Publications by authors named "Wendy Stevens"

316 Publications

Evaluation Protocol for SARS-CoV-2 Serological Assays.

Methods Mol Biol 2022 ;2511:307-319

Department of Immunology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has been identified as the causative agent of COVID-19. Accurate detection of SARS-CoV-2 infection is not only important for management of infected individuals but also to break the chain of transmission. Although the polymerase chain reaction (PCR) is the gold standard for diagnosis of acute SARS-CoV-2 infection, there are a number of limitations of these assays, which include the inability to detect past infection and decline in sensitivity 14 days post-symptom onset. There are several serology tests developed for the detection of SARS-CoV-2 antibodies including high-throughput serology platforms and lateral flow immunoassays. These tests should be evaluated for their performance to meet local regulations acceptance criteria. To optimize the diagnostic algorithm for SARS-CoV-2, this protocol describes the evaluation of serological antibody testing using various automated serology platforms and lateral flow immunoassays. This protocol was evaluated in both serum and plasma samples. The sample preparation, procedure, and data analysis are described. The protocol can be adapted for any serological testing.
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http://dx.doi.org/10.1007/978-1-0716-2395-4_23DOI Listing
July 2022

Guidance for SARS-CoV-2 RNA-Based Molecular Assay Analytical Performance Evaluations.

Methods Mol Biol 2022 ;2511:99-115

Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is frequently diagnosed through detection of viral RNA using nucleic acid amplification testing (NAAT) assays that are usually used in centralized settings. Following the publication of the SARS-CoV-2 genetic sequence, multiple diagnostic assays were launched in 2020. These assays require evaluation beyond manufacturer self-reported performance to determine whether they are suitable for use, meet country acceptance criteria, and are compatible with existing in-country platforms. In order to meet the demand for testing services, rapid yet robust assay performance evaluations are required. In our setting, these evaluation protocols required the use of residual patient specimens and reference materials, as typical clinical trials are time-consuming and limited by cost and the cyclical nature of SARS-CoV-2 infection. This protocol is designed to assist in the rapid and robust evaluation of nucleic acid-based assays for the detection of SARS-CoV-2 using limited specimens, reference materials, and test kits. While it is specific for RNA-based assays, it can be adapted for fully automated analyses. The preparation and processing of evaluation panels is described, followed by methods for analytical precision analysis and data visualization. Assay robustness and scalability are briefly discussed as these can be critical for implementation. This protocol is designed to be flexible and alternative options are provided throughout the text where possible.
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http://dx.doi.org/10.1007/978-1-0716-2395-4_8DOI Listing
July 2022

Genomic and microenvironmental landscape of stage I follicular lymphoma, compared to stage III/IV.

Blood Adv 2022 Jul 11. Epub 2022 Jul 11.

Karolinska Institute, Stockholm, Sweden.

While the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known regarding potential biological differences between stage I and stage III/IV disease. Using next generation sequencing (NGS) and immunohistochemistry, 82 FL nodal stage I cases were analysed and compared to 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations (CNAs) and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T-cells (p=0.02) and STAT6 mutations (FDR<0.001), were more frequent in stage I FL. In contrast, PD1+ T-cells, CD68+/CD163+ macrophages (p<0.001), BCL2 translocation (BCL2trl+) (p<0.0001), KMT2D (FDR=0.003) and CREBBP (FDR=0.04) mutations were found more frequently in stage III/IV FL. By clustering we identified three clusters within stage I, and two within stage III/IV. The BLC2trl+ stage I cluster was comparable to the BCL2trl+ cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) and STAT6 (64%) mutations, without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%) with less CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl- stage I cluster was relatively heterogeneous with more CNAs and linker histone mutations. This exploratory study shows that FL stage I is genetically heterogenous with different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven while BCL2trl- stage III/IV appears to be more BCL6trl driven.
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http://dx.doi.org/10.1182/bloodadvances.2022008355DOI Listing
July 2022

Novel Approaches in Molecular Characterization of Classical Hodgkin Lymphoma.

Cancers (Basel) 2022 Jun 30;14(13). Epub 2022 Jun 30.

Radboud University Medical Center, Department of Pathology, 6525 GA Nijmegen, The Netherlands.

Classical Hodgkin lymphoma (cHL) represents a B-cell lymphoproliferative disease characterized by clonal immunoglobulin gene rearrangements and recurrent genomic aberrations in the Hodgkin Reed-Sternberg cells in a reactive inflammatory background. Several methods are available for the molecular analysis of cHL on both tissue and cell-free DNA isolated from blood, which can provide detailed information regarding the clonal composition and genetic alterations that drive lymphoma pathogenesis. Clonality testing involving the detection of immunoglobulin and T cell receptor gene rearrangements, together with mutation analysis, represent valuable tools for cHL diagnostics, especially for patients with an atypical histological or clinical presentation reminiscent of a reactive lesion or another lymphoma subtype. In addition, clonality assessment may establish the clonal relationship of composite or subsequent lymphoma presentations within one patient. During the last few decades, more insight has been obtained on the molecular mechanisms that drive cHL development, including recurrently affected signaling pathways (e.g., NF-κB and JAK/STAT) and immune evasion. We provide an overview of the different approaches to characterize the molecular composition of cHL, and the implementation of these next-generation sequencing-based techniques in research and diagnostic settings.
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http://dx.doi.org/10.3390/cancers14133222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264882PMC
June 2022

Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa.

Nat Med 2022 Jun 27. Epub 2022 Jun 27.

KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.

Three lineages (BA.1, BA.2 and BA.3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern predominantly drove South Africa's fourth Coronavirus Disease 2019 (COVID-19) wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and similar to BA.2 except for the addition of 69-70 deletion (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild-type amino acid at Q493. The two lineages differ only outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimated growth advantages for BA.4 and BA.5 of 0.08 (95% confidence interval (CI): 0.08-0.09) and 0.10 (95% CI: 0.09-0.11) per day, respectively, over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.
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http://dx.doi.org/10.1038/s41591-022-01911-2DOI Listing
June 2022

Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.

