A Multicomponent Nonpharmacological Intervention to Prevent Delirium for Hospitalized People with Advanced Cancer: A Phase II Cluster Randomized Waitlist Controlled Trial (The PRESERVE Pilot Study).

Background: Delirium is a common debilitating complication of advanced cancer. Objective: To determine if a multicomponent nonpharmacological delirium prevention intervention was feasible for adult patients with advanced cancer, before a phase III (efficacy) trial. Design: Phase II (feasibility) cluster randomized controlled trial. All sites implemented delirium screening and diagnostic assessment. Strategies within sleep, vision and hearing, hydration, orientation, mobility, and family domains were delivered to enrolled patients at intervention site admission days 1-7. Control sites then implemented the intervention ("waitlist sites"). Setting: Four Australian palliative care units. Measurements: The primary outcome was adherence, with an a priori endpoint of at least 60% patients achieving full adherence. Secondary outcomes were interdisciplinary care delivery, delirium measures, and adverse events, analyzed descriptively and inferentially. Results: Sixty-five enrolled patients (25 control, 20 intervention, and 20 waitlist) had 98% delirium screens and 75% diagnostic assessments completed. Nurses (67%), physicians (16%), allied health (8.4%), family (7%), patients (1%), and volunteers (0.5%) delivered the intervention. There was full adherence for 5% patients at intervention sites, partial for 25%. Both full and partial adherence were higher at waitlist sites: 25% and 45%, respectively. One-third of control site patients (32%) became delirious within seven days of admission compared to one-fifth (20%) at both intervention and waitlist sites (p = 0.5). Mean (standard deviation) Delirium Rating Scale-Revised-1998 scores were 16.8 + 12.0 control sites versus 18.4 + 8.2 (p = 0.6) intervention and 18.7 + 7.8 (p = 0.5) waitlist sites. The intervention caused no adverse events. Conclusion: The intervention requires modification for optimal adherence in a phase III trial.

Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas.

Objective Posterior fossa meningiomas are surgically challenging tumors that are associated with high morbidity and mortality. We sought to investigate the anatomical distribution of clinically actionable mutations in posterior fossa meningioma to facilitate identifying patients amenable for systemic targeted therapy trials. Methods Targeted sequencing of clinically targetable AKT1 , SMO , and PIK3CA mutations was performed in 61 posterior fossa meningioma using Illumina NextSeq 500 to a target depth of >500 × . Samples were further interrogated for 53 cancer-relevant RNA fusions by the Archer FusionPlex panel to detect gene rearrangements. Results AKT 1 ( E17K ) mutations were detected in five cases (8.2%), four in the foramen magnum and one in the cerebellopontine angle. In contrast, none of the posterior fossa tumors harbored an SMO ( L412F ) or a PIK3CA ( E545K ) mutation. Notably, the majority of foramen magnum meningiomas (4/7, 57%) harbored an AKT1 mutation. In addition, common clinically targetable gene fusions were not detected in any of the cases. Conclusion A large subset of foramen magnum meningiomas harbor AKT1 E17K mutations and are therefore potentially amenable to targeted medical therapy. Genotyping of foramen magnum meningiomas may enable more therapeutic alternatives and guide their treatment decision process.

A non-exercise method to determine cardiorespiratory fitness identifies females predicted to be at 'high risk' of type 2 diabetes.

This study examined the relationship between cardiorespiratory fitness determined by a non-exercise testing method for estimating fitness and predicted risk of developing type 2 diabetes mellitus using five risk assessments/questionnaires (Leicester Diabetes Risk Score, QDiabetes, Cambridge Risk Score, Finnish Diabetes Risk Score and American Diabetes Association Diabetes Risk Test). Retrospective analysis was performed on 330 female individuals with no prior diagnosis of cardiovascular disease or type 2 diabetes mellitus who participated in the Prosiect Sir Gâr workplace initiative in Carmarthenshire, South Wales. Non-exercise testing method for estimating fitness (expressed as metabolic equivalents) was calculated using a validated algorithm, and females were grouped accordingly into fitness quintiles <6.8 metabolic equivalents (Quintile 1), 6.8-7.6 metabolic equivalents (Quintile 2), 7.6-8.6 metabolic equivalents (Quintile 3), 8.6-9.5 metabolic equivalents (Quintile 4), >9.5 metabolic equivalents (Quintile 5). Body mass index, waist circumference, and HbA1c all decreased between increasing non-exercise testing method for estimating fitness quintiles (p < 0.05), as did risk prediction scores in each of the five assessments/questionnaires (p < 0.05). The proportion of females in Quintile 1 predicted at 'high risk' was between 20.9% and 81.4%, depending on diabetes risk assessment used, compared to none of the females in Quintile 5. A calculated non-exercise testing method for estimating fitness <6.8 metabolic equivalents could help to identify females at 'high risk' of developing type 2 diabetes mellitus as predicted using five risk assessments/questionnaires.

