Classification of death causes after transplantation (CLASS):Evaluation of methodology and initial results

Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry

Alternativa verktyg : Läsande och skrivande med teknikens hjälp ur ett inkluderande perspektiv.

Syftet med studien är att undersöka hur alternativa verktyg används i klassrummet och hur vi kan förstå användningen av dessa kompenserande hjälpmedel i förhållande till upplevelser av inkludering. Uppsatsens två delstudier genererade följande resultat: Vid användning av teknik finns möjligheter för elever i läs- och skrivsvårigheter att delta i den vanliga undervisningen på liknande villkor. Varken lärare eller elever upplever att det finns någon brist på tekniska hjälpmedel i klassrummen. Av studierna framkommer även att alternativa verktyg används mest i klassrumssituationer. Alla elever använder mer teknik ju äldre de blir och mobilen är också ett flitigt använt hjälpmedel hos vissa. Mest används alternativa verktyg till “läsning” och skrivning. Ett program som inte används i någon större utsträckning är dikteringsprogram trots att eleverna ger uttryck för ett behov av detta i intervjuerna.  En viss risk föreligger att elever i vissa situationer väljer bort de alternativa verktygen av rädsla att vara annorlunda. Studiens resultat visar att alternativa verktyg öppnar upp möjligheter för elever med dyslexi och läs- och skrivsvårigheter till att vara inkluderade i klassrumsundervisningen. Samtidigt finns det många faktorer som har betydelse för att en elev ska vara inkluderad, såsom individens inställning, lärarnas kunskaper och motivation och på vilket sätt tekniken används

Alternativa verktyg : Läsande och skrivande med teknikens hjälp ur ett inkluderande perspektiv.

Syftet med studien är att undersöka hur alternativa verktyg används i klassrummet och hur vi kan förstå användningen av dessa kompenserande hjälpmedel i förhållande till upplevelser av inkludering. Uppsatsens två delstudier genererade följande resultat: Vid användning av teknik finns möjligheter för elever i läs- och skrivsvårigheter att delta i den vanliga undervisningen på liknande villkor. Varken lärare eller elever upplever att det finns någon brist på tekniska hjälpmedel i klassrummen. Av studierna framkommer även att alternativa verktyg används mest i klassrumssituationer. Alla elever använder mer teknik ju äldre de blir och mobilen är också ett flitigt använt hjälpmedel hos vissa. Mest används alternativa verktyg till “läsning” och skrivning. Ett program som inte används i någon större utsträckning är dikteringsprogram trots att eleverna ger uttryck för ett behov av detta i intervjuerna.  En viss risk föreligger att elever i vissa situationer väljer bort de alternativa verktygen av rädsla att vara annorlunda. Studiens resultat visar att alternativa verktyg öppnar upp möjligheter för elever med dyslexi och läs- och skrivsvårigheter till att vara inkluderade i klassrumsundervisningen. Samtidigt finns det många faktorer som har betydelse för att en elev ska vara inkluderad, såsom individens inställning, lärarnas kunskaper och motivation och på vilket sätt tekniken används

Associations of functional human leucocyte antigen class I groups with HIV viral load in a heterogeneous cohort

OBJECTIVE: Human leucocyte antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort. DESIGN: Cohort from the Strategic Timing of AntiRetroviral Treatment (START) study. METHODS: We imputed HLA class I alleles from host genetic data (2546 HIV+ participants) and sampled immunopeptidomes from 2079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL. RESULTS: We identified four clades totaling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B∗57:01 and B∗57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, β -0.25; adj. P-value \u3c 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies. CONCLUSION: The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data

Tuberculosis among Patients Undergoing Solid Organ Transplantation or Dialysis in a Low-Endemic Country, 2004-2017

Background. The risk of active TB among solid organ transplant (SOT) recipients and patients initiating chronic dialysis in a country with low incidence of TB is not well elucidated. Methods. Patients aged >18 years who were transplanted with a solid organ or initiated chronic dialysis at Copenhagen University Hospital in the period 2004-2017 were followed from date of transplantation or initiation of dialysis. Data on demographics and outcomes were obtained from nationwide registries. Results. We included 1,989 SOT recipients and 1,305 patients initiating chronic dialysis, who were followed for a total of 9,785 and 4,196 person-years (PY), respectively. Only a minority of patients had been screened for latent TB prior to SOT or initiation of dialysis. The incidence rates (IRs)/100,000 PY of TB among patients from medium/high TB endemic areas were 358 (95% CI 115-1,110) and 1,266 (95% CI 681-2354) for SOT and dialysis patients, respectively, whereas IRs among patients of Danish origin were 11 (95% CI 2-81) and 31 (95% CI 4-218). Conclusion. The incidence of TB among immunosuppressed immigrants from medium/high TB endemic countries was very high, while the risk of TB among patients from low-endemic countries was minimal

The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies

OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals. DESIGN: Cohort study. METHODS: In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios (HRs) for the risk of events among allele carriers versus non-carriers. Models were adjusted for sex, age, geography, race, time-updated CD4+ T-cell counts and HIV viral load (VL) and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini-Hochberg procedure was used to limit the false discovery rate to <5% (i.e. q-value<0.05). RESULTS: Among 4,829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers and 49 herpes virus-related AIDS events. Several associations with q-value <0.05 were found: HLA-DQB1*06:04 and HLA-DRB1*13:02 with AIDS (adjusted HR [95%CI] 2.63 [1.5–4.6] and 2.25 [1.4–3.7], respectively), HLA-B*15:17 and HLA-DPB1*15:01 with bacterial pneumonia (4.93 [2.3–10.7] and 4.33 [2.0–9.3], respectively), and HLA-A*69:01 with infection-related cancer (15.26 [3.5–66.7]). The carriage frequencies of these alleles were ≤10%. CONCLUSIONS: This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of VL and CD4+ T-cell count

Human immunotypes impose selection on viral genotypes through viral epitope specificity

BACKGROUND Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV+ ART-naive clinical trial participants. METHODS HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs) and imputed HLA alleles, using generalized linear models with Bonferroni correction. RESULTS Human (388,501 SNPs) and HIV (3,010 variants) genetic data was available for 2,122 persons. Four HIV variants were associated with VL (p-values<1.66×10 -5). Twelve HIV variants were associated with a range of 1-512 human SNPs (p-value<4.28×10 -11). We found 46 associations between HLA alleles and HIV variants (p-values<1.29×10 -7). We found HIV variants and immunotypes when analyzed separately, were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding prediction showed HLA alleles to be weaker binders of associated HIV AA variants relative to alternative variants on the same position. CONCLUSIONS Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay puts emphasis that viral and human genetics should be studied in the context of each other