Front Genet 2022 8;13:913196. Epub 2022 Jun 8.

Genomics England, Charterhouse Square, London, United Kingdom.

Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype  at genome-wide significance (GWS). We further report statistically significant associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of , previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual's underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.
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http://dx.doi.org/10.3389/fgene.2022.913196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214260PMC
June 2022

Long-term HIV treatment outcomes and associated factors in sub-Saharan Africa: multicountry longitudinal cohort analysis.

AIDS 2022 08 25;36(10):1437-1447. Epub 2022 May 25.

Amsterdam Institute for Global Health and Development, and Department of Global Health, Amsterdam UMC, University of Amsterdam.

Objective: In a multicountry prospective cohort of persons with HIV from six countries between 2007 and 2015, we evaluated long-term outcomes of first-line non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy (ART), and risk factors for loss-to-follow-up, mortality, virological failure, and incomplete CD4 + T-cell recovery.

Methods: We calculated cumulative incidence of lost-to-follow-up, death, virological failure (VL ≥ 1000 cps/ml) and incomplete CD4 + T-cell recovery (<500 cells/μl) at successive years, using Kaplan-Meier and Cox regression.

Results: Of 2735 participants, 58.0% were female, median age was 37 (interquartile range [IQR] 32-43) years, and median pre-ART CD4 + T-cell count was 135 (IQR 63-205)/μl. Total follow-up time was 7208 person-years (median 24.3 months, IQR 18.7-58.3). Deaths by any cause and loss to follow-up occurred mostly during the first year of ART (84%, 201/240 and 56%, 199/353, respectively). During their first 6 years of ART, 71% (95% confidence interval [CI] 69.0-73.7) were retained on first-line, and among those 90-93% sustained viral suppression (<1000 cps/ml); CD4 + T-cell recovery was incomplete in 60% (220/363) of participants. The risk factors associated with poor outcomes during long-term ART were: for loss-to-follow-up, recent VL ≥1000 cps/ml, recent CD4 + T-cell count ≤50 cells/μl, age <30 years, being underweight; for mortality, recent CD4 + T-cell count ≤50 cells/μl; and, for virological failure, age <40 years, recent CD4 + T-cell count ≤200 cells/μl, poor adherence, male sex, and low-level viremia.

Conclusion: To achieve long-term ART success towards the UNAIDS targets, early ART initiation is crucial, coupled with careful monitoring and retention support, particularly in the first year of ART. Male and youth-centred care delivery models are needed to improve outcomes for those vulnerable groups.
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http://dx.doi.org/10.1097/QAD.0000000000003270DOI Listing
August 2022

Antigen-Based Point of Care Testing (POCT) for Diagnosing SARS-CoV-2: Assessing Performance.

Methods Mol Biol 2022 ;2452:45-62

Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Currently, the most accurate way to diagnose an active SARS-CoV-2 (COVID-19) infection is through detection of viral RNA using reverse transcription polymerase chain reaction (RT-PCR) test. While RT-PCR tests are the most sensitive for identifying infection, there are significant limitations, such as global access to sufficient test kits, turnaround times (TAT) from specimen collection to test result is often greater than 24 h and the need for skilled operators in accredited laboratories requiring specialized equipment. A rapid test performed at the point of care (POC) could provide a result within an approximate time of 30 min post specimen collection, be performed by a health care worker and comprise a simple workflow, improving both turnaround time and potentially decreasing costs (e.g., transport, cold-chain, skilled laboratory staff, complex equipment). Determining the performance of SARS-CoV-2 RT-PCR tests is, however, easier to assess than antigen-based POCT, as residual clinical specimens (swabs in universal transport media [UTM]) are readily available in laboratory environments, and do not require patient informed consent. Evaluating the performance of POCT requires informed-consent driven studies, with patients required to provide a standard of care specimen as well as study evaluation specimens, which is often not acceptable as nasopharyngeal swabbing can be invasive, clinical field trials are costly and time consuming. Many institutions and regulatory bodies also require preliminary data prior to use in field settings. Therefore, we have developed a method to determine the performance of antigen based POCT that can be used by implementers in national healthcare programs, regulators and rapid test developers. The method investigates both quantitative and qualitative parameters, with the latter providing insights into the capability for implementation and national program uptake.
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http://dx.doi.org/10.1007/978-1-0716-2111-0_4DOI Listing
May 2022

Challenges and complexities in evaluating severe acute respiratory syndrome coronavirus 2 molecular diagnostics during the COVID-19 pandemic.

Afr J Lab Med 2022 26;11(1):1429. Epub 2022 Apr 26.

Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

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http://dx.doi.org/10.4102/ajlm.v11i1.1429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082082PMC
April 2022

Gastric antral vascular ectasia in systemic sclerosis: a study of its epidemiology, disease characteristics and impact on survival.

Arthritis Res Ther 2022 05 10;24(1):103. Epub 2022 May 10.

Department of Medicine, The University of Melbourne at St Vincent's Hospital (Melbourne), 41 Victoria Parade, Fitzroy, Victoria, 3065, Australia.

Background: To describe the epidemiology, determinants and survival impact of gastric antral vascular ectasia (GAVE) in systemic sclerosis (SSc).

Methods: Consecutive SSc patients prospectively enrolled in the Australian Scleroderma Cohort Study (ASCS) were included. Univariable and multivariable logistic regression were used to determine the associations of GAVE with clinical manifestations and serological parameters. Kaplan-Meier (K-M) survival curves were used to estimate survival.

