Hepatitis C – Assessment to Treatment Trial (HepCATT) in primary care:study protocol for a cluster randomised controlled trial

BACKGROUND: Public Health England (PHE) estimates that there are upwards of 160,000 individuals in England and Wales with chronic hepatitis C virus (HCV) infection, but until now only around 100,000 laboratory diagnoses have been reported to PHE and of these 28,000 have been treated. Targeted case-finding in primary care is estimated to be cost-effective; however, there has been no robust randomised controlled trial evidence available of specific interventions. Therefore, this study aims to develop and conduct a complex intervention within primary care and to evaluate this approach using a cluster randomised controlled trial. METHODS/DESIGN: A total of 46 general practices in South West England will be randomised in a 1:1 ratio to receive either a complex intervention comprising: educational training on HCV for the practice; poster and leaflet display in the practice waiting rooms to raise awareness and encourage opportunistic testing; a HCV risk prediction algorithm based on information on possible risk markers in the electronic patient record run using Audit + software (BMJ Informatica). The audit will then be used to recall and offer patients a HCV test. Control practices will follow usual care. The effectiveness of the intervention will be measured by comparing number and rates of HCV testing, the number and proportion of patients testing positive, onward referral, rates of specialist assessment and treatment in control and intervention practices. Intervention costs and health service utilisation will be recorded to estimate the NHS cost per new HCV diagnosis and new HCV patient initiating treatment. Longer-term cost-effectiveness of the intervention in improving quality-adjusted life years (QALYs) will be extrapolated using a pre-existing dynamic health economic model. Patients' and health care workers' experiences and acceptability of the intervention will be explored through semi-structured qualitative interviews. DISCUSSION: This trial has the potential to make an important impact on patient care and will provide high-quality evidence to help general practitioners make important decisions on HCV testing and onward referral. If found to be effective and cost-effective the intervention is readily scalable and can be used to support the implementation of NICE recommendations on HCV case-finding. TRIAL REGISTRATION: ISRCTN61788850 . Registered on 24 April 2015; Protocol Version: 2.0, 22 May 2015

Grain boundary pinning and glassy dynamics in stripe phases

We study numerically and analytically the coarsening of stripe phases in two spatial dimensions, and show that transient configurations do not achieve long ranged orientational order but rather evolve into glassy configurations with very slow dynamics. In the absence of thermal fluctuations, defects such as grain boundaries become pinned in an effective periodic potential that is induced by the underlying periodicity of the stripe pattern itself. Pinning arises without quenched disorder from the non-adiabatic coupling between the slowly varying envelope of the order parameter around a defect, and its fast variation over the stripe wavelength. The characteristic size of ordered domains asymptotes to a finite value $R_g \sim \lambda_0\ \epsilon^{-1/2}\exp(|a|/\sqrt{\epsilon})$, where$\epsilon\ll 1$is the dimensionless distance away from threshold,$\lambda_0$the stripe wavelength, and$a$ a constant of order unity. Random fluctuations allow defect motion to resume until a new characteristic scale is reached, function of the intensity of the fluctuations. We finally discuss the relationship between defect pinning and the coarsening laws obtained in the intermediate time regime.Comment: 17 pages, 8 figures. Corrected version with one new figur

Computerised cognitive assessment in patients with traumatic brain injury: an observational study of feasibility and sensitivity relative to established clinical scales

