Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes

Background: Early identification of severe dengue patients is important regarding patient management and resource allocation. We investigated the association of 10 biomarkers (VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, CRP) with the development of severe/moderate dengue (S/MD). Methods: We performed a nested case-control study from a multi-country study. A total of 281 S/MD and 556 uncomplicated dengue cases were included. Results: On days 1–3 from symptom onset, higher levels of any biomarker increased the risk of developing S/MD. When assessing together, SDC-1 and IL-1RA were stable, while IP-10 changed the association from positive to negative; others showed weaker associations. The best combinations associated with S/MD comprised IL-1RA, Ang-2, IL-8, ferritin, IP-10, and SDC-1 for children, and SDC-1, IL-8, ferritin, sTREM-1, IL-1RA, IP-10, and sCD163 for adults. Conclusions: Our findings assist the development of biomarker panels for clinical use and could improve triage and risk prediction in dengue patients. Funding: This study was supported by the EU's Seventh Framework Programme (FP7-281803 IDAMS), the WHO, and the Bill and Melinda Gates Foundation

High pre-diagnosis inflammation-related risk score associated with decreased ovarian cancer survival

BACKGROUND: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. METHODS: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. Pre-diagnosis inflammatory-related exposures of interest included alcohol use, aspirin use, other nonsteroidal anti-inflammatory drug use, body mass index, environmental tobacco smoke exposure, history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis, menopausal hormone therapy use, physical inactivity, smoking status, and talc use. Using Cox proportional hazards (PH) models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed and its association with survival was assessed using Cox PH models in the remaining 50% of the data. RESULTS: There was a statistically significant trend of increasing risk of death per quartile of the IRRS (HR=1.09, 95% CI 1.03-1.14). Women in the upper quartile of the IRRS had 31% higher death rate compared to the lowest quartile (95% CI 1.11-1.54). CONCLUSIONS: A higher pre-diagnosis IRRS was associated with increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether post-diagnosis exposures are also associated with survival. IMPACT: Given that pre- and post-diagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among ovarian cancer patients

Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Background: Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. / Methods: A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. / Results: Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. / Conclusions: Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk

The influence of contextual factors on healthcare quality improvement initiatives:a realist review

Background Recognising the influence of context and the context-sensitive nature of quality improvement (QI) interventions is crucial to implementing effective improvements and successfully replicating them in new settings, yet context is still poorly understood. To address this challenge, it is necessary to capture generalisable knowledge, first to understand which aspects of context are most important to QI and why, and secondly, to explore how these factors can be managed to support healthcare improvement, in terms of implementing successful improvement initiatives, achieving sustainability and scaling interventions. The research question was how and why does context influence quality improvement initiatives in healthcare? Methods A realist review explored the contextual conditions that influence healthcare improvement. Realist methodology integrates theoretical understanding and stakeholder input with empirical research findings. The review aimed to identify and understand the role of context during the improvement cycle, i.e. planning, implementation, sustainability and transferability; and distil new knowledge to inform the design and development of context-sensitive QI initiatives. We developed a preliminary theory of the influence of context to arrive at a conceptual and theoretical framework. Results Thirty-five studies were included in the review, demonstrating the interaction of key contextual factors across healthcare system levels during the improvement cycle. An evidence-based explanatory theoretical model is proposed to illustrate the interaction between contextual factors, system levels (macro, meso, micro) and the stages of the improvement journey. Findings indicate that the consideration of these contextual factors would enhance the design and delivery of improvement initiatives, across a range of improvement settings. Conclusions This is the first realist review of context in QI and contributes to a deeper understanding of how context influences quality improvement initiatives. The distillation of key contextual factors offers the potential to inform the design and development of context-sensitive interventions to enhance improvement initiatives and address the challenge of spread and sustainability. Future research should explore the application of our conceptual model to enhance improvement-planning processes

Synergistic antitumour effects of rapamycin and oncolytic reovirus.

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination

A Prognostic Model for Development of Profound Shock among Children Presenting with Dengue Shock Syndrome

PURPOSE: To identify risk factors and develop a prediction model for the development of profound and recurrent shock amongst children presenting with dengue shock syndrome (DSS). METHODS: We analyzed data from a prospective cohort of children with DSS recruited at the Paediatric Intensive Care Unit of the Hospital for Tropical Disease in Ho Chi Minh City, Vietnam. The primary endpoint was "profound DSS", defined as ≥2 recurrent shock episodes (for subjects presenting in compensated shock), or ≥1 recurrent shock episodes (for subjects presenting initially with decompensated/hypotensive shock), and/or requirement for inotropic support. Recurrent shock was evaluated as a secondary endpoint. Risk factors were pre-defined clinical and laboratory variables collected at the time of presentation with shock. Prognostic model development was based on logistic regression and compared to several alternative approaches. RESULTS: The analysis population included 1207 children of whom 222 (18%) progressed to "profound DSS" and 433 (36%) had recurrent shock. Independent risk factors for both endpoints included younger age, earlier presentation, higher pulse rate, higher temperature, higher haematocrit and, for females, worse hemodynamic status at presentation. The final prognostic model for "profound DSS" showed acceptable discrimination (AUC=0.69 for internal validation) and calibration and is presented as a simple score-chart. CONCLUSIONS: Several risk factors for development of profound or recurrent shock among children presenting with DSS were identified. The score-chart derived from the prognostic models should improve triage and management of children presenting with DSS in dengue-endemic areas