Prostate cancer risk in men of differing genetic ancestry and approaches to disease screening and management in these groups

Prostate cancer is the second most common solid tumour in men worldwide and it is also the most common cancer affecting men of African descent. Prostate cancer incidence and mortality vary across regions and populations. Some of this is explained by a large heritable component of this disease. It has been established that men of African and African Caribbean ethnicity are predisposed to prostate cancer (PrCa) that can have an earlier onset and a more aggressive course, thereby leading to poorer outcomes for patients in this group. Literature searches were carried out using the PubMed, EMBASE and Cochrane Library databases to identify studies associated with PrCa risk and its association with ancestry, screening and management of PrCa. In order to be included, studies were required to be published in English in full-text form. An attractive approach is to identify high-risk groups and develop a targeted screening programme for them as the benefits of population-wide screening in PrCa using prostate-specific antigen (PSA) testing in general population screening have shown evidence of benefit; however, the harms are considered to weigh heavier because screening using PSA testing can lead to over-diagnosis and over-treatment. The aim of targeted screening of higher-risk groups identified by genetic risk stratification is to reduce over-diagnosis and treat those who are most likely to benefit.

Diagnostic Criteria and Lipid Screening of Dyslipidemia in Children

Obesity is associated with significant morbidities and life-threatening conditions. Evidence shows that obesity in the pediatric population has increased by ten folds recently. This has been attributed to the remarkable recent alternations in socioeconomic factors and the overall increase in the incidence of obesity among the different populations. The pathogenesis of atherosclerosis and cardiovascular diseases is usually initiated in childhood. Previous studies indicates that early identification and proper treatment of dyslipidemia in the pediatric population can significantly reduce the risk of developing cardiovascular diseases and associated morbidities. Therefore, it is vital to screen children's lipid profiles to identify dyslipidemia and apply better interventions. This can significantly reduce the risk of premature cardiovascular diseases and accelerated atherosclerosis. The present study aims to identify the diagnostic criteria and various lipid screening approaches proposed in the literature to identify dyslipidemia in children. Two main approaches for screening dyslipidemia in children were reported. These include universal and selective screening approaches. While the latter is recommended to identify high-risk children, universal screening is also recommended to identify children missed by targeted screening (usually treated by pharmacological modalities).

Dutch Founder SDHB Exon 3 Deletion in Patients with Pheochromocytoma-Paraganglioma in South Africa

Objective: Screening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma-paraganglioma (PPGL). Founder effects play an important role in regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa have not been explored in PPGL. Design: We performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors. Methods: Next-generation panel and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes. Results: From a group of 13 patients we identified six with PPGL, four with sporadic or familial isolated pituitary adenomas (FIPA), and three with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHB in two apparently-unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHB exon 3 deletion were also identified. Other PPGL patients had variants in SDHB, SDHD and three MEN1 variants were identified among MEN1 and young-onset pituitary adenoma patients. Conclusions: This is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHB deletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHx genes.

Screening of unruptured intracranial aneurysms in 50 to 60-year-old female smokers: a pilot study

The prevalence of unruptured intracranial aneurysms (UIAs) is around 2–3% in the general population. We hypothesized that the prevalence of small UIAs is higher among 50 to 60-year-old female smokers, since the incidence of aneurysmal subarachnoid hemorrhage (aSAH) is exceptionally high in 60 to 70-year-old female smokers. Ethics approval for this pilot study of 50 women was obtained from the hospital ethics committee. In order to minimize recruitment bias, preliminary invitation letters were sent to 50 to 60-year-old women who were known to be active smokers. Those interested in participating were further informed about the study rationale and protocol. Following written consent, participants filled a detailed questionnaire and underwent computed tomography angiography (CTA) analysis. All abnormalities were recorded. Of the 158 preliminary invitation letters, 70 potential participants initially replied. Of these, 50 returned questionnaires and written consents, 43 of which underwent CTA analysis. Most (39; 91%) were postmenopausal, and 9 (21%) were hypertensive. Two reported a family history (≥ 1 first-degree members) of intracranial aneurysms. UIAs (maximum sizes of 2, 2, 3, 3 and 7 mm) were found in five (12%) female smokers. One woman was operated on, and the remaining four were treated with non-invasive preventive actions (smoking cessation and follow-ups). Small UIAs, which may be best suited for non-invasive preventive actions, may be relatively common in 50 to 60-year-old female smokers. Whether this kind of targeted screening leads to improved health in female smokers requires further investigation.

