Machine Learning Methods Enable Predictive Modeling of Antibody Feature:Function Relationships in RV144 Vaccinees

The adaptive immune response to vaccination or infection can lead to the production of specific antibodies to neutralize the pathogen or recruit innate immune effector cells for help. The non-neutralizing role of antibodies in stimulating effector cell responses may have been a key mechanism of the protection observed in the RV144 HIV vaccine trial. In an extensive investigation of a rich set of data collected from RV144 vaccine recipients, we here employ machine learning methods to identify and model associations between antibody features (IgG subclass and antigen specificity) and effector function activities (antibody dependent cellular phagocytosis, cellular cytotoxicity, and cytokine release). We demonstrate via cross-validation that classification and regression approaches can effectively use the antibody features to robustly predict qualitative and quantitative functional outcomes. This integration of antibody feature and function data within a machine learning framework provides a new, objective approach to discovering and assessing multivariate immune correlates.U.S. Military HIV Research ProgramCollaboration for AIDS Vaccine Discover (OPP1032817)National Institutes of Health (U.S.) (3R01AI080289-02S1)National Institutes of Health (U.S.) (5R01AI080289-03)United States. Army Medical Research and Materiel Command (National Institute of Allergy and Infectious Diseases (U.S.) Interagency Agreement Y1-AI-2642-12)Henry M. Jackson Foundation for the Advancement of Military Medicine (U.S.) (United States. Dept. of Defense Cooperative Agreement W81XWH-07-2-0067

Effect of a 2-tier rapid response system on patient outcome and staff satisfaction

Background: Rapid response systems (RRS) have been recommended as a strategy to prevent and treat deterioration in acute care patients. Questions regarding the most effective characteristics of RRS and strategies for implementing these systems remain. Aims: The aims of this study were to (i) describe the structures and processes used to implement a 2-tier RRS, (ii) determine the comparative prevalence of deteriorating patients and incidence of unplanned intensive care unit (ICU) admission and cardiac arrest prior to and after implementation of the RRS, and (iii) determine clinician satisfaction with the RRS. Method: A quasi-experimental pre-test, post-test design was used to assess patient related outcomes and clinician satisfaction prior to and after implementation of a 2-tier RRS in a tertiary metropolitan hospital. Primary components of the RRS included an ICU Outreach Nurse and a Rapid Response Team. Prevalence of deteriorating patients was assessed through a point prevalence assessment and chart audit. Incidence of unplanned admission to ICU and cardiac arrests were accessed from routine hospital databases. Clinician satisfaction was measured through surveys. Results: Prevalence of patients who met medical emergency call criteria without current treatment reduced from 3% prior to RRS implementation to 1% after implementation; a similar reduction from 9% to 3% was identified on chart review. The number of unplanned admissions to ICU increased slightly from 17.4/month prior to RRS implementation to 18.1/month after implementation (p = 0.45) while cardiac arrests reduced slightly from 7.5/month to 5.6/month (p = 0.22) but neither of these changes were statistically significant. Staff satisfaction with the RRS was generally high. Conclusion: The 2-tier RRS was accessed by staff to assist with care of deteriorating patients in a large, tertiary hospital. High levels of satisfaction have been reported by clinical staff

Complications and Solutions for Post-Operative Liposuction Deformities

In this chapter, the authors will review the complications associated with liposuction and laser liposuction procedures, using published reports as the guide to document these complications and deformities to the readers. In addition, the authors will also report on the use of tumescent anesthesia and the published documentation regarding safety concerns that have been presented via the use of tumescence versus general anesthesia when performing liposuction or laser liposuction. Real-world discussions also will take place in which the authors describe best treatment practices as solutions to those complications described. Liposuction and laser liposuction are wonderful procedures that have been performed for many years. Understanding and being able to identify and treat any untoward complications is extremely important to make everyone a better surgeon and a better physician

Mass media and risk factors for cancer: the under-representation of age

BACKGROUND: Increasing age is a risk factor for developing cancer. Yet, older people commonly underestimate this risk, are less likely to be aware of the early symptoms, and are more likely to be diagnosed with advanced stage cancer. Mass media are a key influence on the public's understanding health issues, including cancer risk. This study investigates how news media have represented age and other risk factors in the most common cancers over time. METHODS: Eight hundred articles about the four most common cancers (breast, prostate, lung and colorectal) published within eight UK national newspapers in 2003, 2004, 2013 and 2014 were identified using the Nexis database. Relevant manifest content of articles was coded quantitatively and subjected to descriptive statistical analysis in SPSS to identify patterns across the data. RESULTS: Risk was presented in half of the articles but this was rarely discussed in any depth and around a quarter of all articles introduced more than one risk factor, irrespective of cancer site. Age was mentioned as a risk factor in approximately 12% of all articles and this varied by cancer site. Age was most frequently reported in relation to prostate cancer and least often in articles about lung cancer. Articles featuring personal narratives more frequently focused on younger people and this was more pronounced in non-celebrity stories; only 15% of non-celebrity narratives were about people over 60. Other common risks discussed were family history and genetics, smoking, diet, alcohol, and environmental factors. Family history and genetics together featured as the most common risk factors. Risk factor reporting varied by site and family history was most commonly associated with breast cancer, diet with bowel cancer and smoking with lung cancer. CONCLUSION: Age and older adults were largely obscured in media representation of cancer and cancer experience. Indeed common risk factors in general were rarely discussed in any depth. Our findings will usefully inform the development of future cancer awareness campaigns and media guidelines. It is important that older adults appreciate their heightened risk, particularly in the context of help-seeking decisions

