Trends in BRCA testing over time and socioeconomic deprivation

OBJECTIVES: BRCA1&2 (BRCA) testing received much publicity following Angelina Jolie’s editorial ‘My Medical Choice’ in the New York Times on the 14th May 2013. In addition, in the UK, guidelines were updated by NICE (clinical guidance CG164) on the 25th June 2013. We analysed the effects of these two events on uptake of BRCA1 and BRCA2 testing in the area covered by Cheshire and Merseyside Regional Genetic Service, and whether this was affected by socioeconomic deprivation. METHODS: A database was collated using routinely collected hospital data for patients who received hereditary breast and ovarian cancer (HBOC) BRCA testing. A total of 1393 patients received BRCA testing. A natural experimental approach was undertaken using segmented linear regression to estimate changes in the level and trend of BRCA testing following the publication of both the Jolie’s editorial and NICE CG164. Regression coefficients were used to calculate average change in rates, adjusted for prior level and trend. The Index of Multiple Deprivation (IMD) of patients from areas who received BRCA testing to those of the catchment population were compared. RESULTS: The month following the publication of Jolie’s editorial and NICE CG164, BRCA testing increased by approximately 84% (P=0.006). Between April 2010 and March 2017, testing rates increased 11-fold from 0.14 to 1.52 tests/100,000 per month. The odds of receiving BRCA testing were higher for patients from socioeconomically advantaged areas pre-publication (OR 1.21 95% CI 0.99-1.48, P=0.06) although this was not significant. After publication the odds were significantly higher for patients from advantaged areas compared with disadvantaged areas (OR 1.18 95% CI 1.08-1.29, P=0.0002). CONCLUSIONS: Our study found that BRCA testing uptake increased following the publication of Jolie’s editorial and NICE CG164. However, uptake was lower in more deprived areas. This inequity should be further investigated, and consideration given to targeted care within areas of greater socioeconomic deprivation

Mercury dynamics in a San Francisco estuary tidal wetland : assessing dynamics using in situ measurements

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Estuaries and Coasts 35 (2012): 1036-1048, doi:10.1007/s12237-012-9501-3.We used high-resolution in situ measurements of turbidity and fluorescent dissolved organic matter (FDOM) to quantitatively estimate the tidally driven exchange of mercury (Hg) between the waters of the San Francisco estuary and Browns Island, a tidal wetland. Turbidity and FDOM—representative of particle-associated and filter-passing Hg, respectively—together predicted 94 % of the observed variability in measured total mercury concentration in unfiltered water samples (UTHg) collected during a single tidal cycle in spring, fall, and winter, 2005–2006. Continuous in situ turbidity and FDOM data spanning at least a full spring-neap period were used to generate UTHg concentration time series using this relationship, and then combined with water discharge measurements to calculate Hg fluxes in each season. Wetlands are generally considered to be sinks for sediment and associated mercury. However, during the three periods of monitoring, Browns Island wetland did not appreciably accumulate Hg. Instead, gradual tidally driven export of UTHg from the wetland offset the large episodic on-island fluxes associated with high wind events. Exports were highest during large spring tides, when ebbing waters relatively enriched in FDOM, dissolved organic carbon (DOC), and filter-passing mercury drained from the marsh into the open waters of the estuary. On-island flux of UTHg, which was largely particle-associated, was highest during strong winds coincident with flood tides. Our results demonstrate that processes driving UTHg fluxes in tidal wetlands encompass both the dissolved and particulate phases and multiple timescales, necessitating longer term monitoring to adequately quantify fluxes.This work was supported by funding from the California Bay Delta Authority Ecosystem Restoration and Drinking Water Programs (grant ERP-00- G01) and matching funds from the United States Geological Survey Cooperative Research Program

Correlates of mobile screen media use among children aged 0-8: Protocol for a systematic review

