BackgroundChronic pain is common, often widespread and has a substantial impact on health and quality of life. The relationship between chronic pain and mortality is unclear. This systematic review aimed to identify and evaluate evidence for a relationship between chronic pain and mortality.MethodsA search of ten electronic databases including EMBASE and MEDLINE was conducted in March 2012, and updated until March 2014. Observational studies investigating the association between chronic or widespread pain (including fibromyalgia) and mortality were included. Risk of bias was assessed and a meta-analysis was undertaken to quantify heterogeneity and pool results. A narrative review was undertaken to explore similarities and differences between the included studies.ResultsTen studies were included in the review. Three reported significant associations between chronic or widespread pain and mortality in unadjusted results. In adjusted analyses, four studies reported a significant association. The remaining studies reported no statistically significant association. A meta-analysis showed statistically significant heterogeneity of results from studies using comparable outcome measures (n = 7)(I2 = 78.8%) and a modest but non-significant pooled estimate (MRR1.14,95%CI 0.95–1.37) for the relationship between chronic pain and all-cause mortality. This association was stronger when analysis was restricted to studies of widespread pain (n = 5,I2 = 82.3%) MRR1.22(95%CI 0.93–1.60). The same pattern was observed with deaths from cancer and cardiovascular diseases. Heterogeneity is likely to be due to differences in study populations, follow-up time, pain phenotype, methods of analysis and use of confounding factors.ConclusionThis review showed a mildly increased risk of death in people with chronic pain, particularly from cancer. However, the small number of studies and methodological differences prevented clear conclusions from being drawn. Consistently applied definitions of chronic pain and further investigation of the role of health, lifestyle, social and psychological factors in future studies will improve understanding of the relationship between chronic pain and mortality.

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BackgroundCannabinoids bind to cannabinoid receptors CB1 and CB2 and have been reported to possess anti-tumorigenic activity in various cancers. However, the mechanisms through which cannabinoids modulate tumor growth are not well known. In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB2 may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.Methodology/Principal FindingsWe observed high expression of both CB2 and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis. We further found that CB2-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays. Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis. In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells. Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems.Conclusions/SignificanceThis study provides novel insights into the crosstalk between CB2 and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis. Furthermore, these studies indicate that CB2 receptors could be used for developing innovative therapeutic strategies against breast cancer.

Moderate to severe chronic pain affects 1 in 5 adults and its impact increases with age. People with chronic pain that interferes with their lives have an increased risk of mortality. Identifying how interfering chronic pain can lead to mortality may highlight potential intervention strategies. This study uses a novel approach to test whether lifestyle, health, social, and psychological factors mediate the relationship between pain and mortality. Survival analyses (Cox's proportional hazard modelling and a technique to assess mediation within survival models) were conducted on a large population study of adults aged 50 years or older from the English Longitudinal Study of Ageing (n = 6324). Data collected at wave 2 (2004) were used as baseline and follow-up was until 2012. The relationship between being "often troubled with pain" and mortality was examined. Lifestyle, health, social, and psychological factors were tested as potential mediators. The strongest mediating factors for the relationship between troubling pain and mortality were functional limitation (hazard ratio 1.31; 95% confidence interval 1.20-1.39), symptoms preventing walking quarter of a mile (1.45 [1.35-1.58]), physical inactivity (1.14 [1.10-1.20]), and poor self-rated health (1.32 [1.23-1.41]). Mediators of the relationship between troubling pain and mortality provide targets for preventive health programmes. Interventions to improve general health, activity, and function could improve long-term survival in patients with this clinical problem.

