•Historic microbial dataset indicates wide spread breaches in water quality.•Sediment coprostanol contamination identified in Doha Bay and Sulaibikhat Bay.•Illegal sewage discharges responsible for a ...proportion of the contamination.
Microbial water quality and concentrations of faecal sterols in sediment have been used to assess the degree of sewage contamination in Kuwait’s marine environment. A review of microbial (faecal coliform, faecal streptococci and Escherichia coli) water quality data identified temporal and spatial sources of pollution around the coastline. Results indicated that bacterial counts regularly breach regional water quality guidelines. Sediments collected from a total of 29 sites contained detectable levels of coprostanol with values ranging from 29 to 2420ngg−1 (dry weight). Hot spots based on faecal sterol sediment contamination were identified in Doha Bay and Sulaibikhat Bay, which are both smaller embayments of Kuwait Bay. The ratio of epicoprostanol/coprostanol indicates that a proportion of the contamination was from raw or partially treated sewage. Sewage pollution in these areas are thought to result from illegal connections and discharges from storm drains, such as that sited at Al-Ghazali.
African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub-Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been ...excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation.
Using whole genome sequencing and best practice workflows, we performed a comprehensive analysis of SVs for 180 (predominantly Gleason score ≥ 8) prostate tumours derived from 115 African, 61 European and four ancestrally admixed patients. We investigated the landscape and relationship of somatic SVs in driving ethnic disparity (African versus European), with a focus on African men from southern Africa.
Duplication events showed the greatest ethnic disparity, with a 1.6- (relative frequency) to 2.5-fold (count) increase in African-derived tumours. Furthermore, we found duplication events to be associated with CDK12 inactivation and MYC copy number gain, and deletion events associated with SPOP mutation. Overall, African-derived tumours were 2-fold more likely to present with a hyper-SV subtype. In addition to hyper-duplication and deletion subtypes, we describe a new hyper-translocation subtype. While we confirm a lower TMPRSS2-ERG fusion-positive rate in tumours from African cases (10% versus 33%), novel African-specific PCa ETS family member and TMPRSS2 fusion partners were identified, including LINC01525, FBXO7, GTF3C2, NTNG1 and YPEL5. Notably, we found 74 somatic SV hotspots impacting 18 new candidate driver genes, with CADM2, LSAMP, PTPRD, PDE4D and PACRG having therapeutic implications for African patients.
In this first African-inclusive SV study for high-risk PCa, we demonstrate the power of SV interrogation for the identification of novel subtypes, oncogenic drivers and therapeutic targets. Identifying a novel spectrum of SVs in tumours derived from African patients provides a mechanism that may contribute, at least in part, to the observed ethnic disparity in advanced PCa presentation in men of African ancestry.
Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to ...identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy.
A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS).
Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients HR = 3.21 (1.35–7.67); P=0.003. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases HR = 2.71 (1.11–6.63); P=0.030. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) HR = 3.23 (1.22–8.59); P=0.019 whilst CAPRA itself was not significant HR = 1.88, (0.52–6.77); P=0.332. A high concordance 100% (61.5–100) for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance.
The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.
Objectives To compare registry and electronic health record (EHR) data mining approaches for cohort ascertainment in patients with pediatric pulmonary hypertension (PH) in an effort to overcome some ...of the limitations of registry enrollment alone in identifying patients with particular disease phenotypes. Study design This study was a single-center retrospective analysis of EHR and registry data at Boston Children's Hospital. The local Informatics for Integrating Biology and the Bedside (i2b2) data warehouse was queried for billing codes, prescriptions, and narrative data related to pediatric PH. Computable phenotype algorithms were developed by fitting penalized logistic regression models to a physician-annotated training set. Algorithms were applied to a candidate patient cohort, and performance was evaluated using a separate set of 136 records and 179 registry patients. We compared clinical and demographic characteristics of patients identified by computable phenotype and the registry. Results The computable phenotype had an area under the receiver operating characteristics curve of 90% (95% CI, 85%-95%), a positive predictive value of 85% (95% CI, 77%-93%), and identified 413 patients (an additional 231%) with pediatric PH who were not enrolled in the registry. Patients identified by the computable phenotype were clinically distinct from registry patients, with a greater prevalence of diagnoses related to perinatal distress and left heart disease. Conclusions Mining of EHRs using computable phenotypes identified a large cohort of patients not recruited using a classic registry. Fusion of EHR and registry data can improve cohort ascertainment for the study of rare diseases. Trial registration ClinicalTrials.gov : NCT02249923.
Polyploidy is increasingly seen as a driver of both evolutionary innovation and ecological success. One source of polyploid organisms' successes may be their origins in the merging and mixing of ...genomes from two different species (e.g., allopolyploidy). Using POInT (the Polyploid Orthology Inference Tool), we model the resolution of three allopolyploidy events, one from the bakers' yeast (Saccharomyces cerevisiae), one from the thale cress (Arabidopsis thaliana) and one from grasses including Sorghum bicolor. Analyzing a total of 21 genomes, we assign to every gene a probability for having come from each parental subgenome (i.e., derived from the diploid progenitor species), yielding orthologous segments across all genomes. Our model detects statistically robust evidence for the existence of biased fractionation in all three lineages, whereby genes from one of the two subgenomes were more likely to be lost than those from the other subgenome. We further find that a driver of this pattern of biased losses is the co-retention of genes from the same parental genome that share functional interactions. The pattern of biased fractionation after the Arabidopsis and grass allopolyploid events was surprisingly constant in time, with the same parental genome favored throughout the lineages' history. In strong contrast, the yeast allopolyploid event shows evidence of biased fractionation only immediately after the event, with balanced gene losses more recently. The rapid loss of functionally associated genes from a single subgenome is difficult to reconcile with the action of genetic drift and suggests that selection may favor the removal of specific duplicates. Coupled to the evidence for continuing, functionally-associated biased fractionation after the A. thaliana At-α event, we suggest that, after allopolyploidy, there are functional conflicts between interacting genes encoded in different subgenomes that are ultimately resolved through preferential duplicate loss.
Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global ...averages
. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown
. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African-European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene-environment interaction-defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa-we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.
Background
The androgen‐regulated gene TMPRSS2 to the ETS transcription factor gene ERG fusion is the most common genomic alteration acquired during prostate tumorigenesis and biased toward men of ...European ancestry. In contrast, African American men present with more advanced disease, yet their tumors are less likely to acquire TMPRSS2‐ERG. Data for Africa is scarce.
Methods
RNA was made available for genomic analyses from 181 prostate tissue biopsy cores from Black South African men, 94 with and 87 without pathological evidence for prostate cancer. Reverse transcription polymerase chain reaction was used to screen for the TMPRSS2‐ERG fusion, while transcript junction coordinates and isoform frequencies, including novel gene fusions, were determined using targeted RNA sequencing.
Results
Here we report a frequency of 13% for TMPRSS2‐ERG in tumors from Black South Africans. Present in 12/94 positive versus 1/87 cancer negative prostate tissue cores, this suggests a 92.62% predictivity for a positive cancer diagnosis (P = 0.0031). At a frequency of almost half that reported for African Americans and roughly a quarter of that reported for men of European ancestry, acquisition of TMPRSS2‐ERG appears to be inversely associated with aggressive prostate cancer. Further support was provided by linking the presence of TMPRSS2‐ERG to low‐grade disease in younger patients (P = 0.0466), with higher expressing distal ERG fusion junction coordinates.
Conclusions
Only the second study of its kind for the African continent, we support a link between TMPRSS2‐ERG status and prostate cancer racial health disparity beyond the borders of the United States. We call for urgent evaluation of androgen deprivation therapy within Africa.
While many studies have reported that individual differences in personality traits are genetically influenced, the neurobiological bases mediating these influences have not yet been well ...characterized. To advance understanding concerning the pathway from genetic variation to personality, here we examined whether measures of heritable variation in neuroanatomical size in candidate regions (amygdala and medial orbitofrontal cortex) were associated with heritable effects on personality. A sample of 486 middle-aged (mean=55years) male twins (complete MZ pairs=120; complete DZ pairs=84) underwent structural brain scans and also completed measures of two core domains of personality: positive and negative emotionality. After adjusting for estimated intracranial volume, significant phenotypic (rp) and genetic (rg) correlations were observed between left amygdala volume and positive emotionality (rp=.16, p<.01; rg=.23, p<.05, respectively). In addition, after adjusting for mean cortical thickness, genetic and nonshared-environmental correlations (re) between left medial orbitofrontal cortex thickness and negative emotionality were also observed (rg=.34, p<.01; re=−.19, p<.05, respectively). These findings support a model positing that heritable bases of personality are, at least in part, mediated through individual differences in the size of brain structures, although further work is still required to confirm this causal interpretation.
•Personality and regional brain size are both heritable.•Regional brain size and personality are phenotypically associated.•Here we examine whether shared genes underpin this association.•Amygdala and positive emotionality were phenotypically and genetically associated.•mOFC and negative emotionality showed genetic and nonshared-environment associations.
ABSTRACT
Background
Dental graduates need to demonstrate clinical competency. This mixed‐methods study explored the perceptions of clinicians who employ or work with new graduates from the University ...of Otago, New Zealand, and identified themes reflecting graduates’ preparedness for independent practice.
Methods
An online survey using a semantic differential scale and open‐ended questions collected opinions and experiences from the workforce. Quantitative data were analysed using SPSS software, and qualitative data were analysed thematically.
Results
A representative sample of the workforce was obtained with a response rate of 35% (N = 83). Most clinicians engage new graduates to support the profession and/or rural communities. They perceived that graduates were well prepared in most areas, could translate theory to clinical practice and demonstrate professionalism. Graduates were reportedly stronger in basic dentistry, communication, ethics, and record keeping however were less strong in complex treatment planning, molar endodontics, fixed prosthodontics and exodontia. Clinical exposure during dental training was perceived as more limited, and mentoring and guidance in the transition to practice were deemed to be important.
Conclusions
New Zealand dental graduates appear prepared for independent practice; however, maximising clinical opportunities during training, mentoring and early professional development in advanced areas of practice is essential to enhance competency and confidence.
This work analyses a 30year water quality data set collated from chemical analyses of Kuwait's marine waters. Spatial patterns across six sites in Kuwait Bay and seven sites located in the Arabian ...Gulf are explored and discussed in terms of the changing influences associated with point and diffuse sources. Statistical modelling demonstrated significant increases for dissolved nutrients over the time period. Kuwait marine waters have been subject to inputs from urban development, untreated sewage discharges and decreasing river flow from the Shatt al-Arab River. Chlorophyll biomass showed a small but significant reduction; the high sewage content of the coastal waters from sewage discharges likely favouring the presence of smaller phytoplankton taxa. This detailed assessment of temporal data of the impacts of sewage inputs into Kuwait's coastal waters establishes an important baseline permitting future assessments to be made as sewage is upgraded, and the river continues to be extracted upstream.
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