Primary Care Support Tools for Digestive Health Care: A Mixed Method Study.

Background: To address the increasing demands for gastroenterology specialty care and increasing wait times, centralized access and triage (CAT) systems, telephone support, and clinical care pathways were implemented to streamline referrals and support management of low-risk gastrointestinal (GI) conditions in the primary care medical home. This study aimed to understand primary care providers (PCPs) and GI specialists' perceptions of these supports, factors that affect support implementation and identify barriers and facilitators for implementing supports from both PCP and GI specialists' perspectives. Methods: We conducted a mixed method study including surveys and interviews with PCPs and GI specialists. Online surveys and semistructured qualitative interviews were conducted from July 2022 to September 2022. All interviews were transcribed and coded to perform a thematic analysis. Survey data were analyzed in SPSS version 25. Descriptive statistics were employed to summarize and describe the data collected. Inferential statistics were used to identify associations and relationships within the dataset. T-test and chi-square tests were applied at 95% confidence level, with a p value <0.05 (two-sided) considered statistically significant. Results: A total of 36 PCPs responded to the survey. Most respondents were working full-time (73.5%, n = 25) and were female (73.5%, n = 25). Overall, 42% used the pathways regularly, 48% (n = 16) used them occasionally, and very few (9.1%, n = 3) said they were aware but had not used pathways. Overall, PCPs were satisfied with CAT processes and the use of primary care pathways, recognizing the importance of fair and equitable access to specialty care. Specific processes in CAT for vulnerable populations and patients using walk-in clinics were recognized as a limitation, given the lack of ease in completing the required testing and follow-up needed when utilizing the care pathway. Of the 112 GI specialists who received the survey, 28 (25%) completed it, with males (50.0%, n = 14) and females (39.2%, n = 11), remainder no response. Most participate in CAT (73.9%, n = 17) and were remunerated by an alternative relationship plan (ARP) (53.6%, n = 15). Overall, GIs were satisfied with central triaging and primary care pathways, reducing unnecessary time and resource expenditure for referrals. There were statistically significant differences in perceptions among fee for service and alternative relationship plan GI specialists regarding the effectiveness of CAT in improving access and use of health system resources. Conclusion: Overall, PCPs and GI specialists believe utilizing CAT and primary care pathways improves referral quality, reduces resource expenditure, and provides fair and equitable access to GI specialty services. Improvement in CAT processes with improved pathway awareness may reduce unnecessary referrals.

Perception of Neighborhood Safety and Maternal and Neonatal Health Outcomes.

This cross-sectional study examines whether perceived neighborhood safety is independently associated with adverse birth outcomes.

Lived experience-centred word clouds may improve research uncertainty gathering in priority setting partnerships.

INTRODUCTION: AO Spine RECODE-DCM was a multi-stakeholder priority setting partnership (PSP) to define the top ten research priorities for degenerative cervical myelopathy (DCM). Priorities were generated and iteratively refined using a series of surveys administered to surgeons, other healthcare professionals (oHCP) and people with DCM (PwDCM). The aim of this work was to utilise word clouds to enable the perspectives of people with the condition to be heard earlier in the PSP process than is traditionally the case. The objective was to evaluate the added value of word clouds in the process of defining research uncertainties in National Institute for Health Research (NIHR) James Lind Alliance (JLA) Priority Setting Partnerships. METHODS: Patient-generated word clouds were created for the four survey subsections of the AO Spine RECODE-DCM PSP: diagnosis, treatment, long-term management and other issues. These were then evaluated as a nested methodological study. Word-clouds were created and iteratively refined by an online support group of people with DCM, before being curated by the RECODE-DCM management committee and expert healthcare professional representatives. The final word clouds were embedded within the surveys administered at random to 50% of participants. DCM research uncertainties suggested by participants were compared pre- and post-word cloud presentation. RESULTS: A total of 215 (50.9%) participants were randomised to the word cloud stream, including 118 (55%) spinal surgeons, 52 (24%) PwDCM and 45 (21%) oHCP. Participants submitted 434 additional uncertainties after word cloud review: word count was lower and more uniform across each survey subsections compared to pre-word cloud uncertainties. Twenty-three (32%) of the final 74 PSP summary questions did not have a post-word cloud contribution and no summary question was formed exclusively on post-word cloud uncertainties. There were differences in mapping of pre- and post-word cloud uncertainties to summary questions, with greater mapping of post-word cloud uncertainties to the number 1 research question priority: raising awareness. Five of the final summary questions were more likely to map to the research uncertainties suggested by participants after having reviewed the word clouds. CONCLUSIONS: Word clouds may increase the perspective of underrepresented stakeholders in the research question gathering stage of priority setting partnerships. This may help steer the process towards research questions that are of highest priority for people with the condition.

NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer.

Identifying cellular drivers responsible for enhancing cancer cell resistance to therapeutics provides critical information for designing more effective drugs. Populations of slowly growing, self-renewing, chemo-resistant cells purportedly contribute to the development of therapeutic resistance in many solid tumors. In the current study, we implemented a tumor spheroid model to determine whether NAD(P)H quinone oxidoreductase-1 (NQO1) was requisite for self-renewal and promotion of the drug-resistant phenotype in non-small cell lung cancer (NSCLC). We found that stable depletion of NQO1 in A549 and H358 human NSCLC tumor models inhibits self-renewal capabilities, as demonstrated by a reduced ability to form primary, secondary, and tertiary spheroids. In contrast, the rescue of NQO1 expression restored the tumor cells' ability to form spheroids. Additionally, we discovered that NQO1 depletion renders cisplatin-refractory tumor spheroids highly susceptible to drug treatment. Together, these results suggest that NQO1 loss reduces the self-renewing capabilities of NSCLC cells and enhances their susceptibility to clinically relevant therapeutics. These findings describe a novel role for NQO1 and suggest that combining NQO1-inhibitors with conventional chemotherapeutics may enhance anti-tumor effects.

Case report: Assessment of a quarantine treatment for sheep on the Caribbean Island of St. Kitts.

Quarantine treatments can be used to prevent bringing resistant parasites onto a farm. However, in the face of growing anthelmintic resistance and variations in farm practices, assessing efficacy of such treatments before full implementation is needed. In this case report, a combination treatment of ivermectin (injectable formulation) and fenbendazole (both approximately double doses) administered orally within minutes of each other was assessed in 19 sheep. The mean pretreatment Strongylid eggs per gram of feces, determined using a McMaster, was 2639. The mean post treatment count (at 14 days) was 2663 with 12 animals having a decrease in egg counts. There was an average increase of 0.9% using pre and post treatment egg count means. This combination treatment was not effective as a quarantine treatment.

Retrospective audit of a convenience cohort of individuals on HIV pre-exposure prophylaxis in Alberta, Canada.

BACKGROUND: We undertook an audit of a province-wide HIV pre-exposure prophylaxis (PrEP) program in Alberta (Canada). METHODS: A retrospective record review of individuals accessing PrEP in Alberta included demographics, PrEP indication(s), and reported non-prescription drug and alcohol use from March 2016 to June 2019. Hepatitis A, B, C, HIV and syphilis serology, serum creatinine, and nucleic acid amplification tests testing for chlamydia and gonorrhea were collected. Descriptive statistics, incidence, and prevalence were calculated. RESULTS: A total of 511 participants were seen at STI, sexual, and reproductive health clinics and private family practitioner (FP) offices; 98.4% (503) were men, median age was 34 years (IQR 28-43 years), and 89.8% (459) were gay or bisexual men who have sex with men. Non-prescription drug use was reported by 39.3% (201) and alcohol use by 55.4% (283). 94.3% (482) reported condomless anal sex in the past 6 months. Testing rates were high (>95%) for all tests except for chlamydia and gonorrhea at the first follow-up visit 89.6%; (3-4 months). There was one HIV seroconversion. The incidence of new bacterial STIs was high: chlamydia 17 cases per 100 person-years (95% CI 13.5% to 21.4%), gonorrhea 11.14 cases per 100 person-years (95% CI 8.3% to 15.0%), and syphilis 1.94 cases per 100 person-years (95% CI 0.73% to 5.12%). CONCLUSIONS: Following implementation of a provincial program for PrEP in Alberta, PrEP initiation and continuation was feasible in a range of settings and by both specialists and FPs.