Results: The prevalence of GAVE in this SSc cohort of 2039 SSc patients was 10.6% (n = 216) over a median follow-up period of 4.3(1.7-8.4) years. SSc patients with a history of GAVE compared with those without a history of GAVE were older at SSc onset [49.5 (40.0-58.2) vs 46.7 (36.0-56.7) years, p = 0.05]; more likely to have diffuse disease subtype (dcSSc) (35.3% vs 24.1%, p < 0.001); be negative for Scl-70, U1RNP and Scl/PM antibody (4.0% vs 16.1%, p < 0.001, 3.5% vs 7.4%, p = 0.041, 0.0% vs 2.0%, p = 0.042; and respectively) and positive for RNAP III antibody (24.9% vs 8.3%, p < 0.001). Those with GAVE had a worse HRQoL (p = 0.002). Independent determinants of GAVE included the presence of RNAP III antibody (OR 3.46, p < 0.001), absence of Scl-70 antibody (OR 0.23, p = 0.001), presence of GIT dysmotility (OR 1.64, p = 0.004), and digital ulcers; pits; or digital amputation (OR 1.59, p = 0.014).

Conclusions: GAVE is an underestimated and underappreciated SSc manifestation of SSc, which occurs with a relatively high frequency. Identifying an at-risk GAVE phenotype, as presented herein, is of practical importance as screening may prove advantageous given GAVE can be easily diagnosed and treated.
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http://dx.doi.org/10.1186/s13075-022-02790-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087964PMC
May 2022

Biological and Clinical Implications of Gene-Expression Profiling in Diffuse Large B-Cell Lymphoma: A Proposal for a Targeted BLYM-777 Consortium Panel as Part of a Multilayered Analytical Approach.

Cancers (Basel) 2022 Apr 7;14(8). Epub 2022 Apr 7.

Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

Gene-expression profiling (GEP) is used to study the molecular biology of lymphomas. Here, advancing insights from GEP studies in diffuse large B-cell lymphoma (DLBCL) lymphomagenesis are discussed. GEP studies elucidated subtypes based on cell-of-origin principles and profoundly changed the biological understanding of DLBCL with clinical relevance. Studies integrating GEP and next-generation DNA sequencing defined different molecular subtypes of DLBCL entities originating at specific anatomical localizations. With the emergence of high-throughput technologies, the tumor microenvironment (TME) has been recognized as a critical component in DLBCL pathogenesis. TME studies have characterized so-called "lymphoma microenvironments" and "ecotypes". Despite gained insights, unexplained chemo-refractoriness in DLBCL remains. To further elucidate the complex biology of DLBCL, we propose a novel targeted GEP consortium panel, called BLYM-777. This knowledge-based biology-driven panel includes probes for 777 genes, covering many aspects regarding B-cell lymphomagenesis (f.e., MYC signature, TME, immune surveillance and resistance to CAR T-cell therapy). Regarding lymphomagenesis, upcoming DLBCL studies need to incorporate genomic and transcriptomic approaches with proteomic methods and correlate these multi-omics data with patient characteristics of well-defined and homogeneous cohorts. This multilayered methodology potentially enhances diagnostic classification of DLBCL subtypes, prognostication, and the development of novel targeted therapeutic strategies.
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http://dx.doi.org/10.3390/cancers14081857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028345PMC
April 2022

Using magnetic resonance imaging to map the hidden burden of muscle involvement in systemic sclerosis.

Arthritis Res Ther 2022 04 11;24(1):84. Epub 2022 Apr 11.

Department of Medicine, The University of Melbourne at St Vincent's Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC, 3065, Australia.

Background: Skeletal muscle can be directly affected by systemic sclerosis (SSc); however, a significant burden of SSc-associated myopathy is undetected because clinical parameters such as weakness and creatine kinase (CK) are unreliable biomarkers of muscle involvement. This study presents qualitative and quantitative magnetic resonance imaging (MRI) findings that quantify the prevalence of myopathy and evaluate any association between skeletal and cardiac muscle involvement in SSc.

Methods: Thirty-two patients with SSc who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria underwent skeletal muscle MRI in addition to cardiac MRI. Skeletal muscles were independently assessed by two musculoskeletal radiologists for evidence of oedema, fatty infiltration and atrophy. Skeletal muscle T2 mapping times and percentage fat fraction were calculated. Linear regression analysis was used to evaluate the clinical and myocardial associations with skeletal muscle oedema and fatty infiltration. Cardiac MRI was performed using post gadolinium contrast imaging and parametric mapping techniques to assess focal and diffuse myocardial fibrosis.

Results: Thirteen participants (40.6%) had MRI evidence of skeletal muscle oedema. Five (15.6%) participants had fatty infiltration. There was no association between skeletal muscle oedema and muscle strength, creatine kinase, inflammatory markers or fibroinflammatory myocardial disease. Patients with skeletal muscle oedema had higher T2-mapping times; there was a significant association between subjective assessments of muscle oedema and T2-mapping time (coef 2.46, p = 0.02) and percentage fat fraction (coef 3.41, p = 0.02). Diffuse myocardial fibrosis was a near-universal finding, and one third of patients had focal myocardial fibrosis. There was no association between skeletal myopathy detected by MRI and burden of myocardial disease.

Conclusions: MRI is a sensitive measure of muscle oedema and systematic assessment of SSc patients using MRI shows that myopathy is highly prevalent, even in patients without symptoms or other signs of muscle involvement. Similarly, cardiac fibrosis is highly prevalent but occurs independently of skeletal muscle changes. These results indicate that novel quantitative MRI techniques may be useful for assessing sub-clinical skeletal muscle disease in SSc.
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http://dx.doi.org/10.1186/s13075-022-02768-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996589PMC
April 2022

Recalcitrant digital calcinosis cutis successfully treated with intralesional sodium thiosulfate under digital nerve blockade.

BMJ Case Rep 2022 Apr 6;15(4). Epub 2022 Apr 6.

Dermatology, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia.

Dystrophic calcinosis cutis can be associated with severe pain, decreased mobility, increased risk of infection and significantly decreased quality of life. We report a case of recalcitrant calcinosis cutis on the background of eosinophilic fasciitis, which achieved rapid reduction in calcium deposits following a novel injecting protocol of intralesional sodium thiosulfate.
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http://dx.doi.org/10.1136/bcr-2021-248707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987704PMC
April 2022

Persistent symptoms of fatigue, neuropathy and role-functioning impairment among indolent non-Hodgkin lymphoma survivors: A longitudinal PROFILES registry study.

