The TARGET_TIA: A complete, flexible and sound territorial impact assessment tool

This chapter presents TARGET_TIA as a relevant and flexible Territorial Impact Assessment (TIA) methodology. TARGET_TIA was created in a context where existing ESPON TIA tools were mainly designed for assessing ex ante territorial impacts of EU directives. Hence, in view of the need to properly assess the main ex post territorial impacts of EU Cohesion Policy in several countries in a relevant and sound way, the author decided to design, test and apply his own TIA methodology, named TARGET_TIA. When compared with other existing TIA methodologies, TARGET_TIA can be used both at ex ante and ex post policy evaluation phases. In addition, it brings to the table the possibility to use counterfactual evaluation elements to allow the production of credible and sound TIA evaluation scores. Following on from its implementation in assessing the main territorial impacts of EU policies and programmes, mostly at the ex post evaluation phase, it is possible to conclude that it is a credible, flexible, easy-to-operate, cost-effective and robust TIA methodology, which can be applied to projects, programmes and policies, at all territorial levels.info:eu-repo/semantics/acceptedVersio

Mediation and moderation of genetic risk of obesity through eating behaviours in two UK cohorts

This is the final version. Available on open access from Oxford University Press (OUP) via the DOI in this recordData availability: The data underlying this article are available upon request to the ALSPAC data portal. The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. Full instructions for applying for data access can be found here: [http://www.bristol.ac.uk/alspac/researchers/access/].Background The mechanisms underlying genetic predisposition to higher body mass index (BMI) remain unclear. Methods We hypothesized that the relationship between BMI-genetic risk score (BMI-GRS) and BMI was mediated via disinhibition, emotional eating and hunger, and moderated by flexible (but not rigid) restraint within two UK cohorts: the Genetics of Appetite Study (GATE) (n = 2101, 2010–16) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 1679, 2014–18). Eating behaviour was measured by the Adult Eating Behaviour Questionnaire and Three-Factor Eating Questionaire-51. Results The association between BMI-GRS and BMI were partially mediated by habitual, emotional and situational disinhibition in the GATE/ALSPAC meta-mediation [standardized betaindirect 0.04, 95% confidence interval (CI) 0.02–0.06; 0.03, 0.01–0.04; 0.03, 0.01–0.04, respectively] external hunger and internal hunger in the GATE study (0.02, 0.01–0.03; 0.01, 0.001–0.02, respectively). There was evidence of mediation by emotional over/undereating and hunger in the ALSPAC study (0.02, 0.01–0.03; 0.01, 0.001–0.02; 0.01, 0.002–0.01, respectively). Rigid or flexible restraint did not moderate the direct association between BMI-GRS and BMI, but high flexible restraint moderated the effect of disinhibition subscales on BMI (reduction of the indirect mediation by -5% to -11% in GATE/ALSPAC) and external hunger (-5%) in GATE. High rigid restraint reduced the mediation via disinhibition subscales in GATE/ALSPAC (-4% to -11%) and external hunger (-3%) in GATE. Conclusions Genetic predisposition to a higher BMI was partly explained by disinhibition and hunger in two large cohorts. Flexible/rigid restraint may play an important role in moderating the impact of predisposition to higher BMI.Medical Research Council (MRC)National Institute for Health and Care Research (NIHR)University of BristolEuropean Research Council (ERC

Simultaneous disruption of two DNA polymerases, Polη and Polζ, in Avian DT40 cells unmasks the role of Polη in cellular response to various DNA lesions

Replicative DNA polymerases are frequently stalled by DNA lesions. The resulting replication blockage is released by homologous recombination (HR) and translesion DNA synthesis (TLS). TLS employs specialized TLS polymerases to bypass DNA lesions. We provide striking in vivo evidence of the cooperation between DNA polymerase η, which is mutated in the variant form of the cancer predisposition disorder xeroderma pigmentosum (XP-V), and DNA polymerase ζ by generating POLη−/−/POLζ−/− cells from the chicken DT40 cell line. POLζ−/− cells are hypersensitive to a very wide range of DNA damaging agents, whereas XP-V cells exhibit moderate sensitivity to ultraviolet light (UV) only in the presence of caffeine treatment and exhibit no significant sensitivity to any other damaging agents. It is therefore widely believed that Polη plays a very specific role in cellular tolerance to UV-induced DNA damage. The evidence we present challenges this assumption. The phenotypic analysis of POLη−/−/POLζ−/− cells shows that, unexpectedly, the loss of Polη significantly rescued all mutant phenotypes of POLζ−/− cells and results in the restoration of the DNA damage tolerance by a backup pathway including HR. Taken together, Polη contributes to a much wide range of TLS events than had been predicted by the phenotype of XP-V cells

Circulating mediators of inflammation and immune activation in AIDS-related non-Hodgkin lymphoma

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed beadbased immunoassays. Results: A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions: These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease. © 2014 Nolen et al

Mortality after discharge from long-term psychiatric care in Scotland, 1977 – 94: a retrospective cohort study

