Frances J. Drummond

Rab4 affects both recycling and degradative endosomal trafficking

The small GTPases Rab4, Rab5 and Rab7 are endosomal proteins which play important roles in the regulation of various stages of endosomal trafficking. Rab4 and Rab5 have both been localized to early endosomes and have been shown to control recycling and endosomal fusion, respectively. Rab7, a marker of the late endosomal compartment, is involved in the regulation of the late endocytic pathway. Here, we compare the role of Rab4, Rab5 and Rab7 in early and late endosomal trafficking in HeLa cells monitoring ligand uptake, recycling and degradation. Expression of the Rab4 dominant negative mutant (Rab4AS22N) leads to a significant reduction in both recycling and degradation while, as expected, Rab7 mutants exclusively affect epidermal growth factor (EGF) and low density lipoprotein degradation. As also expected, expression of the dominant negative Rab5 mutant perturbs internalization kinetics and affects both recycling and degradation. Expression of Rab4WT and dominant positive mutant (Rab4AQ67L) changes dramatically the morphology of the transferrin compartment leading to the formation of membrane tubules. These transferrin positive tubules display swellings (varicosities) some of which are positive for early endosomal antigen‐1 and contain EGF. We propose that the Rab4GTPase is important for the function of the early sorting endosomal compartment, affecting trafficking along both recycling and degradative pathways.

Investigation of the Genetic Influence of the OPG, VDR (Fok1), and COLIA1 Sp1 Polymorphisms on BMD in the Irish Population

Low bone mineral density (BMD) is a major risk factor for the development of osteoporosis and there is strong evidence to suggest that the procurement and preservation of peak BMD is genetically determined. In an effort to identify factors responsible for susceptibility to low BMD in the Irish population, we investigated its possible association with polymorphisms in the Osteoprotegerin (OPG) gene, Type I collagen alpha 1 (COLIA1) Sp1 binding site and vitamin D receptor (VDR) start codon. Following a systematic screening of the regulatory and coding regions of the OPG gene, we identified a novel G1181C polymorphism in exon 1 and a T950C polymorphism in the promoter region of the OPG gene. Participants were recruited from the Bone Densitometry Unit of Cork University Hospital, including 381 postmenopausal women aged 61.26 +/- 8.50 (mean +/- SD) and 130 premenopausal women aged 46.30 +/- 6.50 (mean +/- SD). Following association analysis using both the premenopausal and postmenopausal cohorts we found that postmenopausal women carrying one or more C alleles of the G1181C polymorphism had 14.8% lower BMD (P = 0.05) at the lumbar spine and 14.4% lower BMD (P = 0.04) at the FN. However, both were nonsignificant when the Bonferroni correction factor (0.01 significance level) was applied to correct for multiple hypothesis testing. We found no association between alleles of the T950C OPG polymorphism and BMD. Similarly, we have found a lack of association between the VDR (fok1) polymorphism or COLIA1 Sp1 polymorphism and low BMD in either postmenopausal or premenopausal women in this population.

Patient‐reported ‘ever had’ and ‘current’ long‐term physical symptoms after prostate cancer treatments

To investigate the prevalence of physical symptoms that were ‘ever’ and ‘currently’ experienced by survivors of prostate cancer at a population level, to assess burden and thus inform policy to support survivors.

Cancer-related symptoms predict psychological wellbeing among prostate cancer survivors: results from the PiCTure study.

Prostate cancer treatments are associated with a range of symptoms and physical side‐effects. Cancer can also adversely impact on psychological wellbeing. Because many prostate cancer‐related symptoms and side‐effects are potentially modifiable, we investigated associations between symptoms and psychological wellbeing among prostate cancer survivors.