Br J Haematol 2022 06 2;197(5):590-601. Epub 2022 Apr 2.

Department of Research and Development, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands.

Little is known about the long-term health-related quality of life (HRQoL) and persistence of symptoms among patients with indolent non-Hodgkin lymphoma (iNHL). This large population-based longitudinal study therefore investigated the long-term HRQoL and persistence of symptoms and identified associated sociodemographic, clinical and psychological factors. Patients diagnosed between 1999 and 2014 and four or more months after diagnosis were invited to participate in a longitudinal survey. Sociodemographic and clinical data were obtained from the Netherlands Cancer Registry. The EORTC QLQ-C30 and CLL-16 were completed by 669 patients (74% response rate). Patients completed on average four questionnaires. Primary treatment was active surveillance (52%), systemic therapy (31%) or radiotherapy (13%). Respectively, 36% reported persistent fatigue, 33% persistent neuropathy and 25% persistent role-functioning impairment. This was 2-3 times higher than in the age- and sex-matched normative population. Up to 10 years after diagnosis, scores remained relatively stable without clinically relevant changes. Comorbidities, psychological distress, shorter time since diagnosis, systemic therapy, younger age, education level and having no partner were associated with worse outcomes (all ps < 0.05). Up to a third of patients with iNHL experience long-term persistent symptoms which do not improve over time. Early recognition of symptoms will help in providing tailored supportive care for those in need.
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http://dx.doi.org/10.1111/bjh.18139DOI Listing
June 2022

47XXY and 47XXX in Scleroderma and Myositis.

ACR Open Rheumatol 2022 Jun 29;4(6):528-533. Epub 2022 Mar 29.

National Institute of Environmental Health Science, National Institutes of Health, Bethesda, Maryland, USA.

Objective: We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies.

Methods: The participants met classification criteria for the diseases. All participants underwent single-nucleotide polymorphism typing. We examined X and Y single-nucleotide polymorphism heterogeneity to determine the number of X chromosomes. For statistical comparisons, we used χ analyses with calculation of 95% confidence intervals.

Results: Three of seventy men with SSc had 47,XXY (P = 0.0001 compared with control men). Among the 435 women with SSc, none had 47,XXX. Among 709 men with polymyositis or dermatomyositis (PM/DM), seven had 47,XXY (P = 0.0016), whereas among the 1783 women with PM/DM, two had 47,XXX. Of 147 men with inclusion body myositis (IBM), six had 47,XXY, and 1 of the 114 women with IBM had 47,XXX. For each of these myositis disease groups, the excess 47,XXY and/or 47,XXX was significantly higher compared with in controls as well as the known birth rate of Klinefelter syndrome or 47,XXX.

Conclusion: Klinefelter syndrome (47,XXY) is associated with SSc and idiopathic inflammatory myopathies, similar to other autoimmune diseases with type 1 interferon pathogenesis, namely, systemic lupus erythematosus and Sjögren syndrome.
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http://dx.doi.org/10.1002/acr2.11413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9190224PMC
June 2022

Damage Trajectories in Systemic Sclerosis Using Group-Based Trajectory Modeling.

Arthritis Care Res (Hoboken) 2022 Feb 28. Epub 2022 Feb 28.

Rheumatology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Objective: Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive organ damage, which can be measured using the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI). We aimed to identify whether distinct trajectories of damage accrual exist and determine which variables are associated with different trajectory groups.

Methods: Incident cases of SSc (<2 years) were identified in the Australian Scleroderma Interest Group and Canadian Scleroderma Research Group prospective registries. Group-based trajectory modeling was used to identify SCTC-DI trajectories over the cohort's first 5 annual visits. Baseline variables associated with trajectory membership in a univariate analysis were examined in multivariable models.

Results: 410 patients were included. Three trajectory groups were identified: low (54.6%), medium (36.2%) and high (10.3%) damage. Patients with faster damage accrual had higher baseline SCTC-DI. Older age (OR 1.57, 95% CI 1.18 - 2.10), male sex (OR 2.55, 95% CI 1.10 - 5.88), diffuse disease (OR 6.7, 95% CI 2.57 - 17.48), tendon friction rubs (OR 5.4, 95% CI 1.86 - 15.66), and elevated CRP (OR 1.98, 95% CI 1.49 - 2.63) increased the odds of being in the high damage group versus the reference (low damage), whereas Caucasian ethnicity (OR 0.31, 95% CI 0.12 - 0.75) and anti-centromere antibodies (OR 0.24, 95% CI 0.07 - 0.77) decreased them.

Conclusions: We identified three trajectories of damage accrual in a combined incident SSc cohort. Several characteristics increased the odds of belonging to worse trajectories. These findings may be helpful in recognizing patients in whom early aggressive treatment is necessary.
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http://dx.doi.org/10.1002/acr.24873DOI Listing
February 2022

Monitored Implementation of COVID-19 Rapid Antigen Screening at Taxi Ranks in Johannesburg, South Africa.

Diagnostics (Basel) 2022 Feb 3;12(2). Epub 2022 Feb 3.

FIND, Campus Biotech, Chemin des Mines 9, 1202 Geneva, Switzerland.

Digital tools can support community-based decentralized testing initiatives to broaden access to COVID-19 diagnosis, especially in high-transmission settings. This operational study investigated the use of antigen-detecting rapid diagnostic tests (Ag-RDTs) for COVID-19 combined with an end-to-end digital health solution, in three taxi ranks in Johannesburg, South Africa. Members of the public were eligible if they were aged ≥18 years, could read, and had a cellphone. Over 15,000 participants, enrolled between June and September 2021, were screened for COVID-19 risk factors. A digital risk questionnaire identified 2061 (13%) participants as moderate risk and 2987 (19%) as high risk, based on symptoms and/or recent exposure to a known case. Of this group referred for testing, 3997 (79%) received Ag-RDTs, with positivity rates of 5.1% in the "high-risk" group and 0.8% in the "moderate-risk" group. A subset of 569 randomly selected participants received additional PCR testing. Sensitivity of the Ag-RDT in this setting was 40% (95% CI: 30.3%, 50.3%); most false negatives had high cycle threshold values (>25), hence low viral loads. Over 80% of participants who tested positive completed a 2-week phone-based follow-up questionnaire. Overall, the digital tool combined with Ag-RDTs enhanced community-based decentralized COVID-19 testing service delivery, reporting and follow-up.
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http://dx.doi.org/10.3390/diagnostics12020402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871379PMC
February 2022

Associations between the Composite Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS), survival and other disease measures.

