Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-15 (of 15 Records) |
Query Trace: Milton AS[original query] |
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Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment (preprint)
Nguyen-Van-Tam JS , Killingley B , Enstone J , Hewitt M , Pantelic J , Grantham ML , Bueno de Mesquita PJ , Lambkin-Williams R , Gilbert A , Mann A , Forni J , Noakes CJ , Levine MZ , Berman L , Lindstrom S , Cauchemez S , Bischoff W , Tellier R , Milton DK . medRxiv 2020 2019.12.13.19014381 Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer ‘Donors’ (n=52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). ‘Recipients’ randomized to Intervention (IR, n=40) or Control (CR, n=35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitized frequently to limit large droplet and contact transmission. One transmitted infection was confirmed by serology in a CR, yielding a secondary attack rate of 2.9% among CR, 0% in IR (p=0.47 for group difference), and 1.3% overall, significantly less than 16% (p<0.001) expected based on a proof-of-concept study secondary attack rate and considering that there were twice as many Donors and days of exposure. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols.Author summary Understanding the relative importance of influenza modes of transmission informs strategic use of preventive measures to reduce influenza risk in high-risk settings such as hospitals and is important for pandemic preparedness. Given the increasing evidence from epidemiological modelling, exhaled viral aerosol, and aerobiological survival studies supporting a role for airborne transmission and the potential benefit of respirators (and other precautions designed to prevent inhalation of aerosols) versus surgical masks (mainly effective for reducing exposure to large droplets) to protect healthcare workers, more studies are needed to evaluate the extent of risk posed airborne versus contact and large droplet spray transmission modes. New human challenge-transmission studies should be carefully designed to overcome limitations encountered in the current study. The low secondary attack rate reported herein also suggests that the current challenge-transmission model may no longer be a more promising approach to resolving questions about transmission modes than community-based studies employing environmental monitoring and newer, state-of-the-art deep sequencing-based molecular epidemiological methods.Competing Interest StatementJSN-V-T and BK declare previous consultancy fees from H-Vivo plc, unrelated to the current work. JSN-V-T is currently seconded to the Department of Health and Social Care (DHSC), England; the views expressed in this paper are not necessarily those of DHSC. RLW, AG and AM are employees of H-Vivo plc each of whom hold shares and /or share options in the company.Clinical TrialNCT01710111Funding StatementThis work was supported by U.S. CDC, Cooperative Agreement: Grant Number 1U01P000497-01. The views expressed in this paper are those of the authors and do not necessarily represent the official position of the funding agency.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData required for reproduction of analyses is available upon request. Scripts and other documentati n to reproduce analyses are available at Digital Repositories at the University of Maryland (13) and https://gitlab.com/jacobbueno/emit_quarantine_main. http://drum.lib.umd.edu/handle/1903/25315 |
Analysis of single nucleotide polymorphisms in chronic beryllium disease.
Frye BC , Gaede KI , Saltini C , Rossman MD , Monos DS , Rosenman KD , Schuler CR , Weston A , Wegner R , Noth R , Zissel G , Schreiber S , Nothnagel M , Müller-Quernheim J . Respir Res 2021 22 (1) 107 Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development. |
Whole genome and in-silico analyses of G1P[8] rotavirus strains from pre- and post-vaccination periods in Rwanda.