HISTORIQUE: Les chercheurs ont entrepris une vérification du programme provincial de prophylaxie pré-exposition (PrEP) du VIH en Alberta, au Canada. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective des dossiers des personnes qui ont eu accès à la PrEP en Alberta, y compris les données démographiques, les indications d'administrer une PrEP et la consommation déclarée de médicaments sans ordonnance et d'alcool entre mars 2016 et juin 2019. Ils ont recueilli la sérologie de l'hépatite A, B et C, du VIH et de la syphilis, la créatinine sérique et les tests d'amplification des acides nucléiques de la Chlamydia et de la gonorrhée. Ils ont également calculé les statistiques descriptives, l'incidence et la prévalence de ces maladies. RÉSULTATS: Au total, 511 participants ont été vus dans des cliniques d'ITS, de santé sexuelle et de santé reproductive ainsi qu'au cabinet de médecins de famille privés, soit 98,4 % d'hommes (503), d'un âge médian de 34 ans (ÉIQ : 28 à 43 ans) et 89,8 % (459) d'hommes gay ou bisexuels qui avaient des relations sexuelles avec d'autres hommes. Ainsi, 39,3 % (201) ont déclaré consommer des médicaments sans ordonnance et 55,4 % (283), de l'alcool. De plus, 94,3 % (482) ont indiqué avoir eu des relations sexuelles anales sans préservatif au cours des six mois précédents. Les taux de dépistage étaient élevés (>95 %) à l'égard de tous les tests au premier rendez-vous de suivi (au bout de trois à quatre mois), sauf ceux de la Chlamydia et de la gonorrhée, qui s'élevaient à 89,6 %. Un cas de séroconversion du VIH a été constaté. L'incidence de nouvelles ITS bactérienne était élevée : 17 cas de Chlamydia par 100 années-personnes (IC à 95 %, 13,5 % à 21,4 %), 11,14 cas de gonorrhée par 100 années-personnes (IC à 95 %, 8,3 % à 15,0 %) et 1,94 cas de syphilis par 100 années-personnes (IC à 95 %, 0,73 % à 5,12 %). CONCLUSIONS: Après la mise en œuvre d'un programme provincial de PrEP en Alberta, il a été établi qu'il était possible d'entreprendre et de poursuivre la PrEP dans divers milieux, à l'instigation de spécialistes tout autant que de médecins de famille.

Impact of Human-Animal Interactions on Psychological and Physiological Factors Associated With Veterinary School Students and Donkeys.

There has been an increased interest in evaluating human-animal interactions and assessing the mutual health and wellbeing. In this study, first-year female and male veterinary school students not paired (n = 58) or paired (n = 25) with immature (≤9 mo) donkeys (n = 13) were engaged in three different types of interactions (1st, hands-off remote learning, 2nd, hands-on passive learning, and 3rd, hands-on active learning) for 30 min each during Week 2 (Time 1), Weeks 5-8 (Time 2), and Week 12 (Time 3) over three, 15-week periods. Student psychological data involved the Penn State Worry Questionnaire (PSWQ) scores collected from the interactive (student-donkey pairs) and non-interactive (no student-donkey pairs) groups and modified Comfort from Companion Animals Scale (CCAS) scores collected from the interactive group during Times 1, 2, and 3. Donkey physiological data involved collection of saliva within 10 min pre- and post-interaction during Times 1, 2, and 3 in association with the different types of interactions for immunoanalysis of cortisol. There were no significant effects of the various times and types of interactions on CCAS scores. While there were no significant effects of group and types of interactions on PSWQ scores, there was an effect (P = 0.01) of time. Overall mean PSWQ scores were significantly lower during Week 12 versus Week 2. Correspondingly, while there were no effects pre- vs. post-interaction within or among times on saliva cortisol concentrations in donkeys, there was an effect (P = 0.02) of the type of interaction. Mean concentrations were significantly lower with the hands-on passive and hands-on active learning versus the hands-off remote learning. In conclusion, while this study provides preliminary evidence surrounding student donkey interactions, future studies are required with more comprehensive designs to clarify these benefits and better understand the advantages and challenges surrounding student-donkey interactions.

The development of lived experience-centered word clouds to support research uncertainty gathering in degenerative cervical myelopathy: results from an engagement process and protocol for their evaluation, via a nested randomized controlled trial.