Semin Arthritis Rheum 2022 04 31;53:151973. Epub 2022 Jan 31.

McGill University, Jewish General Hospital, Montreal, Canada. Electronic address:

Objective: Diffuse cutaneous systemic sclerosis (dcSSc) is a multifaceted disease for which the Composite Response Index in dcSSc (CRISS) was developed as a global outcome measure. We aimed to further validate the CRISS by examining its association with other disease measures, patient reported quality of life (QoL), and mortality.

Methods: DcSSc patients with ≤5 year disease duration were recruited from multinational registries. CRISS improvers (score ≥0.6) and non-improvers (score <0.6) were identified after one year. Median changes in European Scleroderma Group Activity Index (EScSG-AI), Medsger Disease Severity Scale (DSS), Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI), and Short Form 36 physical component score (SF-36 PCS) after one year was compared between CRISS groups. Kaplan Meier and adjusted Cox analyses compared SCTC-DI damage accrual and mortality between CRISS groups.

Results: Of 212 patients, 68 (32.1%) were CRISS improvers. CRISS improvers had improved median EScSG-AI (-1.1 points [IQR -2.6, -0.3] vs. 0 [-1.1, 1.0], p<0.001), DSS (-1 [-3, 1] vs. 0 [-2, 2], p = 0.015), and SF-36 PCS (+3.6 [-1.0, 8.9] vs. -0.3 [-5.9, 4.5], p<0.001) compared to non-improvers. CRISS improvers were less likely to accumulate damage on the SCTC-DI (hazard ratio [95% confidence interval] 0.68 [0.47, 0.96]) adjusting for age, sex, disease duration, and immunosuppression use. CRISS improvers had a trend towards better survival.

Conclusion: CRISS improvers had more favourable changes in measures of disease activity, disease severity, and QoL compared to non-improvers. These findings support the construct validity of a CRISS outcome after one year in early dcSSc.
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http://dx.doi.org/10.1016/j.semarthrit.2022.151973DOI Listing
April 2022

Myocardial fibrosis and arrhythmic burden in systemic sclerosis.

Rheumatology (Oxford) 2022 Feb 8. Epub 2022 Feb 8.

Department of Medicine, The University of Melbourne at St Vincent's Hospital, Fitzroy, VIC, Australia.

Objectives: Cardiac complications of systemic sclerosis (SSc) are a leading cause of SSc-associated death. Cardiac imaging for identifying substrate abnormality may be useful in predicting risk of cardiac arrhythmias or future cardiac failure. The aim of this study was to quantify the burden of asymptomatic fibro-inflammatory myocardial disease using cardiac magnetic resonance imaging (CMR) and assess the relationship between asymptomatic myocardial fibrosis and cardiac arrhythmias in SSc.

Methods: Thirty-two patients with SSc with no documented history of pulmonary vascular or heart disease underwent CMR with gadolinium and 24-h ambulatory electrocardiography (ECG). Focal myocardial fibrosis was assessed using post-gadolinium imaging and diffuse fibro-inflammatory myocardial disease quantified using T1 and T2-mapping. CMR results were compared with an age and sex-matched control group.

Results: Post-gadolinium focal fibrosis was prevalent in SSc but not controls (30% vs 0%, p< 0.01) and its presence was associated with impaired left ventricular strain (p= 0.009). T1 mapping values (as a marker of diffuse fibrosis) were greater in SSc than controls (SASHA : 1584 ms vs 1515 ms, p< 0.001; ShMOLLI : 1218 ms vs 1138 ms, p< 0.001). More than one-fifth (22.6%) of the participants had ventricular arrhythmias on ambulatory ECG, but no associations between focal or diffuse myocardial fibrosis and arrhythmias were evident.

Conclusion: In SSc patients without evidence of overt cardiac disease, a high burden of myocardial fibrosis and arrhythmias was identified. However, there was no clear association between focal or diffuse myocardial fibrosis and arrhythmias, suggesting CMR may have limited use as a screening tool to identify SSc patients at risk of future significant arrhythmias.
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http://dx.doi.org/10.1093/rheumatology/keac065DOI Listing
February 2022

Performance of the Abbott SARS-CoV-2 IgG serological assay in South African 2 patients.

PLoS One 2022 4;17(2):e0262442. Epub 2022 Feb 4.

Department of Immunology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

In late December 2019, pneumonia cases of unknown origin were reported in Wuhan, China. This virus was named SARS-CoV2 and the clinical syndrome was named coronavirus disease 19 (COVID-19). South Africa, despite strict and early lockdown has the highest infection rate in Africa. A key component of South Africa's response to SARSCoV2 was the rapid scale-up of diagnostic testing. The Abbott SARS-CoV2 assay detects IgG antibodies against the Nucleocapsid (N) protein of the SARS-CoV2 virus. This study undertook to validate and evaluate performance criteria of the Abbott assay and to establish whether this assay would show clinical utility in our population. Positive patients (n = 391) and negative controls (n = 139) were included. The Architect-i and Alinity-i systems were analyzers that were used to perform the SARS-CoV-2 IgG assay. In-house ELISA was incorporated into the study as a confirmatory serology test. A total of number of 530 participants was tested, 87% were symptomatic with infection and 13% were asymptomatic. When compared to RT-qPCR, the sensitivity of Architect and Alinity SARS-CoV2 assays was 69.5% and 64.8%, respectively. Specificity for Architect and Alinity assays was 95% and 90.3%, respectively. The Abbott assay was also compared to in house ELISA assay, with sensitivity for the Architect and Alinity assays of 94.7% and 92.5%, respectively. Specificity for Abbott Alinity assays was 91.7% higher than Abbott Architect 88.1%. Based on the current findings testing of IgG after 14 days is recommended in South Africa and supports other studies performed around the world.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0262442PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815965PMC
February 2022

Implementation of an mHealth App to Promote Engagement During HIV Care and Viral Load Suppression in Johannesburg, South Africa (iThemba Life): Pilot Technical Feasibility and Acceptability Study.

