Barriers to colorectal cancer screening in Ghana: a qualitative study of patients and physicians.

PURPOSE: The incidence of colorectal cancer (CRC) in Ghana has increased eightfold since the 1960s. In 2011, national guidelines were set forth recommending all patients aged 50-70 years old undergo annual CRC screening with fecal occult blood testing (FOBT), but adherence to these guidelines is poor and screening rates remain low for unclear reasons. METHODS: We performed semi-structured interviews with 28 Ghanaians including physicians (n = 14) and patients (n = 14) from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, to better understand the factors driving screening adherence and perceived barriers identified in an earlier quantitative study. RESULTS: Participants reported sociocultural factors such as reliance on alternative medicine or religion, lack of education, and financial burden as community-level barriers to CRC screening. At the system level, screening was limited by insufficient access to FOBT as well as a perceived lack of national prioritization. This was described as inadequate efforts from the Ministry of Health regarding national education as well as lack of incorporation of CRC screening into the National Health Insurance Scheme. CONCLUSION: Several community- and system-level barriers exist to widespread screening of CRC in Ghana. A multi-level approach will be required to improve rates of CRC screening and ultimately reduce the burden of CRC in Ghana.

Prenatal infection with Mycoplasma pulmonis in rats exaggerates the angiotensin II pressor response in adult offspring.

Exposure to different stressors in utero is linked to adult diseases such as obesity and hypertension. In this study, the impact of prenatal infection (PNI) on adult body weight and cardiovascular function was evaluated using a naturally occurring rodent pathogen, Mycoplasma pulmonis (MP). Pregnant Sprague-Dawley rats were infected with MP on gestationalday 14 and gave birth naturally. Adult PNI offspring weighed more than controls, but resting mean arterial pressure (MAP) was unchanged. Subcutaneous injection of angiotensin II (10 µg/kg) elicited a rise in MAP that was greater in both male and female PNI offspring compared with controls (P < 0.03). The accompanying reflex bradycardia was similar to the controls, suggesting that PNI induced baroreflex dysfunction. Subcutaneous nicotine administration, a potent cardiorespiratory stimulus, also elicited a transient rise in MAP that was generally greater in the PNI group, but the change in MAP from baseline was only significant in the PNI females compared with controls (P < 0.03). Elevated body weight and cardiovascular reactivity in the PNI offspring was associated with an increase in the ratio of hypothalamic corticotrophin-releasing hormone receptors type 1 to type 2 gene expression in both sexes compared with controls. These findings support previous studies demonstrating that PNI induces alterations in cardiovascular function and body weight. Yet, unlike previous studies utilizing other models of PNI (e.g., endotoxin), MP PNI did not induce resting hypertension. Thus, our study provides a foundation for future studies evaluating the cardiovascular risks of offspring exposed to microbial challenges in utero.

Potential unintended consequences of graphic warning labels on sugary drinks: do they promote obesity stigma?

INTRODUCTION: Public health interventions need to balance the benefits with any potential harms. One proposed intervention for reducing sugar-sweetened beverage consumption involves placing graphic warning labels on products and advertisements. A recent study found that a graphic warning label that contained negative imagery of obesity reduced purchases of sugar-sweetened beverages. However, these labels may also promote obesity stigma, which is concerning given that weight stigma is associated with harmful health consequences including weight gain and increased risk of mortality. METHODS: In Study 1 (n = 681), participants viewed a standard soda label or the graphic warning label online and then completed measures of disgust and prejudice towards people with obesity. In Study 2 (n = 506), participants who identified as having overweight or obesity viewed the graphic warning label online before or after completing measures of mood and state self-esteem. RESULTS: In Study 1, participants who had viewed the graphic warning label reported higher disgust and weight bias. In Study 2, the majority of participants perceived the warning label to be stigmatizing, and participants displayed worse mood and, through this, lower self-esteem after viewing the label. CONCLUSIONS: Although the graphic warning label has been found to reduce sugary drink purchases, it also promotes obesity stigma and is perceived as stigmatizing by individuals with overweight and obesity. Given that weight stigma predicts harmful health and well-being consequences, the benefits of graphic warning labels need to be balanced against the potential costs.

What can we learn from the vaginal mesh story?