BACKGROUND: Recent United Kingdom strategies focus on preventable suicide deaths in former psychiatric in-patients, but natural causes of death, accidents and homicide may also be important. This study was intended to find the relative importance of natural and unnatural causes of death in people discharged from long-term psychiatric care in Scotland in 1977 –1994. METHODS: People discharged alive from psychiatric hospitals in Scotland in 1977 – 94 after a stay of one year or longer were identified using routine hospital records. Computer record linkage was used to link hospital discharges to subsequent death records. Mortality was described using a person-years analysis, and compared to the general population rates. RESULTS: 6,776 people were discharged in the time period. 1,994 people (29%) died by the end of follow-up, 732 more deaths than expected. Deaths from suicide, homicide, accident and undetermined cause were increased, but accounted for only 197 of the excess deaths. Deaths from respiratory disease were four times higher than expected, and deaths from other causes, including cardiovascular disease, were also elevated. CONCLUSION: Suicide is an important cause of preventable mortality, but natural causes account for more excess deaths. Prevention activities should not focus only on unnatural causes of death

Perspectives of ammunition users on the use of lead ammunition and its potential impacts on wildlife and humans

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: All data supporting the results in this paper are available from Zenodo (digital repository): https://zenodo.org/record/2653514#.XMbMXKbsZD8 (Newth et al., 2019).1. Recent national and international policy initiatives have aimed to reduce the exposure of humans and wildlife to lead from ammunition. Despite restrictions, in the UK, lead ammunition remains the most widespread source of environmental lead contamination to which wildlife may be exposed. 2. The risks arising from the use of lead ammunition and the measures taken to mitigate these have prompted intense and sometimes acrimonious discussion between stakeholder groups, including those advancing the interests of shooting, wildlife conservation, public health and animal welfare. 3. However, relatively little is known of the perspectives of individual ammunition users, despite their role in adding lead to the environment and their pivotal place in any potential changes to practice. Using Q‐methodology, we identified the perspectives of ammunition users in the UK on lead ammunition in an effort to bring forward evidence from these key stakeholders. 4. Views were characterised by two statistically and qualitatively distinct perspectives: (a) Open to change—comprised ammunition users that refuted the view that lead ammunition is not a major source of poisoning in wild birds, believed that solutions to reduce the risks of poisoning are needed, were happy to use non‐lead alternatives and did not feel that the phasing out of lead shot would lead to the demise of shooting; and (b) Status quo—comprised ammunition users who did not regard lead poisoning as a major welfare problem for wild birds, were ambivalent about the need for solutions and felt that lead shot is better than steel at killing and not wounding an animal. They believed opposition to lead ammunition was driven more by a dislike of shooting than evidence of any harm. 5. Adherents to both perspectives agreed that lead is a toxic substance. There was consensus that involvement of stakeholders from all sides of the debate was desirable and that to be taken seriously by shooters, information about lead poisoning should come from the shooting community

The Effect of Intermittent Fasting on Appetite: A Systematic Review and Meta-Analysis

This is the final version. Available on open access from MDPI via the DOI in this recordData Availability Statement: Data sharing not applicablePreviously, narrative reviews have considered the effects of intermittent fasting on appetite. One suggestion is that intermittent fasting attenuates an increase in appetite that typically accompanies weight loss. Here, we conducted the first systematic review and meta-analysis to quantify the effects of intermittent fasting on appetite, when compared to a continuous energy restriction intervention. Five electronic databases and trial registers were searched in February 2021 and February 2022. Abstracts (N = 2800) were screened and 17 randomized controlled trials (RCTs), consisting of a variety of intermittent fasting regimes, met our inclusion criteria. The total number of participants allocated to interventions was 1111 and all RCTs were judged as having either some concerns or a high risk of bias (Cochrane RoB 2.0 tool). Random effects meta-analyses were conducted on change-from-baseline appetite ratings. There was no clear evidence that intermittent fasting affected hunger (WMD = -3.03; 95% CI [-8.13, 2.08]; p = 0.25; N = 13), fullness (WMD = 3.11; 95% CI [-1.46, 7.69]; p = 0.18; N = 10), desire to eat (WMD = -3.89; 95% CI [-12.62, 4.83]; p = 0.38; N = 6), or prospective food consumption (WMD = -2.82; 95% CI [-3.87, 9.03]; p = 0.43; N = 5), differently to continuous energy restriction interventions. Our results suggest that intermittent fasting does not mitigate an increase in our drive to eat that is often associated with continuous energy restriction.Medical Research Council (MRC)National Institute for Health and Care Research (NIHR

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al

Tamoxifen stimulates arachidonic acid release from rat liver cells by an estrogen receptor-independent, non-genomic mechanism

BACKGROUND: Tamoxifen is widely prescribed for the treatment of breast cancer. Its success has been attributed to the modulation of the estrogen receptor. I have previously proposed that the release of arachidonic acid from cells may also mediate cancer prevention. METHODS: Rat liver cells were radiolabelled with arachidonic acid. The release of [(3)H] arachidonic acid after various times of incubation of the cells with tamoxifen was measured. RESULTS: Tamoxifen, at micromolar concentrations, stimulates arachidonic acid release. The stimulation is rapid and is not affected by pre-incubation of the cells with actinomycin or the estrogen antagonist ICI-182,780. CONCLUSIONS: The stimulation of AA release by tamoxifen is not mediated by estrogen receptor occupancy and is non-genomic