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A new epitaxial layer design with a double mode expander layer, high refractive index claddings, and an aluminum-free active area has been used to demonstrate distributed feedback lasers operating at 778.1 nm wavelength with reduced Lorentzian linewidth aimed at miniature atomic clock applications. The design also reduces the vertical beam divergence to improve the modal matching with optical fibers as well as maintain the high power output and reduce the emission linewidth. The lasers demonstrate single-mode operation with an over 35 dB side-mode suppression ratio, a power output ≤58 mW, a coupling efficiency to tapered fibers ≤40%, and a Lorentzian linewidth of 3.7 kHz. The performance allowed the free-running distributed feedback lasers to demonstrate spectroscopy of Rb vapor, which resolved the 85Rb and 87Rb two-photon transitions.

High n-type doping in germanium is essential for many electronic and optoelectronic applications especially for high performance Ohmic contacts, lasing and mid-infrared plasmonics. We report on the combination of in situ doping and excimer laser annealing to improve the activation of phosphorous in germanium. An activated n-doping concentration of 8.8  ×  1019 cm−3 has been achieved starting from an incorporated phosphorous concentration of 1.1  ×  1020 cm−3. Infrared reflectivity data fitted with a multi-layer Drude model indicate good uniformity over a 350 nm thick layer. Photoluminescence demonstrates clear bandgap narrowing and an increased ratio of direct to indirect bandgap emission confirming the high doping densities achieved. [ABSTRACT FROM AUTHOR]

Approximately 50 % of poor prognosis neuroblastomas arise due to MYCN over-expression. We previously demonstrated that MYCN and PRMT5 proteins interact and PRMT5 knockdown led to apoptosis of MYCN-amplified (MNA) neuroblastoma. Here we evaluate the highly selective first-in-class PRMT5 inhibitor GSK3203591 and its in vivo analogue GSK3326593 as targeted therapeutics for MNA neuroblastoma. Cell-line analyses show MYCN-dependent growth inhibition and apoptosis, with approximately 200-fold greater sensitivity of MNA neuroblastoma lines. RNA sequencing of three MNA neuroblastoma lines treated with GSK3203591 reveal deregulated MYCN transcriptional programmes and altered mRNA splicing, converging on key regulatory pathways such as DNA damage response, epitranscriptomics and cellular metabolism. Stable isotope labelling experiments in the same cell lines demonstrate that glutamine metabolism is impeded following GSK3203591 treatment, linking with disruption of the MLX/Mondo nutrient sensors via intron retention of MLX mRNA. Interestingly, glutaminase (GLS) protein decreases after GSK3203591 treatment despite unchanged transcript levels. We demonstrate that the RNA methyltransferase METTL3 and cognate reader YTHDF3 proteins are lowered following their mRNAs undergoing GSK3203591-induced splicing alterations, indicating epitranscriptomic regulation of GLS; accordingly, we observe decreases of GLS mRNA m6A methylation following GSK3203591 treatment, and decreased GLS protein following YTHDF3 knockdown. In vivo efficacy of GSK3326593 is confirmed by increased survival of Th-MYCN mice, with drug treatment triggering splicing events and protein decreases consistent with in vitro data. Together our study demonstrates the PRMT5-dependent spliceosomal vulnerability of MNA neuroblastoma and identifies the epitranscriptome and glutamine metabolism as critical determinants of this sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Background: Prognostic models that identify individuals with chronic kidney disease (CKD) at greatest risk of developing kidney failure help clinicians to make decisions and deliver precision medicine. It is recognised that people with CKD usually have multiple long-term health conditions (multimorbidity) and often experience frailty. We undertook a systematic review to evaluate the representation and consideration of multimorbidity and frailty within CKD cohorts used to develop and/or validate prognostic models assessing the risk of kidney failure., Methods: We identified studies that described derivation, validation or update of kidney failure prognostic models in MEDLINE, CINAHL Plus and the Cochrane Library-CENTRAL. The primary outcome was representation of multimorbidity or frailty. The secondary outcome was predictive accuracy of identified models in relation to presence of multimorbidity or frailty., Results: Ninety-seven studies reporting 121 different kidney failure prognostic models were identified. Two studies reported prevalence of multimorbidity and a single study reported prevalence of frailty. The rates of specific comorbidities were reported in a greater proportion of studies: 67.0% reported baseline data on diabetes, 54.6% reported hypertension and 39.2% reported cardiovascular disease. No studies included frailty in model development, and only one study considered multimorbidity as a predictor variable. No studies assessed model performance in populations in relation to multimorbidity. A single study assessed associations between frailty and the risks of kidney failure and death., Conclusions: There is a paucity of kidney failure risk prediction models that consider the impact of multimorbidity and/or frailty, resulting in a lack of clear evidence-based practice for multimorbid or frail individuals. These knowledge gaps should be explored to help clinicians know whether these models can be used for CKD patients who experience multimorbidity and/or frailty., Systematic Review Registration: This review has been registered on PROSPERO (CRD42022347295)., (© 2024. The Author(s).)