Rasebotsa S , Mwangi PN , Mogotsi MT , Sabiu S , Magagula NB , Rakau K , Uwimana J , Mutesa L , Muganga N , Murenzi D , Tuyisenge L , Jaimes J , Esona MD , Bowen MD , Mphahlele MJ , Seheri ML , Mwenda JM , Nyaga MM . Sci Rep 2020 10 (1) 13460 Rwanda was the first low-income African country to introduce RotaTeq vaccine into its Expanded Programme on Immunization in May 2012. To gain insights into the overall genetic make-up and evolution of Rwandan G1P[8] strains pre- and post-vaccine introduction, rotavirus positive fecal samples collected between 2011 and 2016 from children under the age of 5 years as part of ongoing surveillance were genotyped with conventional RT-PCR based methods and whole genome sequenced using the Illumina MiSeq platform. From a pool of samples sequenced (n = 158), 36 were identified as G1P[8] strains (10 pre-vaccine and 26 post-vaccine), of which 35 exhibited a typical Wa-like genome constellation. However, one post vaccine strain, RVA/Human-wt/RWA/UFS-NGS:MRC-DPRU442/2012/G1P[8], exhibited a RotaTeq vaccine strain constellation of G1-P[8]-I2-R2-C2-M2-A3-N2-T6-E2-H3, with most of the gene segments having a close relationship with a vaccine derived reassortant strain, previously reported in USA in 2010 and Australia in 2012. The study strains segregated into two lineages, each containing a paraphyletic pre- and post-vaccine introduction sub-lineages. In addition, the study strains demonstrated close relationship amongst each other when compared with globally selected group A rotavirus (RVA) G1P[8] reference strains. For VP7 neutralization epitopes, amino acid substitutions observed at positions T91A/V, S195D and M217T in relation to the RotaTeq vaccine were radical in nature and resulted in a change in polarity from a polar to non-polar molecule, while for the VP4, amino acid differences at position D195G was radical in nature and resulted in a change in polarity from a polar to non-polar molecule. The polarity change at position T91A/V of the neutralizing antigens might play a role in generating vaccine-escape mutants, while substitutions at positions S195D and M217T may be due to natural fluctuation of the RVA. Surveillance of RVA at whole genome level will enhance further assessment of vaccine impact on circulating strains, the frequency of reassortment events under natural conditions and epidemiological fitness generated by such events. |
Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment
Nguyen-Van-Tam JS , Killingley B , Enstone J , Hewitt M , Pantelic J , Grantham ML , Bueno de Mesquita PJ , Lambkin-Williams R , Gilbert A , Mann A , Forni J , Noakes CJ , Levine MZ , Berman L , Lindstrom S , Cauchemez S , Bischoff W , Tellier R , Milton DK . PLoS Pathog 2020 16 (7) e1008704 Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer 'Donors' (n = 52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). 'Recipients' randomized to Intervention (IR, n = 40) or Control (CR, n = 35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitized frequently to limit large droplet and contact transmission. One transmitted infection was confirmed by serology in a CR, yielding a secondary attack rate of 2.9% among CR, 0% in IR (p = 0.47 for group difference), and 1.3% overall, significantly less than 16% (p<0.001) expected based on a proof-of-concept study secondary attack rate and considering that there were twice as many Donors and days of exposure. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols. |
Outcomes of reflex cryptococcal antigen (CrAg) screening in HIV-positive patients with CD4 counts of 100-200 cells/microL in Botswana
Tenforde MW , Milton T , Rulaganyang I , Muthoga C , Tawe L , Chiller T , Greene G , Jordan A , Williams CG , Owen L , Leeme TB , Boose A , Ngidi J , Mine M , Jarvis JN . Clin Infect Dis 2020 72 (9) 1635-1638 Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from </=100 to </=200 cells/microL resulted in a 3-fold increase in numbers screened. CrAg-prevalence was 3.5% at CD4 101-200 and 6.2% </=100 cells/microL. Six-month mortality was 21.4% (9/42) in CrAg-positive CD4 </=100 cells/microL and 3.2% (1/31) in CrAg-positive CD4 101-200 cells/microL. |
Concordance between sites of tumor development in humans and in experimental animals for 111 agents that are carcinogenic to humans
Krewski D , Rice JM , Bird M , Milton B , Collins B , Lajoie P , Billard M , Grosse Y , Cogliano VJ , Caldwell JC , Rusyn II , Portier CJ , Melnick RL , Baan RA , Little J , Zielinski JM . J Toxicol Environ Health B Crit Rev 2019 22 203-236 Since the inception of the IARC Monographs Programme in the early 1970s, this Programme has developed 119 Monograph Volumes on more than 1000 agents for which there exists some evidence of cancer risk to humans. Of these, 120 agents were found to meet the criteria for classification as carcinogenic to humans (Group 1). Volume 100 of the IARC Monographs, compiled in 2008-2009 and published in 2012, provided a review and update of the 107 Group 1 agents identified as of 2009. These agents were divided into six broad categories: (I) pharmaceuticals; (II) biological agents; (III) arsenic, metals, fibers and dusts; (IV) radiation; (V) personal habits and indoor