Protein kinase A activation inhibits DUX4 gene expression in myotubes from patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent of the adult-onset muscular dystrophies. FSHD causes a loss of muscle mass and function, resulting in severe debilitation and reduction in quality of life. Currently, only the symptoms of FSHD can be treated, and such treatments have minimal benefit. The available options are not curative, and none of the treatments address the underlying cause of FSHD. The genetic, epigenetic, and molecular mechanisms triggering FSHD are now quite well-understood, and it has been shown that expression of the transcriptional regulator double homeobox 4 (DUX4) is necessary for disease onset and is largely thought to be the causative factor in FSHD. Therefore, we sought to identify compounds suppressing DUX4 expression in a phenotypic screen using FSHD patient-derived muscle cells, a zinc finger and SCAN domain-containing 4 (ZSCAN4)-based reporter gene assay for measuring DUX4 activity, and ∼3,000 small molecules. This effort identified molecules that reduce DUX4 gene expression and hence DUX4 activity. Among those, ß2-adrenergic receptor agonists and phosphodiesterase inhibitors, both leading to increased cellular cAMP, effectively decreased DUX4 expression by >75% in cells from individuals with FSHD. Of note, we found that cAMP production reduces DUX4 expression through a protein kinase A-dependent mode of action in FSHD patient myotubes. These findings increase our understanding of how DUX4 expression is regulated in FSHD and point to potential areas of therapeutic intervention.

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways.

BACKGROUND: Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined. METHODS: Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up. RESULTS: Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results. CONCLUSIONS: Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018;124:1053-60. © 2018 American Cancer Society.

Depressive symptoms and actigraphy-measured circadian disruption predict head and neck cancer survival.

OBJECTIVE: Depressive symptoms have demonstrated prognostic significance among head and neck cancer patients. Depression is associated with circadian disruption, which is prognostic in multiple other cancer types. We hypothesized that depressive symptoms would be associated with circadian disruption in head and neck cancer, that each would be related to poorer 2-year overall survival, and that relationships would be mediated by tumor response to treatment. METHODS: Patients (N = 55) reported on cognitive/affective and somatic depressive symptoms (PHQ-9) and wore an actigraph for 6 days to continuously record rest and activity cycles prior to chemoradiation. Records review documented treatment response and 2-year survival. Spearman correlations tested depressive symptoms and circadian disruption relationships. Cox proportional hazard models tested the predictive capability of depressive symptoms and circadian disruption, separately, on survival. RESULTS: Depressive symptoms were significantly associated with circadian disruption, and both were significantly associated with shorter survival (somatic: hazard ratio [HR] = 1.325, 95% confidence interval [CI] = 1.089-1.611, P = .005; rest/activity rhythm: HR = 0.073, 95% CI = 0.009-0.563, P = .012; nighttime restfulness: HR = 0.910, 95% CI = 0.848-0.977, P = .009). Tumor response to treatment appeared to partly mediate the nighttime restfulness-survival relationship. CONCLUSIONS: This study replicates and extends prior work with new evidence linking a subjective measure of depression and an objective measure of circadian disruption-2 known prognostic indicators-to shortened overall survival among head and neck cancer patients. Continued examination should elucidate mechanisms by which depressive symptomatology and circadian disruption translate to head and neck cancer progression and mortality.

Developing the health visitor concept of family resilience in Wales using Group Concept Mapping.

INTRODUCTION: A health visitor's ability to assess and analyse aspects of family resilience in daily practice is essential to enable practitioners to support families and facilitate positive lifestyle choices, and improve child health and developmental outcomes. The purpose of this research was to undertake an in-depth exploration of the concept of family resilience as understood by health visitors in Wales and to develop a concept map. This knowledge has been used to develop the Family Resilience Assessment Instrument Tool (FRAIT). This is a standardised form of assessment, measuring instrument, guidance, training package and community of practice for use in health visitor daily practice. This article presents the first stage of the FRAIT research study, that of identifying the clusters within the concept map of what health visitors perceive as 'family resilience'. METHODS: A structured Group Concept Mapping (GCM) methodology using Concept Systems' Global Max online software was used to gain a consensus of the understanding of the concept of family resilience from 62 invited health visitors practising across Wales. This is an integrated qualitative and quantitative approach to brainstorming, idea synthesis, idea sorting, idea rating and group analysis. GCM has six clear steps, with four steps described in the method: 'preparing for concept mapping', 'generating ideas', 'structuring the statements' and 'concept mapping analysis'. Steps 5 and 6, 'interpreting the maps' and 'utilisation', are considered in the results section. RESULTS: Use of multi-dimensional scaling and hierarchical cluster analysis enabled point, cluster, rating and pattern matching maps to be presented to the study group. These were then interpreted, understood and consensus gained on how the concept of family resilience was constructed from both the study group and the health visitor participants. Family resilience understood by health visitors in Wales comprises five clusters: 'family health', 'responsive parenting', 'engagement', 'family support' and 'socioeconomic factors'. Each of the clusters has an identified number of underpinning statements from a total number of 117 statements. CONCLUSION: Family resilience as understood by health visitors is a multidimensional concept. Using online software such as Concept Systems' Global Max enabled health visitors working across Wales to achieve a consensus and generate the data in preparation for building FRAIT for use in their daily practice as required by Welsh Government policy.

