Time from first presentation in primary care to treatment of symptomatic colorectal cancer:effect on disease stage and survival

BACKGROUND: British 5-year survival from colorectal cancer (CRC) is below the European average, but the reasons are unclear. This study explored if longer provider delays (time from presentation to treatment) were associated with more advanced stage disease at diagnosis and poorer survival. METHODS: Data on 958 people with CRC were linked with the Scottish Cancer Registry, the Scottish Death Registry and the acute hospital discharge (SMR01) dataset. Time from first presentation in primary care to first treatment, disease stage at diagnosis and survival time from date of first presentation in primary care were determined. Logistic regression and Cox survival analyses, both with a restricted cubic spline, were used to model stage and survival, respectively, following sequential adjustment of patient and tumour factors. RESULTS: On univariate analysis, those with <4 weeks from first presentation in primary care to treatment had more advanced disease at diagnosis and the poorest prognosis. Treatment delays between 4 and 34 weeks were associated with earlier stage (with the lowest odds ratio occurring at 20 weeks) and better survival (with the lowest hazard ratio occurring at 16 weeks). Provider delays beyond 34 weeks were associated with more advanced disease at diagnosis, but not increased mortality. Following adjustment for patient, tumour factors, emergency admissions and symptoms and signs, no significant relationship between provider delay and stage at diagnosis or survival from CRC was found. CONCLUSIONS: Although allowing for a nonlinear relationship and important confounders, moderately long provider delays did not impact adversely on cancer outcomes. Delays are undesirable because they cause anxiety; this may be fuelled by government targets and health campaigns stressing the importance of very prompt cancer diagnosis. Our findings should reassure patients. They suggest that a health service's primary emphasis should be on quality and outcomes rather than on time to treatment

Electromagnetic modelling of a terahertz-frequency quantum-cascade laser integrated with dual diagonal feedhorns

We present an electromagnetic model of a THz QCL, integrated with a micro-machined waveguide and dual diagonal feedhorns, enabling simultaneous access to both facets of the QCL. A hybrid finite-element/Fourier transform approach enables analysis of both the near and far-fields in agreement with experimental observations. The far-field pattern shows enhancement of the beam profile when compared with an unmounted QCL, in terms of beam divergence and side-lobe suppression ratio

Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

Cancer prevalence in the United Kingdom: estimates for 2008

BACKGROUND: Identifying and addressing the requirements of cancer survivors is currently a high priority for the NHS, yet little is known about the population of cancer survivors in the United Kingdom. METHODS: Data from cancer registries in England, Northern Ireland, Scotland and Wales were analysed to provide limited-duration prevalence estimates for 2004. Log-linear regression models were used to extend these to complete prevalence estimates. Trends in prevalence from 2000 to 2004 were used to project complete prevalence estimates forward from 2004 to 2008. RESULTS: We estimated that in total, there were 2 million cancer survivors in the United Kingdom at the end of 2008, approximately 3% of the population overall and 1 in 8 of those aged 65 years and more. Prostate and female breast cancers were the most prevalent. The number of cancer survivors is increasing by approximately 3% each year. Estimates are also provided by time since diagnosis. CONCLUSION: These estimates are the most up-to-date available, and as such will be useful for statutory and voluntary sector organisations that are responsible for planning and providing treatment and support to cancer survivors in the United Kingdom

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( P≤5×10-8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.Funding Agency Portuguese Foundation for Science and Technology CRESC ALGARVE 2020 European Union (EU) 303745 Maratona da Saude Award DL 57/2016/CP1361/CT0042 SFRH/BPD/99502/2014 CBMR-UID/BIM/04773/2013 POCI-01-0145-FEDER-022184info:eu-repo/semantics/publishedVersio

Electromagnetic-field analysis of diagonal-feedhorn antennas for terahertz-frequency quantum-cascade laser integration

We present an electromagnetic-field analysis of a terahertz-frequency quantum-cascade laser (THz QCL) integrated with a mechanically micro-machined waveguide cavity and diagonal feedhorn. A hybrid finite-element/Fourier transform approach enables analysis of both the near-field and far-field regions and is shown to agree well with experimental observations. The far-field antenna patterns show enhancement of the beam profile when compared with an unmounted QCL, in terms of beam divergence and side-lobe suppression ratio. Furthermore, we demonstrate integration of the QCL with dual diagonal feedhorns, enabling simultaneous access to both facets of the QCL, underpinning future integration with a satellite-based receiver and frequency-stabilization subsystem

