Paramedic views regarding clinical research in out of hospital cardiac arrest

Background: The success of pre-hospital research relies on positive engagement from paramedics. Without adequate participation and protocol compliance trials will not succeed. Aims: To seek feedback from paramedics about trial participation and determine their preferences regarding a future large-scale research study. Methods: Paramedics participating in REVIVE-Airways were sent a feedback questionnaire according to their study allocation. Findings: 99% of respondents were willing to participate in a further large-scale trial. Participants offered recommendations for future pre-hospital trials. Conclusion: There was strong support for further clinical trials of alternative airway management strategies during OHCA. Paramedics welcome opportunities to participate in research and receive feedback about trial progress and patient outcomes

Targeting β-catenin in acute myeloid leukaemia: past, present, and future perspectives

Acute myeloid leukaemia (AML) is an aggressive disease of the bone marrow with a poor prognosis. Evidence suggests long established chemotherapeutic regimens used to treat AML are reaching the limits of their efficacy, necessitating the urgent development of novel targeted therapies. Canonical Wnt signalling is an evolutionary conserved cascade heavily implicated in normal developmental and disease processes in humans. For over 15 years it's been known that the central mediator of this pathway, β-catenin, is dysregulated in AML promoting the emergence, maintenance, and drug resistance of leukaemia stem cells (LSC). Yet, despite this knowledge, and subsequent studies demonstrating the therapeutic potential of targeting Wnt activity in haematological cancers, β-catenin inhibitors have not yet reached the clinic. The aim of this review is to summarise the current understanding regarding the role and mechanistic dysregulation of β-catenin in AML and assess the therapeutic merit of pharmacologically targeting this molecule, drawing on lessons from other disease contexts

gammaCore for cluster headaches: a NICE medical technologies guidance

Cluster headaches are excruciating attacks of pain that can last between 15 min and 3 h. Cluster headaches can be episodic, where patients have long pain-free intervals between attacks, or chronic, where they do not. As part of the Medical Technologies Evaluation Programme, the UK National Institute for Health and Care Excellence (NICE) considered the clinical effectiveness and cost impact of gammaCore (electroCore), a handheld, patient-controlled device used to treat and prevent cluster headache. gammaCore is a non-invasive vagus nerve stimulator, the aim of which is to modify pain signals by stimulating the vagus nerve through the skin of the neck. Evidence suggests that gammaCore reduces the intensity and frequency of cluster headaches and that the addition of gammaCore to standard care is cost saving. Therefore, the guidance published by NICE in December 2019 recommends routine adoption of gammaCore into the UK national health service. However, the guidance noted that gammaCore does not work for everyone and recommended that treatment with gammaCore should stop after 3 months in patients whose symptoms do not improve

Axonics sacral neuromodulation system for treating refractory overactive bladder: a NICE medical technologies guidance

The Axonics sacral neuromodulation (SNM) system can be used by people with refractory overactive bladder (OAB) to reduce symptoms of urge urinary incontinence and urinary frequency, where conservative treatments have failed or are not suitable. It is the first system for this indication that makes use of a rechargeable battery to prolong the lifespan of the implanted device, with the potential advantage of reducing the frequency of surgical replacement procedures and associated complications. We describe the evidence considered by the UK National Institute of Health and Care Excellence (NICE) in their evaluation of this evidence, supported by Cedar Healthcare Technology Research Centre. Two observational studies provided descriptive data that suggested improvement in control of symptoms after implantation of the Axonics SNM system; however, there was no peer-reviewed evidence that directly compared rechargeable and non-rechargeable SNM systems. In the absence of long-term data, economic modelling relies on the accuracy of battery life estimates. The evidence supports the case for adopting the Axonics SNM system for treating refractory OAB, when conservative treatment or treatment with medicines has not worked. This conclusion is consistent with other relevant NICE guidelines. Use of Axonics SNM technology in the UK National Health Service (NHS) is associated with a potential cost saving of £6025 per person over a 15-year period when compared with an equivalent non-rechargeable SNM system, assuming the claimed battery life estimate (a minimum of 15 years) is accurate. The cost savings are estimated to start around 6 years after implantation

MTG570 AposHealth for osteoarthritis (OA) of the knee: External Assessment Group report

AposHealth (previously AposTherapy) is a non-invasive device worn on the foot to adjust the gait of the user to improve symptoms of knee osteoarthritis (OA), a condition that results in joints becoming stiff and painful. It is proposed as an addition to non-surgical standard care, or as an alternative. The comparators included alternative devices such as supports, splints and braces or intra-articular corticosteroid injections. Clinical evidence primarily from low quality non-comparative, observational studies indicates that users of AposHealth experience improvements in symptoms of knee OA including pain, function and stiffness. Quality of life outcomes also show improvements and both clinical and patient experts supported these findings from their own experience. Two comparative studies, one high quality randomised trial and one prospective comparative study, did report improvements with AposHealth however both studies compared with a sham device rather than standard care. There is a lack of evidence comparing AposHealth to non-surgical standard care treatment options such as manual therapy, walking aids, and intra-articular corticosteroid injections and their respective impacts on pain and function. Additionally, there is a lack of evidence relating to the outcome of TKR surgery delay or avoidance and in general there is a lack of long-term follow-up data (beyond 2 years). This is a key gap in the evidence and has a particular impact on the economic assessment

Low meteorological influence found in 2019 Amazonia fires

Technical note. The sudden increase in Amazon fires early in the 2019 fire season made global headlines. While it has been heavily speculated that the fires were caused by deliberate human ignitions or human-induced landscape changes, there have also been suggestions that meteorological conditions could have played a role. Here, we ask two questions: were the 2019 fires in the Amazon unprecedented in the historical record, and did the meteorological conditions contribute to the increased burning? To answer this, we take advantage of a recently developed modelling framework which optimises a simple fire model against observations of burnt area and whose outputs are described as probability densities. This allowed us to test the probability of the 2019 fire season occurring due to meteorological conditions alone. The observations show that the burnt area was higher than in previous years in regions where there is already substantial deforestation activity in the Amazon. Overall, 11 % of the area recorded the highest early season (June–August) burnt area since the start of our observational record, with areas in Brazil's central arc of deforestation recording the highest ever monthly burnt area in August. However, areas outside of the regions of widespread deforestation show less burnt area than the historical average, and the optimised model shows that this low burnt area would have extended over much of the eastern Amazon region, including in Brazil's central arc of deforestation with high fire occurrence in 2019. We show that there is a 9 % likelihood of the observed August fires being caused by meteorological conditions alone, decreasing to 6 %–7 % along the agricultural–humid forest interface in Brazil's central states and 8 % in Paraguay and Bolivia dry forests. Our results suggest that changes in land use, cover or management are the likely drivers of the substantial increase in the 2019 early fire season burnt area, especially in Brazil. Burnt area for September in the arc of deforestation had a 14 %–26 % probability of being caused by meteorological conditions, potentially coinciding with a shift in fire-related policy from South American governments

LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells

Canonical Wnt/β-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia patients; however, some patients exhibit little or no nuclear β-catenin even where cytosolic β-catenin is abundant. Control of the subcellular localization of β-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of β-catenin we carried out the first nuclear/cytoplasmic proteomic analysis of the β-catenin interactome in myeloid leukemia cells and identified putative novel β-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear β-catenin) versus Wnt-unresponsive cells (low nuclear β-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of β-catenin. The relative levels of nuclear LEF-1 and β-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed β-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and β-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first β-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear β-catenin level human myeloid leukemia