Examining the relationship between HbA1c and diabetes risk models in a European population indicates a lower threshold to identify 'high risk' is required.

This study examined whether changes in HbA1c values are reflected in the risk scores and categories of four validated risk-assessment tools (QDiabetes, Leicester Risk Assessment, Finnish Diabetes Risk Score and Cambridge Risk Score). Retrospective analysis was performed on 651 individuals with no prior diagnosis of cardiovascular disease or diabetes who participated in a UK workplace-based risk-assessment initiative. There were significant positive correlations (p < 0.01) revealed between HbA1c values and predicted risk scores: QDiabetes (r = 0.362), Leicester Risk Assessment (r = 0.315), Finnish Diabetes Risk Score (r = 0.202) and Cambridge Risk Score (r = 0.335). HbA1c values increased within risk prediction categories, and at 'high-risk' categories, median HbA1c values were at least 39 mmol mol(-1) (5.7%) irrespective of gender or risk-assessment model. Overall, an association is present between increases in HbA1c scores and predicted risk of type 2 diabetes. Furthermore, the 'high-risk' median HbA1c values in each of the risk assessments are more akin to the lower American recommendations rather than those suggested by the UK expert group.

Different type 2 diabetes risk assessments predict dissimilar numbers at 'high risk': a retrospective analysis of diabetes risk-assessment tools.

BACKGROUND: Use of a validated risk-assessment tool to identify individuals at high risk of developing type 2 diabetes is currently recommended. It is under-reported, however, whether a different risk tool alters the predicted risk of an individual. AIM: This study explored any differences between commonly used validated risk-assessment tools for type 2 diabetes. DESIGN AND SETTING: Cross-sectional analysis of individuals who participated in a workplace-based risk assessment in Carmarthenshire, South Wales. METHOD: Retrospective analysis of 676 individuals (389 females and 287 males) who participated in a workplace-based diabetes risk-assessment initiative. Ten-year risk of type 2 diabetes was predicted using the validated QDiabetes(®), Leicester Risk Assessment (LRA), FINDRISC, and Cambridge Risk Score (CRS) algorithms. RESULTS: Differences between the risk-assessment tools were apparent following retrospective analysis of individuals. CRS categorised the highest proportion (13.6%) of individuals at 'high risk' followed by FINDRISC (6.6%), QDiabetes (6.1%), and, finally, the LRA was the most conservative risk tool (3.1%). Following further analysis by sex, over one-quarter of males were categorised at high risk using CRS (25.4%), whereas a greater percentage of females were categorised as high risk using FINDRISC (7.8%). CONCLUSION: The adoption of a different valid risk-assessment tool can alter the predicted risk of an individual and caution should be used to identify those individuals who really are at high risk of type 2 diabetes.

Cardiorespiratory fitness is a stronger indicator of cardiometabolic risk factors and risk prediction than self-reported physical activity levels.

