Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study

Author version made available following 12 month embargo from date of publication (27 March 2015) in accordance with publisher copyright policy.Purpose Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. Methods Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45–50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. Results Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. Conclusions This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted

Quality of Life Following Repair of Large Hiatal Hernia is Improved but not Influenced by Use of Mesh: Results From a Randomized Controlled Trial

Author version made available following 12 month embargo from date of publication (5 Feb 2015) in accordance with Publisher copyright policy.Introduction Laparoscopic surgery is the treatment of choice for repair of large hiatus hernia, but can be followed by recurrence. Repair with prosthetic mesh has been recommended to prevent recurrence, although complications following mesh repair have generated disagreement about whether or not mesh should be used. The early objective and clinical results of a randomized trial of repair with mesh vs. sutures have been reported, and revealed few differences. In the current study we evaluated quality of life outcomes within this trial at follow-up to 2 years. Methods In a multicenter prospective double-blind randomized trial three methods for repair of large hiatus hernia were compared: sutures vs. repair with absorbable mesh (Surgisis) vs. nonabsorbable (Timesh). Quality of life assessment using the Short-Form 36 (SF-36) questionnaire was undertaken at 3, 6, 12 and 24 months after surgery. SF-36 outcomes (8 individual scales and 2 composite scales) were determined for each group, and compared between groups, and across different follow-up points. Results 126 patients were enrolled - 43 sutures, 41 absorbable mesh and 42 non-absorbable mesh. 115 (91.3%) completed a preoperative questionnaire, and 113 (89.7%) completed the postoperative questionnaire at 3 months, 116 (92.1%) at 6 months, 114 (90.5%) at 12 months, and 91 (72.2%) at 24 months. The SF-36 Physical and Mental Component scores (PCS & MCS) improved significantly following surgery, and this improvement was sustained across 24 months follow-up (p<0.001 for PCS and MCS at each follow-up point). There were no significant differences between the groups for the component scores or the eight SF-36 subscale scores at each follow-up time. 29 individuals had a recurrence at 6 months follow-up, of which 9 were symptomatic. The PCS were higher in patients with recurrence vs. without (p<0.01), and in patients with a symptomatic recurrence vs. asymptomatic recurrence vs. no recurrence (p=0.001). Conclusion SF-36 measured quality of life improved significantly after repair of large hiatal hernia at up to 2 years follow-up, and there were no differences in outcome for the different repair techniques. The use of mesh vs. no mesh in repair of large hiatal hernia did not influence quality of life

Topological Data Analysis for Discovery in Preclinical Spinal Cord Injury and Traumatic Brain Injury

Data-driven discovery in complex neurological disorders has potential to extract meaningful syndromic knowledge from large, heterogeneous data sets to enhance potential for precision medicine. Here we describe the application of topological data analysis (TDA) for data-driven discovery in preclinical traumatic brain injury (TBI) and spinal cord injury (SCI) data sets mined from the Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI) repository. Through direct visualization of inter-related histopathological, functional and health outcomes, TDA detected novel patterns across the syndromic network, uncovering interactions between SCI and co-occurring TBI, as well as detrimental drug effects in unpublished multicentre preclinical drug trial data in SCI. TDA also revealed that perioperative hypertension predicted long-term recovery better than any tested drug after thoracic SCI in rats. TDA-based data-driven discovery has great potential application for decision-support for basic research and clinical problems such as outcome assessment, neurocritical care, treatment planning and rapid, precision-diagnosis

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Play, Learn, and Teach Outdoors—Network (PLaTO-Net): terminology, taxonomy, and ontology

Background: A recent dialogue in the feld of play, learn, and teach outdoors (referred to as “PLaTO” hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the feld evolves and diversifes in its approaches, contents, and contexts over time and in diferent countries, cultures, and settings. Within this paper, we report the systematic and iterative processes under‑taken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). Methods: This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and defnitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then fnalized based on the feedback received from 50 international PLaTO member participants who responded to≥3 rounds of the consultation survey and dialogue. Finally, eforts to share and disseminate project outcomes were made through diferent online platforms. Results: This paper presents the fnal defnitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontol‑ogy model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The fnal terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). Conclusions: This project contributes to advancing PLaTO-based research and facilitating intersectoral and inter‑disciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO’s synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO

Measuring Outcomes of Laparoscopic Anti-reflux Surgery: Quality of Life Versus Symptom Scores?