combustions; and (VI) chemical agents and related occupations. The Group I agents reviewed in Volume 100, as well as five additional Group 1 agents defined in subsequent Volumes of the Monographs, were used to assess the degree of concordance between sites where tumors originate in humans and experimental animals including mice, rats, hamsters, dogs, and non-human primates using an anatomically based tumor nomenclature system, representing 39 tumor sites and 14 organ and tissue systems. This evaluation identified 91 Group 1 agents with sufficient evidence (82 agents) or limited evidence (9 agents) of carcinogenicity in animals. The most common tumors observed in both humans and animals were those of the respiratory system including larynx, lung, and lower respiratory tract. In humans, respiratory system tumors were noted for 31 of the 111 distinct Group 1 carcinogens identified up to and including Volume 109 of the IARC Monographs, comprising predominantly 14 chemical agents and related occupations in category VI; seven arsenic, metals, fibers, and dusts in category III, and five personal habits and indoor combustions in category V. Subsequent to respiratory system tumors, those in lymphoid and hematopoietic tissues (26 agents), the urothelium (18 agents), and the upper aerodigestive tract (16 agents) were most often seen in humans, while tumors in digestive organs (19 agents), skin (18 agents), and connective tissues (17 agents) were frequently seen in animals. Exposures to radiation, particularly X- and gamma-radiation, and tobacco smoke were associated with tumors at multiple sites in humans. Although the IARC Monographs did not emphasize tumor site concordance between animals and humans, substantial concordance was detected for several organ and tissue systems, even under the stringent criteria for sufficient evidence of carcinogenicity used by IARC. Of the 60 agents for which at least one tumor site was identified in both humans and animals, 52 (87%) exhibited tumors in at least one of the same organ and tissue systems in humans and animals. It should be noted that some caution is needed in interpreting concordance at sites where sample size is particularly small. Although perfect (100%) concordance was noted for agents that induce tumors of the mesothelium, only two Group 1 agents that met the criteria for inclusion in the concordance analysis caused tumors at this site. Although the present analysis demonstrates good concordance between animals and humans for many, but not all, tumor sites, limitations of available data may result in underestimation of concordance. |
Microbial aerosols: New diagnostic specimens for pulmonary infections
Fennelly KP , Acuna-Villaorduna C , Jones-Lopez E , Lindsley WG , Milton D . Chest 2019 157 (3) 540-546 Pulmonary infections are important causes of global morbidity and mortality, but diagnostics are often limited by the ability to collect specimens easily, safely and in a cost-effective manner. We review recent advances in the collection of infectious aerosols from patients with tuberculosis and with influenza. Although this research has been focused on assessing the infectious potential of such patients, we propose that these methods have the potential to lead to the use of patient-generated microbial aerosols as non-invasive diagnostic tests of disease as well as tests of infectiousness. |
First Laboratory-Confirmed Outbreak of Human and Animal Rift Valley Fever Virus in Uganda in 48 Years.
Shoemaker TR , Nyakarahuka L , Balinandi S , Ojwang J , Tumusiime A , Mulei S , Kyondo J , Lubwama B , Sekematte M , Namutebi A , Tusiime P , Monje F , Mayanja M , Ssendagire S , Dahlke M , Kyazze S , Wetaka M , Makumbi I , Borchert J , Zufan S , Patel K , Whitmer S , Brown S , Davis WG , Klena JD , Nichol ST , Rollin PE , Lutwama J . Am J Trop Med Hyg 2019 100 (3) 659-671 In March 2016, an outbreak of Rift Valley fever (RVF) was identified in Kabale district, southwestern Uganda. A comprehensive outbreak investigation was initiated, including human, livestock, and mosquito vector investigations. Overall, four cases of acute, nonfatal human disease were identified, three by RVF virus (RVFV) reverse transcriptase polymerase chain reaction (RT-PCR), and one by IgM and IgG serology. Investigations of cattle, sheep, and goat samples from homes and villages of confirmed and probable RVF cases and the Kabale central abattoir found that eight of 83 (10%) animals were positive for RVFV by IgG serology; one goat from the home of a confirmed case tested positive by RT-PCR. Whole genome sequencing from three clinical specimens was performed and phylogenetic analysis inferred the relatedness of 2016 RVFV with the 2006-2007 Kenya-2 clade, suggesting previous introduction of RVFV into southwestern Uganda. An entomological survey identified three of 298 pools (1%) of Aedes and Coquillettidia species that were RVFV positive by RT-PCR. This was the first identification of RVFV in Uganda in 48 years and the 10(th) independent viral hemorrhagic fever outbreak to be confirmed in Uganda since 2010. |
Genome-wide association study to identify variants associated with vaso-occlusive pain in sickle cell anemia.