The effect of systematic screening of the general population on TB case notification rates

BACKGROUND: Understanding how TB case notification rates (TB-CNR) change with TB screening and their association with underlying TB incidence/prevalence could inform how they are best used to monitor screening impact.METHODS: We undertook a systematic review to identify articles published between 1 January 1980 and 13 April 2020 on TB-CNR trends associated with TB screening in the general-population. Using a simple compartmental TB transmission model, we modelled TB-CNRs, incidence and prevalence dynamics during 5 years of screening.RESULTS: Of 27,282 articles, seven before/after studies were eligible. Two involved population-wide screening, while five used targeted screening. The data suggest screening was associated with initial increases in TB-CNRs. Increases were greatest with population-wide screening, where screening identified a large proportion of notified people with TB. Only one study reported on sustained screening; TB-CNR trends were compatible with model simulations. Model simulations always showed a peak in TB-CNRs with screening. Following the peak, TB-CNRs declined but were typically sustained above baseline during the intervention. Incidence and prevalence decreased during the intervention; the relative decline in incidence was smaller than the decline in prevalence.CONCLUSIONS: Published data on TB-CNR trends with TB screening are limited. These data are needed to identify generalisable patterns and enable method development for inferring underlying TB incidence/prevalence from TB-CNR trends.

GM3 Ganglioside Linked to Neurofibrillary Pathology in a Transgenic Rat Model for Tauopathy

Glycosphingolipids (GSLs) are amphipathic lipids composed of a sphingoid base and a fatty acyl attached to a saccharide moiety. GSLs play an important role in signal transduction, directing proteins within the membrane, cell recognition, and modulation of cell adhesion. Gangliosides and sulfatides belong to a group of acidic GSLs, and numerous studies report their involvement in neurodevelopment, aging, and neurodegeneration. In this study, we used an approach based on hydrophilic interaction liquid chromatography (HILIC) coupled to high-resolution tandem mass spectrometry (HRMS/MS) to characterize the glycosphingolipid profile in rat brain tissue. Then, we screened characterized lipids aiming to identify changes in glycosphingolipid profiles in the normal aging process and tau pathology. Thorough screening of acidic glycosphingolipids in rat brain tissue revealed 117 ganglioside and 36 sulfatide species. Moreover, we found two ganglioside subclasses that were not previously characterized—GT1b-Ac2 and GQ1b-Ac2. The semi-targeted screening revealed significant changes in the levels of sulfatides and GM1a gangliosides during the aging process. In the transgenic SHR24 rat model for tauopathies, we found elevated levels of GM3 gangliosides which may indicate a higher rate of apoptotic processes.

Development and Validation of a Predictive Model to Identify Patients With an Ascending Thoracic Aortic Aneurysm

Background Screening protocols do not exist for ascending thoracic aortic aneurysms (ATAAs). A risk prediction algorithm may aid targeted screening of patients with an undiagnosed ATAA to prevent aortic dissection. We aimed to develop and validate a risk model to identify those at increased risk of having an ATAA, based on readily available clinical information. Methods and Results This is a cross‐sectional study of computed tomography scans involving the chest at a tertiary care center on unique patients aged 50 to 85 years between 2013 and 2016. These criteria yielded 21 325 computed tomography scans. The double‐oblique technique was used to measure the ascending thoracic aorta, and an ATAA was defined as >40 mm in diameter. A logistic regression model was fitted for the risk of ATAA, with readily available demographics and comorbidity variables. Model performance was characterized by discrimination and calibration metrics via split‐sample testing. Among the 21 325 patients, there were 560 (2.6%) patients with an ATAA. The multivariable model demonstrated that older age, higher body surface area, history of arrhythmia, aortic valve disease, hypertension, and family history of aortic aneurysm were associated with increased risk of an ATAA, whereas female sex and diabetes were associated with a lower risk of an ATAA. The C statistic of the model was 0.723±0.016. The regression coefficients were transformed to scores that allow for point‐of‐care calculation of patients' risk. Conclusions We developed and internally validated a model to predict patients' risk of having an ATAA based on demographic and clinical characteristics. This algorithm may guide the targeted screening of an undiagnosed ATAA.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.