HPV: a factor in organ preservation for locally advanced larynx and hypopharynx cancer?

PURPOSE/OBJECTIVE: To assess the interaction of HPV/p16 status and therapy rendered in patients with locally advanced squamous cell carcinoma of the larynx and hypopharynx. MATERIALS AND METHODS: Forty-seven consecutive patients receiving definitive treatment between 2009 and 2011 for locally advanced larynx or hypopharynx cancer with high-risk HPV and/or p16 testing performed were identified and retrospectively investigated. Overall survival (OS), disease-free survival (DFS), and local recurrence-free survival (LRFS) were assessed. RESULTS: Of 47 evaluable patients, there were 38 (81%) with laryngeal and 9 (19%) with hypopharyngeal tumors, 13 (28%) of which were found to be either HPV or p16 positive. At a median follow-up of 24 months, comparing HPV/p16+ versus HPV/p16- patients, there was no difference in OS, DFS, or LRFS. There was an improvement in 2-year DFS (60% vs 100%, P=.03) and LRFS (80% vs 100%, P=.08), in HPV/p16+ patients treated with chemo/RT versus surgery. There was an improvement in 2-year DFS (100% vs 68%, P=.04) and LRFS (100% vs 72%, P=.05) in HPV/p16+ versus HPV/p16- patients who received chemo/RT. CONCLUSIONS: Patients with HPV/p16+ tumors fared more favorably with chemo/RT than up-front surgery, with improvements in DFS and LRFS. In patients treated with the intent of organ preservation therapy, HPV/p16+ patients had no observed treatment failures. HPV/p16 status should be taken into account when considering organ preservation for locally advanced larynx and hypopharynx cancers.

Estimating the Reliability and Stability of Cognitive Processes Contributing to Responses on the Implicit Association Test.

Implicit measures were initially assumed to assess stable individual differences, but other perspectives posit that they reflect context-dependent processes. This pre-registered research investigates whether the processes contributing to responses on the race Implicit Association Test are temporally stable and reliably measured using multinomial processing tree modeling. We applied two models-the Quad model and the Process Dissociation Procedure-to six datasets (N = 2,036), each collected over two occasions, examined the within-measurement reliability and between-measurement stability of model parameters, and meta-analyzed the results. Parameters reflecting accuracy-oriented processes demonstrate adequate stability and reliability, which suggests these processes are relatively stable within individuals. Parameters reflecting evaluative associations demonstrate poor stability but modest reliability, which suggests that associations are either context-dependent or stable but noisily measured. These findings suggest that processes contributing to racial bias on implicit measures differ in temporal stability, which has practical implications for predicting behavior using the Implicit Association Test.

Using an integrated competence model to evaluate a health visitor cascade training programme for the Family Resilience Assessment Instrument and Tool (FRAIT).

This paper reports on an evaluation of health visitor trainers' experience of a cascade training programme delivered in Wales, UK. Health visitors used Driscoll's model (What, So What, Now What) to organise their feedback and an integrated competence model developed by Weeks et al. was used to analyse the feedback via category analysis of free text. As well as feedback on the logistics of running the training, the evaluation allowed for cognitive and functional competence to be identified along with personal and meta competence. There was limited scope for identifying ethical competence in the Health Visitor cascade trainer feedback. Suggestions are made for how this may be addressed.

Developing a family resilience assessment tool for health visiting/public health nursing practice using virtual commissioning, high-fidelity simulation and focus groups.

UK public health nurse assessment of family resilience is a necessary component of monitoring family health and children's development and identifying areas for change. This research was part of an exploration of Welsh public health nurses' understanding of 'family resilience' as a concept underpinning their practice. From it, the Family Resilience Assessment Instrument Tool (FRAITTM www.frait.wales/) was developed for public health nurses use. We report on a virtual commissioning process using focus groups and an immersive simulation suite to test a FRAIT prototype in a safe environment before field testing. Virtual commissioning design: Hydra-Minerva Immersive Simulation Suite - individual public health nurses presented with a multi-media scenario as they used the prototype FRAIT. Follow-up focus groups for usability insights before field testing. Virtual commissioning raised real-world issues which public health nurses discussed in focus groups. Issues were scoring, absence of information, focusing on family resilience, identifying adults caring for children, potential for use, identifying need and monitoring change, potential impact of using FRAIT and fitting it to everyday practice. Prototype testing like this allowed us to fine tune the FRAIT for field testing.

