Genetic susceptibility to autoimmune hepatitis is associated with the human leukocyte antigen haplotype A1‐B8‐DR3 and DR4. To date, only one study in Japan has considered the human leukocyte antigen ...DP locus in this disease, and no studies have been reported in whites. In this study we used a series of sequencespecific oligonucleotide probes to determine human leukocyte antigen DPB1 genotypes in 101 unrelated white northern European patients and 105 racially and geographically matched controls. The aims of the study were twofold: first, to determine the degree of DPBencoded susceptibility to autoimmune hepatitis, and, second, to establish whether susceptibility can be extended to include human leukocyte antigen DPB. None of 17 DPB1 alleles was significantly associated with the susceptibility to autoimmune hepatitis. Although one particular seven‐locus haplotype AlB8‐DRB3*010‐DRB1*0301‐DQA1*0501‐DQB1*02001‐DPB1*0401 was significantly associated with the disease (27% vs. 7%, relative risk = 5.14, p < 0.0005), the association with this haplotype was weaker than that for the six‐locus haplotype excluding DPB (40% vs. 11%, RR = 5.52, p < 0.0005). When the patients first seen at ages younger than 16 yr (pediatric patients) were considered separately, the greatest relative risk was for the seven‐locus haplotype (41% vs. 7%; relative risk = 9.60, p < 0.0005). The results of this study further confirm that major histocompatibility complex–encoded susceptibility to autoimmune hepatitis is located at or close to the human leukocyte antigen DR locus; however, the A1‐B8‐DR3‐DQ2‐DPB1*0401 extended haplotype may be important in determining the age of onset and severity of disease. (HEPATOLOGY 1993;18:1334–1337.)
Usage of structured fields in Electronic Health Records (EHRs) to ascertain smoking history is important but fails in capturing the nuances of smoking behaviors. Knowledge of smoking behaviors, such ...as pack year history and most recent cessation date, allows care providers to select the best care plan for patients at risk of smoking attributable diseases.
We developed and evaluated a health informatics pipeline for identifying complete smoking history from clinical notes in EHRs. We utilized 758 patient-visit notes (from visits between 03/28/2016 and 04/04/2016) from our local EHR in addition to a public dataset of 502 clinical notes from the 2006 i2b2 Challenge to assess the performance of this pipeline. We used a machine-learning classifier to extract smoking status and a comprehensive set of text processing regular expressions to extract pack years and cessation date information from these clinical notes.
We identified smoking status with an F1 score of 0.90 on both the i2b2 and local data sets. Regular expression identification of pack year history in the local test set was 91.7% sensitive and 95.2% specific, but due to variable context the pack year extraction was incomplete in 25% of cases, extracting packs per day or years smoked only. Regular expression identification of cessation date was 63.2% sensitive and 94.6% specific.
Our work indicates that the development of an EHR-based Smokers' Registry containing information relating to smoking behaviors, not just status, from free-text clinical notes using an informatics pipeline is feasible. This pipeline is capable of functioning in external EHRs, reducing the amount of time and money needed at the institute-level to create a Smokers' Registry for improved identification of patient risk and eligibility for preventative and early detection services.
Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain ...imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients.
In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES).
We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease.
In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.
Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is ...recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.
: There are currently approximately 16 million people taking NNRTI-based first-line treatment in low-income and middle-income countries. Most of these patients are using the combination of tenofovir ...(TDF), lamivudine (3TC) and efavirenz (EFV). The integrase inhibitor dolutegravir (DTG) has shown an improved safety profile compared with EFV in randomized studies. DTG also has a high barrier to development of drug resistance. New co-formulated tablets with TDF/3TC/DTG are being introduced into LMICs, for a median price of $75 per person-year. The prodrug of TDF, tenofovir alafenamide (TAF) is cheaper to manufacture than TDF. A combined pill with TAF/3TC/DTG is also being launched in LMICs, at a similar low price. However, the clinical development programmes for DTG and TAF did not include extensive analysis of several key populations: pregnant women, people with HIV-tuberculosis (TB) coinfection taking rifampicin-based treatment, and treatment-naive or pretreated patients with NRTI drug resistance. An observational study in Botswana has shown an increased risk of neural tube defects when dolutegravir is used in early pregnancy. In LMICs, only 50% of patients have access to regular viral load testing, and genotypic resistance testing is rarely performed. There is currently no clinical data to support switching patients from TDF/3TC/EFV directly to TDF/3TC/DTG if their viral load is either detectable or unknown. New clinical trials and observational studies will be needed to better understand the consequences of this switch of treatment in LMICs. Clinical trials of new antiretrovirals in key populations should be conducted earlier in their development. This will ensure that new treatments can be introduced into LMICs soon after their launch in high-income countries.
