Revisiting the roles of cAMP signalling in the progression of prostate cancer.

Prostate cancer is one of the most common cancers in men and one of the top causes of death in men worldwide. Development and function of both normal prostate cells and early-stage prostate cancer cells are dependent on the cross-talk between androgen signalling systems and a variety of other transduction pathways which drive differentiation of these cells towards castration-resistance. One such signalling pathway is the ubiquitous cAMP signalling axis which functions to activate spatially restricted pools of cAMP effectors such as protein kinase A (PKA). The importance of both PKA and cAMP in the development of prostate cancer, and their interactions with the androgen receptor, were the focus of a review by Merkle and Hoffmann in 2010. In this updated review, we revisit this topic with analysis of current PKA-related prostate cancer literature and introduce novel information on the relevance of another cAMP effector, the exchange protein directly activated by cAMP (EPAC).

The synovial environment steers cartilage deterioration and regeneration.

Osteoarthritis (OA) was recently defined as an epidemic, and the lack of effective treatment is highly correlated to the limited knowledge regarding the underlying pathophysiology. Failure to regenerate upon trauma is thought to be one of the underlying causes for degenerative diseases, including OA. To investigate why lesions within an OA environment fail to heal, a heterogeneous cell population was isolated from the synovial fluid (SF) of OA patients. The cells' ability to undergo processes required for functional tissue regeneration was evaluated in the presence or absence of autologous SF. The obtained mechanistic findings were then used for the development of an immunomodulatory cell treatment, aimed to restore the pro-regenerative environment. Intra-articular injection in a clinical compassionate use study showed that the treatment restored the articular cartilage and joint homeostasis of OA patients. These findings confirm the role of pro-regenerative immune cells and their targeted influence on progenitor cells for degenerative joint disease therapies.

Detection of Environmental Spread of SARS-CoV-2 and Associated Patient Characteristics.

Understanding transmission of severe acute respiratory syndrome coronavirus 2 informs infection prevention practices. Air sampling devices were placed in patient hospital rooms for consecutive collections with and without masks. With patient mask use, no virus was detected in the room. High viral load and fewer days from symptom onset were associated with viral particulate dispersion.

Barriers and facilitators to screening and treating malnutrition in older adults living in the community: a mixed-methods synthesis.

BACKGROUND: Malnutrition (specifically undernutrition) in older, community-dwelling adults reduces well-being and predisposes to disease. Implementation of screen-and-treat policies could help to systematically detect and treat at-risk and malnourished patients. We aimed to identify barriers and facilitators to implementing malnutrition screen and treat policies in primary/community care, which barriers have been addressed and which facilitators have been successfully incorporated in existing interventions. METHOD: A data-base search was conducted using MEDLINE, Embase, PsycINFO, DARE, CINAHL, Cochrane Central and Cochrane Database of Systematic Reviews from 2012 to June 2016 to identify relevant qualitative and quantitative literature from primary/community care. Studies were included if participants were older, community-dwelling adults (65+) or healthcare professionals who would screen and treat such patients. Barriers and facilitators were extracted and mapped onto intervention features to determine whether these had addressed barriers. RESULTS: Of a total of 2182 studies identified, 21 were included (6 qualitative, 12 quantitative and 3 mixed; 14 studies targeting patients and 7 targeting healthcare professionals). Facilitators addressing a wide range of barriers were identified, yet few interventions addressed psychosocial barriers to screen-and-treat policies for patients, such as loneliness and reluctance to be screened, or healthcare professionals' reservations about prescribing oral nutritional supplements. CONCLUSION: The studies reviewed identified several barriers and facilitators and addressed some of these in intervention design, although a prominent gap appeared to be psychosocial barriers. No single included study addressed all barriers or made use of all facilitators, although this appears to be possible. Interventions aiming to implement screen-and-treat approaches to malnutrition in primary care should consider barriers that both patients and healthcare professionals may face. REVIEW REGISTRATIONS: PROSPERO: CRD42017071398 . The review protocol was registered retrospectively.

Environmental interventions to promote healthier eating and physical activity behaviours in institutions: a systematic review.