Background: Online technology could potentially revolutionise how patients are cognitively assessed and monitored. However, it remains unclear whether assessments conducted remotely can match established pen-and-paper neuropsychological tests in terms of sensitivity and specificity. Methods: This observational study aimed to optimise an online cognitive assessment for use in traumatic brain injury (TBI) clinics. The tertiary referral clinic in which this tool has been clinically implemented typically sees patients a minimum of 6 months post-injury in the chronic phase. Between March and August 2019, we conducted a cross-group, cross-device and factor analyses at the St. Mary's Hospital TBI clinic and major trauma wards at Imperial College NHS trust and St. George's Hospital in London (UK), to identify a battery of tasks that assess aspects of cognition affected by TBI. Between September 2019 and February 2020, we evaluated the online battery against standard face-to-face neuropsychological tests at the Imperial College London research centre. Canonical Correlation Analysis (CCA) determined the shared variance between the online battery and standard neuropsychological tests. Finally, between October 2020 and December 2021, the tests were integrated into a framework that automatically generates a results report where patients’ performance is compared to a large normative dataset. We piloted this as a practical tool to be used under supervised and unsupervised conditions at the St. Mary's Hospital TBI clinic in London (UK). Findings: The online assessment discriminated processing-speed, visual-attention, working-memory, and executive-function deficits in TBI. CCA identified two significant modes indicating shared variance with standard neuropsychological tests (r = 0.86, p < 0.001 and r = 0.81, p = 0.02). Sensitivity to cognitive deficits after TBI was evident in the TBI clinic setting under supervised and unsupervised conditions (F (15,555) = 3.99; p < 0.001). Interpretation: Online cognitive assessment of TBI patients is feasible, sensitive, and efficient. When combined with normative sociodemographic models and autogenerated reports, it has the potential to transform cognitive assessment in the healthcare setting. Funding: This work was funded by a National Institute for Health Research (NIHR) Invention for Innovation (i4i) grant awarded to DJS and AH ( II-LB-0715-20006)

1ES 1927+654: An AGN Caught Changing Look on a Timescale of Months

We study the sudden optical and ultraviolet (UV) brightening of 1ES 1927+654, which until now was known as a narrow-line active galactic nucleus (AGN). 1ES 1927+654 was part of the small and peculiar class of "true Type-2" AGNs that lack broad emission lines and line-of-sight obscuration. Our high-cadence spectroscopic monitoring captures the appearance of a blue, featureless continuum, followed several weeks later by the appearance of broad Balmer emission lines. This timescale is generally consistent with the expected light travel time between the central engine and the broadline emission region in (persistent) broadline AGN. Hubble Space Telescope spectroscopy reveals no evidence for broad UV emission lines (e.g., C iv λ1549, C iii] λ1909, Mg ii λ2798), probably owing to dust in the broadline emission region. To the best of our knowledge, this is the first case where the lag between the change in continuum and in broadline emission of a "changing look" AGN has been temporally resolved. The nature and timescales of the photometric and spectral evolution disfavor both a change in line-of-sight obscuration and a change of the overall rate of gas inflow as driving the drastic spectral transformations seen in this AGN. Although the peak luminosity and timescales are consistent with those of tidal disruption events seen in inactive galaxies, the spectral properties are not. The X-ray emission displays a markedly different behavior, with frequent flares on timescales of hours to days, and will be presented in a companion publication

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

BACKGROUND: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. METHODOLOGY/PRINCIPLE FINDINGS: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). CONCLUSIONS/SIGNIFICANCE: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma

Molecular and functional correction of a deep intronic splicing mutation in CFTR by CRISPR-Cas9 gene editing.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The 10th most common mutation, c.3178-2477C>T (3849+10kb C>T), involves a cryptic, intronic splice site. This mutation was corrected in CF primary cells homozygous for this mutation by delivering pairs of guide RNAs (gRNAs) with Cas9 protein in ribonucleoprotein (RNP) complexes that introduce double-strand breaks to flanking sites to excise the 3849+10kb C>T mutation, followed by DNA repair by the non-homologous end-joining pathway, which functions in all cells of the airway epithelium. RNP complexes were delivered to CF basal epithelial cell by a non-viral, receptor-targeted nanocomplex comprising a formulation of targeting peptides and lipids. Canonical CFTR mRNA splicing was, thus, restored leading to the restoration of CFTR protein expression with concomitant restoration of electrophysiological function in airway epithelial air-liquid interface cultures. Off-target editing was not detected by Sanger sequencing of in silico-selected genomic sites with the highest sequence similarities to the gRNAs, although more sensitive unbiased whole genome sequencing methods would be required for possible translational developments. This approach could potentially be used to correct aberrant splicing signals in several other CF mutations and other genetic disorders where deep-intronic mutations are pathogenic

Conceptualizing pathways linking women's empowerment and prematurity in developing countries.