Chaturvedi S , Bhatnagar P , Bean CJ , Steinberg MH , Milton JN , Casella JF , Barron-Casella E , Arking DE , DeBaun MR . Blood 2017 130 (5) 686-688 Acute vaso-occlusive pain episodes are a hallmark of sickle cell anemia (SCA), one of the most common Mendelian disorders worldwide with an estimated >300 000 births annually.1-3 Although SCA is a monogenic disorder, manifestations and disease severity are highly variable, suggesting additional phenotypic modifiers. The few genetic factors known to act as phenotypic modifiers do not completely explain the clinical heterogeneity in SCA. Previous genetic association studies identified that variants at 3 distinct loci (BCL11A, HBS1L-MYB, and HBB) are strong determinants of fetal hemoglobin level, and the single-nucleotide polymorphism (SNP) variant rs6141803 located upstream of COMMD7 is associated with acute chest syndrome.4 Also, heme oxygenase-1 gene promoter polymorphisms influence heme oxygenase (HO-1) activity and the incidence of acute chest syndrome in children with sickle cell disease (SCD).5,6 We conducted this genome-wide association study (GWAS) to identify the variants associated with acute, severe vaso-occlusive pain in children with SCA enrolled in the Cooperative Study for Sickle Cell Disease (CSSCD) and Silent Infarct Transfusion (SIT) trial. | The CSSCD, a multi-institutional prospective cohort, natural history study of SCD, enrolled 3538 individuals with SCD between 1979 and 1981.7 The SIT trial, a multicenter international trial, screened 1210 children with SCA to test the hypothesis that regular blood transfusions attenuate progression of cerebral infarcts in children with preexisting silent strokes.8 Both studies were approved by the Institutional Review Boards at Boston University School of Medicine and Vanderbilt University Medical Center. |
Immune Responses in U.S. Military Personnel Who Received Meningococcal Conjugate Vaccine (MenACWY) Concomitantly with Other Vaccines Were Higher than in Personnel Who Received MenACWY Alone
Broderick MP , Romero-Steiner S , Rajam G , Johnson SE , Milton A , Kim E , Choi LJ , Radin JM , Schmidt DS , Carlone GM , Messonnier N , Faix DJ . Clin Vaccine Immunol 2016 23 (8) 672-80 Immunological responses to vaccination can differ depending on whether the vaccine is given alone or with other vaccines. This study was a retrospective evaluation of the immunogenicity of a tetravalent meningococcal conjugate vaccine (MenACWY) administered alone (n = 41) or concomitantly with other vaccines (n = 279) to United States military personnel (mean age = 21.6 years) entering the military between 2006 and 2008. Concomitant vaccines included tetanus/diphtheria (Td), inactivated polio vaccine (IPV), hepatitis vaccines, various influenza vaccines, among others; two vaccine groups excluded Tdap and IPV. Immune responses were evaluated in baseline and post-vaccination sera for Neisseria meningitidis serogroups C and Y 1-12 months (mean = 4.96) following vaccination. Functional antibodies were measured by using a serum bactericidal antibody assay with rabbit complement (rSBA) and by measurement of serogroup-specific immunoglobulin G (IgG) antibodies. The percentage of vaccinees reaching threshold levels (IgG ≥2 mug/mL; rSBA titer ≥8) corresponding to an immunologic response was higher post-vaccination than at baseline (p < 0.001). Administration of MenACWY along with other vaccines was associated with higher geometric means of IgG concentrations and rSBA titers than those measured 4.60 months after a single dose of MenACWY. In addition, higher percentages of vaccinees reached the immunological threshold (odds ratios [ORs] range = 1.5 to 21.7) and more of them seroconverted (ORs range = 1.8 to 4.8) when MenACWY was administered with any other vaccine than when administered alone. Additional prospective randomized clinical trials are needed to confirm the observed differences among groups in the immune response to MenACWY when given concomitantly with other vaccines to United States military personnel. |
Molecular epidemiology of the pertussis epidemic in Washington State in 2012.