Questionnaire order significantly increased response to a postal survey sent to primary care physicians

OBJECTIVE Primary care physicians are increasingly being asked to participate in postal surveys. Difficulties in achieving adequate response rates among physicians have been reported. We investigated the effect of two low-cost interventions on response to a primary care physician postal questionnaire. STUDY DESIGN AND SETTING A 2x2 factorial trial was developed within the context of a national survey assessing views and practices of physicians regarding prostate-specific antigen testing. We evaluated questionnaire order (version 1: demographics first, version 2: topic-specific questions first) and written precontact. A national database of primary care physicians was compiled. One thousand five hundred ninety-nine physicians were randomly selected, stratified by health board, and randomized. RESULTS 47.9% of eligible physicians completed a questionnaire. There was a statistically significant 5.1% higher response rate among physicians receiving version 1 of the questionnaire than those receiving version 2 (50.6% vs. 45.4%, P=0.05); the adjusted odds of response were significantly raised (odds ratio=1.24; 95% confidence interval=1.01-1.54). Precontact resulted in a nonsignificant 3.6% increase in response (49.8% vs. 46.2%; P=0.16). The interventions did not interact. CONCLUSION Ordering questionnaires with general questions first can significantly increase response rates, whereas precontact can achieve a modest increase. These strategies may enhance response while adding little to the cost of a physician survey.

Establishing a population-based patient-reported outcomes study (PROMs) using national cancer registries across two jurisdictions: The Prostate Cancer Treatment, your experience (PiCTure) study

Objective To establish an international patient-reported outcomes (PROMs) study among prostate cancer survivors, up to 18 years postdiagnosis, in two countries with different healthcare systems and ethical frameworks. Design A cross-sectional, postal survey of prostate cancer survivors sampled and recruited via two population-based cancer registries. Healthcare professionals (HCPs) evaluated patients for eligibility to participate. Questionnaires contained validated instruments to assess health-related quality of life and psychological well-being, including QLQ-C30, QLQ-PR25, EQ-5D-5L, 21-question Depression, Anxiety and Stress Scale (DASS-21) and the Decisional Regret Scale. Setting Republic of Ireland (RoI) and Northern Ireland (NI). Primary outcome measures Registration completeness, predictors of eligibility and response, data missingness, unweighted and weighted PROMs. Results Prostate cancer registration was 80% (95% CI 75% to 84%) and 91% (95% CI 89% to 93%) complete 2 years postdiagnosis in NI and RoI, respectively. Of 12 322 survivors sampled from registries, 53% (n=6559) were classified as eligible following HCP screening. In the multivariate analysis, significant predictors of eligibility were: being ≤59 years of age at diagnosis (p<0.001), short-term survivor (<5 years postdiagnosis; p<0.001) and from RoI (p<0.001). 3348 completed the questionnaire, yielding a 54% adjusted response rate. 13% of men or their families called the study freephone with queries for assistance with questionnaire completion or to talk about their experience. Significant predictors of response in multivariate analysis were: being ≤59 years at diagnosis (p<0.001) and from RoI (p=0.016). Mean number of missing questions in validated instruments ranged from 0.12 (SD 0.71; EQ-5D-5L) to 3.72 (SD 6.30; QLQ-PR25). Weighted and unweighted mean EQ-5D-5L, QLQ-C30 and QLQ-PR25 scores were similar, as were the weighted and unweighted prevalences of depression, anxiety and distress. Conclusions It was feasible to perform PROMs studies across jurisdictions, using cancer registries as sampling frames; we amassed one of the largest, international, population-based data set of prostate cancer survivors. We highlight improvements which could inform future PROMs studies, including utilising general practitioners to assess eligibility and providing a freephone service.

Factors Driving Inequality in Prostate Cancer Survival: A Population Based Study

Purpose As cancer control strategies have become more successful, issues around survival have become increasingly important to researchers and policy makers. The aim of this study was to examine the role of a range of clinical and socio-demographic variables in explaining variations in survival after a prostate cancer diagnosis, paying particular attention to the role of healthcare provider(s) i.e. private versus public status. Methods Data were extracted from the National Cancer Registry Ireland, for patients diagnosed with prostate cancer from 1998–2009 (N = 26,183). A series of multivariate Cox and logistic regression models were used to examine the role of healthcare provider and socio-economic status (area-based deprivation) on survival, controlling for age, stage, Gleason grade, marital status and region of residence. Survival was based on all-cause mortality. Results Older individuals who were treated in a private care setting were more likely to have survived than those who had not, when other factors were controlled for. Differences were evident with respect to marital status, region of residence, clinical stage and Gleason grade. The effect of socio-economic status was modified by healthcare provider, such that risk of death was higher in those men of lower socio-economic status treated by public, but not private providers in the Cox models. The logistic models revealed a socio-economic gradient in risk of death overall; the gradient was larger for those treated by public providers compared to those treated by private providers when controlling for a range of other confounding factors. Conclusion The role of healthcare provider and socio-economic status in survival of men with prostate cancer may give rise to concerns that warrant further investigation.