This study investigated the relationships of self-reported physical activity levels and cardiorespiratory fitness in 81 males to assess which measurement is the greatest indicator of cardiometabolic risk. Physical activity levels were determined by the General Practice Physical Activity Questionnaire tool and cardiorespiratory fitness assessed using the Chester Step Test. Cardiovascular disease risk was estimated using the QRISK2, Framingham Lipids, Framingham body mass index and Joint British Societies' Guidelines-2 equations, and type 2 diabetes mellitus risk calculated using QDiabetes, Leicester Risk Assessment, Finnish Diabetes Risk Score and Cambridge Risk Score models. Categorising employees by cardiorespiratory fitness categories ('Excellent/Good' vs 'Average/Below Average') identified more differences in cardiometabolic risk factor (body mass index, waist circumference, total cholesterol, total cholesterol:high-density lipoprotein ratio, high-density lipoprotein cholesterol, triglycerides, HbA(1c)) scores than physical activity (waist circumference only). Cardiorespiratory fitness levels also demonstrated differences in all four type 2 diabetes mellitus risk prediction models and both the QRISK2 and Joint British Societies' Guidelines-2 cardiovascular disease equations. Furthermore, significant negative correlations (p < 0.001) were observed between individual cardiorespiratory fitness values and estimated risk in all prediction models. In conclusion, from this preliminary observational study, cardiorespiratory fitness levels reveal a greater number of associations with markers of cardiovascular disease or type 2 diabetes mellitus compared to physical activity determined by the General Practice Physical Activity Questionnaire tool.

Testing implications of varying targets for Bordetella pertussis: comparison of the FilmArray Respiratory Panel and the Focus B. pertussis PCR assay.

BACKGROUND: The FilmArray Respiratory Panel (RP) detects multiple pathogens, including Bordetella pertussis. The multiplex PCR system is appropriate for a core laboratory or point of care due to ease of use. The purpose of this study is to compare the analytical sensitivity of the FilmArray RP, which targets the promoter region of the B. pertussis toxin gene, with the Focus real-time PCR assay, which targets the insertion sequence IS481. METHODS: Seventy-one specimens from patients aged 1 month to 18 years, which had tested positive for B. pertussis using the Focus assay, were analysed using the FilmArray RP. RESULTS: Forty-six specimens were positive for B. pertussis by both the Focus and the FilmArray RP assays. Twenty-five specimens were negative for B. pertussis using the FilmArray RP assay, but positive using the Focus assay. CONCLUSIONS: The FilmArray RP assays will detect approximately 1/3 less cases of B. pertussis than the Focus assay.

Predicted 10-year risk of cardiovascular disease is influenced by the risk equation adopted: a cross-sectional analysis.

BACKGROUND: Validated risk equations are currently recommended to assess individuals to determine those at 'high risk' of cardiovascular disease (CVD). However, there is no longer a risk 'equation of choice'. AIM: This study examined the differences between four commonly-used CVD risk equations. DESIGN AND SETTING: Cross-sectional analysis of individuals who participated in a workplace-based risk assessment in Carmarthenshire, south Wales. METHOD: Analysis of 790 individuals (474 females, 316 males) with no prior diagnosis of CVD or diabetes. Ten-year CVD risk was predicted by entering the relevant variables into the QRISK2, Framingham Lipids, Framingham BMI, and JBS2 risk equations. RESULTS: The Framingham BMI and JBS2 risk equations predicted a higher absolute risk than the QRISK2 and Framingham Lipids equations, and CVD risk increased concomitantly with age irrespective of which risk equation was adopted. Only a small proportion of females (0-2.1%) were predicted to be at high risk of developing CVD using any of the risk algorithms. The proportion of males predicted at high risk ranged from 5.4% (QRISK2) to 20.3% (JBS2). After age stratification, few differences between isolated risk factors were observed in males, although a greater proportion of males aged ≥50 years were predicted to be at 'high risk' independent of risk equation used. CONCLUSIONS: Different risk equations can influence the predicted 10-year CVD risk of individuals. More males were predicted at 'high risk' using the JBS2 or Framingham BMI equations. Consideration should also be given to the number of isolated risk factors, especially in younger adults when evaluating CVD risk.

Prevalence of undiagnosed cardiovascular risk factors and 10-year CVD risk in male steel industry workers.

OBJECTIVE: To assess the prevalence of undiagnosed cardiovascular disease (CVD) in a cohort of male steelworkers in South Wales, UK. METHODS: Male steel industry workers (n = 221) with no prior diagnosis of CVD or diabetes accepted a CVD risk assessment within the work environment. Demographic, anthropometric, family, and medical histories were all recorded and capillary blood samples obtained. The 10-year CVD risk was predicted using the QRISK2-2012 algorithm. RESULTS: Up to 81.5% of workers were either overweight or obese. More than 20% of workers were found to have diastolic hypertension, high total cholesterol, and/or a total cholesterol/high-density lipoprotein ratio of six or more. Over one quarter of workers assessed had an increased 10-year CVD risk. CONCLUSIONS: Despite a physically demanding occupation, risk assessment in the workplace uncovered significant occult factors in CVD risk in a sample of male heavy industry workers.

