Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

Does land-based exercise-therapy improve physical activity in people with knee osteoarthritis? A systematic review with meta-analyses.

PRIMARY OBJECTIVE: Investigate the effects of land-based exercise-therapy on physical activity in people with knee osteoarthritis (KOA). DESIGN: Systematic review and meta-analysis of randomised or quasi-randomised trials investigating land-based exercise-therapy on physical activity, fitness, and general health in people with KOA. We updated a 2013 Cochrane review search on exercise-therapy for KOA in April 2021 and applied the Cochrane Risk-of-Bias Tool 1.0 to included articles. Standardised mean differences (SMDs) and 95% confidence intervals (CI) were calculated. GRADE was used to assess certainty of the evidence. RESULTS: Twenty-eight randomised controlled trials (2,789 participants) evaluating the effects of resistance-training (n = 10), walking (n = 6) and mixed-exercise programs (n = 7) were identified. Low to moderate certainty evidence indicated small increases in physical activity for exercise-therapy compared to non-exercise interventions in the short-term (SMD, 95% CI = 0.29, 0.09 to 0.50), but not the medium- (0.03, -0.11 to 0.18) or long-term (-0.06, -0.34 to 0.22). Low certainty evidence indicated large increases in physical activity for walking programs (0.53, 0.11 to 0.95) and mixed-exercise programs (0.67, 0.37 to 0.97) compared to non-exercise interventions in the short-term. Low certainty evidence indicated moderate and small increases in physical activity for resistance-training combined with education focused on pain coping skills and self-efficacy compared to education alone at medium-term follow-up (0.45, 0.19 to 0.71). CONCLUSION: Walking and mixed-exercise, but not resistance-training, may improve physical activity in people with KOA in the short-term. Combining resistance-training with education may increase physical activity in the medium-, but not the long-term, highlighting the potential importance of developing more effective longer-term interventions for people with KOA. Future studies evaluating land-based exercise-therapy are encouraged to include physical activity outcomes and longer-term follow-up to increase the certainty of evidence.

Thinking outside the shunt-sterile CSF malabsorption in pilocytic astrocytomas: case series and review of the literature.

INTRODUCTION: Ventriculoperitoneal (VP) shunt insertion is the most common cerebrospinal fluid (CSF) diversionary procedure used for the treatment of chronic hydrocephalus. Sterile CSF ascites is a rare complication of VP shunt insertion. This can arise from either an overproduction of CSF or inadequate filtration of CSF at the level of the peritoneum. By either mechanism, the development of CSF ascites requires an intact VP shunt. OBJECTIVE: The authors discuss two paediatric cases diagnosed with suprasellar pilocytic astrocytomas treated with platinum-based chemotherapy, who subsequently developed sterile CSF ascites. We review the literature with regard to CSF malabsorption and discuss it as a contributing factor to shunt malfunction. CONCLUSION: CSF malabsorption with resultant ascites is a rare complication of VP shunting with many etiologies. Two common predisposing factors included the use of platinum-based chemotherapeutic agents, as well as the specific neuropathology. Further analysis of these two entities is needed in order to elucidate their role in contributing to the development of CSF ascites in this patient cohort.

Health coaching for low back pain: a systematic review of the literature.

OBJECTIVE: To systematically review the evidence for health coaching for patients with low back pain and describe the diversity of health coach training and interventions. METHODS: Electronic databases Medline, CINAHL, EMBASE, PsycINFO, AMED and the Cochrane Central Register of Controlled Trials were searched to 24 June 2013 using individually devised strategies. Randomised or quasi randomised controlled trials (RCTs) of health coaching for adults with low back pain of any duration were considered. The overall quality of the body of evidence was assessed using the GRADE approach. Treatment effects were presented as the difference in mean scores with 95% confidence intervals and standardised mean difference at follow-up between health coaching and control groups. Health coaching interventions were compared narratively by their theoretical principles and the training and assessment of heath coaches. RESULTS: Five publications describing three RCTs and one cluster RCT met the criteria for review. A rating of very low was assigned to the body of evidence using the GRADE approach. One RCT found significant improvements in lifting capacity and exercise compliance in favour of the health coaching group at both follow-up points with a large and moderate standardised mean difference. All included studies based health coaching interventions on the transtheoretical model of change however, the content of counselling programmes varied between studies and measures of treatment fidelity were inconclusive. DISCUSSION: Variability in health coaching interventions and a lack of assessment of treatment fidelity in addition to the very low rating of the overall body of evidence identified in the current review renders any estimates of the effect of health coaching on low back pain uncertain. Well-designed RCTs of patients with sub-acute low back pain are required that incorporate clearly described protocols for health coaching interventions and include standardised measures of treatment fidelity.

