Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host

Purpose: In patients with colorectal cancer (CRC), a high-density local inflammatory infiltrate response is associated with improved survival, whereas elevated systemic inflammatory responses are associated with poor survival. One potential unifying mechanism is the IL-6/JAK/STAT3 pathway. The present study examines the relationship between tumour total STAT3 and phosphorylated STAT3Tyr705 (pSTAT3) expression, host inflammatory responses and survival in patients undergoing resection of stage I-III CRC. Experimental Design: Immunohistochemical assessment of STAT3/pSTAT3 expression was performed using a tissue microarray and tumour cell expression divided into tertiles using the weighted histoscore. The relationship between STAT3/pSTAT3 expression and local inflammatory (CD3+, CD8+, CD45R0+, FOXP3+ T-cell density and Klintrup-Mäkinen grade) and systemic inflammatory responses and cancer-specific survival were examined. Results: 196 patients were included in the analysis. Cytoplasmic and nuclear STAT3 expression strongly correlated (r=0.363, P<0.001); nuclear STAT3 and pSTAT3 expression weakly correlated (r=0.130, P=0.068). Cytoplasmic STAT3 was inversely associated with the density of CD3+ (P=0.012), CD8+ (P=0.003) and FOXP3+ T-lymphocytes (P=0.002) within the cancer cell nests and was associated with an elevated systemic inflammatory response as measured by modified Glasgow Prognostic Score (mGPS2: 19% vs. 4%, P=0.004). The combination of nuclear STAT3/pSTAT3 stratified five-year survival from 81% to 62% (P=0.012), however was not associated with survival independent of venous invasion, tumour perforation or tumour budding. Conclusion In patients undergoing CRC resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Up-regulation of tumour STAT3 may be an important mechanism whereby the tumour deregulates local and systemic inflammatory responses

Focus issue: pastoralism and rangelands in mountains

Mountain rangelands (open grasslands, mixed forest meadows, closed forests, and alpine lakes and wetlands) play vital roles for humans, supporting livestock grazing, hunting, and harvesting of plants. They thus provide livelihoods for a large number of rural mountain communities across the globe. These systems are also key for water supply to lowland areas and watershed health, carbon sequestration and storage, fire regulation, and, increasingly, recreational use and tourism. They are vital for the conservation of mountain species and habitats, including endemic species and habitats exclusive to mountains. Many of these ecosystems require management to maintain species diversity and productivity and supply a range of high-quality ecosystem services.info:eu-repo/semantics/publishedVersio

Progress toward curing HIV infection with hematopoietic cell transplantation.

HIV-1 infection afflicts more than 35 million people worldwide, according to 2014 estimates from the World Health Organization. For those individuals who have access to antiretroviral therapy, these drugs can effectively suppress, but not cure, HIV-1 infection. Indeed, the only documented case for an HIV/AIDS cure was a patient with HIV-1 and acute myeloid leukemia who received allogeneic hematopoietic cell transplantation (HCT) from a graft that carried the HIV-resistant CCR5-∆32/∆32 mutation. Other attempts to establish a cure for HIV/AIDS using HCT in patients with HIV-1 and malignancy have yielded mixed results, as encouraging evidence for virus eradication in a few cases has been offset by poor clinical outcomes due to the underlying cancer or other complications. Such clinical strategies have relied on HIV-resistant hematopoietic stem and progenitor cells that harbor the natural CCR5-∆32/∆32 mutation or that have been genetically modified for HIV-resistance. Nevertheless, HCT with HIV-resistant cord blood remains a promising option, particularly with inventories of CCR5-∆32/∆32 units or with genetically modified, human leukocyte antigen-matched cord blood

The association between markers of tumour cell metabolism, the tumour microenvironment and outcomes in patients with colorectal cancer

Tumour cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumour microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I‐III CRC were utilised to assess tumour cell expression of MCT‐1, MCT‐2, LDH‐1 and LDH‐5 by immunohistochemistry. Expression levels were dichotomised and associations with tumour factors, the tumour microenvironment and survival analysed. Nuclear LDH‐5 associates with poor prognosis (HR 1.68 95% CI 0.99–2.84, p = 0.050) and trends toward increased tumour stroma percentage (TSP, p = 0.125). Cytoplasmic MCT‐2 also trends toward increased TSP (p = 0.081). When combined into a single score; nuclear LDH‐5 + TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27–5.35, p = 0.009), increased tumour budding (p = 0.002) and decreased stromal T‐lymphocytes (p = 0.014). Similarly, cytoplasmic MCT‐2 + TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31–4.11, p = 0.003), decreased necrosis (p = 0.039), and increased tumour budding (p = 0.004). The present study reports that the combination of TSP and nuclear LDH‐5 was significantly associated with survival, increased tumour budding, and decreased stromal T‐lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumour progression via modulation of tumour metabolism. Moreover, MCT‐2 and LDH‐5 may provide promising therapeutic targets for patients with stromal‐rich CRC

