Diurnal fuel moisture content variations of live and dead Calluna vegetation in a temperate peatland.

The increasing frequency and severity of UK wildfires, attributed in part to the effects of climate change, highlights the critical role of fuel moisture content (FMC) of live and dead vegetation in shaping wildfire behaviour. However, current models used to assess wildfire danger do not perform well in shrub-type fuels such as Calluna vulgaris, requiring in part an improved understanding of fuel moisture dynamics on diurnal and seasonal scales. To this end, 554 samples of upper live Calluna canopy, live Calluna stems, upper dead Calluna canopy, dead Calluna stems, moss, litter and organic layer (top 5 cm of organic material above mineral soil) were sampled hourly between 10:00 and 18:00 on seven days from March-August. Using a novel statistical method for investigating diurnal patterns, we found distinctive diurnal and seasonal trends in FMC for all fuel layers. Notably, significant diurnal patterns were evident in dead Calluna across nearly all sampled months, while diurnal trends in live Calluna canopy were pronounced in March, June, and August, coinciding with the peak occurrence of UK wildfires. In addition, the moisture content of moss and litter was found to fluctuate above and below their relative ignition thresholds throughout the day on some sampling days. These findings underscore the impact of diurnal FMC variations on wildfire danger during early spring and late summer in Calluna dominated peatlands and the need to consider such fluctuations in management and fire suppression strategies.

Usability evaluation of a self-management mobile application for individuals with a mild traumatic brain injury.

Objective: Mild traumatic brain injuries (mTBIs) are common and may result in persisting symptoms. Mobile health (mHealth) applications enhance treatment access and rehabilitation. However, there is limited evidence to support mHealth applications for individuals with an mTBI. The primary purpose of this study was to evaluate user experiences and perceptions of the Parkwood Pacing and Planning™ application, an mHealth application developed to help individuals manage their symptoms following an mTBI. The secondary purpose of this study was to identify strategies to improve the application. This study was conducted as part of the development process for this application. Methods: A mixed methods co-design encompassing an interactive focus group and a follow-up survey was conducted with patient and clinician-participants (n = 8, four per group). Each group participated in a focus group consisting of an interactive scenario-based review of the application. Additionally, participants completed the Internet Evaluation and Utility Questionnaire (UQ). Qualitative analysis on the interactive focus group recordings and notes was performed using phenomenological reflection through thematic analyses. Quantitative analysis included descriptive statistics of demographic information and UQ responses. Results: On average, clinician and patient-participants positively rated the application on the UQ (4.0 ± .3, 3.8 ± .2, respectively). User experiences and recommendations for improving the application were categorized into four themes: simplicity, adaptability, conciseness, and familiarity. Conclusion: Preliminary analyses indicates patients and clinicians have a positive experience when using the Parkwood Pacing and Planning™ application. However, modifications that improve simplicity, adaptability, conciseness, and familiarity may further improve the user's experience.

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer.

BACKGROUND: Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. RESULTS: In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine's versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model. CONCLUSIONS: Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.

Incorporating fine-scale environmental heterogeneity into broad-extent models.

A key aim of ecology is to understand the drivers of ecological patterns, so that we can accurately predict the effects of global environmental change. However, in many cases, predictors are measured at a finer resolution than the ecological response. We therefore require data aggregation methods that avoid loss of information on fine-grain heterogeneity.We present a data aggregation method that, unlike current approaches, reduces the loss of information on fine-grain spatial structure in environmental heterogeneity for use with coarse-grain ecological datasets. Our method contains three steps: (a) define analysis scales (predictor grain, response grain, scale-of-effect); (b) use a moving window to calculate a measure of variability in environment (predictor grain) at the process-relevant scale (scale-of-effect); and (c) aggregate the moving window calculations to the coarsest resolution (response grain). We show the theoretical basis for our method using simulated landscapes and the practical utility with a case study. Our method is available as the grainchanger r package.The simulations show that information about spatial structure is captured that would have been lost using a direct aggregation approach, and that our method is particularly useful in landscapes with spatial autocorrelation in the environmental predictor variable (e.g. fragmented landscapes) and when the scale-of-effect is small relative to the response grain. We use our data aggregation method to find the appropriate scale-of-effect of land cover diversity on Eurasian jay Garrulus glandarius abundance in the UK. We then model the interactive effect of land cover heterogeneity and temperature on G. glandarius abundance. Our method enables us quantify this interaction despite the different scales at which these factors influence G. glandarius abundance.Our data aggregation method allows us to integrate variables that act at varying scales into one model with limited loss of information, which has wide applicability for spatial analyses beyond the specific ecological context considered here. Key ecological applications include being able to estimate the interactive effect of drivers that vary at different scales (such as climate and land cover), and to systematically examine the scale dependence of the effects of environmental heterogeneity in combination with the effects of climate change on biodiversity.