General practitioners' attitude to sport and exercise medicine services: a questionnaire-based survey.

AIM: Sport and exercise medicine (SEM) aims to manage sporting injuries and promote physical activity. This study explores general practitioners' (GPs) awareness, understanding and utilisation of their local SEM services. DESIGN: A questionnaire survey, including patient case scenarios, was administered between February and May 2011. PARTICIPANTS AND SETTING: 693 GPs working in Cardiff and Vale, Leicester and Tower Hamlets were invited to participate. RESULTS: 244 GPs responded to the questionnaire (35.2% response rate). Less than half (46%; 112/244) were aware of their nearest SEM service and only 38% (92/244) had a clear understanding on referral indications. The majority (82%; 199/244) felt confident advising less active patients about exercise. There were divergent management opinions about the case scenarios of patients who were SEM referral candidates. Overall, GPs were significantly more likely to refer younger patients and patients with sport-related problems rather than patients who would benefit from increasing their activity levels in order to prevent or manage chronic conditions (p<0.01). GPs with previous SEM training were significantly more likely to refer (p<0.01). The majority (62%; 151/244) had never referred patients to their local SEM clinics but of those who had 75% (70/93) rated the service as good. CONCLUSIONS: There is a lack of awareness and understanding among GPs on the role of SEM within the National Health Service which may be resulting in suboptimal utilisation especially for patients who could benefit from increasing their activity levels.

Aqueous oxygen peroxide treatment of VLUs in a primary care-based randomised, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate a novel aqueous oxygen peroxide (AOP) wound therapy (BioxyQuell) in a multi-centre, primary care-based, randomised, double-blind, placebo-controlled, parallel-group trial, monitoring long-term healing outcomes over 12 months. METHOD: Sixty-one patients with chronic, stable venous leg ulceration were treated with either AOP solution or sterile water placebo applied as a lavage over 2 weeks. The patients' wounds were dressed weekly and assessed fortnightly over the following 6 weeks. Patients who completed the initial 8-week trial were invited into a 10-month follow-up trial. The primary endpoints of the study were wound healing at 8 weeks, 12 weeks, 6 months and 12 months, and wound size reduction during the treatment phase. Secondary endpoints were reductions in wound bioburden and pain. RESULTS: Patients treated with AOP were more likely to heal at 6 months (p=0.014) and 12 months (p=0.006), but not at 8 weeks (p=0.979) or 12 weeks (p=0.263). Patients treated with AOP had greater wound area reduction (p=0.015), reductions in pain measured on a 100-point scale (p=0.001) and wound bioburden reduction (p=0.005) during the treatment phase. CONCLUSION: The addition of AOP treatment provides substantial benefits to patients with chronic venous leg ulceration compared with current best practice.

Advance care planning for patients with end-stage kidney disease on dialysis: narrative review of the current evidence, and future considerations.

Patients with end-stage kidney disease (ESKD) have a high symptom-burden and high rates of morbidity and mortality. Despite this, evidence has shown that this patient group does not have timely discussions to plan for deterioration and death, and at the end of life there are unmet palliative care needs. Advance care planning is a process that can help patients share their personal values and preferences for their future care and prepare for declining health. Earlier, more integrated and holistic advance care planning has the potential to improve access to care services, communication, and preparedness for future decision-making and changing circumstances. However, there are many barriers to successful implementation of advance care planning in this population. In this narrative review we discuss the current evidence for advance care planning in patients on dialysis, the data around the barriers to advance care planning implementation, and interventions that have been trialled. The review explores whether the concepts and approaches to advance care planning in this population need to be updated to encompass current and future care. It suggests that a shift from a problem-orientated approach to a goal-orientated approach may lead to better engagement, with more patient-centred and satisfying outcomes.