The stellar initial mass function (IMF) plays a crucial role in the determination of the number of surviving stars in galaxies, of the chemical composition of the interstellar medium and of the ...distribution of light in galaxies. A key unsolved question is whether the IMF is universal in time and space. Here, we use the state-of-the-art results of stellar evolution to show that the IMF of our Galaxy made a transition from an IMF dominated by massive stars to the present-day IMF at an early phase of the Galaxy formation. Updated results from stellar evolution in a wide range of metallicities have been implemented in a binary population synthesis code, and compared with the observations of carbon-enhanced metal-poor (CEMP) stars in our Galaxy. We find that the application of the present-day IMF to Galactic halo stars causes serious contradictions with four observable quantities connected with the evolution of asymptotic giant branch (AGB) stars. Furthermore, a comparison between our calculations and the observations of CEMP stars might help us to constrain the transition metallicity for the IMF, which we tentatively set at Fe/H −2. A novelty of the current study is the inclusion of mass-loss suppression in intermediate-mass AGB stars at low metallicity. This significantly reduces the overproduction of nitrogen-enhanced stars, which was a major problem in previous studies when using the IMF dominated by high-mass stars. Our results also demonstrate that the use of the present-day IMF for all time in chemical evolution models results in the overproduction of Type I.5 supernovae. More data on stellar abundances will help us to understand how the IMF has changed, and what caused such a transition.
Immunodominance hierarchies are a substantial, but poorly understood, characteristic of CD8⁺ T cell-mediated immunity. Factors influencing the differential responses to the influenza A virus ...nucleoprotein ($NP_{366-374}$) and acid polymerase ($PA_{224-233}$) peptides presented by $H2D^{b}$ have been analyzed by disabling (N5→Q substitution) these peptides in their native configuration, then expressing them in the viral neuraminidase protein. This strategy of shifting epitopes within the same viral context resulted in an apparent equalization of $D^{b}NP_{366}$ epitope consisting of viral nucleoprotein (NP) amino acid residues 366-374 complexed with the $H2D^{b}$ MHC class I glycoprotein and $D^{b}PA_{224}$ ($H2D^{b}+PA_{224-233}$) epitope abundance after direct infection in vitro and induced reproducible changes in the magnitude of the $D^{b}NP_{366}-$ and $D^{b}PA_{224}-specific$ T cell subsets generated after infection of mice. Comparison of $D^{b}NP_{366}-$ and $D^{b}PA_{224}-specific$ CD8⁺ T cell responses induced from the native configuration and from the viral neuraminidase stalk demonstrated that the size of both primary and secondary responses is influenced by relative epitope levels and that, at least after secondary challenge, the magnitude of responses is also determined by CD8⁺ T cell precursor frequency. Thus, this immunodominance hierarchy is a direct function of antigen dose and T cell numbers.
Radioactive nuclei were present in the early solar system (ESS), as inferred from analysis of meteorites. Many are produced in massive stars, either during their lives or their final explosions. In ...the first paper of this series (Brinkman et al. 2019), we focused on the production of 26Al in massive binaries. Here, we focus on the production of another two short-lived radioactive nuclei, 36Cl and 41Ca, and the comparison to the ESS data. We used the MESA stellar evolution code with an extended nuclear network and computed massive (10–80 M ⊙), rotating (with initial velocities of 150 and 300 km s−1) and nonrotating single stars at solar metallicity (Z = 0.014) up to the onset of core collapse. We present the wind yields for the radioactive isotopes 26Al, 36Cl, and 41Ca, and the stable isotopes 19F and 22Ne. In relation to the stable isotopes, we find that only the most massive models, ≥60 and ≥40 M ⊙ give positive 19F and 22Ne yields, respectively, depending on the initial rotation rate. In relation to the radioactive isotopes, we find that the ESS abundances of 26Al and 41Ca can be matched with by models with initial masses ≥40 M ⊙, while 36Cl is matched only by our most massive models, ≥60 M ⊙. 60Fe is not significantly produced by any wind model, as required by the observations. Therefore, massive star winds are a favored candidate for the origin of the very short-lived 26Al, 36Cl, and 41Ca in the ESS.
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