The use of vaginal mesh in prolapse surgery has created enormous controversy and unprecedented media interest; it has become the most emotive topic in urogynecology today. The US Food and Drug Administration 510(k) system allowed the proliferation of mesh products which were rapidly adopted by surgeons internationally. The importance of a firm understanding of the biomechanical properties of tissue and implants, surgical skill, patient selection, communication skills, informed consent, and high-quality research are all important lessons we can learn from the mesh story. These lessons need to be applied to all novel treatments in the field of urogynecology and beyond.

DOCA/salt hypertension alters Period1 and orexin-related gene expression in the medulla and hypothalamus of male rats: Diurnal influences.

In peripheral tissues, aldosterone alters expression of multiple genes, including the clock gene Period 1 (Per1), 11 beta-hydroxysteroid dehydrogenase-2 (11-HSD2), and α-ENAC, the epithelial sodium channel subunit. We evaluated the impact of chronic aldosterone exposure (DOCA) and salt intake on nocturnal changes in gene expression in the male Sprague Dawley rat brain. Additionally, genes associated with the orexin (ORX) system were also evaluated based on the role of this neuropeptide in arousal, feeding and hypertension and an interconnection with Per1 expression. DOCA/salt treatment increased saline intake primarily at night, elevated arterial pressure and lowered heart rate. In the medulla oblongata, DOCA/salt upregulated Per1, 11-HSD2, and α-ENAC expression independent of time of day, but did not change ORX receptor type 1 (ORX-R1) or type 2 (ORX-R2) expression. ORX-R1, and ORX-R2 expression in the medulla did however correlate with Per1 expression following DOCA/salt treatment but not in controls. In the hypothalamus, DOCA/salt treatment upregulated Per1, ORX-A, and ORX-R2 expression, in general, and Per1 and ORX-A expression at night. ORX-A, ORX-R1 and ORX-R2 expression in the hypothalamus correlated with Per1 expression following DOCA/salt but not in controls. These findings demonstrate for the first time that DOCA/salt hypertension modulates ORX gene expression in the brain and suggest that changes in expression in the ORX system may occur directly or indirectly via aldosterone-induced changes in Per1 expression. Our findings also build on emerging evidence that monitoring gene expression during both the day and night is critical to understanding the role of specific genes in hypertension.

Coping with weight stigma: development and validation of a Brief Coping Responses Inventory.

People who are overweight or obese are frequently stigmatized because of their weight, but there has been limited exploration of how people cope with these experiences. The Coping Responses Inventory (CRI) assesses a wide range of coping strategies in response to weight stigma; however, its length (99 items) may have prevented it from being widely used. The aim of the current research (four studies; total N = 1,391) was to develop and validate a Brief CRI. This 10-item measure consists of two subscales that assess core coping responses to weight stigma: reappraisal and disengagement coping. Reappraisal coping is an adaptive form of coping that is associated with greater well-being, whereas disengagement coping reflects a maladaptive form of coping that is associated with poorer well-being. The Brief CRI provides a quick and effective way to assess coping with weight stigma, and its use has the potential to advance an understanding of the consequences of weight stigma.

Lymphocyte density determined by computational pathology validated as a predictor of response to neoadjuvant chemotherapy in breast cancer: secondary analysis of the ARTemis trial.

BACKGROUND: We have previously shown lymphocyte density, measured using computational pathology, is associated with pathological complete response (pCR) in breast cancer. The clinical validity of this finding in independent studies, among patients receiving different chemotherapy, is unknown. PATIENTS AND METHODS: The ARTemis trial randomly assigned 800 women with early stage breast cancer between May 2009 and January 2013 to three cycles of docetaxel, followed by three cycles of fluorouracil, epirubicin and cyclophosphamide once every 21 days with or without four cycles of bevacizumab. The primary endpoint was pCR (absence of invasive cancer in the breast and lymph nodes). We quantified lymphocyte density within haematoxylin and eosin (H&E) whole slide images using our previously described computational pathology approach: for every detected lymphocyte the average distance to the nearest 50 lymphocytes was calculated and the density derived from this statistic. We analyzed both pre-treatment biopsies and post-treatment surgical samples of the tumour bed. RESULTS: Of the 781 patients originally included in the primary endpoint analysis of the trial, 609 (78%) were included for baseline lymphocyte density analyses and a subset of 383 (49% of 781) for analyses of change in lymphocyte density. The main reason for loss of patients was the availability of digitized whole slide images. Pre-treatment lymphocyte density modelled as a continuous variable was associated with pCR on univariate analysis (odds ratio [OR], 2.92; 95% CI, 1.78-4.85; P < 0.001) and after adjustment for clinical covariates (OR, 2.13; 95% CI, 1.24-3.67; P = 0.006). Increased pre- to post-treatment lymphocyte density showed an independent inverse association with pCR (adjusted OR, 0.1; 95% CI, 0.033-0.31; P < 0.001). CONCLUSIONS: Lymphocyte density in pre-treatment biopsies was validated as an independent predictor of pCR in breast cancer. Computational pathology is emerging as a viable and objective means of identifying predictive biomarkers for cancer patients. CLINICALTRIALS.GOV: NCT01093235.

Development of multi-disciplinary breast cancer care in Southern Malawi.

The Edinburgh Malawi Breast Cancer Project, a collaborative partnership project between the Queen Elizabeth Central Hospital (QECH) Oncology Unit, Blantyre, Malawi and the Edinburgh Cancer Centre, UK, was established in 2015. The principal objective of the project is to help to develop high quality multi-disciplinary breast cancer care in Malawi. A needs assessment identified three priority areas for further improvement of breast cancer services: multi-disciplinary working, development of oestrogen receptor (ER) testing and management of clinical data. A 3-year project plan was implemented which has been conducted through a series of reciprocal training visits. Key achievements to date have been: (1) Development of a new specialist breast care nursing role; (2) Development of multi-disciplinary meetings; (3) Completion of a programme of oncology nursing education; (4) Development of a clinical database that enables prospective collection of data of all new patients with breast cancer; (5) Training of local staff in molecular and conventional approaches to ER testing. The Edinburgh Malawi Breast Cancer Project is supporting nursing education, data use and cross-specialty collaboration that we are confident will improve cancer care in Malawi. Future work will include the development of a breast cancer diagnostic clinic and a breast cancer registry.

Radiopathological features predictive of involved margins in ductal carcinoma in situ.

INTRODUCTION Ductal carcinoma in situ (DCIS) usually manifests as microcalcification on mammography but may be uncalcified. Consequently, a quarter of patients undergoing excision of a presumed pure DCIS require further surgery to re-excise margins. Patients at highest risk of margin involvement may benefit from additional preoperative assessment. METHODS A retrospective review was carried out of patients treated for screen detected, biopsy proven DCIS in a single centre over a ten-year period (1999-2009). Logistic regression analysis identified factors predictive of need for further surgery to clear margins. RESULTS Overall, 248 patients underwent surgery for DCIS (low/intermediate grade: 82, high grade: 155) and 49 (19.8%) required further surgery. High grade disease was associated with greater mammographic extent (mean: 32mm [range: 5-120mm] vs 25mm [range: 2-100mm]), p=0.009) and higher incidence of mastectomy (38% vs 24%, p=0.034). Factors predictive of involvement of surgical margins necessitating further surgery included negative oestrogen receptor status (OR: 5.2, 95% CI: 2.1-12.8, p<0.001) and mammographic extent (odds ratio [OR]: 1.6, 95% confidence interval [CI]: 1.2-2.1, p=0.004). Once size exceeded 30mm, more than 50% of patients required secondary breast surgery for margins. CONCLUSIONS Reoperation rates for DCIS increase with preoperative size on mammography and negative oestrogen receptor status on core biopsy. Patients with these risk features should be counselled accordingly and consideration should be given to the role of additional preoperative imaging.

Late-onset progressive retinal atrophy in the Gordon and Irish Setter breeds is associated with a frameshift mutation in C2orf71.

Progressive retinal atrophy (PRA) in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 14 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s) responsible have yet to be identified. Using genome-wide association with 16 Gordon Setter PRA cases and 22 controls, we identified a novel PRA locus, termed rod-cone degeneration 4 (rcd4), on CFA17 (Praw  = 2.22 × 10(-8) , Pgenome  = 2.00 × 10(-5) ), where a 3.2-Mb region was homozygous within cases. A frameshift mutation was identified in C2orf71, a gene located within this region. This variant was homozygous in 19 of 21 PRA cases and was at a frequency of approximately 0.37 in the Gordon Setter population. Approximately 10% of cases in our study (2 of 21) are not associated with this C2orf71 mutation, indicating that PRA in this breed is genetically heterogeneous and caused by at least two mutations. This variant is also present in a number of Irish Setter dogs with PRA and has an estimated allele frequency of 0.26 in the breed. The function of C2orf71 remains unknown, but it is important for retinal development and function and has previously been associated with autosomal recessive retinitis pigmentosa in humans.

Cardiorespiratory variability following repeat acute hypoxia in the conscious SHR versus two normotensive rat strains.

A link between exaggerated chemoreceptor sensitivity and hypertension has been documented in the spontaneously hypertensive rat (SHR) but has also been questioned when comparisons with normotensive strains other than the Wistar Kyoto (WKY) rat are made. To further evaluate the link between hypertension and chemoreflex sensitivity, changes in cardiorespiratory variability in response to three successive bouts of 5 min of hypoxia (21%→10%) were evaluated in conscious male SHR, and WKY and Sprague Dawley (SD) rats (n=7-8/group). In response to the first bout of hypoxia, the change in respiratory frequency (RF) was greatest in the SHR, but the increase in mean arterial pressure (MAP) was similar in both SHRs and WKY rats and all strains demonstrated a similar rise in heart rate (HR). All strains showed some level of response accommodation during subsequent bouts of hypoxia. Spectral analysis of HR variability identified a significant difference in high frequency (HF) power between strains during hypoxia, including an increase in HF power in the WKY rats, a decrease in the SHRs and little overall change in the SD rats. Alternatively, all strains demonstrated a rise in systolic arterial pressure (SAP) variability in the low frequency (LF) range in response to hypoxia but the increase was greatest in the SHR. Since SAP LF power is linked to vasosympathetic tone, these results support the hypothesis that essential hypertension is linked to exaggerated sympathetic responses to chemoreceptor stimulation but confirm that estimation of augmented reflex function cannot be determined by quantifying simple changes in MAP or HR.

The influence of clinicopathological features on the predictive accuracy of conventional breast imaging in determining the extent of screen-detected high-grade pure ductal carcinoma in situ.

INTRODUCTION: The extent of calcified ductal carcinoma in situ (DCIS) detected by screening mammography is a determinant for treatment with breast conserving surgery (BCS). However, DCIS may be uncalcified and almost a quarter of patients with DCIS treated initially by BCS either require a second operation or are found to have unexpected invasive disease following surgery. Identification of these cases might guide selective implementation of additional diagnostic procedures. METHODS: A retrospective review of patients with a preoperative diagnosis of pure high-grade DCIS at the Southampton and Salisbury Breast Screening Unit over a ten-year period was carried out. Mammograms were reviewed independently by a consultant radiologist and additional factors including the Breast Imaging Reporting and Data System (BI-RADS(®)) breast density score, DCIS extent and disease location within the breast recorded. RESULTS: Unexpected invasive disease was found in 35 of 144 patients (24%). Within our unit the re-excision rate for all screen-detected DCIS is currently 23% but for patients included in this study with high-grade DCIS the re-excision rate was 39% (34/87). The extent of DCIS (p=0.008) and lack of expression of the oestrogen receptor (ER) predicted the requirement for re-excision in both univariate (p=0.004) and multivariate analysis (p=0.005). CONCLUSIONS: High-grade DCIS may be focally uncalcified, leading to underestimation of disease extent, which might be related to ER status. Invasive foci associated with high-grade DCIS are often mammographically occult. Exploration of additional biomarkers and targeted use of further diagnostic techniques may improve the preoperative staging of DCIS.

Prenatal nicotine exposure alters respiratory long-term facilitation in neonatal rats.