"Much better than I thought it was going to be": Telehealth delivered group-based education and exercise was perceived as acceptable among people with knee osteoarthritis.

Objective: To understand patient perceived acceptability of participating in a telehealth delivered group-based education and exercise-therapy program for knee osteoarthritis. Design: This qualitative study involved semi-structured, one-on-one interviews with knee osteoarthritis patients who have completed the Good Living with osteoArthritis from Denmark (GLA:D®) program via telehealth or in-person. Interviews were recorded, transcribed verbatim, coded, and analysed using an inductive content analysis approach, focusing on themes related to telehealth. Results: Nineteen participants [12 (63%) female, mean aged 62 years, range 49-72 years] were included. Eleven (58%) received GLA:D® via telehealth and 8 (42%) attended in-person sessions. Two overarching themes (6 sub-themes) related to telehealth perceived acceptability were identified: 1) Perceptions of telehealth acceptability was highly influenced by exposure. Individuals who had received telehealth considered it easy, convenient, and flexible, whereas telehealth was perceived to be inferior and misunderstood by those without exposure. 2) Telehealth participants reported similar program benefits to in-person participants, including reduced fear of pain and joint damage, changed beliefs in value of exercise, and stated improvements in pain and function. Conclusions: Telehealth delivery of group-based education and exercise-therapy for knee osteoarthritis was acceptable for people who had experienced it and provides similar benefits as in-person care for pain and beliefs about the safety and value of exercise. Wider implementation of telehealth group-based education and exercise-therapy may improve access to high value care for people with knee osteoarthritis.

Multidisciplinary neurosurgical rounds incorporating antimicrobial stewardship. Are they of benefit?

Background: In an era of increasing antimicrobial resistance, appropriate antimicrobials are essential to optimise patient outcomes. In 2017, antimicrobial use prevalence (AMU) on the two neurosurgical wards in our tertiary teaching hospital varied from 23% on ward A to 33% on ward B with 67% and 100% 'appropriate' prescriptions, respectively. In July 2018, a weekly antimicrobial stewardship multidisciplinary round led by a senior neurosurgery registrar commenced, attended by the antimicrobial stewardship team (AST). Research question: This report evaluates whether a multi-disciplinary approach on neurosurgical prescribing was beneficial, specifically in reducing AMU. Materials and methods: The following data was collected on AST rounds for 30 weeks in total from August 2018 to July 2019: number of patients on antimicrobials, appropriateness and stewardship actions. A questionnaire was distributed to neurosurgical doctors on two occasions to canvass opinions and attitudes on antimicrobial prescribing. Results: 1716 prescriptions were reviewed (mean 57.2 per week). Of these 321 (18.7%) included antimicrobial prescriptions; 200 on ward A (19.8%), and 121 on ward B (17%), representing a decrease in AMU from 2017. The majority of antimicrobial prescriptions, 271 (84.4%) were deemed appropriate. Stewardship actions were taken in 215 (67%) prescriptions.Fifteen questionnaires were completed by neurosurgical doctors. The majority, 87%, stated the AST round was helpful overall. 93% indicated that informal training on the AST round was a source of education in antibiotic prescribing. Discussion and conclusion: The weekly AST round provided a timely opportunity for multidisciplinary discussion, implementation of antimicrobial stewardship actions and opportunistic antimicrobial stewardship education.

The role of the sports and exercise medicine physician in the National Health Service: a questionnaire-based survey.

