Research Articles (Chemical Pathology)

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    Pioneering BRCA1/2 Point-Of-Care Testing for Integration of Germline and Tumor Genetics in Breast Cancer Risk Management: A Vision for the Future of Translational Pharmacogenomics
    (Frontiers Media S.A, 2021-09) Mampunye, Lwando; Van der Merwe, Nerina C.; Grant, Kathleen A.; Peeters, Armand V.; Torrorey-Sawe, Rispah; French, David J.; Moremi, Kelebogile E.; Kidd, Martin; Van Eeden, Petrus C.; Pienaar, Fredrieka M.; Kotze, Maritha J.
    Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.
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    Establishing Ghanaian adult reference intervals for hematological parameters controlling for latent anemia and inflammation
    (Wiley, 2020-09) Bawua, Abigail S. A.; Ichihara, Kiyoshi; Keatley, Rosemary; Arko-Mensah, John; Dei-Adomakoh, Yvonne; Ayeh-Kumi, Patrick F.; Erasmus, Rajiv; Fobil, Julius
    Background: In Ghana, diagnostic laboratories rely on reference intervals (RIs) provided by manufacturers of laboratory analyzers which may not be appropriate. This study aimed to establish RIs for hematological parameters in adult Ghanaian population. Methods: This cross-sectional study recruited 501 apparently healthy adults from two major urban areas in Ghana based on the protocol by IFCC Committee for Reference Intervals and Decision Limits. Whole blood was tested for complete blood count (CBC) by Sysmex XN-1000 analyzer, sera were tested for iron and ferritin by Beckman-Coulter/AU480, for transferrin, vitamin-B12, and folate was measured by Centaur-XP/Siemen. Partitioning of reference values by sex and age was guided by “effect size” of between-subgroup differences defined as standard deviation ratio (SDR) based on ANOVA. RIs were derived using parametric method with application of latent abnormal values exclusion method (LAVE), a multifaceted method of detecting subjects with abnormal results in related parameters. Results: Using SDR ≥ 0.4 as a threshold, RIs were partitioned by sex for platelet, erythrocyte parameters except mean corpuscular constants, and iron markers. Application of LAVE had prominent effect on RIs for majority of erythrocyte and iron parameters. Global comparison of Ghanaian RIs revealed lower-side shift of RIs for leukocyte and neutrophil counts, female hemoglobin and male platelet count, especially compared to non-African countries. Conclusion: The LAVE effect on many hematological RIs indicates the need for de-liberate secondary exclusion for proper derivation of RIs. Obvious differences in Ghanaian RIs compared to other countries underscore the importance of country-specific RIs for improved clinical decision-making.
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    Circulating miR-30a-5p and miR-182-5p in prediabetes and screen-detected diabetes mellitus
    (Dove Press, 2020-12) Weale, Cecil Jack; Matshazi, Don M.; Davids, Saarah F. G.; Raghubeer, Shanel; Erasmus, Rajiv T.; Kengne, Andre Pascal; Davison, Glenda Mary; Matsha, Tandi E.
    Background: microRNAs (miRNAs) have been touted as potential diagnostic and prognostic biomarkers for various diseases. The aim of the present study was to evaluate the diagnostic value of miR-30a-5p and miR-182-5p for prediabetes and screen-detected type 2 diabetes mellitus (T2DM). Methods: The study included 1270 participants (207 prediabetes, 94 screen-detected diabetes and 969 normotolerant) from the Vascular and Metabolic Health (VMH) study. Whole blood levels of miR-30a-5p and miR-182-5p were quantitated by RT-qPCR. Multivariable logistic regressions were used to relate miRNAs with prediabetes or T2DM and receiver operating characteristic (ROC) curves were used to evaluate the ability of each miRNA to diagnose these conditions. Results: Both miRNAs were significantly highly expressed in individuals with prediabetes or T2DM (both ≥3.2-fold, and p<0.001). We also observed significant under-expression in T2DM relative to prediabetes for miR-182-5p (0.49-fold, p=0.001). Age, sex and BMI-adjusted partial correlation coefficient analysis revealed a significant correlation between the two miRNAs across glucose tolerance statuses (r≥0.932, p<0.001). In normotolerant individuals, both miRNAs showed a negative correlation with waist circumference and positive correlation with HDL-cholesterol whilst in T2DM they correlated positively with hip circumference, 2-hour insulin, HDL- and LDL-cholesterol. Multivariable logistic regressions revealed both miRNAs to be consistently and continuously associated with prediabetes or T2DM (OR≥1.18, 95% 95% CI: 1.10-1.28, p<0.001), while only miR-182-5p associated with a reduced prevalence of T2DM relative to prediabetes (OR: 0.89, 95% CI: 0.83-0.96, p=0.003). In ROC analyses, miR-182-5p almost outperformed HbA1c in diagnosing prediabetes; area under the curve 0.74 vs 0.69. Conclusion: Our findings demonstrate that miR-30a-5p and miR-182-5p are associated with dysglycaemia and could potentially predict prediabetes, particularly miR-182-5p.