BackgroundGlobally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity.MethodsThe key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors.ResultsThere is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving access to and receipt of recommended health services during pregnancy and delivery to help prevent prematurity and improve survival of premature babies.ConclusionsWomen's empowerment is an important distal factor that affects prematurity through several intervening factors. Improving women's empowerment will help prevent prematurity and improve survival of preterm babies. Research to empirically show the links between women's empowerment and prematurity is however needed

Non-Linear Neuronal Responses as an Emergent Property of Afferent Networks: A Case Study of the Locust Lobula Giant Movement Detector

In principle it appears advantageous for single neurons to perform non-linear operations. Indeed it has been reported that some neurons show signatures of such operations in their electrophysiological response. A particular case in point is the Lobula Giant Movement Detector (LGMD) neuron of the locust, which is reported to locally perform a functional multiplication. Given the wide ramifications of this suggestion with respect to our understanding of neuronal computations, it is essential that this interpretation of the LGMD as a local multiplication unit is thoroughly tested. Here we evaluate an alternative model that tests the hypothesis that the non-linear responses of the LGMD neuron emerge from the interactions of many neurons in the opto-motor processing structure of the locust. We show, by exposing our model to standard LGMD stimulation protocols, that the properties of the LGMD that were seen as a hallmark of local non-linear operations can be explained as emerging from the dynamics of the pre-synaptic network. Moreover, we demonstrate that these properties strongly depend on the details of the synaptic projections from the medulla to the LGMD. From these observations we deduce a number of testable predictions. To assess the real-time properties of our model we applied it to a high-speed robot. These robot results show that our model of the locust opto-motor system is able to reliably stabilize the movement trajectory of the robot and can robustly support collision avoidance. In addition, these behavioural experiments suggest that the emergent non-linear responses of the LGMD neuron enhance the system's collision detection acuity. We show how all reported properties of this neuron are consistently reproduced by this alternative model, and how they emerge from the overall opto-motor processing structure of the locust. Hence, our results propose an alternative view on neuronal computation that emphasizes the network properties as opposed to the local transformations that can be performed by single neurons

The Rachel Carson Letters and the Making of Silent Spring

Environment, conservation, green, and kindred movements look back to Rachel Carson’s 1962 book Silent Spring as a milestone. The impact of the book, including on government, industry, and civil society, was immediate and substantial, and has been extensively described; however, the provenance of the book has been less thoroughly examined. Using Carson’s personal correspondence, this paper reveals that the primary source for Carson’s book was the extensive evidence and contacts compiled by two biodynamic farmers, Marjorie Spock and Mary T. Richards, of Long Island, New York. Their evidence was compiled for a suite of legal actions (1957-1960) against the U.S. Government and that contested the aerial spraying of dichlorodiphenyltrichloroethane (DDT). During Rudolf Steiner’s lifetime, Spock and Richards both studied at Steiner’s Goetheanum, the headquarters of Anthroposophy, located in Dornach, Switzerland. Spock and Richards were prominent U.S. anthroposophists, and established a biodynamic farm under the tutelage of the leading biodynamics exponent of the time, Dr. Ehrenfried Pfeiffer. When their property was under threat from a government program of DDT spraying, they brought their case, eventually lost it, in the process spent US$100,000, and compiled the evidence that they then shared with Carson, who used it, and their extensive contacts and the trial transcripts, as the primary input for Silent Spring. Carson attributed to Spock, Richards, and Pfeiffer, no credit whatsoever in her book. As a consequence, the organics movement has not received the recognition, that is its due, as the primary impulse for Silent Spring, and it is, itself, unaware of this provenance

Association between germline variants and somatic mutations in colorectal cancer

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n similar or equal to 125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC