Positron emission tomography imaging of coronary atherosclerosis

Inflammation has a central role in the progression of coronary atherosclerosis. Recent developments in cardiovascular imaging with the advent of hybrid positron emission tomography have provided a window into the molecular pathophysiology underlying coronary plaque inflammation. Using novel radiotracers targeted at specific cellular pathways, the potential exists to observe inflammation, apoptosis, cellular hypoxia, microcalcification and angiogenesis in vivo. Several clinical studies are now underway assessing the ability of this hybrid imaging modality to inform about atherosclerotic disease activity and the prediction of future cardiovascular risk. A better understanding of the molecular mechanisms governing coronary atherosclerosis may be the first step toward offering patients a more stratified, personalized approach to treatment

Singing for people with aphasia (SPA): Results of a pilot feasibility randomised controlled trial of a group singing intervention investigating acceptability and feasibility

This is the final version. Available on open access from BMJ Publishing Group via the DOI in this recordObjectives: Pilot feasibility randomised controlled trial (RCT) for the ‘Singing groups for People with Aphasia’ (SPA) intervention to assess: (1) the acceptability and feasibility of participant recruitment, randomisation and allocation concealment; (2) retention rates; (3) variance of continuous outcome measures; (4) outcome measure completion and participant burden; (5) fidelity of intervention delivery; (6) SPA intervention costs; (7) acceptability and feasibility of trial and intervention to participants and others involved. Design: A two-group, assessor-blinded, randomised controlled external pilot trial with parallel mixed methods process evaluation and economic evaluation. Setting: Three community-based cohorts in the South-West of England. Participants: Eligible participants with post-stroke aphasia were randomised 1:1 to SPA or control. Intervention: The manualised SPA intervention was delivered over 10 weekly singing group sessions, led by a music facilitator and assisted by an individual with post-stroke aphasia. The intervention was developed using the Information-Motivation-Behavioural skills model of behaviour change and targeted psychosocial outcomes. Control and intervention participants all received an aphasia information resource pack. Outcome measures: Collected at baseline, 3 and 6 months post-randomisation, candidate primary outcomes were measured (well-being, quality of life and social participation) as well as additional clinical outcomes. Feasibility, acceptability and process outcomes included recruitment and retention rates, and measurement burden; and trial experiences were explored in qualitative interviews. Results: Of 87 individuals screened, 42 participants were recruited and 41 randomised (SPA=20, Control=21); 36 participants (SPA=17, Control=19) completed 3-month follow-up, 34 (SPA=18, Control=16) completed 6-month follow-up. Recruitment and retention (83%) were acceptable for a definitive RCT, and participants did not find the study requirements burdensome. High fidelity of the intervention delivery was shown by high attendance rates and facilitator adherence to the manual, and participants found SPA acceptable. Sample size estimates for a definitive RCT and primary/secondary outcomes were identified. Conclusions: The SPA pilot RCT fulfilled its objectives, and demonstrated that a definitive RCT of the intervention would be both feasible and acceptable.Stroke Associatio

A bovine lymphosarcoma cell line infected with theileria annulata exhibits an irreversible reconfiguration of host cell gene expression

Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner

Current use of smokeless tobacco among adolescents in the Republic of Congo

<p>Abstract</p> <p>Background</p> <p>Tobacco use is a leading cause of global morbidity and mortality. Much of the epidemiologic research on tobacco focuses on smoking, especially cigarette smoking, but little attention on smokeless tobacco (SLT).</p> <p>Methods</p> <p>Using data from the Republic of Congo Global Youth Tobacco Survey (GYTS) of 2006, we estimated the prevalence of SLT use among in-school adolescents. We also assessed the association between SLT use and cigarette smoking as well as the traditional factors which are associated with cigarette smoking among adolescents (e.g. age, sex, parental or peer smoking). Unadjusted odds ratios (OR) and adjusted odds ratios (AOR) together with their 95% confidence intervals (CI) were used to measure magnitudes of associations.</p> <p>Results</p> <p>Of the 3,034 respondents, 18.0% (18.0% males and 18.1% females) reported having used smokeless tobacco (chewing tobacco, sniff or dip) in the last 30 days. In multivariate analysis, no significant associations were observed between age and sex on one hand and current smokeless tobacco use on the other. Cigarette smokers were more than six times likely to report current use of smokeless tobacco (AOR = 6.65; 95% CI [4.84, 9.14]). Having parents or friends smokers was positively associated with using smokeless tobacco (AOR = 1.98; 95% CI [1.51, 2.59] for parents who smoked cigarettes, AOR = 1.82; 95% CI [1.41, 2.69] for some friends who smoked cigarettes, and AOR = 2.02; 95% CI [1.49, 2.47] for most or all friends who smoked cigarettes). Respondents who reported have seen tobacco advertisement on TV, billboards and in newspapers/magazines were 1.95 times more likely to report current use of smokeless tobacco (AOR = 1.95; 95% CI [1.34, 3.08]). Perception that smoking was harmful to health was negatively associated with current use of smokeless tobacco (AOR = 0.60; 95% CI [0.46, 0.78]).</p> <p>Conclusions</p> <p>Prevention programs aimed to reduce teen [cigarette] smoking must also be designed to reduce other forms of tobacco use. The teenagers environment at home, at school and at leisure must also be factored in order to prevent their uptake or maintenance of tobacco use.</p

Structural issues affecting mixed methods studies in health research: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Health researchers undertake studies which combine qualitative and quantitative methods. Little attention has been paid to the structural issues affecting this mixed methods approach. We explored the facilitators and barriers to undertaking mixed methods studies in health research.</p> <p>Methods</p> <p>Face-to-face semi-structured interviews with 20 researchers experienced in mixed methods research in health in the United Kingdom.</p> <p>Results</p> <p>Structural facilitators for undertaking mixed methods studies included a perception that funding bodies promoted this approach, and the multidisciplinary constituency of some university departments. Structural barriers to exploiting the potential of these studies included a lack of education and training in mixed methods research, and a lack of templates for reporting mixed methods articles in peer-reviewed journals. The 'hierarchy of evidence' relating to effectiveness studies in health care research, with the randomised controlled trial as the gold standard, appeared to pervade the health research infrastructure. Thus integration of data and findings from qualitative and quantitative components of mixed methods studies, and dissemination of integrated outputs, tended to occur through serendipity and effort, further highlighting the presence of structural constraints. Researchers are agents who may also support current structures - journal reviewers and editors, and directors of postgraduate training courses - and thus have the ability to improve the structural support for exploiting the potential of mixed methods research.</p> <p>Conclusion</p> <p>The environment for health research in the UK appears to be conducive to mixed methods research but not to exploiting the potential of this approach. Structural change, as well as change in researcher behaviour, will be necessary if researchers are to fully exploit the potential of using mixed methods research.</p

Pregnancy Outcome and Placenta Pathology in Plasmodium berghei ANKA Infected Mice Reproduce the Pathogenesis of Severe Malaria in Pregnant Women

Pregnancy-associated malaria (PAM) is expressed in a range of clinical complications that include increased disease severity in pregnant women, decreased fetal viability, intra-uterine growth retardation, low birth weight and infant mortality. The physiopathology of malaria in pregnancy is difficult to scrutinize and attempts were made in the past to use animal models for pregnancy malaria studies. Here, we describe a comprehensive mouse experimental model that recapitulates many of the pathological and clinical features typical of human severe malaria in pregnancy. We used P. berghei ANKA-GFP infection during pregnancy to evoke a prominent inflammatory response in the placenta that entails CD11b mononuclear infiltration, up-regulation of MIP-1 alpha chemokine and is associated with marked reduction of placental vascular spaces. Placenta pathology was associated with decreased fetal viability, intra-uterine growth retardation, gross post-natal growth impairment and increased disease severity in pregnant females. Moreover, we provide evidence that CSA and HA, known to mediate P. falciparum adhesion to human placenta, are also involved in mouse placental malaria infection. We propose that reduction of maternal blood flow in the placenta is a key pathogenic factor in murine pregnancy malaria and we hypothesize that exacerbated innate inflammatory responses to Plasmodium infected red blood cells trigger severe placenta pathology. This experimental model provides an opportunity to identify cell and molecular components of severe PAM pathogenesis and to investigate the inflammatory response that leads to the observed fetal and placental blood circulation abnormalities

Real-world evidence in a national health service: results of the UK CardioMEMS HF System Post-Market Study

Aims The CardioMEMS HF System Post-Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic-guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. Methods and results COAST is a prospective, international, multicentre, open-label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic-guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system-related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72–88%] than the previous 12 months (0.27 vs. 1.52 events/patient-year, respectively, P < 0.0001). Freedom from device/system-related complications and pressure sensor failure at 2 years was 100% and 99%, respectively. Conclusions Remote haemodynamic-guided HF management, using frequent assessment of pulmonary artery pressures, was successfully implemented at 14 specialist centres in the UK. Haemodynamic-guided HF management was safe and significantly reduced hospitalization in a group of high-risk patients. These results support implementation of this innovative remote management strategy to improve outcome for patients with symptomatic HF. Clinical registration number: ClinicalTrials.gov identifier: NCT02954341

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms

A population-based case–control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m−2 at five years before diagnosis,, was associated with an increased risk of NHL (OR=1.5, 95% CI 1.1–2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR=1.9, 95% CI 1.3–2.8). Genetic variants in the leptin (LEP 19G>A, LEP −2548G>A) and leptin receptor genes (LEPR 223Q>R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR=0.7, 95% CI 0.5–1.0) and increased with LEP −2548GA (OR=1.3, 95% CI 1.0–1.7) and −2548AA (OR=1.4, 95% CI 1.0–1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women

Human MLH1 Protein Participates in Genomic Damage Checkpoint Signaling in Response to DNA Interstrand Crosslinks, while MSH2 Functions in DNA Repair

DNA interstrand crosslinks (ICLs) are among the most toxic types of damage to a cell. For this reason, many ICL-inducing agents are effective therapeutic agents. For example, cisplatin and nitrogen mustards are used for treating cancer and psoralen plus UVA (PUVA) is useful for treating psoriasis. However, repair mechanisms for ICLs in the human genome are not clearly defined. Previously, we have shown that MSH2, the common subunit of the human MutSα and MutSβ mismatch recognition complexes, plays a role in the error-free repair of psoralen ICLs. We hypothesized that MLH1, the common subunit of human MutL complexes, is also involved in the cellular response to psoralen ICLs. Surprisingly, we instead found that MLH1-deficient human cells are more resistant to psoralen ICLs, in contrast to the sensitivity to these lesions displayed by MSH2-deficient cells. Apoptosis was not as efficiently induced by psoralen ICLs in MLH1-deficient cells as in MLH1-proficient cells as determined by caspase-3/7 activity and binding of annexin V. Strikingly, CHK2 phosphorylation was undetectable in MLH1-deficient cells, and phosphorylation of CHK1 was reduced after PUVA treatment, indicating that MLH1 is involved in signaling psoralen ICL-induced checkpoint activation. Psoralen ICLs can result in mutations near the crosslinked sites; however, MLH1 function was not required for the mutagenic repair of these lesions, and so its signaling function appears to have a role in maintaining genomic stability following exposure to ICL-induced DNA damage. Distinguishing the genetic status of MMR-deficient tumors as MSH2-deficient or MLH1-deficient is thus potentially important in predicting the efficacy of treatment with psoralen and perhaps with other ICL-inducing agents