JMIR Form Res 2022 Feb 2;6(2):e26033. Epub 2022 Feb 2.

Molecular Medicine & Haematology, University of the Witwatersrand, Parktown, South Africa.

Background: South Africa has the largest HIV treatment program worldwide. Retention in care and medication adherence remain problematic necessitating innovative solutions for improving HIV care. The increasing availability and use of mobile technology can support positive clinical outcomes for persons living with HIV. iThemba Life is a mobile health app designed with input from South African health professionals and patients, promoting engagement with HIV care through access to medical results.

Objective: This study aimed to test the feasibility and acceptability of receiving HIV viral load (VL) results through the app and compare the time to HIV VL result return for study participants before and after app use.

Methods: Using convenience sampling, adults having routine VL phlebotomy were recruited from 2 Johannesburg health facilities. After signed consent, the app was downloaded on their Android smartphones, phlebotomy was performed, and the sample barcode was scanned through their phone to link the sample and app. Participants received a notification of the result availability and logged into the app to view results, their explanation and recommended action.

Results: Overall, 750 people were screened to enroll 500 participants. Of 750, 113 (15.1%) failed eligibility screening. 21.5% (137/637) had smartphone technical limitations preventing enrollment. Results were released to 92.2% (461/500) of participants' phones. App technical issues and laboratory operational issues limited the number of released results. Approximately 78.1% (360/461) results were viewed in the app. Median time from notification of availability to result viewed being 15.5 hours (0.6; range 0-150 days). Turnaround time from phlebotomy to the result being received was 6 (range 1-167) days for users versus 56 days (range 10-430 days; P<.001) before app use. Overall, 4% (20/500) of participants received unsuppressed results (VL>1000 copies/mL). Turnaround time for unsuppressed results was 7 days for participants versus 37.5 days before app use (P<.001). The difference before and after app use in the suppressed and unsuppressed users for time from sample collection to result delivery was statistically significant. Of 20 participants, 12 (60%) returned for a confirmatory VL during the study period. The time from an unsuppressed VL to a confirmatory VL was 106 days for app users versus 203 days before app use (P<.001). Overall, 52.4% (262/500) of participants completed an exit survey; 23.2% (58/250) reported challenges in viewing their VL results. Moreover, 58% (35/60) reported that they overcame challenges with technical assistance from others, and 97.3% (255/262) wanted to continue using the app for VL results.

Conclusions: Using iThemba Life for VL results was well-received despite limited smartphone access for some participants. App users received results 10 times sooner than before the app and 5 times sooner if their VL >1000 copies/mL. This increased notification speed led to participants wanting to continue using iThemba Life.
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http://dx.doi.org/10.2196/26033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851337PMC
February 2022

Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study.

Lancet 2022 01 19;399(10323):437-446. Epub 2022 Jan 19.

Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Electronic address:

Background: The SARS-CoV-2 omicron variant of concern was identified in South Africa in November, 2021, and was associated with an increase in COVID-19 cases. We aimed to assess the clinical severity of infections with the omicron variant using S gene target failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy.

Methods: We did data linkages for national, South African COVID-19 case data, SARS-CoV-2 laboratory test data, SARS-CoV-2 genome data, and COVID-19 hospital admissions data. For individuals diagnosed with COVID-19 via TaqPath PCR tests, infections were designated as either SGTF or non-SGTF. The delta variant was identified by genome sequencing. Using multivariable logistic regression models, we assessed disease severity and hospitalisations by comparing individuals with SGTF versus non-SGTF infections diagnosed between Oct 1 and Nov 30, 2021, and we further assessed disease severity by comparing SGTF-infected individuals diagnosed between Oct 1 and Nov 30, 2021, with delta variant-infected individuals diagnosed between April 1 and Nov 9, 2021.

Findings: From Oct 1 (week 39), 2021, to Dec 6 (week 49), 2021, 161 328 cases of COVID-19 were reported in South Africa. 38 282 people were diagnosed via TaqPath PCR tests and 29 721 SGTF infections and 1412 non-SGTF infections were identified. The proportion of SGTF infections increased from two (3·2%) of 63 in week 39 to 21 978 (97·9%) of 22 455 in week 48. After controlling for factors associated with hospitalisation, individuals with SGTF infections had significantly lower odds of admission than did those with non-SGTF infections (256 [2·4%] of 10 547 vs 121 [12·8%] of 948; adjusted odds ratio [aOR] 0·2, 95% CI 0·1-0·3). After controlling for factors associated with disease severity, the odds of severe disease were similar between hospitalised individuals with SGTF versus non-SGTF infections (42 [21%] of 204 vs 45 [40%] of 113; aOR 0·7, 95% CI 0·3-1·4). Compared with individuals with earlier delta variant infections, SGTF-infected individuals had a significantly lower odds of severe disease (496 [62·5%] of 793 vs 57 [23·4%] of 244; aOR 0·3, 95% CI 0·2-0·5), after controlling for factors associated with disease severity.

Interpretation: Our early analyses suggest a significantly reduced odds of hospitalisation among individuals with SGTF versus non-SGTF infections diagnosed during the same time period. SGTF-infected individuals had a significantly reduced odds of severe disease compared with individuals infected earlier with the delta variant. Some of this reduced severity is probably a result of previous immunity.

Funding: The South African Medical Research Council, the South African National Department of Health, US Centers for Disease Control and Prevention, the African Society of Laboratory Medicine, Africa Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Fleming Fund.
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http://dx.doi.org/10.1016/S0140-6736(22)00017-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769664PMC
January 2022

Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa.