ObjectiveModerate to severe chronic pain affects one in five adults. Pain may increase the risk of mortality but the relationship is unclear. This study investigated whether mortality risk was influenced by pain phenotype, characterised by pain extent or pain impact on daily life. MethodsThe study population was drawn from two large population cohorts of adults aged ≥50 years; the English Longitudinal Study of Ageing (ELSA) (n=6324) and the North Staffordshire Osteoarthritis Project (NorStOP) (n=10985). Survival analyses (Cox's proportional hazard models) estimated the risk of mortality in participants reporting "any pain" and then separately according to the extent of pain (total number of pain sites; widespread pain according to American College of Rheumatology (ACR) criteria; widespread pain according to Manchester criteria) and pain impact on daily life (pain interference; and often troubled with pain). Models were cumulatively adjusted for age, sex, education and wealth/adequacy of income. ResultsAfter adjustments, the report of any pain (MRR 1.06, 95% CI (0.95, 1.19)) or having widespread pain (ACR 1.07 (0.92, 1.23) or Manchester 1.16 (0.99, 1.36)) was not associated with an increased risk of mortality. Participants who were often troubled with pain (1.29(1.12, 1.49)) and those that reported "quite a bit" (1.38 (1.20,1.59)) and "extreme" (1.88(1.54, 2.29)) pain interference had an increased risk of all-cause mortality.3 ConclusionPain that interferes with daily life, rather than pain per se was associated with an increased risk of mortality. Future studies should investigate the mechanisms through which pain increases mortality risk. 4 Significance and Innovations• Pain impact is key to understanding the relationship between pain and mortality.• An investigation of potential mechanisms of a relationship between pain and mortality is warranted. 5Pain has a major impact on individuals and society (1), is acknowledged by the World Health Organisation and the United Nations as a global problem, and is increasingly recognised as a condition in its own right (2). A significant proportion of people in the general population develop persistent disabling pain, and this contributes to the high number of years lost to disability attributed to painful conditions (3). However, pain may also carry an increased risk of mortality, although the risk is unclear and the evidence contradictory [10,15]. Some of the risk may be attributed to underlying disease such as cancer, which is considered to cause the pain [3], but the important question of whether the experience or nature of chronic pain confers a risk of premature death is unresolved (4-13).A recent systematic review and meta-analysis of the relationship between chronic pain and mortality (14) indicated a modest but non-significant risk of mortality for people with pain, but with high heterogeneity between studies. An important source of variability was differences in pain phenotype between studies, with heterogeneous definitions of pain defined on the basis o...

Purpose The purpose of this paper is to review the development and current position of Business Improvement Districts (BIDs) in the UK, drawing on the content within a State-of-the-Art Review of Business Improvement Districts in the UK: setting the agenda for policy, practice and research, commissioned by The BID Foundation and produced by members of the Institute of Place Management. Design/methodology/approach The paper is divided into seven main sections. The first section defines the concept of BIDs, outlines their process of establishment and provides a brief critique of BIDs from the academic literature. Second, the process of introducing BIDs into the UK is discussed. Third, the different types of BIDs that currently exist are detailed. The fourth section outlines the development of BIDs since their introduction in 2004. Fifth, an analysis of BID ballots is provided, involving details of ballot results, demonstrating a general improvement as BIDs develop over time. The sixth section comprises a discussion of unsuccessful ballots and BID terminations. The paper concludes with a brief analysis of issues BIDs face in the UK, looking into the future. Findings The paper contains three main empirical contributions: first, a numerical analysis of the different types of BIDs in the UK; second, a timeline of their development from 2005 to 2018; and third, a statistical analysis of BID ballot results over this period, with an indication of the numbers of unsuccessful ballots and BID terminations. Originality/value This paper provides the first comprehensive overview of BIDs in the UK detailing development and performance (e.g. ballot results) in the 15 years since their introduction.

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ObjectivesTo identify potentially modifiable factors that mediate the association between symptomatic osteoarthritis (OA) and premature mortality.MethodsA population-based prospective cohort study; primary care medical record data were linked to self-report information collected by questionnaire in adults aged 50 years and over (n=10 415). OA was defined by primary care consultation and moderate-to-severe pain interference in daily life. A Cox proportional hazards analysis determined the total effect (TE) of OA on mortality after adjustment for potential confounders. Within the Cox model, path analysis was used to decompose the TE to assess the indirect and direct effects for selected potential mediators (anxiety, depression, unrefreshed sleep and walking frequency). Results are expressed as HRs with 95% CIs derived from bootstrap resampling.ResultsOA was significantly associated with mortality (TE-adjusted HR 1.14; 95% CI 1.00 to 1.29). The indirect effects for walking frequency were 1.05 (95% CI 1.04 to 1.06), depression 1.02 (95% CI 1.02 to 1.03), anxiety 1.01 (95% CI 1.00 to 1.02) and unrefreshed sleep 1.01 (95% CI 1.00 to 1.01).ConclusionsThe analysis indicates that encouraging people to walk and ‘get out and about’ in addition to targeting OA could be protective against excessive mortality. The findings also suggest that depression, anxiety and unrefreshed sleep have a role in premature mortality for people with OA; however, this has low clinical significance.