The Impact of Age,Sex and Socioeconomic Deprivation on Outcomes in a Colorectal Cancer Screening Programme

Background

Population-based colorectal cancer screening has been shown to reduce cancer specific mortality and is used across the UK. Despite evidence that older age, male sex and deprivation are associated with an increased incidence of colorectal cancer, uptake of bowel cancer screening varies across demographic groups. The aim of this study was to assess the impact of age, sex and deprivation on outcomes throughout the screening process.

Methods

A prospectively maintained database, encompassing the first screening round of a faecal occult blood test screening programme in a single geographical area, was analysed.

Results

Overall, 395 096 individuals were invited to screening, 204 139 (52%) participated and 6 079 (3%) tested positive. Of the positive tests, 4 625 (76%) attended for colonoscopy and cancer was detected in 396 individuals (9%). Lower uptake of screening was associated with younger age, male sex and deprivation (all p<0.001). Only deprivation was associated with failure to proceed to colonoscopy following a positive test (p<0.001). Despite higher positivity rates in those that were more deprived (p<0.001), the likelihood of detecting cancer in those attending for colonoscopy was lower (8% most deprived vs 10% least deprived, p = 0.003).

Conclusion

Individuals who are deprived are less likely to participate in screening, less likely to undergo colonoscopy and less likely to have cancer identified as a result of a positive test. Therefore, this study suggests that strategies aimed at improving participation of deprived individuals in colorectal cancer screening should be directed at all stages of the screening process and not just uptake of the test.     

Multi-Allelic Major Effect Genes Interact with Minor Effect QTLs to Control Adaptive Color Pattern Variation in Heliconius erato

Recent studies indicate that relatively few genomic regions are repeatedly involved in the evolution of Heliconius butterfly wing patterns. Although this work demonstrates a number of cases where homologous loci underlie both convergent and divergent wing pattern change among different Heliconius species, it is still unclear exactly how many loci underlie pattern variation across the genus. To address this question for Heliconius erato, we created fifteen independent crosses utilizing the four most distinct color pattern races and analyzed color pattern segregation across a total of 1271 F2 and backcross offspring. Additionally, we used the most variable brood, an F2 cross between H. himera and the east Ecuadorian H. erato notabilis, to perform a quantitative genetic analysis of color pattern variation and produce a detailed map of the loci likely involved in the H. erato color pattern radiation. Using AFLP and gene based markers, we show that fewer major genes than previously envisioned control the color pattern variation in H. erato. We describe for the first time the genetic architecture of H. erato wing color pattern by assessing quantitative variation in addition to traditional linkage mapping. In particular, our data suggest three genomic intervals modulate the bulk of the observed variation in color. Furthermore, we also identify several modifier loci of moderate effect size that contribute to the quantitative wing pattern variation. Our results are consistent with the two-step model for the evolution of mimetic wing patterns in Heliconius and support a growing body of empirical data demonstrating the importance of major effect loci in adaptive change.     

The evolution of microendemism in a reef fish (Hypoplectrus maya)

Marine species tend to have extensive distributions, which are commonly attributed to the dispersal potential provided by planktonic larvae and the rarity of absolute barriers to dispersal in the ocean. Under this paradigm, the occurrence of marine microendemism without geographic isolation in species with planktonic larvae poses a dilemma. The recently described Maya hamlet (Hypoplectrus maya, Serranidae) is exactly such a case, being endemic to a 50‐km segment of the Mesoamerican Barrier Reef System (MBRS). We use whole‐genome analysis to infer the demographic history of the Maya hamlet and contrast it with the sympatric and pan‐Caribbean black (H. nigricans), barred (H. puella) and butter (H. unicolor) hamlets, as well as the allopatric but phenotypically similar blue hamlet (H. gemma). We show that H. maya is indeed a distinct evolutionary lineage, with genomic signatures of inbreeding and a unique demographic history of continuous decrease in effective population size since it diverged from congeners just ~3,000 generations ago. We suggest that this case of microendemism may be driven by the combination of a narrow ecological niche and restrictive oceanographic conditions in the southern MBRS, which is consistent with the occurrence of an unusually high number of marine microendemics in this region. The restricted distribution of the Maya hamlet, its decline in both census and effective population sizes, and the degradation of its habitat place it at risk of extinction. We conclude that the evolution of marine microendemism can be a fast and dynamic process, with extinction possibly occurring before speciation is complete.     

