Cancer and systemic inflammation: treat the tumour and treat the host

Determinants of cancer progression and survival are multifactorial and host responses are increasingly appreciated to have a major role. Indeed, the development and maintenance of a systemic inflammatory response has been consistently observed to confer poorer outcome, in both early and advanced stage disease. For patients, cancer-associated symptoms are of particular importance resulting in a marked impact on day-to-day quality of life and are also associated with poorer outcome. These symptoms are now recognised to cluster with one another with anorexia, weight loss and physical function forming a recognised cluster whereas fatigue, pain and depression forming another. Importantly, it has become apparent that these symptom clusters are associated with presence of a systemic inflammatory response in the patient with cancer. Given the understanding of the above, there is now a need to intervene to moderate systemic inflammatory responses, where present. In this context the rationale for therapeutic intervention using nonselective anti-inflammatory agents is clear and compelling and likely to become a part of routine clinical practice in the near future. The published literature on therapeutic intervention using anti-inflammatory agents for cancer-associated symptoms was reviewed. There are important parallels with the development of useful treatments for the systemic inflammatory response in patients with rheumatological disease and cardiovascular disease

Union effects on performance and employment relations: Evidence from China

This paper empirically studies union effects on the performance of, and employment relations in, China's private enterprises. The study finds a positive and statistically significant union effect on labor productivity, but not on profitability. It further finds that unions lead to better employee benefits and increased contract signing in employment. These findings suggest that, in the era of transition from a centrally planned to a market economy, unions in China's private enterprises do promote workers' interests as unions do in other economies. And they do that without abandoning their traditional role of harmonizing employment relations, as required by the Party. © 2010 Elsevier Inc. All rights reserved.preprin

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase

Little is known about quality control of proteins that aberrantly or persistently engage the endoplasmic reticulum (ER)-localized translocon en route to membrane localization or the secretory pathway. Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets of misfolded or otherwise abnormal proteins based primarily on degradation signal (degron) location. We report the surprising observation that fusing Deg1, a cytoplasmic degron normally recognized by Doa10, to the Sec62 membrane protein rendered the protein a Hrd1 substrate. Hrd1-dependent degradation occurred when Deg1-Sec62 aberrantly engaged the Sec61 translocon channel and underwent topological rearrangement. Mutations that prevent translocon engagement caused a reversion to Doa10-dependent degradation. Similarly, a variant of apolipoprotein B, a protein known to be cotranslocationally targeted for proteasomal degradation, was also a Hrd1 substrate. Hrd1 therefore likely plays a general role in targeting proteins that persistently associate with and potentially obstruct the translocon

Machine Learning in Automated Text Categorization

The automated categorization (or classification) of texts into predefined categories has witnessed a booming interest in the last ten years, due to the increased availability of documents in digital form and the ensuing need to organize them. In the research community the dominant approach to this problem is based on machine learning techniques: a general inductive process automatically builds a classifier by learning, from a set of preclassified documents, the characteristics of the categories. The advantages of this approach over the knowledge engineering approach (consisting in the manual definition of a classifier by domain experts) are a very good effectiveness, considerable savings in terms of expert manpower, and straightforward portability to different domains. This survey discusses the main approaches to text categorization that fall within the machine learning paradigm. We will discuss in detail issues pertaining to three different problems, namely document representation, classifier construction, and classifier evaluation.Comment: Accepted for publication on ACM Computing Survey

Variations in achievement of evidence-based, high-impact quality indicators in general practice : An observational study