Endometrial health is vital for the reproductive efficiency of broodmares and accurate diagnostic testing is crucial for directing the best treatment options and outcomes. Confocal laser endomicroscopy (CLE) is an endoscopic technique for obtaining in-vivo, real-time microscopic imaging of tissues using a fiber optic probe. CLE relies on induced tissue fluorescence and fluorescein sodium, given intravenously, is the contrast agent most used in human medicine. This study aimed to determine the feasibility of CLE for imaging equine endometrium and determine a standard dose of fluorescein sodium to achieve optimal cellular imaging. In-vivo CLE was performed on 44 mares, and the images were compared with routine histopathological analysis of endometrial biopsies. No adverse reactions occurred after IV fluorescein sodium administration and a dose of 4 mg/kg was established (0.04 mL/kg of 10 % fluorescein sodium solution) to achieve optimal image contrast. CLE enabled multiple regions of the endometrium to be assessed quickly. Distinct tissue architecture patterns could be appreciated using CLE, and the luminal epithelium could be assessed for integrity (ulceration) and exocytosed inflammatory cells. Endometrial gland distribution, density, shape, and epithelial height were evaluated. Blood vessels were clearly outlined, and inflammatory cells and fibrosis were discernable within the interstitium. Image quality varied between mares, and the stage of oestrous cycle may have been a factor of influence. This novel imaging modality enables collection of "virtual" biopsies and facilitates critical assessment of multiple regions of the uterus compared with the standard histopathologic assessment of a single random tissue biopsy., Competing Interests: Declaration of Competing Interest Optiscan supplied the CLE device used in this study but played no role in the study design nor in the collection, analysis, and interpretation of data, nor in the decision to submit the manuscript for publication. None of the authors has any other financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024. Published by Elsevier Ltd.)

Context: Treatment burden is defined as the workload of healthcare for people with long-term conditions and the impact on wellbeing. Stroke survivors often live with considerable treatment burden because of high healthcare workload alongside deficiencies in care provision that can make navigating healthcare systems and managing health more difficult. Ways of measuring treatment burden after stroke are currently lacking. The Patient Experience with Treatment and Self-Management measure (PETS) is a 60-item patient-reported measure that was developed to measure treatment burden in a multi-morbid population. Although comprehensive, this is not a stroke-specific measure and therefore omits some burdens associated with stroke rehabilitation. Objective: Our aim was to adapt (PETS) (version 2.0, English), a patient-reported measure of treatment burden in multimorbidity, to create a stroke-specific measure (PETS-stroke), and to conduct content validity testing in a UK stroke survivor population. Study Design and analysis: PETS items were adapted to create PETS-stroke, using a previously developed conceptual model of treatment burden in stroke. Content validation involved three rounds of qualitative cognitive interviews with stroke survivors in Scotland recruited through stroke groups and primary care. Participants were asked for feedback on the importance, relevance and clarity of content of PETS-stroke. Framework analysis was used to explore responses. Setting: Community. Population studied: Stroke survivors. Instrument: Patient Experience with Treatment and Self-Management in stroke (PETS-stroke) scale. Results: Interviews (n=15) resulted in changes to the wording of instructions and items; location of items within the measure; answer options; and recall period. The final PETS-stroke tool has 34-items, spanning 13 domains. It includes 10 items unchanged from PETS, 6 new and 18 amended. Conclusions: The development of a systematic method of quantifying treatment burden from the perspective of stroke survivors will allow for the identification of patients at high risk of treatment burden and will aid the design and testing of tailored interventions aimed at lessening treatment burden., Competing Interests: None, (© 2023 Annals of Family Medicine, Inc.)