Cognitive Biases Questionnaire for psychosis.

OBJECTIVE: The Cognitive Biases Questionnaire for psychosis (CBQp) was developed to capture 5 cognitive distortions (jumping to conclusions, intentionalising, catastrophising, emotional reasoning, and dichotomous thinking), which are considered important for the pathogenesis of psychosis. Vignettes were adapted from the Cognitive Style Test (CST),(1) relating to "Anomalous Perceptions" and "Threatening Events" themes. METHOD: Scale structure, reliability, and validity were investigated in a psychosis group, and CBQp scores were compared with those of depressed and healthy control samples. RESULTS: The CBQp showed good internal consistency and test-retest reliability. The 5 biases were not independent, with a 2-related factor scale providing the best fit. This structure suggests that the CBQp assesses a general thinking bias rather than distinct cognitive errors, while Anomalous Perception and Threatening Events theme scores can be used separately. Total CBQp scores showed good convergent validity with the CST, but individual biases were not related to existing tasks purporting to assess similar reasoning biases. Psychotic and depressed populations scored higher than healthy controls, and symptomatic psychosis patients scored higher than their nonsymptomatic counterparts, with modest relationships between CBQp scores and symptom severity once emotional disorders were partialled out. Anomalous Perception theme and Intentionalising bias scores showed some specificity to psychosis. CONCLUSIONS: Overall, the CBQp has good psychometric properties, although it is likely that it measures a different construct to existing tasks, tentatively suggested to represent a bias of interpretation rather than reasoning, judgment or decision-making processes. It is a potentially useful tool in both research and clinical arenas.

Mechanism of antimicrobial action of sodium metasilicate against Salmonella enterica serovar Typhimurium.

Sodium metasilicate (SMS) is an alkaline antimicrobial approved by the U.S. Department of Agriculture for use in poultry processing and ready-to-eat poultry products. The objectives of this study were to determine the effectiveness of SMS against Salmonella enterica serovar Typhimurium in suspension and to elucidate the antimicrobial mechanism of action of SMS. Salmonella Typhimurium (ATCC 14028) was exposed to 0 (positive control), 0.5%, 1%, 2% (wt/vol) SMS and 0.1 N NaOH (high pH) solutions for 1, 10, and 30 min. The viability of Salmonella Typhimurium cells treated with different SMS concentrations and high pH was determined on selective and nonselective media and by staining with fluorescent propidium iodide (PI) and SYTO9 nucleic acid stains in combination with flow cytometry. Transmission electron microscopy of Salmonella Typhimurium cells was performed to observe the changes at the cellular level following exposure to SMS and high pH treatments. Treating Salmonella Typhimurium cells with SMS (as low as 0.5%) resulted in immediate inactivation of Salmonella with no detectable survivors. The breakage in membrane integrity and loss of cell viability was observed by PI uptake by cells treated with SMS with subsequent flow cytometry. Salmonella Typhimurium cells exposed to SMS and high pH appeared wrinkled, vacuolated, and lysed with their cytoplasmic material leaking into extracellular matrix on transmission electron micrographs. The findings from this study indicate that SMS acts on the cytoplasmic membrane and causes lysis of the cells and leakage of intracellular contents.

Pasturella multicoda infection of an abdominal aortic endograft.

Both surgical and endovascular grafts have the rare risk of late secondary infection. Treatment varies based on the clinical setting, but in general the recommendations are that infected endografts be removed and reconstruction performed. In the abdominal aorta this may vary from homograft or other impregnated grafts to excision and extra-anatomic bypass. We discuss an unusual case which we believe serves as a useful review of this still debated area. A 58-year-old male presented with abdominal and back pain. Prior history was notable for human immunodeficiency virus positive status, pulmonary embolism (currently on Coumadin) and two years previously repair of a saccular infra-renal aneurysm with tube graft. The week prior to the onset of symptoms he suffered a noticeable scratch from his cat. Blood cultures were positive for pasturella multicoda. He was transferred to our institution and underwent resection and explantation, with homograft reconstruction. At one year he is alive and well.