BACKGROUND: There are widely recognised variations in the delivery and outcomes of healthcare but an incomplete understanding of their causes. There is a growing interest in using routinely collected 'big data' in the evaluation of healthcare. We developed a set of evidence-based 'high impact' quality indicators (QIs) for primary care and examined variations in achievement of these indicators using routinely collected data in the United Kingdom (UK). METHODS: Cross-sectional analysis of routinely collected, electronic primary care data from a sample of general practices in West Yorkshire, UK (n = 89). The QIs covered aspects of care (including processes and intermediate clinical outcomes) in relation to diabetes, hypertension, atrial fibrillation, myocardial infarction, chronic kidney disease (CKD) and 'risky' prescribing combinations. Regression models explored the impact of practice and patient characteristics. Clustering within practice was accounted for by including a random intercept for practice. RESULTS: Median practice achievement of the QIs ranged from 43.2% (diabetes control) to 72.2% (blood pressure control in CKD). Considerable between-practice variation existed for all indicators: the difference between the highest and lowest performing practices was 26.3 percentage points for risky prescribing and 100 percentage points for anticoagulation in atrial fibrillation. Odds ratios associated with the random effects for practices emphasised this; there was a greater than ten-fold difference in the likelihood of achieving the hypertension indicator between the lowest and highest performing practices. Patient characteristics, in particular age, gender and comorbidity, were consistently but modestly associated with indicator achievement. Statistically significant practice characteristics were identified less frequently in adjusted models. CONCLUSIONS: Despite various policy and improvement initiatives, there are enduring inappropriate variations in the delivery of evidence-based care. Much of this variation is not explained by routinely collected patient or practice variables, and is likely to be attributable to differences in clinical and organisational behaviour

Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.)

Factors associated with lower disease-specific and generic health-related quality of life in Rome IV irritable bowel syndrome

Background Little is known about associations with reduced quality of life in irritable bowel syndrome (IBS) or impact of IBS on quality of life compared with other chronic conditions. Methods We collected demographic, gastrointestinal and psychological symptoms, healthcare usage, direct healthcare costs, impact on work and activities of daily living data from 752 individuals with Rome IV-defined IBS. We used the irritable bowel syndrome quality of life (IBS-QOL) and the EQ-5D-5L questionnaires to examine characteristics associated with lower quality of life. Results The mean IBS-QOL among all 752 individuals with Rome IV IBS was 48.4 (SD 22.3) and the mean EQ-5D score was 0.570 (SD 0.283), the latter being comparable to people with stroke, leg ulcers or chronic obstructive pulmonary disease. Lower levels of both disease-specific and generic quality of life were associated with severe IBS symptom scores, abnormal anxiety or depression scores, and higher somatoform symptom-reporting and gastrointestinal symptom-specific anxiety scores (p < 0.001 for all analyses). Those with lower quality of life had significantly higher healthcare usage and direct healthcare costs and more impairment in work and activities of daily living (p < 0.01 for all analyses). Avoidance of alcohol, lower educational level, abnormal anxiety, depression or somatoform symptom-reporting scores, and impairment in social leisure activities, home management or maintaining close relationships were all independently associated with lower quality of life. Conclusion IBS has a substantial impact on the quality of life of those affected, and worse than observed in some severe chronic organic conditions

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Primary care transformation in Scotland:a comparison two cross-sectional national surveys of general practitioners' views in 2018 and 2023

BACKGROUND: The 2018 Scottish GP contract established GP clusters and multidisciplinary team (MDT) expansion. Qualitative studies have suggested suboptimal progress with these initiatives.AIM: To quantify progress since the introduction of the new contract.DESIGN AND SETTING: A cross-sectional postal survey of all qualified GPs was undertaken in Scotland in 2023.METHOD: GPs' working lives, career intentions, and views on the new contract were compared with a similar survey conducted in 2018.RESULTS: In total, 1385/4529 (31%) GPs responded to the 2023 survey compared with 2465/4371 (56%) in 2018. Job satisfaction and negative job attributes were similar in both surveys. Both positive job attributes ( P = 0.011) and job pressures ( P = 0.004) increased but the changes were small (effect sizes &lt;0.2). Significantly more GPs were planning to reduce hours ( P&lt;0.001) and leave direct patient care ( P = 0.008) in 2023 than in 2018. Quality leads' views on cluster working were unchanged, with 70%-80% reporting insufficient support. Cluster knowledge and engagement was unchanged but there were small increases in knowledge of quality improvement. More than half of the GPs reported that access to MDT staff was insufficient to reduce their workload in all staff categories except vaccinations. Significantly more practices were trying to recruit GPs ( P&lt;0.01), and GPs reported worsening NHS services, higher workload, and lower practice sustainability in 2023 ( P&lt;0.001). Only 5% of GPs in the 2023 survey thought that the new contract had improved the care of patients with complex needs. CONCLUSION: GPs report few improvements in working life 5 years after the new contract was introduced, and are responding by planning to reduce their hours or leave direct patient care.</p