Bowden KE , Williams MM , Cassiday PK , Milton A , Pawloski L , Harrison M , Martin SW , Meyer S , Qin X , DeBolt C , Tasslimi A , Syed N , Sorrell R , Tran M , Hiatt B , Tondella ML . J Clin Microbiol 2014 52 (10) 3549-57 Although pertussis disease is vaccine-preventable, Washington State experienced a substantial rise in pertussis incidence beginning in 2011. By June 2012, the reported cases reached 2,520 (37.5 cases per 100,000 residents), a 1,300% increase compared with the same period in 2011. We assessed the molecular epidemiology of this statewide epidemic using 240 isolates collected from case-patients reported from 19 of 39 Washington counties during 2012-2013. Typing methods included pulsed-field gel electrophoresis (PFGE), multilocus variable number tandem repeat analysis (MLVA), multilocus sequence typing (MLST), and pertactin gene (prn) mutational analysis. Using the scheme PFGE-MLVA-MLST-prn mutations-Prn deficiency, the 240 isolates comprised 65 distinct typing profiles. Thirty-one PFGE types were found, with the most common types, CDC013 (n=51), CDC237 (n=44), and CDC002 (n=42), accounting for 57% of them. Eleven MLVA types were observed, mainly comprising type 27 (n=183; 76%). Seven MLST types were identified, with the majority of the isolates typing as prn2-ptxP3-ptxA1-fim3-1 (n=157; 65%). Four different prn mutations accounted for the 76% of isolates exhibiting pertactin-deficiency. PFGE provided the highest discriminatory power (D=0.87) and was found to be a more powerful typing method than MLVA and MLST combined (D=0.67). This study provides evidence for the continued predominance of MLVA 27 and prn2-ptxP3-ptxA1, along with the reemergence of the fim3-1 allele. Our results indicate that the B. pertussis population causing this epidemic was diverse, with a few molecular types predominating. PFGE, MLVA, and MLST profiles were consistent with predominate types circulating in the US and other countries. For prn, several mutations were present in multiple molecular types. |
Persistence of serogroup C antibody responses following quadrivalent meningococcal conjugate vaccination in United States military personnel
Patel M , Romero-Steiner S , Broderick MP , Thomas CG , Plikaytis BD , Schmidt DS , Johnson SE , Milton AS , Carlone GM , Clark TA , Messonnier NE , Cohn AC , Faix DJ . Vaccine 2014 32 (30) 3805-9 Serogroup C meningococcal (MenC) disease accounts for one-third of all meningococcal cases and causes meningococcal outbreaks in the U.S. Quadrivalent meningococcal vaccine conjugated to diphtheria toxoid (MenACYWD) was recommended in 2005 for adolescents and high risk groups such as military recruits. We evaluated anti-MenC antibody persistence in U.S. military personnel vaccinated with either MenACYWD or meningococcal polysaccharide vaccine (MPSV4). Twelve hundred subjects vaccinated with MenACYWD from 2006 to 2008 or MPSV4 from 2002 to 2004 were randomly selected from the Defense Medical Surveillance System. Baseline serologic responses to MenC were assessed in all subjects; 100 subjects per vaccine group were tested during one of the following six post-vaccination time-points: 5-7, 11-13, 17-19, 23-25, 29-31, or 35-37 months. Anti-MenC geometric mean titers (GMT) were measured by rabbit complement serum bactericidal assay (rSBA) and geometric mean concentrations (GMC) by enzyme-linked immunosorbent assay (ELISA). Continuous variables were compared using the Wilcoxon rank sum test and the proportion of subjects with an rSBA titer ≥8 by chi-square. Pre-vaccination rSBA GMT was <8 for the MenACWYD group. rSBA GMT increased to 703 at 5-7 months post-vaccination and decreased by 94% to 43 at 3 years post-vaccination. GMT was significantly lower in the MenACWYD group at 5-7 months post-vaccination compared to the MPSV4 group. The percentage of MenACWYD recipients achieving an rSBA titer of ≥8 decreased from 87% at 5-7 months to 54% at 3 years. There were no significant differences between vaccine groups in the proportion of subjects with a titer of ≥8 at any time-point. GMC for the MenACWYD group was 0.14mug/mL at baseline, 1.07mug/mL at 5-7 months, and 0.66mug/mL at 3 years, and significantly lower than the MPSV4 group at all time-points. Anti-MenC responses wane following vaccination with MenACYWD; a booster dose is needed to maintain protective levels of circulating antibody. |
Molecular signatures of antibody responses derived from a systems biology study of five human vaccines.