Hearing the voices of service user researchers in collaborative qualitative data analysis: the case for multiple coding.

BACKGROUND: Health research is frequently conducted in multi-disciplinary teams, with these teams increasingly including service user researchers. Whilst it is common for service user researchers to be involved in data collection--most typically interviewing other service users--it is less common for service user researchers to be involved in data analysis and interpretation. This means that a unique and significant perspective on the data is absent. AIM: This study aims to use an empirical report of a study on Cognitive Behavioural Therapy for psychosis (CBTp) to demonstrate the value of multiple coding in enabling service users voices to be heard in team-based qualitative data analysis. DESIGN: The CBTp study employed multiple coding to analyse service users' discussions of CBT for psychosis (CBTp) from the perspectives of a service user researcher, clinical researcher and psychology assistant. Multiple coding was selected to enable multiple perspectives to analyse and interpret data, to understand and explore differences and to build multi-disciplinary consensus. RESULTS: Multiple coding enabled the team to understand where our views were commensurate and incommensurate and to discuss and debate differences. Through the process of multiple coding, we were able to build strong consensus about the data from multiple perspectives, including that of the service user researcher. DISCUSSION: Multiple coding is an important method for understanding and exploring multiple perspectives on data and building team consensus. This can be contrasted with inter-rater reliability which is only appropriate in limited circumstances. CONCLUSION: We conclude that multiple coding is an appropriate and important means of hearing service users' voices in qualitative data analysis.

Antimicrobial effects of sodium metasilicate against Listeria monocytogenes.

Sodium metasilicate (SMS) is a U.S. Department of Agriculture-approved antimicrobial for use in meat and poultry processing and has been known to be effective against various foodborne pathogens. However, its antimicrobial mechanism has not yet been revealed. In this study, we attempted to elucidate the mechanism by which SMS inactivates Listeria monocytogenes, a Gram-positive bacterial pathogen encountered commonly in ready-to-eat meat and poultry products. L. monocytogenes (Scott A) cells were treated with different concentrations of SMS (1.0, 2.0, 3.0, 4.0, 5.0, and 6.0% [wt/vol]) and compared with high pH treatment (0.1, 0.2, and 0.3N NaOH solutions) for 1, 10, and 30 min. SMS exhibited concentration and time effects on inactivation of L. monocytogenes. The effect of SMS on the membrane integrity and viability of L. monocytogenes was determined by use of propidium iodide (PI) and SYTO9 nucleic acid stains with subsequent flow cytometry. The breakage in membrane integrity was observed by uptake of PI by cells treated with SMS with subsequent flow cytometry. Ultrastructural changes from corresponding transmission electron micrographs further revealed the disruption in the cytoplasmic membrane and changes in the morphology of the cells treated with SMS and high pH. The results from flow cytometry experiment and transmission electron microscopy study indicated that following SMS treatment, the membrane integrity of L. monocytogenes was compromised leading to leakage of intracellular contents and subsequent cell death.

Academic partnerships to increase nursing education capacity: centralized faculty resource and clinical placement centers.

The North Texas Consortium of Professional Nursing Programs and Practice Partners is a regional academic partnership of nursing education and practice organizational leaders working together to share innovative ideas and best practices and to improve efficiencies that impact nursing education. The region's 15 nursing schools produced 25% of the Texas graduates, or 1,782 graduates, in 2008-2009. Yet, 3,522 graduates are needed in 2013-2014 to meet the projected north Texas demand. Barriers to increasing enrollment and graduation numbers were the lack of sufficient faculty to meet demand and insufficient numbers of clinical placement sites. To increase the capacity for graduating the numbers of nurses needed, the region developed a three-pronged plan to overcome each of these barriers: expansion of partnership members and development of a regional computerized clinical placement center and faculty resource center. The academic partnership expanded its members to include the 15 schools of nursing, more than 50 hospitals, and the Dallas Fort Worth Hospital Council (DFWHC) Foundation for the purposes of governance of the two proposed computerized centers and strategic planning for increased capacity. The faculty resource center is a centralized, one-stop shop for those interested in teaching and those needing faculty. The Centralized Clinical Placement Center is expected to streamline the nursing student clinical placements process and monitor the numbers of students per site at a given time so as to ensure that placements are at capacity and that schools of nursing benefit fairly in placing students in specialty areas to meet course objectives.

