THERMORESPONSIVE, REDOX-POLYMERIZED CELLULOSIC HYDROGELS UNDERGO IN SITU GELATION AND RESTORE INTERVERTEBRAL DISC BIOMECHANICS POST DISCECTOMY

Back and neck pain are commonly associated with intervertebral disc (IVD) degeneration. Structural augmentation of diseased nucleus pulposus (NP) tissue with biomaterials could restore degeneration-related IVD height loss and degraded biomechanical behaviors; however, effective NP replacement biomaterials are not commercially available. This study developed a novel, crosslinked, dual-polymer network (DPN) hydrogel comprised of methacrylated carboxymethylcellulose (CMC) and methylcellulose (MC), and used in vitro, in situ and in vivo testing to assess its efficacy as an injectable, in situ gelling, biocompatible material that matches native NP properties and restores IVD biomechanical behaviors. Thermogelling MC was required to enable consistent and timely gelation of CMC in situ within whole IVDs. The CMC-MC hydrogel was tuned to match compressive and swelling NP tissue properties. When injected into whole IVDs after discectomy injury, CMC-MC restored IVD height and compressive biomechanical behaviors, including range of motion and neutral zone stiffness, to intact levels. Subcutaneous implantation of the hydrogels in rats further demonstrated good biocompatibility of CMC-MC with a relatively thin fibrous capsule, similar to comparable biomaterials. In conclusion, CMC-MC is an injectable, tunable and biocompatible hydrogel with strong potential to be used as an NP replacement biomaterial since it can gel in situ, match NP properties, and restore IVD height and biomechanical function. Future investigations will evaluate herniation risk under severe loading conditions and assess long-term in vivo performance

Helicobacter pylori and cancer among adults in Uganda

Data from Africa on infection with Helicobacter pylori (H. pylori) are sparse. Therefore, as part of an epidemiological study of cancer in Uganda, we investigated the prevalence and determinants of antibodies against H. pylori among 854 people with different cancer types and benign tumours. Patients were recruited from hospitals in Kampala, Uganda, interviewed about various demographic and lifestyle factors and tested for antibodies against H. pylori. In all patients combined, excluding those with stomach cancer (which has been associated with H. pylori infection), the prevalence of antibodies was 87% (723/833) overall, but declined with increasing age (p = 0.02) and was lower among people who were HIV seropositive compared to seronegative (p <0.001). Otherwise, there were few consistent epidemiological associations. Among those with stomach cancer, 18/21 (86%) had anti-H. pylori antibodies (odds ratio 0.8, 95% confidence intervals 0.2–2.9, p = 0.7; estimated using all other patients as controls, with adjustment for age, sex and HIV serostatus). No other cancer site or type was significantly associated with anti-H. pylori antibodies. The prevalence of H. pylori reported here is broadly in accord with results from other developing countries, although the determinants of infection and its' role in the aetiology of gastric cancer in Uganda remain unclear

Moving research into practice: lessons from the US Agency for Healthcare Research and Quality's IDSRN program

BACKGROUND: The U.S. Agency for Healthcare Research and Quality's (AHRQ) Integrated Delivery Systems Research Network (IDSRN) program was established to foster public-private collaboration between health services researchers and health care delivery systems. Its broad goal was to link researchers and delivery systems to encourage implementation of research into practice. We evaluated the program to address two primary questions: 1) How successful was IDSRN in generating research findings that could be applied in practice? and 2) What factors facilitate or impede such success? METHODS: We conducted in-person and telephone interviews with AHRQ staff and nine IDSRN partner organizations and their collaborators, reviewed program documents, analyzed projects funded through the program, and developed case studies of four IDSRN projects judged promising in supporting research implementation. RESULTS: Participants reported that the IDSRN structure was valuable in creating closer ties between researchers and participating health systems. Of the 50 completed projects studied, 30 had an operational effect or use. Some kinds of projects were more successful than others in influencing operations. If certain conditions were met, a variety of partnership models successfully supported implementation. An internal champion was necessary for partnerships involving researchers based outside the delivery system. Case studies identified several factors important to success: responsiveness of project work to delivery system needs, ongoing funding to support multiple project phases, and development of applied products or tools that helped users see their operational relevance. Factors limiting success included limited project funding, competing demands on potential research users, and failure to reach the appropriate audience. CONCLUSION: Forging stronger partnerships between researchers and delivery systems has the potential to make research more relevant to users, but these benefits require clear goals and appropriate targeting of resources. Trade-offs are inevitable. The health services research community can best consider such trade-offs and set priorities if there is more dialogue to identify areas and approaches where such partnerships may have the most promise. Though it has unique features, the IDSRN experience is relevant to research implementation in diverse settings