Laser cooled atoms have proven transformative for precision metrology, playing a pivotal role in state-of-the-art clocks and interferometers and having the potential to provide a step-change in our modern technological capabilities. To successfully explore their full potential, laser cooling platforms must be translated from the laboratory environment and into portable, compact quantum sensors for deployment in practical applications. This transition requires the amalgamation of a wide range of components and expertise if an unambiguously chip-scale cold atom sensor is to be realized. We present recent developments in cold-atom sensor miniaturization, focusing on key components that enable laser cooling on the chip-scale. The design, fabrication, and impact of the components on sensor scalability and performance will be discussed with an outlook to the next generation of chip-scale cold atom devices.

Context: To aid prioritisation of funding for stroke research, a Stroke Priority Setting Partnership is being conducted in the UK by The Stroke Association using surveys and workshops with stroke survivors, stroke carers and health professionals. Another valuable source of information about topics that require research is the social media platform Twitter. Objective: To ascertain common topics of discussion in relation to stroke recovery on Twitter amongst stroke survivors, their carers, and the general public. Study design and analysis: Content analysis of public posts on Twitter. Dataset: An electronic search of Twitter was performed to analyse the content of two major stroke discussion tags: #strokesurvivor and #strokerecovery. Tweets were collected using NCapture, an open-source extension for the internet browser Chrome. Tweets spanning 5 weeks over the course of January to February 2021 were analysed. Population studied: Tweets made by stroke survivors and their carers or other interested members of the public were included and those made by health professionals or organisations (e.g. charities or health care providers) were excluded. All tweets were fully anonymised and edited where necessary to omit any identifying information. Outcome measures: The content of each tweet was analysed thematically using NVIVO, with tweets being coded by their content and sentiment to identify trends in discussion. Results: 486 tweets were analysed following the removal of duplicate and unrelated material. From these, 6 themes were identified: motivation & positivity; raising of stroke awareness; experience of the stroke rehabilitation process; symptomatic aspects of stroke recovery; sharing of stroke-related resources; and concerns about COVID-19. Conclusions: Twitter's role as a space for peer-support and motivation amongst survivors was evident, as was its potential for promoting awareness of stroke and its sequalae to the public. Amongst the most prominent aspects of recovery discussed was the psychological impact of stroke, with users expressing difficulty in addressing the emotional sequalae in comparison to the physical aspects. This may be addressed by targeted funding of mental health services, and recognition of the specialised needs of stroke survivors. It is hoped that the findings of this project will be useful in guiding the apportioning of funding, as well as complementing the findings of the James Lind Alliance's Priority Setting Partnership., Competing Interests: Authors report none., (2021 Annals of Family Medicine, Inc.)

Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population. We characterized leaders emerging from epithelial monolayers in cell culture and found that they activated the stress sensor p53, which was sufficient to initiate leader cell behavior. p53 activated the cell cycle inhibitor p21 WAF1/CIP1 , which in turn induced leader behavior through inhibition of cyclin-dependent kinase activity. p53 also induced crowding hypersensitivity in leader cells such that, upon epithelial closure, they were eliminated by cell competition. Thus, mechanically induced p53 directs emergence of a transient population of leader cells that drive migration and ensures their clearance upon epithelial repair.