Apicoplast lipoic acid protein ligase B is not essential for Plasmodium falciparum

Lipoic acid (LA) is an essential cofactor of alpha-keto acid dehydrogenase complexes (KADHs) and the glycine cleavage system. In Plasmodium, LA is attached to the KADHs by organelle-specific lipoylation pathways. Biosynthesis of LA exclusively occurs in the apicoplast, comprising octanoyl-[acyl carrier protein]: protein N-octanoyltransferase (LipB) and LA synthase. Salvage of LA is mitochondrial and scavenged LA is ligated to the KADHs by LA protein ligase 1 (LplA1). Both pathways are entirely independent, suggesting that both are likely to be essential for parasite survival. However, disruption of the LipB gene did not negatively affect parasite growth despite a drastic loss of LA (>90%). Surprisingly, the sole, apicoplast-located pyruvate dehydrogenase still showed lipoylation, suggesting that an alternative lipoylation pathway exists in this organelle. We provide evidence that this residual lipoylation is attributable to the dual targeted, functional lipoate protein ligase 2 (LplA2). Localisation studies show that LplA2 is present in both mitochondrion and apicoplast suggesting redundancy between the lipoic acid protein ligases in the erythrocytic stages of P. falciparum.     

AVP V1 receptor-mediated decrease in Cl- efflux and increase in dark cell number in choroid plexus epithelium

The cerebrospinalfluid (CSF)-generating choroid plexus (CP) has manyV₁ binding sites for argininevasopressin (AVP). AVP decreases CSF formation rate and choroidal bloodflow, but little is known about how AVP alters ion transport across theblood-CSF barrier. Adult rat lateral ventricle CP was loaded with³⁶Cl,exposed to AVP for 20 min, and then placed in isotope-free artificial CSF to measure release of³⁶Cl.Effect of AVP at 10¹² to10⁷ M on theCl efflux rate coefficient(in s¹) was quantified.Maximal inhibition (by 20%) ofCl extrusion at10⁹ M AVP was prevented bythe V₁ receptor antagonist[-mercapto-,-cyclopentamethyleneproprionyl¹,O-Me-Tyr²,Arg⁸]vasopressin.AVP also increased by more than twofold the number of dark and possiblydehydrated but otherwise morphologically normal choroid epithelialcells in adult CP. The V₁ receptorantagonist prevented this AVP-induced increment in dark cell frequency.In infant rats (1 wk) with incomplete CSF secretory ability,10⁹ M AVP altered neitherCl efflux nor dark cellfrequency. The ability of AVP to elicit functional and structuralchanges in adult, but not infant, CP epithelium is discussed in regardto ion transport, CSF secretion, intracranial pressure, and hydrocephalus.

     

Structure of an elastin-mimetic polypeptide by solid-state NMR chemical shift analysis

The conformation of an elastin-mimetic recombinant protein, [(VPGVG)4(VPGKG)]39, is investigated using solid-state NMR spectroscopy. The protein is extensively labeled with 13C and 15N, and two-dimensional 13C-13C and 15N-13C correlation experiments were carried out to resolve and assign the isotropic chemical shifts of the various sites. The Pro 15N, 13Calpha, and 13Cbeta isotropic shifts, and the Gly-3 Calpha isotropic and anisotropic chemical shifts support the predominance of type-II beta-turn structure at the Pro-Gly pair but reject a type-I beta-turn. The Val-1 preceding Pro adopts mostly beta-sheet torsion angles, while the Val-4 chemical shifts are intermediate between those of helix and sheet. The protein exhibits a significant conformational distribution, shown by the broad line widths of the 15N and 13C spectra. The average chemical shifts of the solid protein are similar to the values in solution, suggesting that the low-hydration polypeptide maintains the same conformation as in solution. The ability to measure these conformational restraints by solid-state NMR opens the possibility of determining the detailed structure of this class of fibrous proteins through torsion angles and distances.