Nature 2022 03 7;603(7902):679-686. Epub 2022 Jan 7.

Department of Zoology, University of Oxford, Oxford, UK.

The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function. Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.
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http://dx.doi.org/10.1038/s41586-022-04411-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942855PMC
March 2022

Establishing the cost of Xpert MTB/RIF mobile testing in high-burden peri-mining communities in South Africa.

Afr J Lab Med 2021 30;10(1):1229. Epub 2021 Nov 30.

Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Background: Globally, tuberculosis remains a major cause of mortality, with an estimated 1.3 million deaths per annum. The Xpert MTB/RIF assay is used as the initial diagnostic test in the tuberculosis diagnostic algorithm. To extend the national tuberculosis testing programme in South Africa, mobile units fitted with the GeneXpert equipment were introduced to high-burden peri-mining communities.

Objective: This study sought to assess the cost of mobile testing compared to traditional laboratory-based testing in a peri-mining community setting.

Methods: Actual cost data for mobile and laboratory-based Xpert MTB/RIF testing from 2018 were analysed using a bottom-up ingredients-based approach to establish the annual equivalent cost and the cost per result. Historical cost data were obtained from supplier quotations and the local enterprise resource planning system. Costs were obtained in rand and reported in United States dollars (USD).

Results: The mobile units performed 4866 tests with an overall cost per result of $49.16. Staffing accounted for 30.7% of this cost, while reagents and laboratory equipment accounted for 20.7% and 20.8%. The cost per result of traditional laboratory-based testing was $15.44 US dollars (USD). The cost for identifying a tuberculosis-positive result using mobile testing was $439.58 USD per case, compared to $164.95 USD with laboratory-based testing.

Conclusion: Mobile testing is substantially more expensive than traditional laboratory services but offers benefits for rapid tuberculosis case detection and same-day antiretroviral therapy initiation. Mobile tuberculosis testing should however be reserved for high-burden communities with limited access to laboratory testing where immediate intervention can benefit patient outcomes.
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http://dx.doi.org/10.4102/ajlm.v10i1.1229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8661292PMC
November 2021

Web-Based Return of Individual Patient-Reported Outcome Results Among Patients With Lymphoma: Randomized Controlled Trial.

J Med Internet Res 2021 12 14;23(12):e27886. Epub 2021 Dec 14.

Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Utrecht, Netherlands.

Background: There has been a cultural shift toward patient engagement in health, with a growing demand from patients to access their results.

Objective: The Lymphoma Intervention (LIVE) trial is conducted to examine the impact of return of individual patient-reported outcome (PRO) results and a web-based self-management intervention on psychological distress, self-management, satisfaction with information, and health care use in a population-based setting.

Methods: Return of PRO results included comparison with age- and sex-matched peers and was built into the Patient-Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship registry. The self-management intervention is an adaptation of a fully automated evidence-based intervention for breast cancer survivors. Patients with lymphoma who completed the web-based questionnaire were equally randomized to care as usual, return of PRO results, and return of PRO results plus self-management intervention. Patients completed questionnaires 9 to 18 months after diagnosis (T0; n=227), 4 months (T1; n=190), 12 months (T2; n=170), and 24 months (T3; n=98).

Results: Of all invited patients, 51.1% (456/892) responded and web-based participants (n=227) were randomly assigned to care as usual (n=76), return of PRO results (n=74), or return of PRO results and access to Living with lymphoma (n=77). Return of PRO results was viewed by 76.7% (115/150) of those with access. No statistically significant differences were observed for psychological distress, self-management, satisfaction with information provision, and health care use between patients who received PRO results and those who did not (P>.05). Use of the self-management intervention was low (2/76, 3%), and an effect could therefore not be determined.

Conclusions: Return of individual PRO results seems to meet patients' wishes but had no beneficial effects on patient outcome. No negative effects were found when individual PRO results were disclosed, and the return of individual PRO results can therefore be safely implemented in daily clinical practice.

Trial Registration: Netherlands Trial Register NTR5953; https://www.trialregister.nl/trial/5790.

International Registered Report Identifier (irrid): RR2-10.1186/s13063-017-1943-2.
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http://dx.doi.org/10.2196/27886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8715355PMC
December 2021

Axillary lymph nodes on PET in Hodgkin lymphoma after COVID-19 vaccination.

EJHaem 2021 Nov 13;2(4):885-886. Epub 2021 Oct 13.

Department of Haematology Radboud University Medical Center Nijmegen The Netherlands.

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http://dx.doi.org/10.1002/jha2.297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656373PMC
November 2021

The emerging association between bronchiectasis and systemic sclerosis: assessing prevalence and potential causality.

Intern Med J 2021 Dec 11. Epub 2021 Dec 11.

Institute for Health Research, University of Notre Dame, Fremantle, Western Australia.

Background: Bronchiectasis has been observed in association with systemic sclerosis (SSc). Theorised aetiology includes aspiration related to oesophageal dysmotility, immunosuppressant medication use and the direct effect of collagen deposition on airway calibre.

Aims: In this study we detail bronchiectasis prevalence in an SSc population who have had a high-resolution computed tomography (HRCT) thorax. We assessed whether oesophageal dysmotility, demographic variables, SSc duration or subclass were associated with bronchiectasis.

Methods: Participants in the Australian Scleroderma Cohort Study (ASCS) with an HRCT were included. The ASCS provided demographic and clinical data. HRCT studies were reviewed for bronchiectasis, oesophageal dilatation and interstitial lung disease (ILD). Traction bronchiectasis associated with ILD was recorded as a separate entity to bronchiectasis. Oesophageal dysmotility was defined by symptoms and/or oesophageal dilatation.

Results: 16.4% (n=42) of the 256 participants had bronchiectasis. Logistic regression analysis revealed no significant association between bronchiectasis and oesophageal dysmotility (observed in 95.7%), any demographic variable, SSc duration or subclass. A negative association between bronchiectasis and ILD was observed (p=0.009, odds ratio 0.322, 95% confidence intervals 0.137-0.756).