OBJECTIVES: AO Spine REsearch objectives and Common Data Elements for Degenerative Cervical Myelopathy [RECODE-DCM] is a multi-stakeholder consensus process aiming to promote research efficiency in DCM. It aims to establish the top 10 research uncertainties, through a James Lind Alliance Priority Setting Partnership [PSP]. Through a consensus process, research questions are generated and ranked. The inclusion of people with cervical myelopathy [PwCM] is central to the process. We hypothesized that presenting PwCM experience through word cloud generation would stimulate other key stakeholders to generate research questions better aligned with PwCM needs. This protocol outlines our plans to evaluate this as a nested methodological study within our PSP. METHODS: An online poll asked PwCM to submit and vote on words associated with aspects of DCM. After review, a refined word list was re-polled for voting and word submission. Word clouds were generated and an implementation plan for AO Spine RECODE-DCM PSP surveys was subsequently developed. RESULTS: Seventy-nine terms were submitted after the first poll. Eighty-seven refined words were then re-polled (which added a further 39 words). Four word clouds were generated under the categories of diagnosis, management, long-term effects, and other. A 1:1 block randomization protocol to assess word cloud impact on the number and relevance of PSP research questions was generated. CONCLUSIONS: We have shown it is feasible to work with PwCM to generate a tool for the AO Spine RECODE-DCM nested methodological study. Once the survey stage is completed, we will be able to evaluate the impact of the word clouds. Further research will be needed to assess the value of any impact in terms of stimulating a more creative research agenda.

Detection of Coxiella burnetii antibodies in sheep and cattle on a veterinary campus in St. Kitts: Implications for one health in the Caribbean region.

Coxiella burnetii is a ubiquitous zoonotic bacterium reported worldwide that causes Q-fever. Infections result in profound economic losses to livestock producers by causing abortions and low birth weights. Current information about the disease in the Caribbean region is scarce. With multiple small islands and territories, it is often considered that the bacterium is absent or circulates at a low prevalence. Our study aimed to determine whether sheep and cattle housed at a veterinary campus in St Kitts had previous exposure to C. burnetii. Blood samples were taken from cattle (n = 63; 72% of the herd) and sheep (n = 133; 71% of the flock). Antibodies to C. burnetii were detected by a commercial indirect enzyme-linked immunosorbent assay (IDvet® ELISA) test. The seroprevalence was estimated at 26.3% (95% CI: 19.1-34.7%) in sheep and 0% (95% CI: 0-5.7%) in cattle. Sheep importation to St. Kitts is very rare, thus, these results suggest that C. burnetii is present on the island. The seronegativity of all the cattle highlights the absence of the bacterium on the veterinary campus. The high seroprevalence in sheep, however, has potentially important implications for animal health and public health as well as for wildlife conservation. Further investigation about animal seroprevalence and human exposure are warranted in St. Kitts and in the Caribbean region.

Molecular Diagnosis of Vaginitis: Comparing Quantitative PCR and Microbiome Profiling Approaches to Current Microscopy Scoring.

Vaginitis is often diagnosed by microscopy and limited to testing for bacterial vaginosis (BV), vulvovaginal candidiasis, and trichomoniasis. Approximately 10% of vaginal swabs are negative but designated "altered flora" by BV Nugent score, leaving clinicians unsure how to treat patients. Accurate and comprehensive vaginitis diagnostics are needed to direct treatment and reduce risks of recurrent or more severe infections. Vaginal swabs were collected from 93 women (mean age, 23.53 years; range, 18 to 42 years) in a cross-sectional study. Microscopy results for BV and Candida were compared to those from two molecular approaches: (i) a comprehensive quantitative PCR (qPCR) assay, including testing for aerobic vaginitis (AV), Candida, sexually transmitted infections (STI), and BV (Applied Biosystems) with an accompanying BV interpretive algorithm (Coriell Life Sciences), and (ii) microbiome profiling of the 16S rRNA gene (Illumina). Microscopy plus BV Nugent score had 76% overall agreement with the qPCR plus BV interpretive algorithm method (24 positive, 47 negative). OF the nine samples designated altered flora by Nugent, five were categorized BV positive and four were BV negative by the qPCR method. Although BV negative, 3/4 of the latter samples had positive AV targets with one also was STI positive. Microscopic identification of Candida versus that by qPCR had 94% agreement (9 positive, 78 negative). The comprehensive qPCR assay revealed alternative etiologies summarized as 38% BV, 10% AV, 5% Candida, 2% STI, 10% mixed infection (positive targets in multiple panels), and 35% negative for all targets. 16S microbiome analysis confirmed the bacterial qPCR results and identified differentiating patterns between AV, BV, and Lactobacillus-dominated vaginal microbiomes.