Causes of death among homeless people: a population-based cross-sectional study of linked hospitalisation and mortality data in England. [version 1; peer review: 2 approved]

Background: Homelessness has increased by 165% since 2010 in England, with evidence from many settings that those affected experience high levels of mortality. In this paper we examine the contribution of different causes of death to overall mortality in homeless people recently admitted to hospitals in England with specialist integrated homeless health and care (SIHHC) schemes.  Methods: We undertook an analysis of linked hospital admission records and mortality data for people attending any one of 17 SIHHC schemes between 1st November 2013 and 30th November 2016. Our primary outcome was death, which we analysed in subgroups of 10th version international classification of disease (ICD-10) specific deaths; and deaths from amenable causes. We compared our results to a sample of people living in areas of high social deprivation (IMD5 group). Results: We collected data on 3,882 individual homeless hospital admissions that were linked to 600 deaths. The median age of death was 51.6 years (interquartile range 42.7-60.2) for SIHHC and 71.5 for the IMD5 (60.67-79.0).  The top three underlying causes of death by ICD-10 chapter in the SIHHC group were external causes of death (21.7%; 130/600), cancer (19.0%; 114/600) and digestive disease (19.0%; 114/600).  The percentage of deaths due to an amenable cause after age and sex weighting was 30.2% in the homeless SIHHC group (181/600) compared to 23.0% in the IMD5 group (578/2,512). Conclusion: Nearly one in three homeless deaths were due to causes amenable to timely and effective health care. The high burden of amenable deaths highlights the extreme health harms of homelessness and the need for greater emphasis on prevention of homelessness and early healthcare interventions

Exploring the measurement of markedness and its relationship with other linguistic variables

Antonym pair members can be differentiated by each word's markedness-that distinction attributable to the presence or absence of features at morphological or semantic levels. Morphologically marked words incorporate their unmarked counterpart with additional morphs (e.g., "unlucky" vs. "lucky"); properties used to determine semantically marked words (e.g., "short" vs. "long") are less clearly defined. Despite extensive theoretical scrutiny, the lexical properties of markedness have received scant empirical study. The current paper employs an antonym sequencing approach to measure markedness: establishing markedness probabilities for individual words and evaluating their relationship with other lexical properties (e.g., length, frequency, valence). Regression analyses reveal that markedness probability is, as predicted, related to affixation and also strongly related to valence. Our results support the suggestion that antonym sequence is reflected in discourse, and further analysis demonstrates that markedness probabilities, derived from the antonym sequencing task, reflect the ordering of antonyms within natural language. In line with the Pollyanna Hypothesis, we argue that markedness is closely related to valence; language users demonstrate a tendency to present words evaluated positively ahead of those evaluated negatively if given the choice. Future research should consider the relationship of markedness and valence, and the influence of contextual information in determining which member of an antonym pair is marked or unmarked within discourse

Outcomes of specialist discharge coordination and intermediate care schemes for patients who are homeless: analysis protocol for a population-based historical cohort

Introduction People who are homeless often experience poor hospital discharge arrangements, reflecting ongoing care and housing needs. Specialist integrated homeless health and care provision (SIHHC) schemes have been developed and implemented to facilitate the safe and timely discharge of homeless patients from hospital. Our study aims to investigate the health outcomes of patients who were homeless and seen by a selection of SIHHC services. Methods and analysis Our study will employ a historical population-based cohort in England. We will examine health outcomes among three groups of adults: (1) homeless patients seen by specialist discharge schemes during their hospital admission; (2) homeless patients not seen by a specialist scheme and (3)admitted patients who live in deprived neighbourhoods and were not recorded as being homeless. Primary outcomes will be: time from discharge to next hospital inpatient admission; time from discharge to next accident and emergency attendance and 28-day emergency readmission. Outcome data will be generated through linkage to hospital admissions data (Hospital Episode Statistics) and mortality data for November 2013 to November 2016. Multivariable regression will be used to model the relationship between the study comparison groups and each of the outcomes. Ethics and dissemination Approval has been obtained from the National Health Service (NHS) Confidentiality Advisory Group (reference 16/CAG/0021) to undertake this work using unconsented identifiable data. Health Research Authority Research Ethics approval (REC 16/EE/0018) has been obtained in addition to local research and development approvals for data collection at NHS sites. We will feedback the results of our study to our advisory group of people who have lived experience of homelessness and seek their suggestions on ways to improve or take this work further for their benefit. We will disseminate our findings to SIHHC schemes through a series of regional workshops