A post-trial survey to assess the impact of dissemination of results and unmasking on participants in a 13-year randomised controlled trial on age-related cataract.

BACKGROUND: The Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract was designed to assess the impact of a multivitamin-mineral supplement on age-related cataract. Trial results showed evidence of a beneficial effect of the supplement on all types of cataract combined, opposite effects on two of the three types of cataract (beneficial for nuclear opacities and harmful for posterior sub-capsular opacities) and no statistically significant effect on cortical opacities. No treatment recommendations were made. A post-trial survey was conducted on 817 surviving elderly participants to assess their satisfaction, their understanding of treatment assignment to supplement or placebo and the success of masking. METHODS: Trial results were communicated by letter and the level of satisfaction and of understanding of the results was assessed by a questionnaire. Participants were offered the option of being unmasked: a second questionnaire was administered to this subset to assess their understanding of the randomisation process and the success of masking. RESULTS: 610 participants (74.7%) responded to the survey:94.6% thought the description of the results was "very clear" or "quite clear", 5.4% "not clear" or "do not know"; 89.8% considered the results "very interesting" or "quite interesting", 10.2% "not interesting" or "do not know"; 60.3% expressed "satisfaction", 17.2% "both satisfaction and concern", 2.6% "concern", 19.9% "indifference" or "do not know".480 participants (78.7%) accepted the offer to be unmasked to their treatment assignment: 395 (82.3%) recalled/understood the possibility of assignment to vitamins or placebo, 85 (17.7%) did not. 68 participants (17.2%) thought they had taken vitamins (79.4% were correct; p = 0.0006), 47 (11.9%) thought they had taken placebo (59.6% were correct; p = 0.46) and 280 (70.9%) declared they did not know. CONCLUSIONS: The results were made difficult to explain to study participants by the qualitatively different effect of treatment on the two most visually significant types of cataract. Although the study did not lead to a recommendation to use the dietary supplement, the vast majority of participants reported satisfaction after they received the results but almost 20% of the participants expressed some concern. Masking to treatment assignment was successful in the majority of participants.

CHoice of Outcome In Cbt for psychosEs (CHOICE): the development of a new service user-led outcome measure of CBT for psychosis.

Outcome measures for cognitive behavior therapy for psychosis (CBTp) have been derived from pharmacological studies, focusing on symptom change rather than outcomes such as distress or fulfillment. This study presents the development and psychometric properties of a new outcome measure (CHoice of Outcome In Cbt for psychosEs [CHOICE]), which reflects more strongly the aims of CBTp and the priorities of service users. Service users who had received CBTp participated in focus groups to discuss their outcome priorities, using a topic guide generated by a panel of experts in CBTp. A qualitative thematic analysis was undertaken to reach consensus on themes and generate items. Response scales were constructed for 3 dimensions: severity, satisfaction, and importance. The resulting questionnaire was piloted with service users who had not received CBTp, stratified by service type, ethnicity, and first language to ensure that it was user friendly and applicable prior to CBTp. The psychometric properties of the measure were then examined in a sample of 152 service users. Twenty-four items, and 2 of the dimensions (severity and satisfaction), were retained in the final measure. A factor analysis revealed a single psychological recovery factor interspersed throughout with both CBTp and recovery items. Test-retest reliability, construct validity, and sensitivity to change following CBTp were confirmed. The CHOICE measure is unique in being the first psychometrically adequate service user-led outcome measure of CBTp. It provides the opportunity to examine the evidence base for CBTp with an assessment approach that prioritizes service user definitions of recovery and CBT aims.

The APC Variant p.Glu1317Gln predisposes to colorectal adenomas by a novel mechanism of relaxing the target for tumorigenic somatic APC mutations.