Quantum‐Cascade Laser emission at 3.5 THz from dual diagonal feedhorns

The LOCUS satellite (Linking Observations of Climate, the Upper Atmosphere and Space weather) is a proposed mission to explore and observe key gas species within the upper atmosphere using a novel terahertz-frequency (THz) heterodyne spectrometer, in which the emission spectra are simultaneously recorded in four channels in the 0.8–4.7 THz band [1]. THz quantum-cascade lasers (QCLs) will be exploited as local oscillators for the first time in space because they are powerful, yet compact THz sources, providing > 1 mW continuous-wave output at key LOCUS frequencies (3.5 and 4.7 THz). Furthermore, they have been integrated successfully into precision-micro-machined waveguide blocks and operated in space-qualified Stirling-cycle cryo-coolers (~60 K) [2]. A key development challenge will be stabilising the emission frequency of the QCL by locking it to a stable reference oscillator. In this paper, we present a new QCL dual-feedhorn integration technique, which advances this goal by enabling access to radiation emitted from both facets of the QCL simultaneously. In this configuration, the THz emission may be coupled simultaneously to a mixer and to a stabilisation subsystem. Figure 1(a) shows the integration of a 3.5 THz QCL into a precision micro-machined channel in a copper block. A second, symmetrical copper block is placed on top of this to form a rectangular waveguide around the QCL, with a diagonal feedhorn at either end. Figure 1(b) shows the simulated far-field beam pattern for a single feedhorn at 3.5 THz, in which the maximum collected power is represented in the bright central area. Figure 1(c) shows the experimental results for the dual-feedhorn waveguide block, in which the radiation from each horn is reflected onto the same plane, and measured using a raster-scanned Golay-cell detector. Good agreement with the simulated single-feedhorn emission has been observed, with similar beam width and side-lobe content. In conclusion, the integration of a 3.5-THz QCL into a dual-feedhorn waveguide block has been demonstrated. This opens the way towards simultaneous integration of the QCL with a frequency stabilisation system and a supra-THz mixer

3.5 THz quantum-cascade laser emission from dual diagonal feedhorns

Antenna-pattern measurements obtained from a double-metal supra-terahertz-frequency (supra-THz) quantum cascade laser (QCL) are presented. The QCL is mounted within a mechanically micro-machined waveguide cavity containing dual diagonal feedhorns. Operating in continuous-wave mode at 3.5 THz, and at an ambient temperature of ∼60 K, QCL emission has been directed via the feedhorns to a supra-THz detector mounted on a multi-axis linear scanner. Comparison of simulated and measured far-field antenna patterns shows an excellent degree of correlation between beamwidth (full-width-half-maximum) and sidelobe content and a very substantial improvement when compared with unmounted devices. Additionally, a single output has been used to successfully illuminate and demonstrate an optical breadboard arrangement associated with a future supra-THz Earth observation space-borne payload. Our novel device has therefore provided a valuable demonstration of the effectiveness of supra-THz diagonal feedhorns and QCL devices for future space-borne ultra-high-frequency Earth-observing heterodyne radiometers

An analysis of temporal and generational trends in the incidence of anal and other HPV-related cancers in Southeast England

Patients diagnosed in 1960–2004 with cancer of the cervix, anus, vulva, vagina or penis were identified from the Thames Cancer Registry database, and age-standardised period (temporal) incidence rates calculated by direct standardisation. Age-cohort modelling techniques were used to estimate age-specific incidence rates in the earlier and later cohorts, enabling the calculation of age-standardised cohort (generational) rates. Incidence of anal cancer increased for both men and women over the period studied, mainly in those born from 1940 onwards. Similar generational patterns were seen for cancers of the vulva and vagina, but those for penile cancer were different. For cervix cancer, the steep downward trend in cohort rates due to screening levelled off in women born from 1940 onwards. Our findings are compatible with the hypothesis that changes in sexual practices were a major contributor to the increases of these cancers. Programmes of vaccination against HPV, aimed at reducing the burden of cervical cancer, may also help to reduce the incidence of cancer at other anogenital sites

Predictors of anti-convulsant treatment failure in children presenting with malaria and prolonged seizures in Kampala, Uganda

BACKGROUND: In endemic areas, falciparum malaria remains the leading cause of seizures in children presenting to emergency departments. In addition, seizures in malaria have been shown to increase morbidity and mortality in these patients. The management of seizures in malaria is sometimes complicated by the refractory nature of these seizures to readily available anti-convulsants. The objective of this study was to determine predictors of anti-convulsant treatment failure and seizure recurrence after initial control among children with malaria. METHODS: In a previous study, the efficacy and safety of buccal midazolam was compared to that of rectal diazepam in the treatment of prolonged seizures in children aged three months to 12 years in Kampala, Uganda. For this study, predictive models were used to determine risk factors for anti-convulsant treatment failure and seizure recurrence among the 221 of these children with malaria. RESULTS: Using predictive models, focal seizures (OR 3.21; 95% CI 1.42-7.25, p = 0.005), cerebral malaria (OR 2.43; 95% CI 1.20-4.91, p = 0.01) and a blood sugar >or=200 mg/dl at presentation (OR 2.84; 95% CI 1.11-7.20, p = 0.02) were independent predictors of treatment failure (seizure persistence beyond 10 minutes or recurrence within one hour of treatment). Predictors of seizure recurrence included: 1) cerebral malaria (HR 3.32; 95% CI 1.94-5.66, p < 0.001), 2) presenting with multiple seizures (HR 2.45; 95% CI 1.42-4.23, p = 0.001), 3) focal seizures (HR 2.86; 95% CI 1.49-5.49, p = 0.002), 4) recent use of diazepam (HR 2.43; 95% CI 1.19-4.95, p = 0.01) and 5) initial control of the seizure with diazepam (HR 1.96; 95% CI 1.16-3.33, p = 0.01). CONCLUSION: Specific predictors, including cerebral malaria, can identify patients with malaria at risk of anti-convulsant treatment failure and seizure recurrence