Clinical and genetic ancestry profile of a large multi-centre sickle cell disease cohort in Brazil.
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ABSTRACT:
SUBMITTER: Carneiro-Proietti ABF
PROVIDER: S-EPMC8019534 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This multi-centre UK study assesses the impact of predictive testing for breast and ovarian cancer predisposition genes (BRCA1/2) in the clinical context. In the year following predictive testing, 261 adults (59 male) from nine UK genetics centres participated; 91 gene mutation carriers and 170 noncarriers. Self-report questionnaires were completed at baseline (pre-genetic testing) and 1, 4 and 12 months following the genetic test result. Men were assessed for general mental health (by general health questionnaire (GHQ)) and women for general mental health, cancer-related worry, intrusive and avoidant thoughts, perception of risk and risk management behaviour. Main comparisons were between female carriers and noncarriers on all measures and men and women for general mental health. Female noncarriers benefited psychologically, with significant reductions in cancer-related worry following testing (P<0.001). However, younger female carriers (<50 years) showed a rise in cancer-related worry 1 month post-testing (P<0.05). This returned to pre-testing baseline levels 12 months later, but worry remained significantly higher than noncarriers throughout (P<0.01). There were no significant differences in GHQ scores between males and females (both carriers and noncarriers) at any time point. Female carriers engaged in significantly more risk management strategies than noncarriers in the year following testing (e.g. mammograms; 92% carriers vs 30% noncarriers). In the 12 months post-testing, 28% carriers had bilateral risk-reducing mastectomy and 31% oophorectomy. Oophorectomy was confined to older (mean 41 yrs) women who already had children. However, worry about cancer was not assuaged by surgery following genetic testing, and this requires further investigation. In all, 20% of female carriers reported insurance problems. The data show persistent worry in younger female gene carriers and confirm changes in risk management consistent with carrier status. Men were not adversely affected by genetic testing in terms of their general mental health.
| S-EPMC2410052 | biostudies-other
Project description:Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels.Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels.Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2.Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.
| S-EPMC4552443 | biostudies-literature
Project description:Introduction:Priapism is the persistent and painful erection of the penis and is a common sickle cell disease (SCD) complication.Aim:The goal of this study was to characterize clinical and genetic factors associated with priapism within a large multi-center SCD cohort in Brazil.Methods:Cases with priapism were compared to SCD type-matched controls within defined age strata to identify clinical outcomes associated with priapism. Whole blood single nucleotide polymorphism genotyping was performed using a customized array, and a genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms associated with priapism.Main outcome measure:Of the 1,314 male patients in the cohort, 188 experienced priapism (14.3%).Results:Priapism was more common among older patients (P = .006) and more severe SCD genotypes such as homozygous SS (P < .0001). In the genotype- and age-matched analyses, associations with priapism were found for pulmonary hypertension (P = .05) and avascular necrosis (P = .01). The GWAS suggested replication of a previously reported candidate gene association of priapism for the gene transforming growth factor beta receptor 3 (TGFBR3) (P = 2 × 10-4).Clinical implications:Older patients with more severe genotypes are at higher risk of priapism, and there is a lack of consensus on standard treatment strategies for priapism in SCD.Strengths & limitations:This study characterizes SCD patients with any history of priapism from a large multi-center cohort. Replication of the GWAS in an independent cohort is required to validate the results.Conclusion:These findings extend the understanding of risk factors associated with priapism in SCD and identify genetic markers to be investigated in future studies to further elucidate priapism pathophysiology. Ozahata M, Page GP, Guo Y, et al. Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study. J Sex Med 2019;16:1988-1999.
| S-EPMC6904926 | biostudies-literature
Project description:AimsAcute aortic dissection (AD) requires immediate treatment, but is a diagnostic challenge. We studied how often AD was missed initially, which patients were more likely to be missed and how this influenced patient management and outcomes.MethodsA retrospective cohort study including 200 consecutive patients with AD as the final diagnosis, admitted to a tertiary hospital between 1998 and 2008. The first differential diagnosis was identified and patients with and without AD included were compared. Characteristics associated with a lower level of suspicion were identified using multivariable logistic regression, and Cox regression was used for survival analyses. Missing data were imputed.ResultsMean age was 63 years, 39% were female and 76% had Stanford type A dissection. In 69% of patients, AD was included in the first differential diagnosis; this was less likely in women (adjusted relative risk [aRR]: 0.66, 95% CI: 0.44-0.99), in the absence of back pain (aRR: 0.51, 95% CI: 0.30-0.84), and in patients with extracardiac atherosclerosis (aRR: 0.64, 95% CI: 0.43-0.96). Absence of AD in the differential diagnosis was associated with the use of more imaging tests (1.8 vs. 2.3, p = 0.01) and increased time from admission to surgery (1.8 vs. 10.1 h, p < 0.01), but not with a difference in the adjusted long-term all-cause mortality (hazard ratio: 0.76, 95% CI: 0.46-1.27).ConclusionAcute aortic dissection was initially not suspected in almost one-third of patients, this was more likely in women, in the absence of back pain and in patients with extracardiac atherosclerosis. Although the number of imaging tests was higher and time to surgery longer, patient outcomes were similar in both groups.
| S-EPMC5313444 | biostudies-literature
Project description:BACKGROUND:Multi-centre randomized controlled clinical trials play an important role in modern evidence-based medicine. Advantages of collecting data from more than one site are numerous, including accelerated recruitment and increased generalisability of results. Mixed models can be applied to account for potential clustering in the data, in particular when many small centres contribute patients to the study. Previously proposed methods on sample size calculation for mixed models only considered balanced treatment allocations which is an unlikely outcome in practice if block randomisation with reasonable choices of block length is used. METHODS:We propose a sample size determination procedure for multi-centre trials comparing two treatment groups for a continuous outcome, modelling centre differences using random effects and allowing for arbitrary sample sizes. It is assumed that block randomisation with fixed block length is used at each study site for subject allocation. Simulations are used to assess operation characteristics such as power of the sample size approach. The proposed method is illustrated by an example in disease management systems. RESULTS:A sample size formula as well as a lower and upper boundary for the required overall sample size are given. We demonstrate the superiority of the new sample size formula over the conventional approach of ignoring the multi-centre structure and show the influence of parameters such as block length or centre heterogeneity. The application of the procedure on the example data shows that large blocks require larger sample sizes, if centre heterogeneity is present. CONCLUSION:Unbalanced treatment allocation can result in substantial power loss when centre heterogeneity is present but not considered at the planning stage. When only few patients by centre will be recruited, one has to weigh the risk of imbalance between treatment groups due to large blocks and the risk of unblinding due to small blocks. The proposed approach should be considered when planning multi-centre trials.
| S-EPMC6267841 | biostudies-other
Project description:We described the clinical, laboratory and molecular characteristics of individuals with Hb S (HBB: c.20A>T)/?-thalassemia (Hb S/?-thal) participating in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) Brazil Sickle Cell Disease cohort. HBB gene sequencing was performed to genotype each ?-thal mutation. Patients were classified as Hb S/?0-thal, Hb S/?+-thal-severe or Hb S/?+-thal based on prior literature and databases of hemoglobin (Hb) variants. Characteristics of patients with each ?-thal mutation were described and the clinical profile of patients grouped into Hb S/?0-thal, Hb S/?+-thal and Hb S/?+-thal-severe were compared. Of the 2793 patients enrolled, 84 (3.0%) had Hb S/?0-thal and 83 (3.0%) had Hb S/?+-thal; 40/83 (48.2%) patients with Hb S/?+-thal had mutations defined as severe. We identified 19 different ?-thal mutations, eight Hb S/?0-thal, three Hb S/?+-thal-severe and eight Hb S/?+-thal. The most frequent ?0 and ?+ mutations were codon 39 (HBB: c.118C>T) and IVS-I-6 (T>C) (HBB: c.92+6T>C), respectively. Individuals with Hb S/?0-thal had a similar clinical and laboratory phenotype when compared to those with Hb S/?+-thal-severe. Individuals with Hb S/?+-thal-severe had significantly lower total Hb and Hb A levels and higher Hb S, white blood cell (WBC) count, platelets and hemolysis markers when compared to those with Hb S/?+-thal. Likewise, individuals with Hb S/?+-thal-severe showed a significantly higher occurrence of hospitalizations, vaso-occlusive events (VOE), acute chest syndrome (ACS), splenic sequestration, blood utilization, and hydroxyurea (HU) therapy.
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Project description:Acute pulmonary thromboembolism is associated with high mortality, similar to that of myocardial infarction and stroke. We studied the clinical presentation and management of pulmonary thromboembolism in the Indian population. An analysis of 140 patients who presented with acute pulmonary thromboembolism at a large volume center in India from June 2015 through December 2018 was performed. The mean age of our study population was 50 years with 59% being male. Comorbidities including deep vein thrombosis, diabetes mellitus, hypertension, and chronic obstructive pulmonary disease were present in 52.9%, 40%, 35.7% and 7.14% of patients, respectively. Out of 140 patients, 40 (28.6%) patients had massive pulmonary thromboembolism, 36 (25.7%) sub-massive pulmonary thromboembolism, and 64 (45.7%) had low-risk pulmonary thromboembolism. Overall, in-hospital mortality was 25.7%. Multivariate regression analysis found chronic kidney disease and pulmonary thromboembolism severity to be the only independent risk factors. Thrombolysis was performed in 62.5% of patients with a massive pulmonary thromboembolism and 63.9% of patients with a sub-massive pulmonary thromboembolism. In the massive pulmonary thromboembolism group, patients receiving thrombolytic therapy had lower mortality compared with patients who did not receive therapy (p=0.022), whereas this difference was not observed in patients in the sub-massive pulmonary thromboembolism group. We conclude that patients with acute pulmonary thromboembolism in India presented more than a decade earlier than our western counterparts, and it was associated with poor clinical outcomes. Thrombolysis was associated with significantly reduced in-hospital mortality in patients with massive pulmonary thromboembolism.