Mapping access to domestic water supplies from incomplete data in developing countries: An illustrative assessment for Kenya.

Water point mapping databases, generated through surveys of water sources such as wells and boreholes, are now available in many low and middle income countries, but often suffer from incomplete coverage. To address the partial coverage in such databases and gain insights into spatial patterns of water resource use, this study investigated the use of a maximum entropy (MaxEnt) approach to predict the geospatial distribution of drinking-water sources, using two types of unimproved sources in Kenya as illustration. Geographic locations of unprotected dug wells and surface water sources derived from the Water Point Data Exchange (WPDx) database were used as inputs to the MaxEnt model alongside geological/hydrogeological and socio-economic covariates. Predictive performance of the MaxEnt models was high (all > 0.9) based on Area Under the Receiver Operator Curve (AUC), and the predicted spatial distribution of water point was broadly consistent with household use of these unimproved drinking-water sources reported in household survey and census data. In developing countries where geospatial datasets concerning drinking-water sources often have necessarily limited resolution or incomplete spatial coverage, the modelled surface can provide an initial indication of the geography of unimproved drinking-water sources to target unserved populations and assess water source vulnerability to contamination and hazards.

Dual-Task Assessment Protocols in Concussion Assessment: A Systematic Literature Review.

Study Design Systematic review. Background When assessed in isolation, balance and neurocognitive testing may not be sufficiently responsive to capture changes that occur with concussion. Normal daily activities require simultaneous cognitive and physical demands. Therefore, a dual-task assessment paradigm should be considered to identify performance deficits. Objectives To evaluate the literature and to identify dual-task testing protocols associated with changes in gait after concussion. Methods A systematic review of articles of individuals with concussion who underwent dual-task testing with a combination of motor and cognitive tasks was conducted. The AMED, CINAHL, Embase, PsycINFO, PubMed, Scopus, SPORTDiscus, and Web of Science databases and gray literature were searched from inception to January 29, 2017. Title and abstract, full-text, and quality review and data abstraction were performed by 2 independent reviewers. Results Twenty-four articles met the inclusion criteria. Eleven articles reported decreased gait velocity and increased medial-lateral displacement for individuals with concussion during dual-task conditions. Overall, included articles were of poor to moderate methodological quality. Fifteen articles used the same participants and data sets, creating a threat to validity and limiting the ability to make conclusions. Conclusion A deterioration in gait performance during dual-task testing is present among people with concussion. Specific recommendations for the use of a dual-task protocol to assess individuals with suspected concussion injury in a clinical setting have yet to be determined. J Orthop Sports Phys Ther 2018;48(2):87-103. Epub 7 Nov 2017. doi:10.2519/jospt.2018.7432.

Metapopulation modelling of long-term urban habitat-loss scenarios.

CONTEXT: Increasing human populations in urban areas pose a threat to species' persistence through habitat loss and fragmentation. It is therefore essential that we develop methods to investigate critical habitat loss thresholds and least detrimental landscape configurations. OBJECTIVES: We develop a framework to assess how the pattern of habitat loss impacts the ecological and social characteristics of a landscape and how this varies depending on the species and criteria by which it is judged. METHODS: We use a scenario-based approach to test six propositions in which habitat is lost preferentially based on patch characteristics. We use eight bird and two amphibian species as indicator species. To compare scenarios, we present a method combining the output from a metapopulation model with measures of social impacts of land-cover change in a multiple criteria decision analysis. We also determine whether a habitat loss threshold exists, below which small loss of habitat can lead to large loss of species' occupancy. RESULTS: We found that, of the scenarios presented, preferentially losing common habitats and smaller patches was least detrimental for both ecological and social factors. Threshold effects were found for all but the generalist bird species. CONCLUSIONS: We have outlined a workflow which allows for transparent, repeatable comparison between landscapes. This workflow can be used to compare urban landscape plans, or to develop general understanding of the impacts of different forms of habitat loss. Reassuringly, the recommendations based on the scenarios presented are in keeping with received conservation wisdom: to prioritise larger and/or rarer patches.

DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer.

Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer.

Near-infrared imaging of adoptive immune cell therapy in breast cancer model using cell membrane labeling.