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    Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2)
    (BMJ Publishing Group Ltd & Association of Clinical Pathologists, 2021-04) Wiese, Owen; Zemlin, Annalise E.; Pillay, Tahir S.
    The renin–angiotensin system is mainly associated with the regulation of blood pressure, but recently many other functions of this system have been described. ACE2, an 805-amino acid monocarboxypeptidase type I transmembrane glycoprotein, was discovered in 2000 and has sequence similarity to two other proteins, namely ACE and collectrin. The ACE2 gene is located on Xp22 and is highly polymorphic. ACE2 is expressed in numerous tissues especially the lung alveolar epithelial cells, heart, kidney and gastrointestinal tract. Animal studies have found that ACE2 is central in diseases affecting almost all organ systems, among other cardiac, respiratory, renal and endocrine functions. ACE2 was identified as the cellular contact point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the global pandemic (COVID-19), and is a potential drug target. SARS-CoV-2 infection has several effects on the renin–angiotensin system and conversely, regulation of this receptor may affect the progress of infection. We describe the genetics and functions of ACE2, explore its various physiological functions in the renin–angiotensin system and discuss its role in the pathophysiology of disease. ACE2 opposes the vasopressor ACE pathway of the renin–angiotensin system by converting angiotensin (Ang) I to Ang (1–9) and Ang II to Ang (1–7) which initiates the vasodilatory pathway. ACE2 may have a protective effect in the lung and kidney as knockout mice display susceptibility to acute respiratory distress and hypertensive nephropathy. Binding of SARS-CoV-2 and the subsequent fusion and downregulation of this pathway during SARS-CoV-2 infection may explain some of the unusual sequelae seen in COVID-19. This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
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    Assessment of the association of plant- based diets with cardiovascular disease risk profile in Africa: a systematic review and meta-analysis protocol
    (BMJ Publishing, 2020-06) Lopes, Tatum; Zemlin, Annalise E.; Erasmus, Rajiv T.; Faber, Mieke; Kengne, Andre P.
    Introduction Cardiovascular disease (CVD) is currently the leading cause of death worldwide. In Africa where infectious diseases are still the leading cause of death, the contribution of non-communicable diseases led by CVDs has significantly increased in recent years. The rise of CVDs in Africa is attributed at least in part to the adoption of sedentary behaviours and unhealthy eating habits, which are linked with urbanisation and westernisation of cultures. Dietary attributes associated with CVD risk have been less investigated in Africa. However, evidence from developed nations has reported a protective effect of healthy dietary patterns such as plant-based diets (PBDs) on cardiometabolic health. The current protocol is for a review aiming to assess existing evidence on the association of PBDs with CVD risk profile in African populations. Methods and analysis This protocol was developed following the 2015 guidelines of the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols. We will conduct a comprehensive search of the literature for published studies on PBDs in relation to CVD risk profile in African populations. Observational studies published between January 1990 and December 2019 will be screened. A search strategy using keywords and medical subject headings terms will be applied across multiple scientific databases including PubMed-Medline, Scopus and EBSCOhost and the African Journals Online platform. Manual searches of reference lists from relevant articles will be performed. Citations will be traced using the ISI Web of Science to further identify eligible studies. Grey literature will also be screened for relevant abstracts from conference proceedings, and experts in the field will be contacted where appropriate. Two investigators will independently screen all the titles and abstracts to determine which records are eligible for full-text review. Subsequently, two investigators will review the eligible full text using the selection criteria. A third investigator will be consulted to resolve any discrepancies. Data will be extracted from studies that are eligible for the review. Meta-analysis will be performed for studies with similar or comparable methods and reported outcome measures. This will be performed overall, and by major study-level characteristics. Heterogeneity in the estimates across studies will be assessed and quantified with the use of Cochrane Q and I2 statistics, respectively. Publication biases will be investigated through funnel plots and Egger test of bias. Relevant sensitivity analyses will be performed to confirm the robustness of the findings