OBJECTIVE: The present review evaluated the effectiveness of environmental-based interventions aimed at improving the dietary and physical activity behaviours and body composition indices of adults in institutions. DESIGN: A systematic review was conducted. Electronic databases (MEDLINE, Embase, PsycINFO, CINAHL, The Cochrane Library, Web of Science, ProQuest Dissertation and Theses, Scopus and Athena) were searched for relevant articles published between database inception and October 2017. Searching, selecting and reporting were undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. SETTING: Military establishments and maritime workplaces.ParticipantsAdults in institutions, aged 18-45 years. RESULTS: A total of 27842 articles were screened for eligibility, nine studies (reported in eleven articles) were included in the review. Five studies used multilevel strategies and four used environmental strategies only. Duration of follow-up ranged from 3 weeks to 10 years. Eight of the studies reported significant positive effects on dietary behaviours, but effect sizes varied. The study that targeted physical activity had no effect on activity levels but did have a significant positive effect on physical fitness. No evidence was identified that the studies resulted in improvements in body composition indices. CONCLUSIONS: The evidence base appears to be in favour of implementing environmental interventions in institutions to improve the dietary behaviours of adults. However, due to the small number of studies included in the review, and the variable methodological quality of the studies and intervention reporting, further well-designed evaluation studies are required.

Cost-effectiveness of oral nutritional supplements in older malnourished care home residents.

BACKGROUND & AIMS: Malnutrition is common in care home residents, but information on the cost-effectiveness of nutritional interventions is lacking. This study, involving a randomised trial in care home residents, aimed to examine whether oral nutritional supplements (ONS) are cost-effective relative to dietary advice. METHODS: An incremental cost-effectiveness analysis was undertaken prospectively in 104 older care home residents (88 ± 8 years) without overt dementia, who were randomised to receive either ONS or dietary advice for 12 weeks. Costs were estimated from resource use and quality adjusted life years (QALYs) from health-related quality of life, assessed using EuroQoL (EQ-5D-3L, time-trade-off) and mortality. The incremental cost-effectiveness ratio (ICER) was calculated using 'intention to treat' and 'complete case' analyses. RESULTS: The ONS group gained significantly more QALYs than the dietary advice group at significantly greater costs. The ICER (extra cost per QALY gained), adjusted for nutritional status, type of care, baseline costs and quality of life, was found to be £10,961 using the 'intention to treat' analysis (£190.60 (cost)/0.0174 (QALYs); n = 104) and £11,875 using 'complete case' analysis (£217.30/0.0183; n = 76) (2016 prices). Sensitivity analysis based on 'intention to treat' data indicated an 83% probability that the ICER was ≤£20,000 and 92% that it was ≤£30,000. With the 'complete case data' the probabilities were 80% and 90% respectively. CONCLUSION: This pragmatic randomised trial involving one of the oldest populations subjected to a cost-utility analysis, suggests that use of oral nutritional supplements in care homes are cost-effective relative to dietary advice.

Oral nutritional supplements in a randomised trial are more effective than dietary advice at improving quality of life in malnourished care home residents.

BACKGROUND & AIMS: Few trials have explored the effect of nutrition support on quality of life (QoL). This study examined the effects of oral nutritional supplements (ONS) vs dietary advice on QoL in malnourished care home residents. METHODS: 104 malnourished, care home residents (medium + high risk), identified using the Malnutrition Universal Screening Tool ('MUST'), (mean age 88.5 ± 7.9y) were randomised to receive either oral nutritional supplements (ONS) (n = 53) or dietary advice (n = 51) for 12 weeks. Dietary intake was measured using 24 h dietary recall, and QoL assessed using EuroQol (EQ-5D), including time trade off (TTO) (range -0.59 to 1) and visual analogue scale (VAS) (score 0 to 100) for self-perceived health. RESULTS: QoL (adjusted for baseline QOL, malnutrition risk, type of care received (nursing or residential)) was significantly higher in the ONS than the dietary advice group (intention to treat analysis at week 12; n = 104 ). EQ-5D TTO scores (mean ± SE) were 0.50 ± 0.04 vs 0.36 ± 0.05 (P = 0.005), VAS rescaled scores were 0.54 + 0.03 vs 0.046 + 0.03 (P = 0.006) and VAS scores were 61.3 ± 4.5 vs 54.6 ± 6.3 (P = 0.533) for ONS vs dietary advice respectively. Total energy, protein and the majority of micronutrient intakes were significantly greater in the ONS group, with energy intake being 423 kcal greater in the ONS than the dietary advice group at week 12. CONCLUSIONS: This study in malnourished care home residents indicates that ONS can improve QoL and nutritional intake more effectively than dietary advice alone. CLINICAL TRIAL REGISTRY: This trial was registered with clinicaltrials.gov on 10th August 2007. Clinical trials identifier is NCT00515125http://www.clinicaltrials.gov/ct2/show/NCT00515125?term=nutrition+support&rank=60.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer.