Intermittent hypoxia can evoke persistent increases in ventilation (V (E)) in neonates (i.e. long-term facilitation, LTF) (Julien et al., 2008). Since prenatal nicotine (PN) exposure alters neonatal respiratory control (Fregosi and Pilarski, 2008), we hypothesized that PN would influence LTF of ventilation (V (E)) in neonatal rats. An osmotic minipump delivered nicotine 6 mg/kg per day or saline to pregnant dams. V (E) was assessed in unanesthetized pups via whole body plethysmography at post-natal (P) days 9-11 or 15-17 during baseline (BL, 21% O(2)), hypoxia (10 x 5 min, 5% O(2)) and 30 min post-hypoxia. PN pups had reduced BL V (E) (p<0.05) but greater increases in V (E) during hypoxia (p<0.05). Post-hypoxia V (E) (i.e. LTF) showed an agex treatment interaction (p<0.01) with similar values at P9-11 but enhanced LTF in saline (30+/-8%BL) vs. PN pups (6+/-5%BL; p=0.01) at P15-17. We conclude that the post-natal developmental time course of hypoxia-induced LTF is influenced by PN.

Effects of systemic administration of mirtazapine on respiratory muscle activity in sleeping rats.

Mirtazapine (MIRT) is an antidepressant with mixed noradrenergic and serotonergic effects in central nervous system. The present study was undertaken to assess whether MIRT can stimulate genioglossus muscle (GG) activity in the conscious, behaving rat. Nine male rats were chronically instrumented with GG and neck muscle EMG electrodes. EEG electrodes were implanted to acquire sleep stage. Results demonstrated a dose-dependent effect of MIRT on GG activity during sleep, although no changes reached statistical significance. Low dose MIRT (0.1 mg/kg) showed a slight increase in GG phasic activity. In contrast, higher doses of MIRT (0.5-1.0 mg/kg) tended to decrease GG activity relative to vehicle, in addition to decreasing total sleep time.

Disinhibition of the dorsomedial hypothalamus increases the frequency of augmented breaths in the anesthetized rat.

The present study was undertaken to identify if activation of the dorsomedial hypothalamus (DMH) elicits augmented breaths (ABs). DMH disinhibition in urethane anesthetized rats produced both an increase in baseline respiratory rate (RR) and an increase in the number of ABs. The increase in RR was associated with a decrease in both the time of inspiration (T(i)) and expiration (T(e)) and the peak change in RR was observed 5 min post DMH activation. In contrast, the increase in ABs was greatest during the first 1.25 min, and both T(i)s of the ABs did not change significantly from pre-injection values. The T(e) of the ABs did decrease but remained significantly greater than the T(e) of the normal breath during DMH disinhibition. Our results support the hypothesis that the central neural pathway involved in the maintenance of normal respiratory pattern may be distinct from pathways involved in the generation of ABs.

Mitek QuickAnchor fixation of cochlear implants using a minimal access technique.

RATIONALE: In children with thick cortical bone, surgical exposure for cochlear implant fixation is difficult when using a minimal access technique. We report our experience in these children using the Mitek QuickAnchor system. METHODS: A retrospective review of all children undergoing cochlear implantation over a 12-month period was performed to identify those children in which a Mitek QuickAnchor was used. Measurements of cortical bone thickness at the receiver-stimulator well site were obtained from pre-operative CT scans of temporal bones of all children. The application of the Mitek QuickAnchor system was also reviewed. RESULTS: Cochlear implant fixation using the Mitek QuickAnchor system was performed in 14 children (mean age 12 years) during the study period. The mean cortical bone thickness was 5.6mm in patients receiving the Mitek QuickAnchor system and 3.2mm in patients undergoing conventional fixation. The difference in cortical thickness was highly statistically significant. Successful secure fixation was obtained in all cases. CONCLUSIONS: The Mitek QuickAnchor system provides an effective method of cochlear implant fixation when using a minimal access technique in children with thick cortical bone.

Screening large-scale association study data: exploiting interactions using random forests.