RE-CODE DCM (REsearch Objectives and Common Data Elements for Degenerative Cervical Myelopathy): A Consensus Process to Improve Research Efficiency in DCM, Through Establishment of a Standardized Dataset for Clinical Research and the Definition of the Research Priorities.

STUDY DESIGN: Mixed-method consensus process. OBJECTIVES: Degenerative cervical myelopathy (DCM) is a common and disabling condition that arises when mechanical stress damages the spinal cord as a result of degenerative changes in the surrounding spinal structures. RECODE-DCM (REsearch Objectives and Common Data Elements for Degenerative Cervical Myelopathy) aims to improve efficient use of health care resources within the field of DCM by using a multi-stakeholder partnership to define the DCM research priorities, to develop a minimum dataset for DCM clinical studies, and confirm a definition of DCM. METHODS: This requires a multi-stakeholder partnership and multiple parallel consensus development processes. It will be conducted via 4 phases, adhering to the guidance set out by the COMET (Core Outcomes in Effectiveness Trials) and JLA (James Lind Alliance) initiatives. Phase 1 will consist of preliminary work to inform online Delphi processes (Phase 2) and a consensus meeting (Phase 3). Following the findings of the consensus meeting, a synthesis of relevant measurement instruments will be compiled and assessed as per the COSMIN (Consensus-based Standards for the Selection of Health Measurement Instruments) criteria, to allow recommendations to be made on how to measure agreed data points. Phase 4 will monitor and promote the use of eventual recommendations. CONCLUSIONS: RECODE-DCM sets out to establish for the first time an index term, minimum dataset, and research priorities together. Our aim is to reduce waste of health care resources in the future by using patient priorities to inform the scope of future DCM research activities. The consistent use of a standard dataset in DCM clinical studies, audit, and clinical surveillance will facilitate pooled analysis of future data and, ultimately, a deeper understanding of DCM.

Transcription factors WT1 and p53 combined: a prognostic biomarker in ovarian cancer.

BACKGROUND: New approaches to ovarian cancer are needed to improve survival. Wilms' tumour 1 (WT1) is a tumour-associated antigen expressed in many ovarian cancers. P53 is also often altered. The clinical significance of the combined expression of these two transcription factors has not been studied. METHODS: One hundred ninety-six ovarian tumours were classified histopathologically. Tumours were stained for WT1 and p53 immunohistochemically. Stains were analysed according to tumour type, grade and FIGO stage. Kaplan-Meier analyses on 96 invasive carcinomas determined whether categorical variables were related to survival. RESULTS: WT1 and p53 were related to ovarian tumour type, grade, FIGO stage and patient survival. Uniform nuclear p53 expression was associated with invasion and WT1 expression was associated with advanced grade, FIGO stage and poor survival. When WT1 and p53 were both in the age-adjusted Cox model, WT1 was significant while p53 was not. When we combined tumours expressing WT1 and p53, then adjusted for age and tumour subtype, the hazard ratio compared to tumours without WT1 and with normal p53 was 2.70; when adjusted for age and FIGO stage, the hazard ratio was 2.40. CONCLUSIONS: WT1, an antigen target, is a biomarker for poor prognosis, particularly when combined with altered p53.

Metabolic Disruption Early in Life is Associated With Latent Carcinogenic Activity of Dichloroacetic Acid in Mice.

Early-life environmental factors can influence later-life susceptibility to cancer. Recent evidence suggests that metabolic pathways may mediate this type of latency effect. Previously, we reported that short-term exposure to dichloroacetic acid (DCA) increased liver cancer in mice 84 weeks after exposure was stopped. Here, we evaluated time course dynamics for key events related to this effect. This study followed a stop-exposure design in which 28-day-old male B6C3F1 mice were given the following treatments in drinking water for up to 93 weeks: deionized water (dH2O, control); 3.5 g/l DCA continuously; or 3.5 g/l DCA for 4-52 weeks followed by dH2O. Effects were evaluated at eight interim time points. A short-term biomarker study was used to evaluate DCA effects at 6, 15, and 30 days. Liver tumor incidence was higher in all DCA treatment groups, including carcinomas in 82% of mice previously treated with DCA for only 4 weeks. Direct effects of DCA in the short-term study included decreased liver cell proliferation and marked mRNA changes related to mitochondrial dysfunction and altered cell metabolism. However, all observed short-term effects of DCA were ultimately reversible, and prior DCA treatment did not affect liver cell proliferation, apoptosis, necrosis, or DNA sequence variants with age. Key intermediate events resulting from transient DCA exposure do not fit classical cytotoxic, mitogenic, or genotoxic modes of action for carcinogenesis, suggesting a distinct mechanism associated with early-life metabolic disruption.