Multiple rare nonsynonymous variants in APC predispose to colorectal adenomas. The mechanisms through which such variants act have been unclear, but it has been proposed that a specific ("just-right") level of beta-catenin signaling is required for colorectal tumorigenesis. This appears to be mediated by selection for APC genotypes that retain one, or rarely two, 20 amino acid beta-catenin downregulating repeats (20AARs). We investigated the mechanism through which the variant p.Glu1317Gln (c.3949G>C) contributes to colorectal tumorigenesis. We compared the patterns of somatic APC mutations in tumors from patients with attenuated familial adenomatous polyposis (AFAP) who did, or did not, coinherit p.Glu1317Gln with their AFAP-causing APC mutations. Only 8.2% (4/49) of tumors carrying p.Glu1317Gln had somatic mutations predicted to result in mutant polypeptides retaining a single 20AAR, compared to 62.1% (36/58) of those which did not carry this variant (P=5.64 x 10(-9)). Furthermore, tumors with p.Glu1317Gln often carried somatic mutations that were unusually early or late (downstream of the second 20AAR) in the APC open reading frame. These data support a novel mechanism in which p.Glu1317Gln in combination with other weak mutant APC alleles (generating polypepetides with zero, two, or three 20AARs) can provide the necessary growth advantage for colorectal tumorigenesis.

Effects of multivitamin/mineral supplementation on plasma levels of nutrients. Report No. 4 of the Italian-American clinical trial of nutritional supplements and age-related cataract.

The use of multivitamin-mineral supplements has become increasingly common, but whether the use of such supplements improves micronutrient status remains still unclear. The objective of this report is to investigate how a long-term vitamin-mineral supplementation following the US Recommended Daily Intake (RDI) affected the plasma levels of selected nutrients in a subset (No. = 407) of participants in the Italian-American Clinical Trial of Nutritional Supplements and Age-related Cataract (CTNS). The CTNS was a double-blind, single centre, controlled clinical trial of 1020 participants aged 55-75 years randomized to a daily tablet of Centrum(R) or placebo. A representative sample of 40% of the 1020 subjects, whom plasma level of selected vitamins was determined at the baseline, was retested throughout the treatment period that averaged 9.0 +/- 2.4 years. Participants assigned to Centrum(R) showed a significant increase (p < 0.005) in mean/median plasma levels of vitamin E, beta-carotene, folate, and vitamin B12, and an improved riboflavin status when compared with participants assigned to placebo. Differences concerning vitamin C were statistically less relevant and those concerning vitamin A were at a borderline level. In the treated group the effect of supplementation on plasma levels of vitamins A, E, and C, and on the glutathione reductase activation coefficient was significantly higher in participants with lower nutritional status at baseline.

A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities. Clinical trial of nutritional supplements and age-related cataract report no. 3.

OBJECTIVE: To evaluate the effect of a multivitamin/mineral supplement on development or progression of age-related lens opacities. DESIGN: Randomized, double-masked, single center, placebo-controlled clinical trial. PARTICIPANTS: One thousand twenty participants, 55 to 75 years old and with early or no cataract, were randomly assigned to a daily tablet of a multivitamin/mineral formulation or a placebo. METHODS: Baseline and annual lens photographs were graded for severity of lens opacities according to a modification of the Age-Related Eye Disease Study system for classifying cataracts. MAIN OUTCOME MEASURES: The primary outcome was a prespecified increase from baseline in nuclear, cortical, or posterior subcapsular cataract (PSC) opacity grades or cataract surgery. Secondary outcomes included an increase in type-specific opacity grades, cataract surgery, and visual acuity (VA) loss from baseline > or =15 letters. RESULTS: Participants were observed for an average of 9.0+/-2.4 years. There was a decrease in total lens events in participants assigned to the multivitamin/mineral formulation compared with those assigned to the placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.68-0.98; P = 0.03). Nuclear events were significantly less common (HR, 0.66; 95% CI, 0.50-0.88; P = 0.004) and PSC events significantly more common (HR, 2.00; 95% CI, 1.35-2.98; P<0.001) in participants taking the multivitamin/mineral formulation than in those assigned to the placebo. No statistically significant treatment effects were seen for cortical opacities, moderate VA loss, or cataract surgery. CONCLUSIONS: Lens events were less common in participants who took the multivitamin/mineral formulation, but treatment had opposite effects on the development or progression of nuclear and PSC opacities, the 2 most visually important opacity subtypes.