Agreement between telehealth and in-person assessment of patients with chronic musculoskeletal conditions presenting to an advanced-practice physiotherapy screening clinic

Objective: To determine the level of agreement between a telehealth and in-person assessment of a representative sample of patients with chronic musculoskeletal conditions referred to an advanced-practice physiotherapy screening clinic. Design: Repeated-measures study design. Participants: 42 patients referred to the Neurosurgical & Orthopaedic Physiotherapy Screening Clinic (Queensland, Australia) for assessment of their chronic lumbar spine, knee or shoulder condition. Intervention: Participants underwent two consecutive assessments by different physiotherapists within a single clinic session. In-person assessments were conducted as per standard clinical practice. Telehealth assessments took place remotely via videoconferencing. Six Musculoskeletal Physiotherapists were paired together to perform both assessment types. Main outcome measures: Clinical management decisions including (i) recommended management pathways, (ii) referral to allied health professions, (iii) clinical diagnostics, and (iv) requirement for further investigations were compared using reliability and agreement statistics. Results: There was substantial agreement (83.3%; 35/42 cases) between in-person and telehealth assessments for recommended management pathways. Moderate to near perfect agreement (AC1 = 0.58–0.9) was reached for referral to individual allied health professionals. Diagnostic agreement was 83.3% between the two delivery mediums, whilst there was substantial agreement (81%; AC1 = 0.74) when requesting further investigations. Overall, participants were satisfied with the telehealth assessment. Conclusion: There is a high level of agreement between telehealth and in-person assessments with respect to clinical management decisions and diagnosis of patients with chronic musculoskeletal conditions managed in an advanced-practice physiotherapy screening clinic. Telehealth can be considered as a viable and effective medium to assess those patients who are unable to attend these services in person

Functional neurological disorder is a feminist issue

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need

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

A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins

Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition of C. difficile and the subsequent activation of the immune system. Bone marrow derived dendritic cells (DCs) exposed to SLPs were assessed for production of inflammatory cytokines, expression of cell surface markers and their ability to generate T helper (Th) cell responses. DCs isolated from C3H/HeN and C3H/HeJ mice were used in order to examine whether SLPs are recognised by TLR4. The role of TLR4 in infection was examined in TLR4-deficient mice. SLPs induced maturation of DCs characterised by production of IL-12, TNFα and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNγ and IL-17. SLPs were unable to activate DCs isolated from TLR4-mutant C3H/HeJ mice and failed to induce a subsequent Th cell response. TLR4−/− and Myd88−/−, but not TRIF−/− mice were more susceptible than wild-type mice to C. difficile infection. Furthermore, SLPs activated NFκB, but not IRF3, downstream of TLR4. Our results indicate that SLPs isolated from C. difficile can activate innate and adaptive immunity and that these effects are mediated by TLR4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

Oldest Cretaceous sequence, Giralia Anticline, Carnarvon Basin, Western Australia: late Hauterivian-Barremian

Outcrop of the oldest Cretaceous sequence in the Giralia Anticline and the Giralia No. 1 well, penetrating the same sequence, are described and biostratigraphically assessed in detail. The Cretaceous rocks lie on an erosion surface cut into Permian strata. A 10 m thick basal sand unit, the Birdrong Sandstone, is overlain by 56 m of carbonaceous siltstone-mudstone (Muderong Shale). The Birdrong Sandstone in the anticline belongs to the Muderongia australis Zone of late Hauterivian-Barremian age, as does the lower part of the Muderong Shale. The age of the upper Muderong Shale is uncertain, as is the age of a 10 m thick sandstone unit (probable Windalia Sand Member) which separates the Muderong Shale from the late Aptian Windalia Radiolarite. Abundant fossil conifer wood, much of it with Teredolites borings, is present in outcrop referred to the upper part of the Birdrong Sandstone. Scattered ichthyosauran bones, probable plesiosauran remains, and rare ammonites also are present at this level. A growth-ring analysis of the wood suggests that-sa seasonal humid mesothermal climate prevailed in the region. Changes in sediment composition, palynomorph assemblages, and foraminiferal biofacies reflect retrogradation of marine facies during deposition of the Birdrong Sandstone and lowermost Muderong Shale, followed by aggradation through most of the Muderong Shale with maximum water depths less than 50 m. Within the sequence, the Birdrong Sandstone and the lowermost Muderong Shale represent a transgressive systems tract, whereas most of the Muderong Shale belongs to a highstand systems tract. The sequence reflects a transgressive pulse that was part of the progressive submergence of vast areas of the Australian continent during the Early Cretaceous. This late HauterivianBarremian transgressive pulse is recognised in widely separated basins and may represent a synchronous continent-wide sea-level rise

Design and methodology of SNAP-1: a Sprint National Anaesthesia Project to measure patient reported outcome after anaesthesia.

BACKGROUND: Patient satisfaction is an important metric of health-care quality. Accidental awareness under general anaesthesia (AAGA) is a serious complication of anaesthesia care which may go unrecognised in the immediate perioperative period but leads to long-term psychological harm for affected patients. The SNAP-1 study aimed to measure patient satisfaction with anaesthesia care and the incidence of AAGA, reported on direct questioning within 24 h of surgery, in a large multicentre cohort. A secondary aim of SNAP-1 was to test the effectiveness of a new network of Quality Audit and Research Coordinators in NHS anaesthetic departments, to achieve widespread study participation and high patient recruitment rates. This manuscript describes the study methodology. METHODS: SNAP-1 was a prospective observational cohort study. The study protocol was approved by the National Research Ethics Service. All UK NHS hospitals with anaesthetic departments were invited to participate. Adult patients undergoing any type of non-obstetric surgery were recruited in participating hospitals on 13th and 14th May 2014. Demographic data were collected by anaesthetists providing perioperative care. Patients were then approached within 24 h of surgery to complete two questionnaires-the Bauer patient satisfaction questionnaire (to measure patient reported outcome) and the modified Brice questionnaire (to detect possible accidental awareness). Completion of postoperative questionnaires was taken as evidence of implied consent. Results were recorded on a standard patient case report form, and local investigators entered anonymised data into an electronic database for later analysis by the core research team. RESULTS: Preliminary analyses indicate that over 15,000 patients were recruited across the UK, making SNAP-1 the largest NIHR portfolio-adopted study in anaesthesia to date. Both descriptive and analytic epidemiological analyses will be used to answer specific questions about the patient perception of anaesthesia care overall and in surgical sub-specialties and to determine the incidence of AAGA. CONCLUSIONS: The SNAP-1 study recruited a large number of UK hospitals and thousands of perioperative patients using newly established networks in the UK anaesthetic profession. The results will provide benchmarking information to aid interpretation of patient satisfaction data and also determine the incidence of AAGA reported on a single postoperative visit