Health state utilities for metastatic breast cancer

The aim of the study was to obtain United Kingdom-based societal preferences for distinct stages of metastatic breast cancer (MBC) and six common toxicities. Health states were developed based on literature review, iterative cycles of interviews and a focus group with clinical experts. They described the burden of progressive, responding and stable disease on treatment; and also febrile neutropenia, stomatitis; diarrhoea/vomiting; fatigue; hand-foot syndrome (grade 3/4 toxicities) and hair loss. One hundred members of the general public rated them using standard gamble to determine health state utility. Data were analysed with a mixed model analysis. The study sample was a good match to the general public of England and Wales by demographics and current quality of life. Stable disease on treatment had a utility value of 0.72, with a corresponding gain of +0.07 following a treatment response and a decline by 0.27 for disease progression. Toxicities lead to declines in utility between 0.10 (diarrhoea/vomiting) and 0.15 (febrile neutropenia). This study underlines the value that society place on the avoidance of disease progression and severe side effects in MBC. This may be the largest preference study in breast cancer designed to survey a representative general public sample

Language Model Co-occurrence Linking for Interleaved Activity Discovery

As ubiquitous computer and sensor systems become abundant, the potential for automatic identification and tracking of human behaviours becomes all the more evident. Annotating complex human behaviour datasets to achieve ground truth for supervised training can however be extremely labour-intensive, and error prone. One possible solution to this problem is activity discovery: the identification of activities in an unlabelled dataset by means of an unsupervised algorithm. This paper presents a novel approach to activity discovery that utilises deep learning based language production models to construct a hierarchical, tree-like structure over a sequential vector of sensor events. Our approach differs from previous work in that it explicitly aims to deal with interleaving (switching back and forth between between activities) in a principled manner, by utilising the long-term memory capabilities of a recurrent neural network cell. We present our approach and test it on a realistic dataset to evaluate its performance. Our results show the viability of the approach and that it shows promise for further investigation. We believe this is a useful direction to consider in accounting for the continually changing nature of behaviours

Free choice activates a decision circuit between frontal and parietal cortex

We often face alternatives that we are free to choose between. Planning movements to select an alternative involves several areas in frontal and parietal cortex that are anatomically connected into long-range circuits. These areas must coordinate their activity to select a common movement goal, but how neural circuits make decisions remains poorly understood. Here we simultaneously record from the dorsal premotor area (PMd) in frontal cortex and the parietal reach region (PRR) in parietal cortex to investigate neural circuit mechanisms for decision making. We find that correlations in spike and local field potential (LFP) activity between these areas are greater when monkeys are freely making choices than when they are following instructions. We propose that a decision circuit featuring a sub-population of cells in frontal and parietal cortex may exchange information to coordinate activity between these areas. Cells participating in this decision circuit may influence movement choices by providing a common bias to the selection of movement goals

Team reasoning and the rational choice of payoff-dominant outcomes in games

Standard game theory cannot explain the selection of payoff-dominant outcomes that are best for all players in common-interest games. Theories of team reasoning can explain why such mutualistic cooperation is rational. They propose that teams can be agents and that individuals in teams can adopt a distinctive mode of reasoning that enables them to do their part in achieving Pareto-dominant outcomes. We show that it can be rational to play payoff-dominant outcomes, given that an agent group identifies. We compare team reasoning to other theories that have been proposed to explain how people can achieve payoff-dominant outcomes, especially with respect to rationality. Some authors have hoped that it would be possible to develop an argument that it is rational to group identify. We identify some large—probably insuperable—problems with this project and sketch some more promising approaches, whereby the normativity of group identification rests on morality

Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells

Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment.Career Development Award: (#IK2 CX000538); U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program (MJH); U.S.Department of Veterans Affairs Biomedical Laboratory Research and Development Program (DML) Merit Award: (#I01 BX000533); American Lung Association: (RT-350058)