Background: A Learning Health System (LHS) is a model of how routinely collected health data can be used to improve care, creating 'virtuous cycles' between data and improvement. This requires the active involvement of health service stakeholders, including patients themselves. However, to date, research has explored the acceptability of being 'data donors' rather than considering patients as active contributors. The study aimed to understand how patients should be actively involved in an LHS., Design: Ten participatory codesign workshops were conducted with eight experienced public contributors using visual, collective and iterative methods. This led contributors to challenge and revise not only the idea of an LHS but also revise the study aims and outputs., Results: The contributors proposed three exemplar roles for patients in patient-driven LHS, which aligned with the idea of three forms of transparency: informational, participatory and accountability. 'Epistemic injustice' was considered a useful concept to express the risks of an LHS that did not provide active roles to patients (testimonial injustice) and that neglected their experience through collecting data that did not reflect the complexity of their lives (hermeneutic injustice)., Discussion: Patient involvement in an LHS should be 'with and by' patients, not 'about or for'. This requires systems to actively work with and respond to patient feedback, as demonstrated within the study itself by the adaptive approach to responding to contributor questions, to work in partnership with patients to create a 'virtuous alliance' to achieve change., Patient or Public Contribution: Public contributors were active partners throughout, and co-authored the paper., (© 2021 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Introduction: The transition of patients across care settings is associated with a high risk of errors and preventable medication-related harm. Ensuring effective communication of information between health professionals is considered important for improving patient safety. A National Health Service(NHS) organisation in the North West of England introduced an electronic transfer of care around medicines (TCAM) system which enabled hospital pharmacists to send information about patient's medications to their nominated community pharmacy. We aimed to understand the adoption, and the implications for sustainable use in practice of the TCAM service., Methods: We evaluated the TCAM service in a Clinical Commissioning Group (CCG) and NHS Foundation Trust in Salford, United Kingdom (UK). Participants were opportunistically recruited to take part in qualitative interviews through stakeholder networks and during hospital admission, and included hospital pharmacists, hospital pharmacy technicians, community pharmacists, general practice-based pharmacists, patients and their carers. A thematic analysis, that was iterative and concurrent with data collection, was undertaken using a template approach. The interpretation of the data was informed by broad sociotechnical theory., Results: Twenty-three interviews were conducted with health care professionals patients and carers. The ways in which the newly implemented TCAM intervention was adopted and used in practice and the perceptions of it from different stakeholders were conceptualised into four main thematic areas: The nature of the network and how it contributed to implementation, use and sustainability; The material properties of the system; How work practices for medicines safety were adapted and evolved; and The enhancement of medication safety activities. The TCAM intervention was perceived as effective in providing community pharmacists with timely, more accurate and enhanced information upon discharge. This allowed for pharmacists to enhance clinical services designed to ensure that accurate medication reconciliation was completed, and the correct medication was dispensed for the patient., Conclusions: By providing pharmacy teams with accurate and enhanced information the TCAM intervention supported healthcare professionals to establish and/or strengthen interprofessional networks in order to provide clinical services designed to ensure that accurate medication reconciliation and dispensing activities were completed. However, the intervention was implemented into a complex and at times fragmented network, and we recommend opportunities be explored to fully integrate this network to involve patients/carers, general practice pharmacists and two-way communication between primary and secondary care to further enhance the reach and impact of the TCAM service., Competing Interests: The authors have declared that no competing interests exist.

Background Despite common use, anticholinergic medications have been associated with serious health risks. Interventions to reduce their use are being developed and there is a need to understand their implementation into clinical care. Aim of review This systematic review aims to identify and analyse qualitative research studies exploring the barriers and facilitators to reducing anticholinergic burden. Methods Medline (OVID), EMBASE (OVID), CINAHL (EMBSCO) and PsycINFO (OVID) were searched using comprehensive search terms. Peer reviewed studies published in English presenting qualitative research in relation to the barriers and facilitators of deprescribing anticholinergic medications, involving patients, carers or health professionals were eligible. Normalization Process Theory was used to explore and explain the data. Results Of 1764 identified studies, two were eligible and both involved healthcare professionals (23 general practitioners, 13 specialist clinicians and 12 pharmacists). No studies were identified that involved patients or carers. Barriers to collaborative working often resulted in poor motivation to reduce anticholinergic use. Low confidence, system resources and organisation of care also hindered anticholinergic burden reduction. Good communication and relationships with patients, carers and other healthcare professionals were reported as important for successful anticholinergic burden reduction. Having a named person for prescribing decisions, and clear role boundaries, were also important facilitators. Conclusions This review identified important barriers and facilitators to anticholinergic burden reduction from healthcare provider perspectives which can inform implementation of such deprescribing interventions. Studies exploring patient and carer perspectives are presently absent but are required to ensure person-centeredness and feasibility of future interventions., (© 2021. The Author(s).)

