A hybrid memory kernel approach for condensed phase non-adiabatic dynamics

The spin-boson model is a simplified Hamiltonian often used to study non-adiabatic dynamics in large condensed phase systems, even though it has not been solved in a fully analytic fashion. Herein, we present an exact analytic expression for the dynamics of the spin-boson model in the infinitely slow bath limit and generalize it to approximate dynamics for faster baths. We achieve the latter by developing a hybrid approach that combines the exact slow-bath result with the popular NIBA method to generate a memory kernel that is formally exact to second order in the diabatic coupling but also contains higher-order contributions approximated from the second order term alone. This kernel has the same computational complexity as NIBA, but is found to yield dramatically superior dynamics in regimes where NIBA breaks down---such as systems with large diabatic coupling or energy bias. This indicates that this hybrid approach could be used to cheaply incorporate higher order effects into second order methods, and could potentially be generalized to develop alternate kernel resummation schemes

The effectiveness of Ultrasound guided Hydrodistension and physiotherapy in the treatment of Frozen shoulder/Adhesive Capsulitis in Primary Care: a single centre service evaluation

Background: Evidence for optimal non-operative treatment of frozen shoulder is lacking. The aim of this study is to evaluate a treatment strategy for stage II-III Frozen shoulder provided by the current primary care Musculoskeletal Service. Methods: GP referrals of shoulder pain to the musculoskeletal service diagnosed with stage II-III frozen shoulder and who opted for a treatment strategy of hydrodistension and guided physiotherapy exercise programme over a 12 month period were evaluated for 6 months. Thirty three patients were diagnosed with stage II-III frozen shoulder by specialist physiotherapists and opted for the treatment strategy. Outcome measures included SPADI and QuickDASH, pain score and range of movement. Data was collected at baseline, 6 weeks, 12 weeks and 6 months. Results: All patients significantly improved in shoulder symptoms on the SPADI and QuickDASH scores (p< 0.001). Pain scores and range of shoulder movement flexion, abduction, external rotation showed significant improvement at all time points (p<0.001). Conclusions: This service evaluation demonstrates that management of frozen shoulder stage II-III, by physiotherapists in a primary care setting utilizing hydrodistension and guided exercise programme is an effective non-operative treatment strategy. Level of evidence: Level III, Service evaluation

Effect of personal activity intelligence (PAI) monitoring in the maintenance phase of cardiac rehabilitation: a mixed methods evaluation

Abstract Background Personal activity intelligence (PAI) is a single physical activity metric based upon heart rate responses to physical activity. Maintaining 100 PAI/week is associated with a 25% risk reduction in cardiovascular disease mortality and 50 PAI/week provides 60% of the benefits. The effect of utilising this metric within a cardiac population has not been previously investigated. The aim of this study was to determine the effect of PAI monitoring on the amount and/or intensity of physical activity for people in the maintenance phase of cardiac rehabilitation and to explore participants’ perceptions of this approach. Methods A concurrent mixed methods approach was undertaken. Participants in the maintenance phase of cardiac rehabilitation monitored PAI for six weeks via a wearable physical activity monitoring device (WPAM). In the first three weeks participants were blinded to their PAI score. A quality-of-life questionnaire (EQ-5D-5L) was completed, and semi-structured interviews conducted to investigate attitudes to PAI monitoring. Daily PAI data was collected throughout the 6-week period. Results Twenty participants completed the trial. PAI earned/day was increased after participants could view their data (mean difference: 2.1 PAI/day (95% CI 0.3, 4.0), p = 0.027). The median change in percentage of days participants achieved a Total PAI score of 25 (p = 0.023) and 50 (p = 0.015) were also increased. The mean change in total scores for the EQ-5D-5L and EQVAS were improved after 6 weeks (0.6 ± 1.05; 95% CI (0.11–1.09); p = 0.019); (5.8/100; 95% CI (2.4–9.2); p = 0.002 respectively). Thematic framework analysis identified three global themes (perceptions on the WPAM, PAI and factors affecting exercise). Most participants stated motivation to exercise increased after they could view their PAI data. Many of the participants believed they would continue to use PAI long-term. Others were undecided; the latter primarily due to technical issues and/or preferring devices with greater functionality and attractiveness. All participants would recommend PAI. Conclusion This exploratory study showed monitoring PAI via a WPAM increased the amount and/or intensity of physical activity within the cardiac population. Participants found PAI interesting, beneficial, and motivating. If technical issues, aesthetics, and functionality of the WPAM were improved, participants may continue to use the approach long-term. PAI may be a viable strategy to assist people with cardiac disease maintain physical activity adherence

Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model.