OBJECTIVES: To investigate the opinions of general practitioners, orthopaedic surgeons, rheumatologists, sport and exercise medicine (SEM) registrars and public health consultants on training, caseload, the most appropriate setting and the position of SEM within the National Health Service (NHS) in the UK. METHOD: A cross-sectional questionnaire-based survey investigated the opinions of the above professionals from three primary care trusts and associated hospitals in London and Birmingham. RESULTS: With a 50% response rate (n = 226), 93% (208/224) of participants felt that there was a role for SEM in the NHS. 56% (124/223) agreed that this role should be in both primary and secondary care. 64% (136/212) of participants felt that their practice would benefit from the input of a SEM physician and 95% (191/202) would consider referring patients to SEM services. 74% (165/222) agreed that SEM should have a public health role, and 63% (140/222) believed that these responsibilities should be evenly balanced with the treatment of sports injuries. Despite the emphasis on public health work from SEM policy makers, none of the SEM registrars selected public health as an important training area. 31% (44/140) of participants felt that a lack of education in the medical profession regarding SEM represented the greatest hindrance to its development in the NHS. CONCLUSION: Several areas of agreement were demonstrated across the specialties, many of which matched the views of policy makers. This study involved participants from a range of cognate disciplines and was the first to investigate this issue since SEM was recognised as a specialty in 2005.

Psychodynamic formulation, consensual response method, and interpersonal problems.

We describe a new method for aggregating psychodynamic formulations of independent clinicians. 15 patients (10 female and 5 male, aged 23-41) were interviewed before they began brief dynamic psychotherapy. Different panels of 8 formulators (drawn from a pool of 72 psychodynamic clinicians with 10-38 years of clinical experience) observed each videotaped interview and wrote individual formulations. The text of each formulation was divided into thought-units, and thought-units that occurred 3 or more times were combined into a final consensual formulation. (One case was formulated twice to demonstrate the replicability of the method). Other clinical raters then read each consensual formulation and judged, for a list of interpersonal problems, whether each problem was apt to be distressing for that patient. The raters were very successful in predicting which problems were later discussed in treatment. Predictions were best for formulations with a high proportion of interpersonal content.

The Family Attitude Scale: reliability and validity of a new scale for measuring the emotional climate of families.

Research on outcomes from psychiatric disorders has highlighted the importance of expressed emotion (EE), but its cost-effective measurement remains a challenge. This article describes development of the Family Attitude Scale (FAS), a 30-item instrument that can be completed by any informant. Its psychometric characteristics are reported in parents of undergraduate students and in 70 families with a schizophrenic member. The total FAS had high internal consistency in all samples, and reports of angry behaviour in FAS items showed acceptable inter-rater agreement. The FAS was associated with the reported anger, anger expression and anxiety of respondents. Substantial associations between the parents' FAS and the anger and anger expression of students was also observed. Parents of schizophrenic patients had higher FAS scores than parents of students, and the FAS was higher if disorder duration was longer or patient functioning was poorer. Hostility, high criticism and low warmth on the Camberwell Family Interview (CFI) were associated with a more negative FAS. The highest FAS in the family was a good predictor of a highly critical environment on the CFI. The FAS is a reliable and valid indicator of relationship stress and expressed anger that has wide applicability.

Effect of health lifestyle pattern on dietary change.

PURPOSE: To examine the effect of lifestyle on the effectiveness of a low-intensity dietary intervention. DESIGN: A secondary data analysis was performed using data from the Eating Patterns Study, a randomized controlled trial that found that self-help materials with physician advice was effective in changing dietary intake and behavior. SETTING: Primary care clinics in a large health maintenance organization. SUBJECTS: A total of 2111 patients with a routine scheduled appointment with their primary care physicians. MEASURES: Participants were grouped into one of six health lifestyle patterns based on similarities in baseline measures of alcohol intake, smoking, diet quality, and exercise. Within each lifestyle pattern, changes from baseline in usual fat and fiber intake (based on a food frequency) and a fat and fiber behavior score were compared at 3 months and 12 months for intervention vs. control participants. INTERVENTION: Self-help materials delivered by a physician with advice to change diet. RESULTS: Intervention participants in the fitness lifestyle group made the largest changes relative to controls for each dietary outcome at 3 and 12 months. For intervention participants defined by their alcohol intake or current smoking, either no changes in diet were observed compared with controls, or early changes were not sustained over time. Intervention-control comparisons within the remaining lifestyle patterns showed smaller dietary changes compared with the fitness lifestyle. This finding was similar to previously published results. CONCLUSIONS: This randomized controlled trial had limited power to detect subgroup differences; however, these results suggest that lifestyle patterns may be useful in the development of effective, targeted interventions to change behavior.