The overall objective of this study is to non-invasively image and assess tumor targeting and retention of directly labeled T-lymphocytes following their adoptive transfer in mice. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in-vitro with Bryostatin/Ionomycin for 18 hours, and were grown in the presence of Interleukin-2 for 6 days. T-lymphocytes were then directly labeled with 1,1-dioctadecyltetramethyl indotricarbocyanine Iodide (DiR), a lipophilic near infrared fluorescent dye that labels the cell membrane. Assays for viability, proliferation, and function of labeled T-lymphocytes showed that they were unaffected by DiR labeling. The DiR labeled cells were injected via tail vein in mice bearing 4T1 tumors in the flank. In some cases labeled 4T1 specific T-lymphocytes were injected a week before 4T1 tumor cell implantation. Multi-spectral in vivo fluorescence imaging was done to subtract the autofluorescence and isolate the near infrared signal carried by the T-lymphocytes. In recipient mice with established 4T1 tumors, labeled 4T1 specific T-lymphocytes showed marked tumor retention, which peaked 6 days post infusion and persisted at the tumor site for up to 3 weeks. When 4T1 tumor cells were implanted 1-week post-infusion of labeled T-lymphocytes, T-lymphocytes responded to the immunologic challenge and accumulated at the site of 4T1 cell implantation within two hours and the signal persisted for 2 more weeks. Tumor accumulation of labeled 4T1 specific T-lymphocytes was absent in mice bearing Meth A sarcoma tumors. When lysate of 4T1 specific labeled T-lymphocytes was injected into 4T1 tumor bearing mice the near infrared signal was not detected at the tumor site. In conclusion, our validated results confirm that the near infrared signal detected at the tumor site represents the DiR labeled 4T1 specific viable T-lymphocytes and their response to immunologic challenge can be imaged in vivo.

"Any movement at all is exercise": a focused ethnography of rural community-dwelling older adults' perceptions and experiences of exercise as self-care.

PURPOSE: To understand rural community-dwelling older adult participants' shared values, beliefs, and behaviours related to exercise as self-care. METHODS: We conducted a constructivist-focused ethnography involving semi-structured interviews and participant observation with 17 individuals 65 years and older. Interviews were transcribed and inductively coded to develop themes related to exercise, self-care, and exercise as self-care. Field notes were triangulated with follow-up interviews and dialogue between authors to enhance interpretation. RESULTS: Participants described exercise broadly as movement and not as a central self-care behaviour. However, awareness of the importance and health-related benefits of exercise increased after a significant personal health-related event. Participants preferred exercise that was enjoyable and previously experienced. CONCLUSIONS: Prescribing exercise for older adults may be particularly effective if the focus is on enjoyable and previously experienced physical activity and if it incorporates interpretation of exercise guidelines and training principles in relation to chronic conditions and potential health benefits.

Objectif : Comprendre les valeurs, les croyances et les comportements partagés des participants adultes âgés vivant dans des logements communautaires en ce qui concerne l'exercice comme soins autodirigés. Méthode : Nous avons procédé à une ethnographie convergente constructiviste comportant des entrevues semi-structurées et l'observation de participants, qui a porté sur 17 personnes de 65 ans et plus. Les entrevues ont été transcrites et codées de façon inductive de façon à dégager des thèmes liés à l'exercice, aux soins autodirigés et à l'exercice comme soins autodirigés. On a comparé les notes pratiques aux entrevues de suivi et au dialogue entre les auteurs afin d'améliorer l'interprétation. Résultats : Les participants ont décrit l'exercice de façon générale comme le fait de bouger et non un comportement central des soins autodirigés. La sensibilisation à l'importance de l'exercice et à ses bienfaits pour la santé a toutefois augmenté après un événement important lié à la santé personnelle. Les participants préféraient un exercice agréable et qu'ils connaissaient déjà. Conclusions : Il peut être particulièrement efficace de prescrire des exercices à des adultes âgés si l'on vise une activité physique agréable et déjà connue et si l'activité consiste aussi à interpréter des lignes directrices sur l'exercice et des principes d'entraînement par rapport à des problèmes chroniques et à des bienfaits possibles pour la santé.

