Health system interventions to integrate genetic testing in routine oncology services: A systematic review

Background Integration of genetic testing into routine oncology care could improve access to testing. This systematic review investigated interventions and the tailored implementation strategies aimed at increasing access to genetic counselling and testing and identifying hereditary cancer in oncology. Methods The search strategy results were reported using the PRISMA statement and four electronic databases were searched. Eligible studies included routine genetic testing for breast and ovarian cancer or uptake after universal tumour screening for colorectal or endometrial cancer. The titles and abstracts were reviewed and the full text articles screened for eligibility. Data extraction was preformed using a designed template and study appraisal was assessed using an adapted Newcastle Ottawa Scale. Extracted data were mapped to Proctor’s et al outcomes and the Consolidated Framework for Implementation Research and qualitatively synthesised. Results Twenty-seven studies, published up to May 2020, met the inclusion criteria. Twenty-five studies ranged from poor (72%), fair to good (28%) quality. Most interventions identified were complex (multiple components) such as; patient or health professional education, interdisciplinary practice and a documentation or system change. Forty-eight percent of studies with complex interventions demonstrated on average a 35% increase in access to genetic counselling and a 15% increase in testing completion. Mapping of study outcomes showed that 70% and 32% of the studies aligned with either the service and client or the implementation level outcome and 96% to the process or inner setting domains of the Consolidated Framework for Implementation Research. Conclusion Existing evidence suggests that complex interventions have a potentially positive effect towards genetic counselling and testing completion rates in oncology services. Studies of sound methodological quality that explore a greater breadth of pre and post implementation outcomes and informed by theory are needed. Such research could inform future service delivery models for the integration of genetics into oncology services

Global Optimization Algorithms in Multidisciplinary DesignOptimization

While Multidisciplinay Design Optimization (MDO) literature focuses mainly on the development of different formulations, through the manipulation of design variables, less attention is generally devoted to the combination of specific MDO formulations with existing nonlinear optimization algorithms. In this paper, the focus is on the application of a Global Optimization (GO) algorithm to an MDO problem. We first introduce and describe some MDO approaches from the literature. Then, we consider our MDO formulation where we deal with the GO box-constrained problem min_{a R We assume that the solution of the latter problem requires the use of a derivative-free methods since the derivatives of f(x) are unavailable and/or the function must be treated as a `black-box'. Within this framework we study some globally convergent modifications of the evolutionary Particle Swarm Optimization (PSO) algorithm, suitably adapted for box-constrained optimization. Finally, we report our numerical experience. Preliminary results are provided for a simple hydroelastic problem. Two different numerical tools are involved: a fluid dynamic solver, to simulate the ow around hydrofoils traveling in proximity of the air-water interface, and a simplified torsion-flexional wing model

The effects of emotional states and traits on risky decision-making.

Understanding the role of emotional states is critical for predicting the kind of decisions people will make in risky situations. Currently, there is little understanding as to how emotion influences decision-making in situations such as terrorist attacks, natural disasters, pandemics, and combat. To help address this, we used behavioral and neuroimaging methods to examine how emotion states and traits influence decisions. Specifically, this study used a wheel of fortune behavioral task and functional magnetic resonance imaging (fMRI) to examine the effects of emotional states and traits on decision-making pertaining to the degree of risk people are willing to make in specific situations. The behavioral results are reported here. The neural data requires additional time to analyze and will be reported at a future date. Biases caused by emotion states and traits were found regarding the likelihood of making risky decisions. The behavioral results will help provide a solid empirical foundation for modeling the effects of emotion on decision in risky situations

Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data

Background:Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods.Methods and Findings:Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone.The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000-380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000-180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%-31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys.Conclusions:With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns.Please see later in the article for the Editors' Summary

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis

Operational aspects of an externally driven neutron multiplier assembly concept using a Z-pinch 14-MeV Neutron Source (ZEDNA).