Constructions, reconstructions and deconstructions of 'family' amongst people who live apart together (LATs).

This article explores how people who live apart from their partners in Britain describe and understand 'family'. It investigates whether, and how far, non-cohabiting partners, friends, 'blood' and legal ties are seen as 'family', and how practices of care and support, and feelings of closeness are related to these constructions. It suggests that people in LAT relationships creatively draw and re-draw the boundaries of family belonging in ways that involve emotionally subjective understandings of family life, and that also refer to normative constructions of what 'family' ought to be, as well as to practical recognitions of lived family 'realities'. This often involves handling uncertainties about what constitutes 'family'.

Increased Suicidal Ideation in Patients with Co-Occurring Bipolar Disorder and Post-Traumatic Stress Disorder.

Suicide risk increases for those with Bipolar Disorder or PTSD, however little research has focused on risk for co-occurring Bipolar Disorder and PTSD. The aim of this article was to evaluate increased suicide risk in co-occurring disorders, and differences in suicide risk for patients with Bipolar I versus Bipolar II. This study evaluated suicide risk in patients with co-occurring PTSD and Bipolar Disorder (n = 3,158), using the MADRS and Suicide Questionnaire. Those with history of PTSD had significantly higher suicidal ideation than those without (U = 1063375.00, p < .0001). Those with Bipolar I had higher risk than those with Bipolar II. Patients with Bipolar I and PTSD were at higher risk for suicidal ideation, implying the importance of diagnosis and risk assessment.

Stromal-Based Signatures for the Classification of Gastric Cancer.

Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.

Phosphorylation of eIF4E serine 209 is associated with tumour progression and reduced survival in malignant melanoma.

BACKGROUND: Melanoma is a disease that primarily arises in the skin but is a derivative of the neural crest. Eukaryotic translation initiation factor 4E (eIF4E) regulates translation of multiple malignancy-associated mRNAs and is overexpressed in many epithelial tumours. However, expression in human tumours derived from the neural crest is unknown. Here, we determined the association of eIF4E and phospho-eIF4E expression in melanocytic lesions with malignant conversion, metastatic potential and patient survival. METHODS: Archived formalin-fixed, paraffin-embedded surgical specimens from 114 patients with melanocytic lesions were stained immunohistochemically for eIF4E and phospho-eIF4E and evaluated semiquantitatively. The relationship between cytoplasmic and nuclear eIF4E and phospho-eIF4E protein expression, melanocytic lesion subtype and tumour progression was determined. Kaplan-Meier survival analyses and Cox proportional hazard regression were performed. RESULTS: Increased eIF4E and phospho-eIF4E expression was highly associated with malignancy (P<0.0001). High nuclear phospho-eIF4E was associated with synchronous or future metastasis (P=0.0059). Kaplan-Meier analyses demonstrated highly significant associations between high histoscores for cytoplasmic and nuclear phospho-eIF4E and reduced survival in all patients (P=0.0003 and 0.0009, respectively). CONCLUSIONS: Increased melanoma expression of eIF4E and phospho-eIF4E is associated with metastatic potential, reduced survival and increased risk of death.

Sustained Obesity and Depressive Symptoms over 6 Years: Race by Gender Differences in the Health and Retirement Study.