Discussion: Those with SSc appear to have an increased risk for bronchiectasis. Since bronchiectasis was not more frequent in participants with a longer duration of SSc, we hypothesise that its development is not related to immunosuppression alone. Oesophageal dysmotility was almost universal in our population such that its effect on bronchiectasis development could not be concluded. A negative association between bronchiectasis and ILD reflects that bronchiectasis occurring alongside ILD was recorded as a separate entity. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15661DOI Listing
December 2021

CloneRetriever: An Automated Algorithm to Identify Clonal B and T Cell Gene Rearrangements by Next-Generation Sequencing for the Diagnosis of Lymphoid Malignancies.

Clin Chem 2021 11;67(11):1524-1533

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD.

Background: Clonal immunoglobulin and T-cell receptor rearrangements serve as tumor-specific markers that have become mainstays of the diagnosis and monitoring of lymphoid malignancy. Next-generation sequencing (NGS) techniques targeting these loci have been successfully applied to lymphoblastic leukemia and multiple myeloma for minimal residual disease detection. However, adoption of NGS for primary diagnosis remains limited.

Methods: We addressed the bioinformatics challenges associated with immune cell sequencing and clone detection by designing a novel web tool, CloneRetriever (CR), which uses machine-learning principles to generate clone classification schemes that are customizable, and can be applied to large datasets. CR has 2 applications-a "validation" mode to derive a clonality classifier, and a "live" mode to screen for clones by applying a validated and/or customized classifier. In this study, CR-generated multiple classifiers using 2 datasets comprising 106 annotated patient samples. A custom classifier was then applied to 36 unannotated samples.

Results: The optimal classifier for clonality required clonal dominance ≥4.5× above background, read representation ≥8% of all reads, and technical replicate agreement. Depending on the dataset and analysis step, the optimal algorithm yielded sensitivities of 81%-90%, specificities of 97%-100%, areas under the curve of 91%-94%, positive predictive values of 92-100%, and negative predictive values of 88%-98%. Customization of the algorithms yielded 95%-100% concordance with gold-standard clonality determination, including rescue of indeterminate samples. Application to a set of unknowns showed concordance rates of 83%-96%.

Conclusions: CR is an out-of-the-box ready and user-friendly software designed to identify clonal rearrangements in large NGS datasets for the diagnosis of lymphoid malignancies.
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http://dx.doi.org/10.1093/clinchem/hvab141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8965457PMC
November 2021

Cost-effectiveness of lenalidomide plus rituximab versus rituximab monotherapy in patients with previously treated follicular lymphoma: a societal view.

Expert Rev Anticancer Ther 2021 12 2;21(12):1411-1422. Epub 2021 Sep 2.

Section Health Technology Assessment, Erasmus School of Health Policy and Management/Institute for Medical Technology Assessment, Erasmus University, Rotterdam, The Netherlands.

Introduction: Efficacy of lenalidomide plus rituximab (R-LEN) compared to rituximab monotherapy (R-mono) for patients with previously treated follicular lymphoma (FL) was investigated in AUGMENT (NCT01938001). Our aim was to evaluate the cost-effectiveness of R-LEN versus R-mono in this setting from a Dutch perspective.

Areas Covered: Cost-effectiveness was assessed through a partitioned survival model from three perspectives (i.e. societal, healthcare, and societal, including future non-medical costs). Patient-level data from AUGMENT informed effectiveness parameters (i.e. long-term survival) and health state utilities. Resource use and prices were based on AUGMENT and the literature. Clinical experts validated efficacy input parameters and results. Uncertainty was explored through sensitivity and scenario analyses.

Expert Opinion: R-LEN resulted in 1.7 incremental discounted quality-adjusted life years (QALYs). Total incremental discounted costs were 67,161 EUR from a societal perspective. In conclusion, R-LEN was cost-effective at a willingness-to-pay (WTP) threshold of 50,000 EUR/QALY in the base-case analyses(incremental cost-effectiveness ratio = 40,493 EUR/QALY). Scenario and sensitivity analyses indicated some level of uncertainty regarding this conclusion, depending on the chosen WTP-threshold and perspective.
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http://dx.doi.org/10.1080/14737140.2021.1971520DOI Listing
December 2021

Impact of rituximab biosimilars on overall survival in diffuse large B-cell lymphoma: a Dutch population-based study.

Blood Adv 2021 08;5(15):2958-2964

Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.

In 2017, the European Medicines Agency approved rituximab biosimilars (R-biosimilars) for treatment of diffuse large B-cell lymphoma (DLBCL). Thereafter, the Netherlands was one of the first countries to implement R-biosimilars, given lower costs compared with rituximab originator (R-originator). This study's objective was to investigate whether overall survival (OS) of patients with DLBCL receiving R-biosimilars is similar to patients treated with R-originator. DLBCL patients ≥18 years, diagnosed between 2014 and 2018, who received at least 1 cycle of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) were identified in the Netherlands Cancer Registry. Patients were categorized into R-originator or R-biosimilars groups based on data from a central repository of the Dutch medicinal drug market. The primary end point was 3-year OS, defined as the time between diagnosis and all-cause death. By the end of 2018, 91% of purchased rituximab were biosimilars. In total, 4429 patients were identified with 876 in the R-biosimilars group and 3553 in the R-originator group. Patients in the R-biosimilars group less frequently received >6 cycles of R-CHOP compared with patients treated with R-originator (24% vs 30%, P = .003). The 3-year OS did not differ between patients treated with R-originator or R-biosimilars (73% vs 73%, P = .855). This was confirmed with a multivariable Cox regression analysis accounting for sex, age, International Prognostic Index score, and number of R-CHOP cycles. In conclusion, the 3-year OS is similar for patients treated with CHOP in combination with R-originator or R-biosimilars and, therefore, favors the use of R-biosimilars in DLBCL treatment management.
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http://dx.doi.org/10.1182/bloodadvances.2021004295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361456PMC
August 2021
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