Background and Purpose: Stroke is the second commonest cause of death worldwide and a leading cause of severe disability, yet there are no published trials of palliative care in stroke. To design and evaluate palliative care interventions for people with stroke, researchers need to know what measurable outcomes matter most to patients and families, stroke professionals, and other service providers., Methods: A multidisciplinary steering group of professionals and laypeople managed the study. We synthesized recommendations from respected United Kingdom and international consensus documents to generate a list of outcome domains and then performed a rapid scoping literature review to identify potential outcome measures for use in future trials of palliative care after stroke. We then completed a 3-round, online Delphi survey of professionals, and service users to build consensus about outcome domains and outcome measures. Finally, we held a stakeholder workshop to review and finalize this consensus., Results: We generated a list of 36 different outcome domains from 4 key policy documents. The rapid scoping review identified 43 potential outcome measures that were used to create a shortlist of 16 measures. The 36 outcome domains and 16 measures were presented to a Delphi panel of diverse healthcare professionals and lay service users. Of 48 panelists invited to take part, 28 completed all 3 rounds. Shared decision-making and quality of life were selected as the most important outcome domains for future trials of palliative care in stroke. Additional comments highlighted the need for outcomes to be feasible, measurable, and relevant beyond the initial, acute phase of stroke. The stakeholder workshop endorsed these results., Conclusions: Future trials of palliative care after stroke should include pragmatic outcome measures, applicable to the evolving patient and family experiences after stroke and be inclusive of shared decision-making and quality of life.

Introduction: People living with type 2 diabetes undertake a range of tasks to manage their condition, collectively referred to as self-management. Interventions designed to support self-management vary in their content, and efficacy. This systematic review will analyse self-management interventions for type 2 diabetes drawing on theoretical models of patient workload and capacity., Methods and Analysis: Five electronic databases (Medline, Embase, CENTRAL, CINAHL and PsycINFO) will be searched from inception to 27th April 2021, supplemented by citation searching and hand-searching of reference lists. Two reviewers will independently review titles, abstracts and full texts. Inclusion criteria include Population: Adults with type 2 diabetes mellitus; Intervention: Randomised controlled trials of self-management support interventions; Comparison: Usual care; Outcomes: HbA1c (primary outcome) health-related quality of life (QOL), medication adherence, self-efficacy, treatment burden, healthcare utilization (e.g. number of appointment, hospital admissions), complications of type 2 diabetes (e.g. nephropathy, retinopathy, neuropathy, macrovascular disease) and mortality; Setting: Community. Study quality will be assessed using the Effective Practice and Organisation of Care (EPOC) risk of bias tool. Interventions will be classified according to the EPOC taxonomy and the PRISMS self-management taxonomy and grouped into similar interventions for analysis. Clinical and methodological heterogeneity will be assessed within subgroups, and random effects meta-analyses performed if appropriate. Otherwise, a narrative synthesis will be performed. Interventions will be graded on their likely impact on patient workload and support for patient capacity. The impact of these theoretical constructs on study outcomes will be explored using meta-regression. Conclusion This review will provide a broad overview of self-management interventions, analysed within the cumulative complexity model theoretical framework. Analyses will explore how the workload associated with self-management, and support for patient capacity, impact on outcomes of self-management interventions., Registration Number: PROSPERO CRD42021236980., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Hanlon P et al.)

Background: Knowledge mobilisation requires the effective elicitation and blending of different types of knowledge or ways of knowing, to produce hybrid knowledge outputs that are valuable to both knowledge producers (researchers) and knowledge users (health care stakeholders). Patients and service users are a neglected user group, and there is a need for transparent reporting and critical review of methods used to co-produce knowledge with patients. This study aimed to explore the potential of participatory codesign methods as a mechanism of supporting knowledge sharing, and to evaluate this from the perspective of both researchers and patients., Methods: A knowledge mobilisation research project using participatory codesign workshops to explore patient involvement in using health data to improve services. To evaluate involvement in the project, multiple qualitative data sources were collected throughout, including a survey informed by the Generic Learning Outcomes framework, an evaluation focus group, and field notes. Analysis was a collective dialogic reflection on project processes and impacts, including comparing and contrasting the key issues from the researcher and contributor perspectives., Results: Authentic involvement was seen as the result of "space to talk" and "space to change". "Space to talk" refers to creating space for shared dialogue, including space for tension and disagreement, and recognising contributor and researcher expertise as equally valuable to the discussion. 'Space to change' refers to space to adapt in response to contributor feedback. These were partly facilitated by the use of codesign methods which emphasise visual and iterative working, but contributors emphasised that relational openness was more crucial, and that this needed to apply to the study overall (specifically, how contributors were reimbursed as a demonstration of how their input was valued) to build trust, not just to processes within the workshops., Conclusions: Specific methods used within involvement are only one component of effective involvement practice. The relationship between researcher and contributors, and particularly researcher willingness to change their approach in response to feedback, were considered most important by contributors. Productive tension was emphasised as a key mechanism in leading to genuinely hybrid outputs that combined contributor insight and experience with academic knowledge and understanding.