Li S , Rouphael N , Duraisingham S , Romero-Steiner S , Presnell S , Davis C , Schmidt DS , Johnson SE , Milton A , Rajam G , Kasturi S , Carlone GM , Quinn C , Chaussabel D , Palucka AK , Mulligan MJ , Ahmed R , Stephens DS , Nakaya HI , Pulendran B . Nat Immunol 2013 15 (2) 195-204 Many vaccines induce protective immunity via antibodies. Systems biology approaches have been used to determine signatures that can be used to predict vaccine-induced immunity in humans, but whether there is a 'universal signature' that can be used to predict antibody responses to any vaccine is unknown. Here we did systems analyses of immune responses to the polysaccharide and conjugate vaccines against meningococcus in healthy adults, in the broader context of published studies of vaccines against yellow fever virus and influenza virus. To achieve this, we did a large-scale network integration of publicly available human blood transcriptomes and systems-scale databases in specific biological contexts and deduced a set of transcription modules in blood. Those modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines, which provided key insights into primary viral, protein recall and anti-polysaccharide responses. Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling. |
A multi-center ring trial of allergen analysis using fluorescent multiplex array technology
King EM , Filep S , Smith B , Platts-Mills T , Hamilton RG , Schmechel D , Sordillo JE , Milton D , van Ree R , Krop EJ , Heederik DJ , Metwali N , Thorne PS , Zeldin DC , Sever ML , Calatroni A , Arbes SJ Jr , Mitchell HE , Chapman MD . J Immunol Methods 2013 387 89-95 BACKGROUND: Consistent performance of allergen assays is essential to ensure reproducibility of exposure assessments for investigations of asthma and occupational allergic disease. This study evaluated intra- and inter-laboratory reproducibility of a fluorescent multiplex array, which simultaneously measures eight indoor allergens in a single reaction well. METHODS: A multi-center study was performed in nine laboratories in the US and Europe to determine the inter-laboratory variability of an 8-plex array for dust mite, cat, dog, rat, mouse and cockroach allergens. Aliquots of 151 dust extract samples were sent to participating centers and analyzed by each laboratory on three separate occasions. Agreement within and between laboratories was calculated by the concordance correlation coefficient (CCC). RESULTS: Results were obtained for over 32,000 individual allergen measurements. Levels covered a wide range for all allergens from below the lower limit of detection (LLOD=0.1-9.8ng/ml) to higher than 6800ng/ml for all allergens except Mus m 1, which was up to 1700ng/ml. Results were reproducible within as well as between laboratories. Within laboratories, 94% of CCC were ≥0.90, and 80% of intra-laboratory results fell within a 10% coefficient of variance (CV%). Results between laboratories also showed highly significant positive correlations for all allergens (~0.95, p<0.001). Overall means of results were comparable, and inter-laboratory CV% for all allergens except Rat n 1 ranged between 17.6% and 26.6%. CONCLUSION: The data indicate that performance criteria for fluorescent multiplex array technology are reproducible within and between laboratories. Multiplex technology provides standardized and consistent allergen measurements that will streamline environmental exposure assessments in allergic disease. |
A genome-wide association study of total bilirubin and cholelithiasis risk in sickle cell anemia.
Milton JN , Sebastiani P , Solovieff N , Hartley SW , Bhatnagar P , Arking DE , Dworkis DA , Casella JF , Barron-Casella E , Bean CJ , Hooper WC , Debaun MR , Garrett ME , Soldano K , Telen MJ , Ashley-Koch A , Gladwin MT , Baldwin CT , Steinberg MH , Klings ES . PLoS One 2012 7 (4) e34741 Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5x10(-8)). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08x10(-25)). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15x10(-4)). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities. |
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