Supporting children’s wellbeing through music participation during the COVID-19 pandemic:Evidence from Scotland

The COVID-19 pandemic has highlighted the importance of strengthening the health and wellbeing of children as a global priority. This paper explores the impact of an inclusive music programme, that was delivered, prior to and during the pandemic, in an area of deprivation in Scotland. The main research question was, ‘How does an inclusive music programme support wellbeing of children living in areas of multiple deprivation during COVID?’. Multiple perspectives and data collection methods were included, e.g.,comic strips, interviews, focus groups and questionnaires. Results suggest that the programme provided continuity and stability to children, especially during lockdown. All participants highlighted the positive impact the programme had on the emotional wellbeing of children, which was linked to a sense of security and trusting relationships that were formed as part of the programme, not only during COVID but prior to it too

Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

The Herschel SPIRE Fourier Transform Spectrometer Spectral Feature Finder III. Line Identification and Off-Axis Spectra

The ESA Herschel Spectral and Photometric Imaging Receiver (SPIRE) Fourier Transform Spectrometer (FTS) Spectral Feature Finder (FF) project is an automated spectral feature fitting routine developed within the SPIRE instrument team to extract all prominent spectral features from all publicly available SPIRE FTS observations. We present the extension of the FF to include the off-axis detectors of the FTS in sparsely sampled single-pointing observations, the results of which have been ingested into the catalogue. We also present the results from an automated routine for identifications of the atomic/molecular transitions that correspond to the spectral features extracted by the FF. We use a template of 307 atomic fine structure and molecular lines that are commonly found in SPIRE FTS spectra for the cross-match. The routine makes use of information provided by the line identification to search for low signal-to-noise ratio features that have been excluded or missed by the iterative FF. In total, the atomic/molecular transitions of 178,942 lines are identified (corresponding to 83% of the entire FF catalogue), and an additional 33,840 spectral lines associated with missing features from SPIRE FTS observations are added to the FF catalogue.Comment: 15 pages (+2 appendix pages), 14 figures, 7 tables, final version accepted by MNRAS June 202

Inhibition of cyclin-dependent kinase 9 downregulates cytokine production without detrimentally affecting human monocyte-derived macrophage viability

Cyclin-dependent kinase (CDK) inhibitor drugs (CDKi), such as R-roscovitine and AT7519, induce neutrophil apoptosis in vitro and enhance the resolution of inflammation in a number of in vivo models. This class of compounds are potential novel therapeutic agents that could promote the resolution of acute and chronic inflammatory conditions where neutrophil activation contributes to tissue damage and aberrant tissue repair. In this study we investigated CDKi effects on macrophage pro-inflammatory mediator production and viability. Treatment of human monocyte-derived macrophages (MDMs) with the CDKi AT7519 and R-roscovitine at concentrations that induce neutrophil apoptosis had no significant effect on control or LPS-activated MDM apoptosis and viability, and did not detrimentally affect MDM efferocytosis of apoptotic cells. In addition, enhanced efferocytosis, induced by the glucocorticoid dexamethasone, was also unaffected after a short time treatment with R-roscovitine. Macrophage cytokine responses to inflammatory stimuli are also of importance during inflammation and resolution. As a key target of CDKi, CDK9, is involved in protein transcription via the RNA polymerase II complex, we investigated the effect of CDKi drugs on cytokine production. Our data show that treatment with AT7519 significantly downregulated expression and release of key MDM cytokines IL-6, TNF, IL-10 and IL-1β, as well as markers of pro-inflammatory macrophage polarisation. R-Roscovitine was also able to downregulate inflammatory cytokine protein secretion from MDMs. Using siRNA transfection, we demonstrate that genetic knock-down of CDK9 replicates these findings, reducing expression and release of pro-inflammatory cytokines. Furthermore, overexpression of CDK9 in THP-1 cells can promote a pro-inflammatory phenotype in these cells, suggesting that CDK9 plays an important role in the inflammatory phenotype of macrophages. Overall, this study demonstrates that pharmacological and genetic targeting of CDK9 inhibits an inflammatory phenotype in human MDMs. As such these data indicate that CDK9 may be key to therapeutically targeting pro-inflammatory macrophage functions during chronic inflammation