Background: Childhood is a crucial period for shaping healthy behaviours; however, it currently appears to be dominated by screen time. A large proportion of young children do not adhere to the screen time recommendations, with the use of mobile screen devices becoming more common than fixed screens. Existing systematic reviews on correlates of screen time have focused largely on the traditional fixed screen devices such as television. Reviews specially focused on mobile screen media are almost non-existent. This paper describes the protocol for conducting a systematic review of papers published between 2009 and 2015 to identify the correlates of mobile screen media use among children aged 0–8 years. Methods: A systematic literature search of electronic databases will be carried out using different combinations of keywords for papers published in English between January 2009 and December 2015. Additionally, a manual search of reference lists and citations will also be conducted. Papers that have examined correlates of screen time among children aged 0–8 will be included in the review. Studies must include at least one type of mobile screen media (mobile phones, electronic tablets or handheld computers) to be eligible for inclusion. This study will identify correlates of mobile screen-viewing among children in five categories: (i) child biological and demographic correlates, (ii) behavioural correlates, (iii) family biological and demographic correlates, (iv) family structure-related correlates and (v) socio-cultural and environmental correlates. PRISMA statement will be used for ensuring transparency and scientific reporting of the results.Discussion: This study will identify the correlates associated with increased mobile screen media use among young children through the systematic review of published peer-reviewed papers. This will contribute to addressing the knowledge gap in this area. The results will provide an evidence base to better understand correlates of mobile screen media use and potentially inform the development of recommendations to reduce screen time among those aged 0–8 years

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Wired for Her Face? Male Attentional Bias for Female Faces

Under conditions of inattention or deficits in orienting attention, special classes of stimuli (e.g. faces, bodies) are more likely to be perceived than other stimuli. This suggests that biologically salient visual stimuli automatically recruit attention, even when they are task-irrelevant or ignored. Here we report results from a behavioral experiment with female and male subjects and two magnetoencephalography (MEG) experiments with male subjects only, in which we investigated attentional capture with face and hand stimuli. In both the behavioral and MEG experiments, subjects were required to count the number of gender-specific targets from either face or hand categories within a block of stimuli. In the behavioral experiment, we found that male subjects were significantly more accurate in response to female than male face target blocks. There was no corresponding effect found in response to hand target blocks. Female subjects did not show a gender-based difference in response to face or hand target blocks. MEG results indicated that the male subjects’ responses to face stimuli in primary visual cortex (V1) and the face-selective part of the fusiform gyrus (FG) were reduced when male face stimuli were not relevant to the task, whereas female faces maintained a strong response in these areas in both task-relevant and task-irrelevant conditions. These results suggest that within the male brain, female face stimuli are more resilient to suppression than male faces, once attention is drawn to the part of the visual field where the face appears

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

The long and the short of it: Mechanisms of synchronous and compensatory dynamics across temporal scales

Synchronous dynamics (fluctuations that occur in unison) are universal phenomena with widespread implications for ecological stability. Synchronous dynamics can amplify the destabilizing effect of environmental variability on ecosystem functions such as productivity, whereas the inverse, compensatory dynamics, can stabilize function. Here we combine simulation and empirical analyses to elucidate mechanisms that underlie patterns of synchronous versus compensatory dynamics. In both simulated and empirical communities, we show that synchronous and compensatory dynamics are not mutually exclusive but instead can vary by timescale. Our simulations identify multiple mechanisms that can generate timescale-specific patterns, including different environmental drivers, diverse life histories, dispersal, and non-stationary dynamics. We find that traditional metrics for quantifying synchronous dynamics are often biased toward long-term drivers and may miss the importance of short-term drivers. Our findings indicate key mechanisms to consider when assessing synchronous versus compensatory dynamics and our approach provides a pathway for disentangling these dynamics in natural systems

Identification of T-Cell Antigens Specific for Latent Mycobacterium Tuberculosis Infection

BACKGROUND: T-cell responses against dormancy-, resuscitation-, and reactivation-associated antigens of Mycobacterium tuberculosis are candidate biomarkers of latent infection in humans. METHODOLOGY/PRINCIPAL FINDINGS: We established an assay based on two rounds of in vitro restimulation and intracellular cytokine analysis that detects T-cell responses to antigens expressed during latent M. tuberculosis infection. Comparison between active pulmonary tuberculosis (TB) patients and healthy latently M. tuberculosis-infected donors (LTBI) revealed significantly higher T-cell responses against 7 of 35 tested M. tuberculosis latency-associated antigens in LTBI. Notably, T cells specific for Rv3407 were exclusively detected in LTBI but not in TB patients. The T-cell IFNgamma response against Rv3407 in individual donors was the most influential factor in discrimination analysis that classified TB patients and LTBI with 83% accuracy using cross-validation. Rv3407 peptide pool stimulations revealed distinct candidate epitopes in four LTBI. CONCLUSIONS: Our findings further support the hypothesis that the latency-associated antigens can be exploited as biomarkers for LTBI