BACKGROUND: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. RESULTS: Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). MATERIALS AND METHODS: Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. CONCLUSIONS: Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation

Development and therapeutic manipulation of the head and neck cancer tumor environment to improve clinical outcomes

The clinical response to cancer therapies involves the complex interplay between the systemic, tumoral, and stromal immune response as well as the direct impact of treatments on cancer cells. Each individual's immunological and cancer histories are different, and their carcinogen exposures may differ. This means that even though two patients with oral tumors may carry an identical mutation in TP53, they are likely to have different pre-existing immune responses to their tumors. These differences may arise due to their distinct accessory mutations, genetic backgrounds, and may relate to clinical factors including previous chemotherapy exposure and concurrent medical comorbidities. In isolation, their cancer cells may respond similarly to cancer therapy, but due to their baseline variability in pre-existing immune responses, patients can have different responses to identical therapies. In this review we discuss how the immune environment of tumors develops, the critical immune cell populations in advanced cancers, and how immune interventions can manipulate the immune environment of patients with pre-malignancies or advanced cancers to improve therapeutic outcomes

A microbial-based cancer vaccine for induction of EGFRvIII-specific CD8+ T cells and anti-tumor immunity.

Dysregulated signaling via the epidermal growth factor receptor (EGFR)-family is believed to contribute to the progression of a diverse array of cancers. The most common variant of EGFR is EGFRvIII, which results from a consistent and tumor-specific in-frame deletion of exons 2-7 of the EGFR gene. This deletion generates a novel glycine at the junction and leads to constitutive ligand-independent activity. This junction forms a novel shared tumor neo-antigen with demonstrated immunogenicity in both mice and humans. A 21-amino acid peptide spanning the junctional region was selected, and then one or five copies of this 21-AA neo-peptide were incorporated into live-attenuated Listeria monocytogenes-based vaccine vector. These vaccine candidates demonstrated efficient secretion of the recombinant protein and potent induction of EGFRvIII-specific CD8+ T cells, which prevented growth of an EGFRvIII-expressing squamous cell carcinoma. These data demonstrate the potency of a novel cancer-specific vaccine candidate that can elicit EGFRvIII-specific cellular immunity, for the purpose of targeting EGFRvIII positive cancers that are resistant to conventional therapies

Attitudes towards the surgical safety checklist and factors associated with its use : a global survey of frontline medical professionals:a global survey of frontline medical professionals

Background: The Surgical Safety Checklist (SSC) has been shown to reduce perioperative errors and complications and its implementation is recommended by the World Health Organisation (WHO). However, it is unknown how widely this intervention is used. We investigated attitudes and factors associated with use of WHO SSC in frontline medical professionals across the globe using a survey distributed through social networks. Methods: A survey of usage and opinions regarding the SSC was posted on the Facebook and Twitter pages of a not-for-profit surgical news website for one month (March 2013). Respondents were grouped into four groups based on their country's Gross National Income: high, upper middle, lower middle and low income. Univariate and multivariate analyses were performed to investigate how different factors were associated with the use of the SSC. Results: 6269 medical professionals from 69 countries responded to the survey: most respondents were from lower middle (47.4%) countries, followed by: high (35.0%), upper middle (14.6%), and low (3.0%) income countries. In total, 57.5% reported that they used the WHO SSC perioperatively. Fewer respondents used the WHO SSC in upper middle, lower middle and low income countries (LMICs) compared to high income countries (43.5% vs. 83.5%, p < 0.001). Female (61.3% vs. 56.4% males, p = 0.001), consultant surgeons (59.6% vs. 53.2% interns, p < 0.001) and working in university hospitals (61.4% vs. 53.7% non-university hospitals, p < 0.001) were more likely to use the SSC. Believing the SSC was useful, did not work or caused delays was independently associated with the respondents reported use of the SSC (OR 1.22 95% CI 1.07–1.39; OR 0.47 95% CI 0.36–0.60; OR 0.64 95% CI 0.53–0.77, respectively). Conclusion: This study suggests the use of the WHO SSC is variable across countries, especially in LMICs where it has the most potential to improve patient safety. Critical appraisal of the documented benefits of the WHO SSC may improve its adoption by those not currently using it