PURPOSE: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. PATIENTS AND METHODS: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. RESULTS: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. CONCLUSIONS: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer.

BACKGROUND: Human papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes. METHODS/DESIGN: The study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint. DISCUSSION: PATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov identifier NCT02215265 .

Designing a national clinical audit of nutritional care in health and social care settings: consideration and future directions.

The aim of this review paper is to consider how the principles of clinical audit could be applied to the development of an audit of nutritional care in hospitals and care homes, based on criteria derived from the Essence of Care: Food and Drink. A literature review identified fifteen key papers that included guidance or standards for nutritional care in hospitals or care homes. These were used to supplement the ten factors suggested by the Essence of Care to develop a set of potential audit criteria covering all aspects of the nutritional care pathway including the identification of risk of malnutrition, implementation of nutritional care plans, referral to healthcare professionals for further nutritional assessment and nutritional support strategies. A series of audit tools have been developed, including an organisational level audit tool, a staff questionnaire, a patients' and residents' records audit tool and a patients' and residents' experiences questionnaire. Further issues to consider in designing a national nutritional audit include the potential role of direct observation of care, the use of trained auditors and the scope for including the results of pre-existing local audits. In conclusion, a national audit would need to encompass a very large number of health and care organisations of widely varying sizes and types and a diverse range of people.

The effect of cleft lip on adults' responses to faces: cross-species findings.

Cleft lip and palate is the most common of the congenital conditions affecting the face and cranial bones and is associated with a raised risk of difficulties in infant-caregiver interaction; the reasons for such difficulties are not fully understood. Here, we report two experiments designed to explore how adults respond to infant faces with and without cleft lip, using behavioural measures of attractiveness appraisal ('liking') and willingness to work to view or remove the images ('wanting'). We found that infants with cleft lip were rated as less attractive and were viewed for shorter durations than healthy infants, an effect that was particularly apparent where the cleft lip was severe. Women rated the infant faces as more attractive than men did, but there were no differences in men and women's viewing times of these faces. In a second experiment, we found that the presence of a cleft lip in domestic animals affected adults' 'liking' and 'wanting' responses in a comparable way to that seen for human infants. Adults' responses were also remarkably similar for images of infants and animals with cleft lip, although no gender difference in attractiveness ratings or viewing times emerged for animals. We suggest that the presence of a cleft lip can substantially change the way in which adults respond to human and animal faces. Furthermore, women may respond in different ways to men when asked to appraise infant attractiveness, despite the fact that men and women 'want' to view images of infants for similar durations.

Sustainable Communities Awards. A sense of place.

The ingredients for sustainable communities vary. Local area agreements are concentrating on a core set of outcomes, which have been streamlined. PCTs should ideally be coterminous with the upper tier of local authorities.

Detection of cryptic MLL insertions using a commercial dual-color fluorescence in situ hybridization probe.

Involvement of the MLL gene located at chromosome region 11q23 is a frequent occurrence in both acute myelocytic leukemia and acute lymphoblastic leukemia. More than 30 loci have now been associated with MLL, usually by reciprocal translocation. Deletions, insertions, and more complex rearrangements of MLL are rarely seen. We present three cases of AML M5 showing no cytogenetic evidence of 11q23 rearrangement, in which a commercial MLL dual-color fluorescence in situ hybridization probe revealed a nonstandard abnormal signal pattern, suggesting cryptic insertion of the MLL gene into its partner gene site.