Lm McGregor

Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.

Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs

Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs (my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggesting that calcium binding in the CALXβ-cadherin motif is important for normal functioning of FREM2.

Effects of evidence-based strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme (ASCEND): four cluster-randomised controlled trials

Summary Background Uptake in the national colorectal cancer screening programme in England varies by socioeconomic status. We assessed four interventions aimed at reducing this gradient, with the intention of improving the health benefits of screening. Methods All people eligible for screening (men and women aged 60–74 years) across England were included in four cluster-randomised trials. Randomisation was based on day of invitation. Each trial compared the standard information with the standard information plus the following supplementary interventions: trial 1 (November, 2012), a supplementary leaflet summarising the gist of the key information; trial 2 (March, 2012), a supplementary narrative leaflet describing peoples stories; trial 3 (June, 2013), general practice endorsement of the programme on the invitation letter; and trial 4 (July–August, 2013) an enhanced reminder letter with a banner that reiterated the screening offer. Socioeconomic status was defined by the Index of Multiple Deprivation score for each home address. The primary outcome was the socioeconomic status gradient in uptake across deprivation quintiles. This study is registered, number ISRCTN74121020. Findings As all four trials were embedded in the screening programme, loss to follow-up was minimal (less than 0·5%). Trials 1 (n=163 525) and 2 (n=150 417) showed no effects on the socioeconomic gradient of uptake or overall uptake. Trial 3 (n=265 434) showed no effect on the socioeconomic gradient but was associated with increased overall uptake (adjusted odds ratio [OR] 1·07, 95% CI 1·04–1·10, p<0·0001). In trial 4 (n=168 480) a significant interaction was seen with socioeconomic status gradient (p=0·005), with a stronger effect in the most deprived quintile (adjusted OR 1·11, 95% CI 1·04–1·20, p=0·003) than in the least deprived (1·00, 0·94–1·06, p=0·98). Overall uptake was also increased (1·07, 1·03–1·11, p=0·001). Interpretation Of four evidence-based interventions, the enhanced reminder letter reduced the socioeconomic gradient in screening uptake, but further reducing inequalities in screening uptake through written materials alone will be challenging. Funding National Institute for Health Research.

The Influence of Health Literacy on Comprehension of a Colonoscopy Preparation Information Leaflet

BACKGROUND: Successful bowel preparation is important for safe, efficacious, cost-effective colonoscopy procedures; however, poor preparation is common. OBJECTIVE: We sought to determine whether there was an association between health literacy and comprehension of typical written instructions on how to prepare for a colonoscopy to enable more targeted interventions in this area. DESIGN: This is a cross-sectional observational study. SETTING: This study was performed at primary care clinics and federally qualified health centers in Chicago, Illinois. PATIENTS: Seven hundred sixty-four participants (mean age, 63 years; SD, 5.42) were recruited. The sample was from a mixed sociodemographic background, and 71.9% of the participants were classified as having adequate health literacy scores. INTERVENTION: Seven hundred sixty-four participants were presented with an information leaflet outlining the bowel preparatory instructions for colonoscopy. MAIN OUTCOME MEASURES: Five questions were used to assess participants’ comprehension of the instructions in an “open book” test. RESULTS: Comprehension scores on the bowel preparation items were low. The mean number of items correctly answered was 3.2 (SD, 1.2) of a possible 5. Comprehension scores overall and for each individual item differed significantly by health literacy level (all p < 0.001). After controlling for sex, age, race, socioeconomic status, and previous colonoscopy experience in a multivariable model, health literacy was a significant predictor of comprehension (inadequate vs adequate: &bgr; = −0.2; p < 0.001; marginal vs adequate: &bgr; = −0.2; p < 0.001). LIMITATIONS: The outcome represents a simulated task and not actual comprehension of preparation instructions for participants’ own recommended behavior. CONCLUSIONS: Comprehension of a written colonoscopy preparation leaflet was generally low and significantly lower among people with low health literacy. Poor comprehension has implications for the safety and economic impact of gastroenterological procedures such as colonoscopy. Therefore, future interventions should aim to improve comprehension of complex medical information by reducing literacy-related barriers.

What do people fear about cancer? A systematic review and meta‐synthesis of cancer fears in the general population

Cancer has long inspired fear, but the effect of fear is not well understood; it seems both to facilitate and to deter early diagnosis behaviours. To elucidate fears behavioural effects, we systematically reviewed and synthesised qualitative literature to explore what people fear about cancer.

Facilitators and barriers to help-seeking for breast and cervical cancer symptoms: A qualitative study with an ethnically diverse sample in London

Earlier diagnosis of cancer has become a policy priority. There is evidence that minority ethnic groups are more likely to delay help‐seeking for cancer symptoms, but few studies have explored reasons for delay in these groups. The present study explored facilitators and barriers to help‐seeking for breast and cervical cancer in an ethnically diverse sample of women.

Uptake of Bowel Scope (Flexible Sigmoidoscopy) Screening in the English National Programme: the first 14 months.