Development of a telehealth intervention for head and neck cancer patients.

Treatment for head and neck cancer precipitates a myriad of distressing symptoms. Patients may be isolated both physically and socially and may lack the self-efficacy to report problems and participate as partners in their care. The goal of this project was to design a telehealth intervention to address such isolation, develop patient self-efficacy, and improve symptom management during the treatment experience. Participatory action research and a review of the literature were used to develop electronically administered symptom management algorithms addressing all major symptoms experienced by patients undergoing treatment for head and neck cancers. Daily questions and related messages were then programmed into an easy-to-use telehealth messaging device, the Health Buddy(R). Clinician and patient acceptance, feasibility, and technology issues were measured. Using participatory action research is an effective means for developing electronic algorithms acceptable to both clinicians and patients. The use of a simple tele-messaging device as an adjunct to symptom management is feasible, affordable, and acceptable to patients. This telehealth intervention provides support and education to patients undergoing treatment for head and neck cancers.

Prognostic factors and selection criteria in the retreatment of head and neck cancers.

OBJECTIVES: To determine predictors of treatment selection, outcome, and survival, we examined a cohort of previously irradiated head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: We retrospectively analyzed 100 patients at our institution who were treated for recurrent or second primary (RSP) HNSCC, focusing on subgroups receiving reirradiation (ReRT) alone and those undergoing surgical salvage (SS) with or without post-operative reirradiation therapy (POReRT). Logistic regression modeling was performed to identify factors predictive of retreatment modality. Cox regression modeling was used to determine prognostic factors for progression free survival (PFS) and overall survival (OS). RESULTS: ReRT alone was less likely in current smokers and neck recurrences, with reirradiation more likely in primary site recurrences. POReRT was significantly more likely in patients with positive surgical margins (PSM), neck dissection, or organ dysfunction. POReRT omission negatively impacted PFS when PSM (HR: 8.894, 95% CI: 1.742-45.403) and perineural invasion (PNI) (HR: 3.391, 95% CI: 1.140-10.089) were present. Tracheostomy was associated with worse OS, but ReRT alone and POReRT improved OS. PSM correlated with worse OS, regardless of whether POReRT was given (HR: 14.260, 95% CI: 2.064-98.547). CONCLUSION: This analysis confirms known factors for predicting outcome and shows nonsmoking status and primary site recurrence as predictors for ReRT alone. POReRT for PSM and PNI improves PFS. Tracheostomy patients are more likely to have ReRT due to acute toxicity not limiting treatment and POReRT improves OS compared to surgery alone. The presence of PSM negatively impacts survival which cannot be overcome by POReRT.

Relocating patients from a specialist homeless healthcare centre to general practices: a multi-perspective study.

BACKGROUND: The relocation of formerly homeless patients eligible to transfer from a specialist homeless healthcare centre (SHHC) to mainstream general practices is key to patient integration in the local community. Failure to transition patients conferring eligibility for relocation may also negatively impact on SHHC service delivery. AIM: To explore barriers and facilitators of relocation from the perspectives of formerly homeless patients and healthcare staff involved in their care. DESIGN AND SETTING: Qualitative semi-structured face-to-face and telephone interviews conducted in the north east of Scotland. METHOD: Participants were patients and healthcare staff including GPs, nurses, substance misuse workers, administrative, and local community pharmacy staff recruited from one SHHC, two mainstream general practices, and four community pharmacies. Interview schedules based on the 14 domains of the Theoretical Domains Framework (TDF) were drafted. Transcripts of the interviews were analysed by two independent researchers using a framework approach. RESULTS: Seventeen patients and 19 staff participated. Key barriers and facilitators aligned to TDF domains included: beliefs about consequences regarding relocation; patient intention to relocate; environmental context and resources in relation to the care of the patients and assessing patient eligibility; patient skills in relation to integration; social and professional role and identity of staff and patients; and emotional attachment to the SHHC. CONCLUSION: Implementation of services, which promote relocation and integration, may optimise patient relocation from SHHCs to mainstream general practices. These include peer support networks for patients, better information provision on the relocation process, and supporting patients in the journey of identifying and adjusting to mainstream practices.

Children's views of hospitalization: an exploratory study of data collection.