BACKGROUND: Genome-wide association studies for complex diseases will produce genotypes on hundreds of thousands of single nucleotide polymorphisms (SNPs). A logical first approach to dealing with massive numbers of SNPs is to use some test to screen the SNPs, retaining only those that meet some criterion for further study. For example, SNPs can be ranked by p-value, and those with the lowest p-values retained. When SNPs have large interaction effects but small marginal effects in a population, they are unlikely to be retained when univariate tests are used for screening. However, model-based screens that pre-specify interactions are impractical for data sets with thousands of SNPs. Random forest analysis is an alternative method that produces a single measure of importance for each predictor variable that takes into account interactions among variables without requiring model specification. Interactions increase the importance for the individual interacting variables, making them more likely to be given high importance relative to other variables. We test the performance of random forests as a screening procedure to identify small numbers of risk-associated SNPs from among large numbers of unassociated SNPs using complex disease models with up to 32 loci, incorporating both genetic heterogeneity and multi-locus interaction. RESULTS: Keeping other factors constant, if risk SNPs interact, the random forest importance measure significantly outperforms the Fisher Exact test as a screening tool. As the number of interacting SNPs increases, the improvement in performance of random forest analysis relative to Fisher Exact test for screening also increases. Random forests perform similarly to the univariate Fisher Exact test as a screening tool when SNPs in the analysis do not interact. CONCLUSIONS: In the context of large-scale genetic association studies where unknown interactions exist among true risk-associated SNPs or SNPs and environmental covariates, screening SNPs using random forest analyses can significantly reduce the number of SNPs that need to be retained for further study compared to standard univariate screening methods.

Cochlear implant positioning in children: a survey of patient satisfaction.

INTRODUCTION: The past decade has been witness to significant diminution in incision size and placement for pediatric cochlear implantation at our institution. Furthermore, the orientation of the long axis of the implant relative to the skull base plane has generally evolved from a retro-verted to ante-verted direction to accommodate the ear level receiver stimulator and the new minimal access technique. OBJECTIVE: To characterize the cosmetic, functional and clinical implications of this evolution in cochlear implant positioning by means of a patient satisfaction survey. METHODS: A survey of patient satisfaction was administered to 100 cochlear implant recipients or their parents. The survey elicits the patient's level of satisfaction with respect to implant position and functional limitations. In addition, the angle formed by the long axis of the implant and the skull base plane (implant angle) was determined from lateral skull radiographs to detect the temporal evolution in implant positioning. RESULTS: Analysis of the radiographs revealed an implant angle of 65.4-125 degrees in patients implanted prior to 1997, an implant angle of 56.3-87.5 degrees in patients implanted from 1997 to 2001, and an implant angle of 35.1-78.1 degrees after 2002. In spite of this evolution in positioning, the patient satisfaction survey did not reveal any change in incidence of cosmetic, functional or clinical problems. DISCUSSION: The significant changes in incision and implant positioning represent a technical evolution in pediatric cochlear implant surgery. The fact that patients have been consistently satisfied over time suggests that the cosmetic, functional and clinical implications are minimal.

What is the prevalence of visual impairment in the general and diabetic populations: are there ethnic and gender differences?

AIMS: To estimate the prevalence of blindness and partial sight in the general and diabetic populations and to measure the impact of ethnicity and gender on these rates. METHODS: Data on visual impairment in the population to be studied was obtained from the Royal Leicestershire Rutland and Wycliffe Society for the Blind (RLRWSB). Using the validated technique of capture-mark-recapture (CMR), a census day was set and data from four sources collected: hospital admissions data, GP returns, wards, and mass media. Computer cross-linkage to Leicestershire Health Authority data ensured patients were alive and resident in Leicestershire at the census date. Estimates of diabetes, ethnicity and gender prevalence were calculated using the 1991 census. RESULTS: CMR calculations revealed that there was under ascertainment of visual impairment in the RLRWSB data. The CMR calculations with direct age standardization estimate the prevalence of blindness and partial sight in the general and diabetic populations to be 51.8/10 000 (CI 50.6-53.0) and 148.8/10 000 (CI 122.1-175.5), respectively. In the diabetic population there was a higher proportion of visually impaired females than males (P < 0.05), with no overall ethnic differences; however, rates were lower than expected in female Indo-Asians. In the general population there was a higher proportion of visually impaired Indo-Asian people (P < 0.01). CONCLUSIONS: Our study has shown the prevalence of visual impairment in both the general and diabetic populations and has demonstrated both ethnic and gender differences. CMR allows the calculation of prevalence of blindness and partial sight from existing data. When comparing the prevalence of visual impairment, whether from diabetes or other causes, it is important to know the gender and ethnicity of the 'at risk' population, as well as the rates in the background population.