Social recovery therapy: a treatment manual

Social Recovery Therapy is an individual psychosocial therapy developed for people with psychosis. The therapy aims to improve social recovery through increasing the amount of time individuals spend in meaningful structured activity. Social Recovery Therapy draws on our model of social disability arising as functional patterns of withdrawal in response to early socio-emotional difficulties and compounded by low hopefulness, self-agency and motivation. The core components of Social Recovery Therapy include using an assertive outreach approach to promote a positive therapeutic relationship, with the focus of the intervention on using active behavioural work conducted outside the clinical room and promoting hope, values, meaning, and positive schema. The therapy draws on traditional Cognitive Behavioural Therapy techniques but differs with respect to the increased use of behavioural and multi-systemic work, the focus on the development of hopefulness and positive self, and the inclusion of elements of case management and supported employment. Our treatment trials provide evidence for the therapy leading to clinically meaningful increases in structured activity for individuals experiencing first episode and longer-term psychosis. In this paper, we present the core intervention components with examples in order to facilitate evaluation and implementation of the approach

A Cluster Randomized Controlled Trial for a Multi-Level, Clinic-Based Smoking Cessation Program with Women in Appalachian Communities: Study Protocol for the Break Free Program

BACKGROUND: The cervical cancer burden is high among women living in Appalachia. Cigarette smoking, a cervical cancer risk factor, is also highly prevalent in this population. This project aims to increase smoking cessation among women living in Appalachia by embedding a smoking cessation program within a larger, integrated cervical cancer prevention program. METHODS: The broader program, the Take CARE study, is a multi-site research collaborative designed to address three risk factors for cervical cancer incidence and mortality: tobacco use, human papillomavirus (HPV) infection, and cervical cancer screening. Break Free is a primary care clinic-based implementation program that aims to promote smoking cessation among female smokers in Appalachia by standardizing clinical practice protocols. Break Free includes: (1) implementation of a tobacco user identification system in the Electronic Health Record, (2) clinic staff and provider training on the Ask, Advise and Refer (AAR) model, (3) provider implementation of AAR to identify and treat women who want to quit smoking within the next 6 months, (4) facilitated access to cessation phone counseling plus pharmacotherapy, and (5) the bundling of Break Free tobacco cessation with HPV vaccination and cervical cancer screening interventions in an integrated approach to cervical cancer prevention. The study spans 35 Appalachian health clinics across 10 healthcare systems. We aim to enroll 51 adult female smokers per health system (total N = 510). Baseline and follow-up data will be obtained from participant (provider and patient) surveys. The primary outcome is self-reported 12-month point prevalence abstinence among enrolled patients. All randomized patients are asked to complete follow-up surveys, regardless of whether they participated in tobacco treatment. Data analysis of the primary aims will follow intent-to-treat methodology. Secondary outcomes will assess program implementation and cost effectiveness. DISCUSSION: Addressing high tobacco use rates is critical for reducing cervical cancer morbidity and mortality among women living in Appalachia. This study evaluates the implementation and effectiveness of a smoking cessation program in increasing smoking cessation among female smokers. If results demonstrate effectiveness and sustainability, implementation of this program into other health care clinics could reduce both rates of smoking and cervical cancer. Trial registration NCT04340531 (April 9, 2020)

Improving uptake of Fracture Prevention drug treatments: a protocol for Development of a consultation intervention (iFraP-D).

Funder: Wellcome TrustINTRODUCTION: Prevention of fragility fractures, a source of significant economic and personal burden, is hindered by poor uptake of fracture prevention medicines. Enhancing communication of scientific evidence and elicitation of patient medication-related beliefs has the potential to increase patient commitment to treatment. The Improving uptake of Fracture Prevention drug treatments (iFraP) programme aims to develop and evaluate a theoretically informed, complex intervention consisting of a computerised web-based decision support tool, training package and information resources, to facilitate informed decision-making about fracture prevention treatment, with a long-term aim of improving informed treatment adherence. This protocol focuses on the iFraP Development (iFraP-D) work. METHODS AND ANALYSIS: The approach to iFraP-D is informed by the Medical Research Council complex intervention development and evaluation framework and the three-step implementation of change model. The context for the study is UK fracture liaison services (FLS), which enact secondary fracture prevention. An evidence synthesis of clinical guidelines and Delphi exercise will be conducted to identify content for the intervention. Focus groups with patients, FLS clinicians and general practitioners and a usual care survey will facilitate understanding of current practice, and investigate barriers and facilitators to change. Design of the iFraP intervention will be informed by decision aid development standards and theories of implementation, behaviour change, acceptability and medicines adherence. The principles of co-design will underpin all elements of the study through a dedicated iFraP community of practice including key stakeholders and patient advisory groups. In-practice testing of the prototype intervention will inform revisions ready for further testing in a subsequent pilot and feasibility randomised trial. ETHICS AND DISSEMINATION: Ethical approval was obtained from North West-Greater Manchester West Research Ethics Committee (19/NW/0559). Dissemination and knowledge mobilisation will be facilitated through national bodies and networks, publications and presentations. TRIAL REGISTRATION NUMBER: researchregistry5041