Identifying children's views of their experience of hospitalization is essential to the development of appropriate services. Previous research has mainly concentrated on specific paediatric populations or negative aspects of their experience. This study had two aims. First, to investigate a broader range of experiences in a general paediatric population, and second, to determine the most effective way of obtaining the information. School-aged children (n = 213) from the paediatric wards of two district general hospitals completed one of four questionnaire types. The themes identified were generally positive and mainly related to the children's physical surroundings. A verbal structured questionnaire was found to be the most efficient at obtaining the children's views, whereas a visual structured questionnaire was the only method which recognized the children's sequence of feelings before, during and after hospitalization.

Risk factors for hemorrhage after chemoradiation for oropharyngeal squamous cell carcinoma.

IMPORTANCE: Knowledge of the risk factors for oropharyngeal hemorrhage after chemoradiation therapy will guide clinicians in monitoring high-risk patients in order to prevent a life-threatening complication. OBJECTIVE: To determine risk factors for the development of oropharyngeal hemorrhage following chemoradiation therapy without surgery for oropharyngeal squamous cell carcinoma. DESIGN: Retrospective review of medical records of patients treated during the period January 2005 through December 2010. SETTING: University of Louisville Hospital. PARTICIPANTS: The study population comprised 139 patients with a diagnosis of oropharyngeal squamous cell carcinoma who were treated with chemoradiation therapy without surgery. All patients received primary treatment from our institution. Those with recurrent tumors or prior oropharyngeal resections, with the exception of tonsillectomy, were excluded from the study. Patients were divided into 2 groups: those who did not hemorrhage following treatment (n = 129) and those who developed oropharyngeal hemorrhage (n = 10), defined as hemorrhage necessitating procedural intervention. MAIN OUTCOMES AND MEASURES: Four clinical variables were measured: T category, radiation therapy method, weight loss, and age. RESULTS: Results from logistic regression analysis showed that significant risk factors for hemorrhage were advanced T category (odds ratio [OR], 8.40 [95% CI, 2.44-46.61]; P < .001), radiation therapy method (OR, 79.94 [95% CI, 2.64-<999.90]; P = .008), weight loss (OR, 0.89 [95% CI, 0.79-0.98]; P = .01), and increased age (OR, 0.93 [95% CI, 0.86-0.99]; P = .03). After multiple logistic regression analyses, only advanced T category remained statistically significant (adjusted OR, 6.6 [95% CI, 1.2-∞]; P = .02). Results from Kaplan-Meier survival analysis on all patients showed that those who hemorrhaged had significantly shorter survival time than those who did not (P = .04). However, after multivariate analysis with a Cox proportional hazards regression model, hemorrhage no longer remained a significant factor (P = .13). CONCLUSIONS: For patients with oropharyngeal squamous cell carcinoma treated with chemoradiation without surgery, advanced T category is the most important determinant of developing oropharyngeal hemorrhage; furthermore, hemorrhage occurs in the presence of either recurrent and/or persistent disease or radiation necrosis. Survival analysis indicates that development of hemorrhage is a poor prognostic marker for overall survival.

Treatment outcome in the residually positive neck after definitive chemotherapy and irradiation.

OBJECTIVE: Determine prevalence of viable malignancy in patients undergoing neck dissection (ND) for residual neck disease following concomitant chemotherapy and irradiation (chemo/xrt) for upper aerodigestive squamous carcinoma. To determine survival in groups with a neck complete response to those who had residual disease requiring neck dissection. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective chart review of 230 patients who underwent definitive chemo/xrt for primary squamous cell carcinoma cancer (SCCa) of the head and neck from 2005 to 2009 in one institution. RESULTS: Thirty-nine (17%) patients underwent ND for residual neck mass within 4 months posttreatment. Forty-nine percent (19/39) were pathologically positive for malignancy and 51% (20/39) were negative. The probability of a +ND based on original N-stage was not statistically significant (P = .368). Primary site did not yield significant probability of having +ND, except in the oral cavity (P = .02). Patients had similar overall 5-year survival, among those with a delayed complete response in the neck (66%), ND for residual disease (71%), or those with initial complete response (71%). Lower initial N-stage demonstrated improved survival in all outcome groups. Tonsil SCCa patients who underwent ND had improved survival compared to those with delayed complete response (87.5 vs. 75.8%), both of which had increased survival compared to initial complete responders (65%). CONCLUSIONS: This study supports the use of ND in the postchemo/xrt positive neck regardless of primary site or initial N-stage. ND in this setting conveys survival equal to patients with complete response in the neck after chemo/xrt. These survivorship implications of postchemo/xrt neck dissection extend to all sites, including tonsils.