Prestroke modified rankin stroke scale has moderate interobserver reliability and validity in an acute stroke setting.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is the recommended functional outcome assessment in stroke trials. Utility of mRS may be limited by interobserver variability. prestroke function, described using mRS, is often used as trial entry criterion. We assessed the reliability and validity of prestroke mRS in acute stroke. METHODS: We present two complementary analyses of the properties of prestroke mRS: (1) Paired interviewers (trained in mRS) performed independently a blinded assessment of mRS and prestroke mRS. Interobserver variability was described using percentage agreement and weighted (kw) κ statistics with 95% confidence interval (95% CI). Validity was assessed by comparing prestroke mRS with other markers of function (comorbidity; medication count; need for carers). (2) We further assessed validity using a larger retrospective dataset. We compared prestroke mRS with Charlson comorbidity index (CCI) and the Rockwood frailty index. Rank correlation coefficient or Fisher exact test were used as appropriate. RESULTS: Paired interviewers assessed 74 stroke survivors. Median standard mRS was 4 (interquartile range [IQR], 2-4), median prestroke mRS was 1 (IQR, 0-3; range, 0-4). Reliability for standard mRS interview was 56% agreement, kw=0.55 (95% CI, 0.39-0.71). Reliability for prestroke mRS was 70%, kw=0.70 (95% CI, 0.53-0.87). The retrospective dataset described 231 subjects. In this data set, Spearman Rho for prestroke mRS and frailty index was J. 0.82 (95% CI, 0.78-0.86); CCI 0.50 (95% CI, 0.40-0.59); patient age 0.45 (95% CI, 0.34-0.54); medication count 0.28 (95% CI, 0.15-0.40). There was no association between need for carers and prestroke mRS (p=0.10). CONCLUSIONS: Interobserver reliability of prestroke mRS is limited but comparable with standard mRS. Poor correlation of prestroke mRS with certain markers of function suggests limited validity. Our data would suggest that relying on mRS alone may be a suboptimal measure of prestroke function and could potentially bias trial samples.

The role of Tyk2 in regulation of breast cancer growth.

The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFNγ stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFNα/ß) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFNγ, IFNα receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2(-/-) mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2(+/+) animals. Accelerated growth of 4T1 cells in Tyk2(-/-) animals does not appear to be due to decreased function of CD4(+), CD8(+) T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2(-/-) mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer.

Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells.

Studies were performed to determine the influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to adriamycin (doxorubicin) in four human breast tumor cell lines and one murine breast tumor line. Sildenafil did not interfere with the effectiveness of adriamycin in any of the cell lines tested. Sildenafil also failed to protect MDA-MB231 cells against the cytotoxicity of cisplatin, taxol or camptothecin. Sildenafil enhanced sensitivity to adriamycin markedly in the p53 mutant MDA-MB231 and p53 null MCF-7/E6 cells and moderately in the MCF-7/caspase 3 and 4T1 cell lines. In the MDA-MB231 cells, sildenafil increased the extent of DNA damage induced by adriamycin as well as the extent of apoptotic cell death. Sildenafil did not influence sensitivity to adriamycin in bone marrow cells or macrophages. In an immunocompetent model of breast cancer (4T1 mammary carcinoma in Balb/c mice), sildenafil did not attenuate the antitumor effects of adriamycin; furthermore, the combination of sildenafil with adriamycin was no more toxic to the animals than adriamycin alone. Given that sildenafil has been shown to have the potential to protect the heart against the toxicity of adriamycin, these studies suggest that the inclusion of sildenafil with conventional chemotherapeutic protocols involving adriamycin (and possibly cisplatin, camptothecin and/or paclitaxel) should not compromise the antitumor effectiveness of these drugs nor enhance their toxicity to the patient.

Successful adoptive immunotherapy with vaccine-sensitized T cells, despite no effect with vaccination alone in a weakly immunogenic tumor model.

Tumor cell vaccines have been successful at inducing immunity in naïve mice, but only in a few reports has vaccination alone induced regression of established tumors and, generally, only when they are very small. Clinically, vaccinations alone may not be able to cause regression of established human cancers, which tend to be weakly immunogenic. We hypothesized that pharmacologic ex vivo amplification of a vaccination-induced immune response with subsequent adoptive immunotherapy (AIT) to tumor-bearing animals would be more effective in treatment of these animals than vaccination alone. The 4T1 and 4T07 mammary carcinomas are derived from the same parental cell line, but 4T1 is much less immunogenic and more aggressive than 4T07. Vaccination with either 4T1, 4T1-IL-2, or 4T07-IL-2 was not effective as treatment for established 4T1 tumors. However, 4T1 or 4T07-IL-2-vaccine-sensitized draining lymph node (DLN) cells, activated ex vivo with bryostatin 1 and ionomycin and expanded in culture, induced complete tumor regressions when adoptively transferred to 4T1 tumor-bearing animals. This was effective against small tumors as well as more advanced tumors, 10 days after tumor cell inoculation. Furthermore, as would be required for this approach to be used clinically, vaccine-DLN cells obtained from mice with established progressive 4T1 tumors (inoculated 10 days before vaccination) also induced regression of 4T1 tumors in an adoptive host. In none of these experiments was exogenous IL-2 required to induce tumor regression. The response to tumor cell vaccine can be amplified by ex vivo pharmacologic activation of sensitized T cells, which can then cure an established, weakly immunogenic and highly aggressive tumor that was resistant to vaccination alone.