''Bird in the hand'' cash was more effective than prize draws in increasing physician questionnaire response

OBJECTIVE To investigate the effects of two monetary incentives on response rates to postal questionnaires from primary care physicians (PCPs). STUDY DESIGN AND SETTING The PCPs were randomized into three arms (n=550 per arm), namely (1) €5 sent with the questionnaire (cash); (2) entry into a draw on return of completed questionnaire (prize); or (3) no incentive. Effects of incentives on response rates and item nonresponse were examined, as was cost-effectiveness. RESULTS Response rates were significantly higher in the cash (66.1%; 95% confidence interval [CI]: 61.9, 70.4%) and prize arms (44.8%; 95% CI: 40.1, 49.3%) compared with the no-incentive arm (39.9%; 95% CI: 35.4, 44.3%). Adjusted relative risk of response was 1.17 (95% CI: 1.02, 1.35) and 1.68 (95% CI: 1.48, 1.91) in the prize and cash arms, respectively, compared with the no-incentive group. Costs per completed questionnaire were €9.85, €11.15, and €6.31 for the cash, prize, and no-incentive arms, respectively. Compared with the no-incentive arm, costs per additional questionnaire returned in the cash and prize arms were €14.72 and €37.20, respectively. CONCLUSION Both a modest cash incentive and entry into a prize draw were effective in increasing response rates. The cash incentive was most effective and the most cost-effective. Where it is important to maximize response, a modest cash incentive may be cost-effective.

Men's information‐seeking behavior regarding cancer risk and screening: A meta‐narrative systematic review

Preventive strategies are known to reduce cancer risk and incidence and improve prognosis. Men seldom seek medical information about cancer prevention and risk reduction. The aim of this meta‐narrative systematic review was to critically appraise evidence from qualitative, quantitative, and mixed‐methods studies that explored mens information‐seeking behaviors in relation to cancer prevention and risk reduction.

Physical after-effects in men undergoing prostate biopsy in routine clinical practice: Results from the PiCTure study

BACKGROUND As the incidence of prostate cancer has, until recently, increased in most developed countries, the rates of prostate biopsies, required for histological diagnosis, will also have increased. Little is known about the physical after-effects of prostate biopsy outside randomised control trials. We investigate reports on the physical effect of prostate biopsy undertaken in men in routine practice. METHODS A self-completed questionnaire was given to men living in the Republic of Ireland (RoI) or Northern Ireland 4 to 6 weeks after prostate biopsy. Men were asked about whether they experienced specific physical after-effects postbiopsy (raised temperature/pain/bleeding/erectile dysfunction/urinary retention) and, if so, their severity and duration, and any associated health care uses. Binomial and ordinal logistic regression was used to investigate factors associated with postbiopsy after-effects (presence/absence) and number of after-effects reported, respectively. RESULTS Postbiopsy after-effects were common with 88.1% of 335 respondents reporting at least 1 after-effect; 21% reported at least 3. The odds of increasing number of after-effects was over 2-fold in men with both intermediate (odds ratio [OR] = 2.59, 95% CI: 1.52-4.42) and high (OR = 2.52, 95% CI: 1.28-4.94) levels of health anxiety and for men who had had multiple previous biopsies (adjusted OR = 2.02, 95% CI: 1.20-3.41). A total of 21.3% of men who experienced after-effects reported that they were worse than expected, 11.5% with after-effects reported contacting their doctor or local pharmacy, 14.6% contacted hospital services, and 3.1% of men with after-effects were admitted to hospital with an average stay of 5.4 nights (standard deviation = 6.3). CONCLUSION Physical after-effects following prostate biopsy in routine practice are common, and in some men, serious enough to warrant contacting hospital or community services. Men with increased health anxiety or who undergo multiple biopsies might benefit from additional support.