up to 30 mg daily was permitted within the first 2 months, and patients on methotrexate, azathioprine, or mycophenolate mofetil continued these agents. Patients remained on study until common closing or early termination. Of the 20 patients, 18 (90%) had disease improvement, 16 (80%) achieved remission (BVAS/WG=0) at a median of 1.9 months, and 14 (70%) reached common closing. Six patients (30%) met criteria for early termination due to increased disease activity; 3 of 6 achieved remission and relapsed at a median of 8.6 months. The median duration of remission before common closing was 14.4 months, with the median duration of time on study for all patients being 12.3 months (range 2-35 months). Eleven of the 15 (73%) patients on prednisone reached 0 mg. Nine severe adverse events occurred in 7 patients, including 7 infections that were successfully treated. In this study of patients with non-severe relapsing GPA, abatacept was well tolerated and was associated with a high frequency of disease remission and prednisone discontinuation.
    Annals of the rheumatic diseases 12/2013; · 8.11 Impact Factor
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    ABSTRACT: Objective We previously reported that two years of co-stimulation modulation with abatacept slowed decline of beta-cell function in recent-onset type 1 diabetes mellitus (T1DM). Subsequently, abatacept was discontinued, and subjects followed to determine whether there was persistence of effect.Research Design and Methods In 112 subjects (ages 6-36) with T1DM, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over two years. The primary outcome - baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide during a mixed meal tolerance test (MMTT) at two years - showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months.ResultsC-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 (95% CI: 0.168, 0.268) and 0.141 (95% CI: 0.071, 0.215) nmol/L for abatacept and placebo groups, respectively (p=0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remainded lower in the abatacept group than in the placebo group. The slightly lower (non-significant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years.Conclusions Co-stimulation modulation with abatacept slowed decline of beta-cell function and improved HbA1c in recent-onset T1DM. The beneficial effect was sustained for at least one year after cessation of abatacept infusions, or three years from T1DM diagnosis.
    Diabetes care 12/2013; · 7.74 Impact Factor
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    ABSTRACT: Rationale: Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized. Objectives: To use a standard protocol for measuring nNO to establish a disease-specific cutoff value at one site, and then validate at six other sites. Methods: At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD. Measurements and Main Results: At the lead site, nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5-867.0 nl/min), asthma (267.8 ± 103.2; 125.0-589.7 nl/min), or chronic obstructive pulmonary disease (223.7 ± 87.1; 109.7-449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6-386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD. Conclusions: Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.
    Annals of the American Thoracic Society. 12/2013; 10(6):574-8.

Publication Stats

6k Citations
1,512.08 Total Impact Points

Institutions

  • 1997–2014
    • University of South Florida
      • • Department of Pediatrics
      • • Pediatrics Epidemiology Center
      • • Department of Computer Science & Engineering
      • • Moffitt Cancer Center
      • • Department of Family Medicine
      Tampa, Florida, United States
  • 2013
    • Cleveland Clinic
      Cleveland, Ohio, United States
  • 2010–2013
    • National Institute for Health and Welfare, Finland
      • Nutrition Unit
      Helsinki, Southern Finland Province, Finland
  • 2006–2013
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 2012
    • Boston University
      • Section of Rheumatology
      Boston, MA, United States
  • 2011
    • University of Cincinnati
      Cincinnati, Ohio, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • University of Toronto
      • Hospital for Sick Children
      Toronto, Ontario, Canada
    • The University of Western Ontario
      • Department of Epidemiology and Biostatistics
      London, Ontario, Canada
  • 2005–2011
    • Benaroya Research Institute
      Seattle, Washington, United States
  • 1990–2011
    • University of Alabama at Birmingham
      • Department of Pediatrics
      Birmingham, Alabama, United States
  • 2008–2010
    • Cincinnati Children's Hospital Medical Center
      • Division of Pulmonary Biology
      Cincinnati, OH, United States
    • University of Rochester
      • Department of Neurology
      Rochester, NY, United States
  • 2001–2007
    • University of Colorado
      • Barbara Davis Center for Childhood Diabetes
      Denver, CO, United States
  • 2000–2004
    • Moffitt Cancer Center
      Tampa, Florida, United States
    • University of Southern California
      Los Angeles, California, United States
  • 1988–2004
    • University of Florida
      • Department of Pediatrics
      Gainesville, FL, United States
    • University of California, San Diego
      San Diego, California, United States
  • 2000–2001
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 1999
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
    • Research Institute for Children at Children's Hospital New Orleans
      New Orleans, Louisiana, United States
  • 1995
    • University at Buffalo, The State University of New York
      • School of Medicine and Biomedical Sciences
      Buffalo, NY, United States
  • 1990–1993
    • McGill University
      Montréal, Quebec, Canada
  • 1992
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States
    • University of Oklahoma Health Sciences Center
      Oklahoma City, Oklahoma, United States
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 1991
    • Kansas City University of Medicine and Biosciences
      Kansas City, Missouri, United States
    • Emory University
      Atlanta, Georgia, United States
  • 1988–1991
    • Baylor College of Medicine
      • Department of Pediatrics
      Houston, Texas, United States
  • 1984–1991
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States