Background: Although obesity and physical activity influence psychosocial well-being, these effects may vary based on race, gender, and their intersection. Using 6-year follow-up data of a nationally representative sample of adults over age of 50 in the United States, this study aimed to explore race by gender differences in additive effects of sustained high body mass index (BMI) and physical activity on sustained depressive symptoms (CES-D) and self-rated health (SRH). Methods: Data came from waves 7, 8, and 10 (2004-2010) of the Health and Retirement Study (HRS), an ongoing national cohort started in 1992. The study enrolled a representative sample of Americans (n = 19,280) over the age of 50. Latent factors were used to calculate sustained high BMI and physical activity (predictors) and sustained poor SRH and high depressive symptoms (outcomes) based on measurements in 2004, 2006, and 2010. Age, education, and income were confounders. Multi-group structural equation modeling (SEM) was used to test the additive effects of BMI and physical activity on depressive symptoms and SRH, where the groups were defined based on race by gender. Results: Group differences were apparent in the direction and significance of the association between sustained high BMI and depressive symptoms. The association between sustained high BMI and depressive symptoms was positive and significant for White women (B = 0.03, p = 0.007) and non-significant for White men (B = -0.03, p = 0.062), Black men (B = -0.02, p = 0.564) and Black women (B = 0.03, p = 0.110). No group differences were found in the paths from sustained physical activity to depressive symptoms, or from physical activity or BMI to SRH. Conclusion: Sustained high BMI and high depressive symptoms after age 50 are positively associated only for White women. As the association between sustained health problems such as depression and obesity are not universal across race and gender groups, clinical and public health interventions and programs that simultaneously target multiple health problems may have differential effects across race by gender groups.

Comparative time course profiles of phthalate stereoisomers in mice.

More efficient models are needed to assess potential carcinogenicity hazard of environmental chemicals based on early events in tumorigenesis. Here, we investigated time course profiles for key events in an established cancer mode of action. Using a case study approach, we evaluated two reference phthalates, di(2-ethylhexyl) phthalate (DEHP) and its stereoisomer di-n-octyl phthalate (DNOP), across the span of a two-year carcinogenicity bioassay. Male B6C3F1 mice received diets with no phthalate added (control), DEHP at 0.12, 0.60, or 1.20%, or DNOP at 0.10, 0.50, or 1.00% (n = 80-83/group) for up to 104 weeks with six interim evaluations starting at week 4. Mean phthalate doses were 139, 845, and 3147 mg/kg/day for DEHP and 113, 755, and 1281 mg/kg/day for DNOP groups, respectively. Incidence and number of hepatocellular tumors (adenoma and/or carcinoma) were greater at ≥ 60 weeks for all DEHP groups with time and dose trends, whereas DNOP had no significant effects. Key events supported a peroxisome proliferator-activated receptor alpha (PPARα) mode of action for DEHP, with secondary cytotoxicity at the high dose, whereas DNOP induced modest increases in PPARα activity without proliferative or cytotoxic effects. Threshold estimates for later tumorigenic effects were identified at week 4 for relative liver weight (+24%) and PPARα activity (+79%) relative to the control group. Benchmark doses (BMDs) for these measures at week 4 clearly distinguished DEHP and DNOP and showed strong concordance with values at later time points and tumorigenic BMDs. Other target sites included testis and kidney, which showed degenerative changes at higher doses of DEHP but not DNOP. Our results highlight marked differences in the chronic toxicity profiles of structurally similar phthalates and demonstrate quantitative relationships between early bioindicators and later tumor outcomes.

eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival.

Elevated eukaryotic translation initiation factor 4E (eIF4E) function induces malignancy in experimental models by selectively enhancing translation of key malignancy-related mRNAs (c-myc and BCL-2). eIF4E activation may reflect increased eIF4E expression or phosphorylation of its inhibitory binding proteins (4E-BP). By immunohistochemical analyses of 148 tissues from 89 prostate cancer patients, we now show that both eIF4E expression and 4E-BP1 phosphorylation (p4E-BP1) are increased significantly, particularly in advanced prostate cancer versus benign prostatic hyperplasia tissues. Further, increased eIF4E and p4E-BP1 levels are significantly related to reduced patient survival, whereas uniform 4E-BP1 expression is significantly related to better patient survival. Both immunohistochemistry and Western blotting reveal that elevated eIF4E and p4E-BP1 are evident in the same prostate cancer tissues. In two distinct prostate cancer cell models, the progression to androgen independence also involves increased eIF4E activation. In these prostate cancer cells, reducing eIF4E expression with an eIF4E-specific antisense oligonucleotide currently in phase I clinical trials robustly induces apoptosis, regardless of cell cycle phase, and reduces expression of the eIF4E-regulated proteins BCL-2 and c-myc. Collectively, these data implicate eIF4E activation in prostate cancer and suggest that targeting eIF4E may be attractive for prostate cancer therapy.