Prevalence and microbiological characteristics of clinically infected foot-ulcers in patients with rheumatoid arthritis: A retrospective exploratory study

Background: The prevalence of foot ulcers in patients with rheumatoid arthritis (RA) has been reported at almost 10 %. These foot ulcers often occur at multiple sites and are reoccurring, with the potential risk of infection increased due to RA diagnosis and disease modifying medications. The objective of this study was to estimate the prevalence of clinical infection in foot-ulcers of patients with RA; describe the microbiological characteristics and investigate risk factors. Methods: Retrospective clinical data was collected for all patients attending a rheumatology foot ulcer clinic between 1st May 2012 and 1st May 2013: wound swab data was collected from those with clinical infection. Results: Twenty-eight patients with RA and foot-ulcers were identified; eight of these patients had clinical infection and wound swabs taken (29 %). Of these eight patients there were equal men and women, with median age 74 years, and average disease duration 22 years. Cardiovascular disease/peripheral-vascular disease (CVD/PVD) were reported in six patients, diabetes in two patients. Six patients were treated with disease-modifying anti-rheumatic drugs (DMARDs); three were on biologic medications and two on steroids. Five wound swabs cultured skin flora, one staphylococcus aureus, one had no growth after culture; and one was rejected due to labelling error. Conclusion: Almost a third of people with RA and foot ulcers attending clinic over one year had clinical infection, however microbiological analysis failed to isolate pathogens in six of seven wound swabs. This may be due to inaccurate diagnosis of ulcer infection or to issues with sampling, collection, transport, analysis or reporting. There was insufficient data to relate risk of clinical infection with risk factors. Further research is required to identify the most appropriate techniques for infection diagnosis, wound sampling and processing. Trial registration: Ethical approval was obtained from University of Leeds, Faculty of Medicine and Health (Reference number: SHREC/RP/349)

STING expression and response to treatment with STING ligands in premalignant and malignant disease.

Human papilloma virus positive (HPV+) tumors represent a large proportion of anal, vulvar, vaginal, cervical and head and neck squamous carcinomas (HNSCC) and late stage invasive disease is thought to originate from a premalignant state. Cyclic dinucleotides that activate STimulator of INterferon Genes (STING) have been shown to cause rapid regression of a range of advanced tumors. We aimed to investigate STING ligands as a novel treatment for papilloma. We tested therapies in a spontaneous mouse model of papilloma of the face and anogenital region that histologically resembles human HPV-associated papilloma. We demonstrate that STING ligands cause rapid regression of papilloma, associated with T cell infiltration, and are significantly more effective than Imiquimod, a current immunotherapy for papilloma. In humans, we show that STING is expressed in the basal layer of normal skin and lost during keratinocyte differentiation. We found STING was expressed in all HPV-associated cervical and anal dysplasia and was strongly expressed in the cancer cells of HPV+ HNSCC but not in HPV-unrelated HNSCC. We found no strong association between STING expression and progressive disease in non-HPV oral dysplasia and oral pre-malignancies that are not HPV-related. These data demonstrate that STING is expressed in basal cells of the skin and is retained in HPV+ pre-malignancies and advanced cancers, but not in HPV-unrelated HNSCC. However, using a murine HNSCC model that does not express STING, we demonstrate that STING ligands are an effective therapy regardless of expression of STING by the cancer cells