| S-EPMC8164559 | biostudies-literature
Project description:PurposeThe Oxford Parkinson's Disease Centre (OPDC) Discovery Cohort MRI substudy (OPDC-MRI) collects high-quality multimodal brain MRI together with deep longitudinal clinical phenotyping in patients with Parkinson's, at-risk individuals and healthy elderly participants. The primary aim is to detect pathological changes in brain structure and function, and develop, together with the clinical data, biomarkers to stratify, predict and chart progression in early-stage Parkinson's and at-risk individuals.ParticipantsParticipants are recruited from the OPDC Discovery Cohort, a prospective, longitudinal study. Baseline MRI data are currently available for 290 participants: 119 patients with early idiopathic Parkinson's, 15 Parkinson's patients with pathogenic mutations of the leucine-rich repeat kinase 2 or glucocerebrosidase (GBA) genes, 68 healthy controls and 87 individuals at risk of Parkinson's (asymptomatic carriers of GBA mutation and patients with idiopathic rapid eye movement sleep behaviour disorder-RBD).Findings to dateDifferences in brain structure in early Parkinson's were found to be subtle, with small changes in the shape of the globus pallidus and evidence of alterations in microstructural integrity in the prefrontal cortex that correlated with performance on executive function tests. Brain function, as assayed with resting fMRI yielded more substantial differences, with basal ganglia connectivity reduced in early Parkinson'sand RBD. Imaging of the substantia nigra with the more recent adoption of sequences sensitive to iron and neuromelanin content shows promising results in identifying early signs of Parkinsonian disease.Future plansOngoing studies include the integration of multimodal MRI measures to improve discrimination power. Follow-up clinical data are now accumulating and will allow us to correlate baseline imaging measures to clinical disease progression. Follow-up MRI scanning started in 2015 and is currently ongoing, providing the opportunity for future longitudinal imaging analyses with parallel clinical phenotyping.
| S-EPMC7430482 | biostudies-literature
Project description:PURPOSE:Maternal and Child Health and Nutrition in Acre, Brazil (MINA-Brazil) is a longitudinal, prospective population-based birth cohort, set-up to understand the effects of early environmental exposures and maternal lifestyle choices on growth and development of the Amazonian children. PARTICIPANTS:Mother-baby pairs (n=1246) were enrolled at delivery from July 2015 to June 2016 in Cruzeiro do Sul, Acre, Brazil. Mothers of 43.7% of the cohort were recruited in the study during pregnancy from February 2015 to January 2016. Study visits took place during pregnancy, delivery, at 1?month, 6 months, 1?year and 2 years after delivery. In addition to clinical and epidemiological data, samples collected by the MINA-Brazil study include plasma, serum and extracted DNA from blood and faeces, which are stored in a biobank. FINDINGS TO DATE:Key baseline reports found a high prevalence of gestational night blindness (11.5%; 95% CI 9.97% to 13.25%) and maternal anaemia (39.4%; 95% CI 36.84% to 41.95%) at delivery. Antenatal malaria episodes (74.6% of Plasmodium vivax) were diagnosed in 8.0% of the women and were associated with an average reduction in birth weight z-scores of 0.35 (95% CI 0.14 to 0.57) and in birth length z-scores of 0.31 (95% CI 0.08 to 0.54), compared with malaria-free pregnancies. At 2-year follow-up, data collection strategies combined telephone calls, WhatsApp, social media community and home visits to minimise losses of follow-up (retention rate of 79.5%). FUTURE PLANS:A 5-year follow-up visit is planned in 2021 with similar interviews and biospecimens collection. The findings from this prospective cohort will provide novel insights into the roles of prenatal and postnatal factors in determining early childhood development in an Amazonian population.
| S-EPMC7045011 | biostudies-literature
Project description:Proptosis, the forward protrusion of the eyeball, is a common manifestation of a wide variety of diseases inside the orbit and its spaces. Its diagnosis is usually a combined effort of the ophthalmologist, otolaryngologist, neurosurgeon, and radiologist. A clinical study of twenty-five cases with unilateral proptosis were studied in different age groups over a period of about 3 years under different headings like distribution, clinical features, radiological features, histopathological aspects, management, and outcomes of diseases. Proptosis measurement was done by simple/plastic ruler exophthalmometry, and diagnosis was made after a detailed clinical examination and ancillary tests. Treatment modality was decided based on radiological and histopathological examination reports, which included medical surgery, radiotherapy, and chemotherapy or a combination of all. In our study, most of the patients were in the age group of more than 60 years. The M : F ratio is 3 : 1. One case had a large proptosis of 18 mm above normal and 2 cases were as small as 3 mm. Diagnosis was mainly done by clinical features and confirmed by radiological and histopathological features. Most of them were treated medically (13 cases, i.e., 52%) and the rest by surgery with a combination of radiotherapy/chemotherapy (12 cases, i.e., 48%).
| S-EPMC5646318 | biostudies-other