Onset and offset pharmacodynamics of propofol.

Propofol whole blood and plasma concentrations at offset of hypnosis in eighteen patients were inversely related to patient age and body fat. The relationship between propofol concentrations and body fat is derived from the relationship between age and body fat and age was the single independent predictor of concentrations at offset of propofol hypnosis.

Patient-controlled analgesia compared with nurse-controlled infusion analgesia after heart surgery.

A randomized, controlled clinical trial was conducted on 66 patients undergoing elective cardiac surgery to compare patient-controlled analgesia (PCA) to nurse-controlled analgesia (NCA) with continuous morphine infusion. Hourly assessment of pain (at rest and on movement) using a visual analogue scale (VAS), of respiratory rate, and level of sedation took place for the 24 h following extubation. The incidence of nausea was also recorded. Mean pain scores were calculated, and peak pain and sedation scores, together with lowest respiratory rates, were identified. Morphine consumption was measured at 24 h. No significant differences were found between the groups' scores for pain or sedation. The PCA group had significantly lower respiratory rates (P = 0.02) and a lower incidence of nausea (P = 0.008). The PCA group also consumed significantly more morphine (P = 0.0001). The study suggests a beneficial effect from PCA after cardiac surgery in reducing nausea, compared to NCA. It confirms nurse-controlled infusion analgesia as an effective form of pain relief in an intensive care and high-dependency setting.

Recovery entails bridging the multiple realms of best practice: towards a more integrated approach to evidence-based clinical treatment and psychosocial disability support for mental health recovery.

While mental health recovery is a very personal process, the approach also offers possibilities as a meta-framework for improving quality of services to support people with severe and enduring mental illness. This paper explores how a recovery paradigm offers opportunities to better understand how efforts within the personal, clinical, and psychosocial disability domains of well-being relate and need bridging and integration with an evidence-based framework of practice to optimise outcomes. Recovery from a severe and persisting mental illness such as schizophrenia is optimised by a holistic approach integrating the domains of clinical treatment and psychosocial rehabilitation with the personal efforts of individuals. For service providers, a monolithic or single paradigm approach with an exclusive or predominant biological, psychological, social, or cultural focus is unable to offer effective guidance on the treatment and rehabilitation support needed to enable community participation and ameliorate the impact which problems associated with mental illness have on individuals, their families, and their wider communities. Moreover, recovery-oriented services need to be effective, embracing evidence-based policy, practice and service delivery by providing treatment and support which actually work to improve outcomes for consumers and families.

Preliminary results from an Australian psychosocial rehabilitation program for people with serious mental illness.

Psychosocial rehabilitation, for those with a serious mental illness, is of significant importance due to both its frequency and cost to government. This paper describes the implementation and preliminary assessments of a new psychosocial rehabilitation program in New South Wales. Of particular urgency was the requirement to establish baseline measures for ongoing service evaluation at the unit. An extensive array of assessment tools (Brief Psychiatric Rating Scale, BPRS; Scale for the Assessment of Negative Symptoms, SANS; Quality Of Life Scale, QOLS) was applied to determine the functioning of clients prior to the program. Following the initial assessments, subsequent measures were undertaken on completion of the program and then at 1 year follow-up. It was hypothesized that the clients would demonstrate significant improvements on these measures with a reduction in their psychopathology as assessed by the BPRS, improvement in their quality-of-life as measured by the QOLS and improvement in their negative symptoms as measured by the SANS. The final outcome demonstrated improvement in the assessment scores by 34%. A positive correlation to the above results showed a 54% reduction in the re-admission rate of clients and length of stay in hospital. The paper describes further developments regarding this psychosocial rehabilitation unit and suggests other psychosocial rehabilitation initiatives.