Objective To examine uptake in the first six pilot centres of the English Bowel Scope Screening (BSS) programme, which began in early 2013 and invites adults aged 55 for a one off Flexible Sigmoidoscopy. Methods Between March 2013 and May 2014 the six pilot centres sent 21,187 invitations. Using multivariate logistic regression analysis, we examined variation in uptake by gender, socioeconomic deprivation (using the Index of Multiple Deprivation), area-based ethnic diversity (proportion of non-white residents), screening centre, and appointment time (routine: daytime vs out-of-hours: evening/weekend). Results Uptake was 43.1%. Men were more likely to attend than women (45% vs 42%; OR 1.136, 95% CI 1.076, 1.199, p < 0.001). Combining data across centres, there was a socioeconomic gradient in uptake, ranging from 33% in the most deprived to 53% in the least deprived quintile. Areas with the highest level of ethnic diversity also had lower uptake (39%) than other areas (41–47%) (all p < 0.02), but there was no gradient. Individuals offered a routine appointment were less likely to attend than those offered an out-of-hours appointment (42% vs. 44%; OR 0.931, 95% CI 0.882, 0.983, p = 0.01). Multivariate analyses confirmed independent effects of deprivation, gender, and centre, but not of ethnic diversity or appointment time. Conclusion Early indications of uptake are encouraging. Future efforts should focus on increasing public awareness of the programme and reducing socioeconomic inequalities.

Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening

Background:There is a socioeconomic gradient in the uptake of screening in the English NHS Bowel Cancer Screening Programme (BCSP), potentially leading to inequalities in outcomes. We tested whether endorsement of bowel cancer screening by an individual’s general practice (GP endorsement; GPE) reduced this gradient.Methods:A cluster-randomised controlled trial. Over 20 days, individuals eligible for screening in England from 6480 participating general practices were randomly allocated to receive a GP-endorsed or the standard invitation letter. The primary outcome was the proportion of people adequately screened and its variation by quintile of Index of Multiple Deprivation.Results:We enrolled 265 434 individuals. Uptake was 58.2% in the intervention arm and 57.5% in the control arm. After adjusting for age, sex, hub and screening episode, GPE increased the overall odds of uptake (OR=1.07, 95% CI 1.04–1.10), but did not affect its socioeconomic gradient. We estimated that implementing GPE could result in up to 165 more people with high or intermediate risk colorectal adenomas and 61 cancers detected, and a small one-off cost to modify the standard invitation (£78 000).Conclusions:Although GPE did not improve its socioeconomic gradient, it offers a low-cost approach to enhancing overall screening uptake within the NHS BCSP.

Inequalities in cancer screening participation: examining differences in perceived benefits and barriers

Inequalities exist in colorectal cancer (CRC) screening uptake, with people from lower socioeconomic status backgrounds less likely to participate. Identifying the facilitators and barriers to screening uptake is important to addressing screening disparities. We pooled data from 2 trials to examine educational differences in psychological constructs related to guaiac fecal occult blood testing.

Use of a 12 months' self-referral reminder to facilitate uptake of bowel scope (flexible sigmoidoscopy) screening in previous non-responders: a London-based feasibility study.

Background:In March 2013, NHS England extended its national Bowel Cancer Screening Programme to include ‘one-off’ Flexible Sigmoidoscopy screening (NHS Bowel Scope Screening, BSS) for men and women aged 55. With less than one in two people currently taking up the screening test offer, there is a strong public health mandate to develop system-friendly interventions to increase uptake while the programme is rolling out. This study aimed to assess the feasibility of sending a reminder to previous BSS non-responders, 12 months after the initial invitation, with consideration for its potential impact on uptake.Method:This study was conducted in the ethnically diverse London Boroughs of Brent and Harrow, where uptake is below the national average. Between September and November 2014, 160 previous non-responders were randomly selected to receive a reminder of the opportunity to self-refer 12 months after their initial invitation. The reminder included instructions on how to book an appointment, and provided options for the time and day of the appointment and the gender of the endoscopist performing the test. To address barriers to screening, the reminder was sent with a brief locally tailored information leaflet designed specifically for this study. Participants not responding within 4 weeks were sent a follow-up reminder, after which there was no further intervention. Self-referral rates were measured 8 weeks after the delivery of the follow-up reminder and accepted as final.Results:Of the 155 participants who received the 12 months’ reminder (returned to sender, n=5), 30 (19.4%) self-referred for an appointment, of which 24 (15.5%) attended and were successfully screened. Attendance rates differed by gender, with significantly more women attending an appointment than men (20.7% vs 8.8%, respectively; OR=2.73, 95% CI=1.02–7.35, P=0.05), but not by area (Brent vs Harrow) or area-level deprivation. Of the 30 people who self-referred for an appointment, 27 (90%) indicated a preference for a same-sex practitioner, whereas three (10%) gave no preference. Preference for a same-sex practitioner was higher among women than men (χ2=7.78, P<0.05), with only 67% of men (six of nine) requesting a same-sex practitioner, compared with 100% of women (n=21).Conclusions:Sending previous non-responders a 12 months’ reminder letter with a brief information leaflet is a feasible and efficacious intervention, which merits further investigation in a randomised controlled trial.