This report documents the key safety and operational aspects of a Z-pinch Externally Driven Nuclear Assembly (ZEDNA) reactor concept which is envisioned to be built and operated at the Z-machine facility in Technical Area IV. Operating parameters and reactor neutronic conditions are established that would meet the design requirements of the system. Accident and off-normal conditions are analyzed using a point-kinetics, one-dimensional thermo-mechanical code developed specifically for ZEDNA applications. Downwind dose calculations are presented to determine the potential dose to the collocated worker and public in the event of a hypothetical catastrophic accident. Current and magnetic impulse modeling and the debris shield design are examined for the interface between the Z machine and the ZEDNA. This work was performed as part of the Advanced Fusion Grand Challenge Laboratory Directed Research and Development Program. The conclusion of this work is that the ZEDNA concept is feasible and could be operated at the Z-machine facility without undue risk to collocated workers and the public

MicroRNAs: exploring a new dimension in the pathogenesis of kidney cancer

Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. The role of the von-Hippel-Lindeau (VHL) tumour suppressor gene is well established in RCC with a loss of VHL protein leading to accumulated hypoxia-induced factor (HIF) and the subsequent transcriptional activation of multiple downstream targets. Recently, microRNAs (miRNAs) have been shown to be differentially expressed in RCC and their role in RCC pathogenesis is emerging. This month, in BMC Medicine, Gleadle and colleagues show that certain miRNAs are regulated by VHL in either a hypoxia-inducible factor (HIF)-dependent or HIF-independent manner in RCC. They also show that miRNA expression correlates with the survival of RCC patients

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures

Inhibition of sialidase activity and cellular invasion by the bacterial vaginosis pathogen Gardnerella vaginalis

Bacterial vaginosis is a genital tract infection, thought to be caused by transformation of a lactobacillus-rich flora to a dysbiotic microbiota enriched in mixed anaerobes. The most prominent of these is Gardnerella vaginalis (GV), an anaerobic pathogen that produces sialidase enzyme to cleave terminal sialic acid residues from human glycans. Notably, high sialidase activity is associated with preterm birth and low birthweight. We explored the potential of the sialidase inhibitor Zanamavir against GV whole cell sialidase activity using methyl-umbelliferyl neuraminic acid (MU-NANA) cleavage assays, with Zanamavir causing a 30% reduction in whole cell GV sialidase activity (p < 0.05). Furthermore, cellular invasion assays using HeLa cervical epithelial cells, infected with GV, demonstrated that Zanamivir elicited a 50% reduction in cell association and invasion (p < 0.05). Our data thus highlight that pharmacological sialidase inhibitors are able to modify BV-associated sialidase activity and influence host-pathogen interactions and may represent novel therapeutic adjuncts

Local Gene Regulation Details a Recognition Code within the LacI Transcriptional Factor Family

The specific binding of regulatory proteins to DNA sequences exhibits no clear patterns of association between amino acids (AAs) and nucleotides (NTs). This complexity of protein-DNA interactions raises the question of whether a simple set of wide-coverage recognition rules can ever be identified. Here, we analyzed this issue using the extensive LacI family of transcriptional factors (TFs). We searched for recognition patterns by introducing a new approach to phylogenetic footprinting, based on the pervasive presence of local regulation in prokaryotic transcriptional networks. We identified a set of specificity correlations –determined by two AAs of the TFs and two NTs in the binding sites– that is conserved throughout a dominant subgroup within the family regardless of the evolutionary distance, and that act as a relatively consistent recognition code. The proposed rules are confirmed with data of previous experimental studies and by events of convergent evolution in the phylogenetic tree. The presence of a code emphasizes the stable structural context of the LacI family, while defining a precise blueprint to reprogram TF specificity with many practical applications.Ministerio de Ciencia e Innovación, Spain (Formación de Profesorado Universitario fellowship)Ministerio de Ciencia e Innovación, Spain (grant BFU2008-03632/BMC)Madrid (Spain : Region) (grant CCG08-CSIC/SAL-3651