Author manuscript made available following 12 month embargo from date of publication (Jan 16 2016) in accordance with publisher policy.Introduction Outcome following fundoplication for gastroesophageal reflux can be measured using objective tests, symptom scores and quality of life (QoL) measures. Which is best and how these assessments correlate is uncertain. To determine the utility of assessment measures we compared a general QoL measure (SF-36) and a disease-specific measure (GERD-hr-QoL) with symptom and satisfaction scores in individuals following fundoplication. Methods 329 individuals underwent fundoplication between 2000 and 2015 in 2 centres in Australia and the Netherlands. Patients were assessed before and 3, 12 and 24 months after surgery using 10-point Likert scales to assess heartburn and satisfaction, the SF-36 questionnaire and the GERD-hr-QoL questionnaire. SF-36 scores were converted into component scores: Physical Component Scale (PCS) score and Mental Component Scale (MCS) score. Correlations between QoL measures and clinical outcomes were determined. Results Surgery relieved heartburn (7.0 vs. 0.0 median, P < 0.001) and patients were highly satisfied with the outcome (median 9.0). PCS and MCS scores improved after surgery (PCS 40.9 vs. 46.0, P < 0.001; MCS 47.6 vs. 50.3, P = 0.027). GERD-hr-QoL scores also improved after surgery (15.7 vs. 3.7, P < 0.001). Correlations between PCS and MCS scores versus heartburn and satisfaction scores were generally weak or absent. However, correlations between GERD-hr-QoL versus heartburn and satisfaction scores were moderate to strong. Conclusion Despite improvements in scores, the SF-36 correlated poorly with clinical outcome measures, and its use to measure outcome following fundoplication is questioned. However, the GERD-hr-QoL correlated well with the symptom scores, suggesting this disease-specific QoL measure is a better tool for assessing anti-reflux surgery outcome

Topological data analysis for discovery in preclinical spinal cord injury and traumatic brain injury.

Data-driven discovery in complex neurological disorders has potential to extract meaningful syndromic knowledge from large, heterogeneous data sets to enhance potential for precision medicine. Here we describe the application of topological data analysis (TDA) for data-driven discovery in preclinical traumatic brain injury (TBI) and spinal cord injury (SCI) data sets mined from the Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI) repository. Through direct visualization of inter-related histopathological, functional and health outcomes, TDA detected novel patterns across the syndromic network, uncovering interactions between SCI and co-occurring TBI, as well as detrimental drug effects in unpublished multicentre preclinical drug trial data in SCI. TDA also revealed that perioperative hypertension predicted long-term recovery better than any tested drug after thoracic SCI in rats. TDA-based data-driven discovery has great potential application for decision-support for basic research and clinical problems such as outcome assessment, neurocritical care, treatment planning and rapid, precision-diagnosis

In a bovine model of onchocerciasis, protective immunity exists naturally, is absent in drug-cured hosts, and is induced by vaccination

Onchocerciasis (river blindness) is a major parasitic disease of humans in sub-Saharan Africa caused by the microfilarial stage of the nematode Onchocerca volvulus. Using Onchocerca ochengi, a closely related species which infects cattle and is transmitted by the same black fly vector (Simulium damnosum sensu lato) as O. volvulus, we have conducted longitudinal studies after either natural field exposure or experimental infection to determine whether, and under what circumstances, protective immunity exists in onchocerciasis. On the basis of the adult worm burdens (nodules) observed, we determined that cattle reared in endemic areas without detectable parasites (putatively immune) were significantly less susceptible to heavy field challenge than age-matched, naïve controls (P = 0.002), whereas patently infected cattle, cured of infection by adulticide treatment with melarsomine, were fully susceptible. Cattle immunized with irradiated third-stage larvae were significantly protected against experimental challenge (100% reduction in median nodule load, P = 0.003), and vaccination also conferred resistance to severe and prolonged field challenge (64% reduction in median nodule load, P = 0.053; and a significant reduction in microfilarial positivity rates and density, P < 0.05). These results constitute evidence of protective immunity in a naturally evolved host–Onchocerca sp. relationship and provide proof-of-principle for immunoprophylaxis under experimental and field conditions