Background: Patients and carers should be actively involved in patient safety and empowered to use person-centred approaches where they are asked to both identify safety concerns and partner in preventing them., Objectives: The aim of this study was to co-design a patient safety guide for primary care (PSG-PC) to support patients and carers to address key patient safety questions and identify key points where they can make their care safer. The objectives were to i) identify when and how patients and carers can be involved in primary care patient safety, and ii) identify the relevant information to include in the PSG-PC., Design: An experience-based co-design approach., Setting and Participants: We conducted three workshops with patients, carers, community pharmacists and general practitioners to develop and refine the PSG-PC., Results: Participants identified both explicit and implicit issues of primary care patient safety especially relating to technical and relational components of involving patients and carers. The importance of communication, understanding roles and responsibilities, and developing partnerships between patients and health-care providers were considered essential for actively involving patients in patient safety. Co-developing the PSG-PC provided insight to improve care to develop the PSG-PC., Discussion: The PSG-PC is the first guide to be developed for primary care, co-designed with patients, carers, general practitioners and pharmacists. The PSG-PC will support patients and carers to partner with health-care professionals to improve patient safety addressing international and national priorities to continuously improve patient safety., (© 2020 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Introduction: Patients and carers should be active partners in patient safety with healthcare professionals and be empowered to use personalised approaches to identify safety concerns and work together to prevent them. This protocol paper details a study to examine the feasibility of a multicomponent intervention to involve patients and/or carers in patient safety in primary care in the UK., Methods and Analysis: This is a two-phase, non-randomised feasibility mixed methods pragmatic study of a patient safety guide for primary care (PSG-PC). 8 general practices will recruit 120 patient and/or carer participants. All patient and/or carer participants will receive the PSG-PC. It will examine the feasibility and acceptability of the PSG-PC in primary care settings in patients aged 18 years or older who attend appointments at general practice with health professionals four or more times per year as either patients or carers. It will identify secondary outcomes for improving patient safety, health status and patient empowerment, and reducing health service utilisation over 6 months between baseline and 6-month follow-ups. The findings will inform whether a main effectiveness trial is feasible and, if so, how it should be designed, and how many patients and practices will be needed. The study will be undertaken between January 2020 and September 2021., Ethics and Dissemination: Ethical approval was obtained from the National Health Service London-West London and Gene Therapy Advisory Committee Research Ethics Committee (reference: 19/LO/1289). Research findings will be disseminated with participating general practices and shared in a range of different ways to engage different audiences, including presenting at international and national conferences, publishing in open-access, peer-reviewed journals and facilitating dissemination workshops within local communities with patients, carers and healthcare professionals., Trial Registration Number: ISRCTN90222092., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A novel spectroscopy technique to enable the rapid characterization of discrete mid-infrared integrated photonic waveguides is demonstrated. The technique utilizes lithography patterned polymer blocks that absorb light strongly within the molecular fingerprint region. These act as integrated waveguide detectors when combined with an atomic force microscope that measures the photothermal expansion when infrared light is guided to the block. As a proof of concept, the technique is used to experimentally characterize propagation loss and grating coupler response of Ge-on-Si waveguides at wavelengths from 6 to 10 µm. In addition, when the microscope is operated in scanning mode at fixed wavelength, the guided mode exiting the output facet is imaged with a lateral resolution better than 500 nm i.e. below the diffraction limit. The characterization technique can be applied to any mid-infrared waveguide platform and can provide non-destructive in-situ testing of discrete waveguide components.

Background: The NHS Health Check Programme is a risk-reduction programme offered to all adults in England aged 40-74 years. Previous studies mainly focused on patient perspectives and programme delivery; however, delivery varies, and costs are substantial. We were therefore working with key stakeholders to develop and co-produce an NHS Health Check Programme modelling tool (workHORSE) for commissioners to quantify local effectiveness, cost-effectiveness, and equity. Here we report on Workshop 1, which specifically aimed to facilitate engagement with stakeholders; develop a shared understanding of current Health Check implementation; identify what is working well, less well, and future hopes; and explore features to include in the tool., Methods: This qualitative study identified key stakeholders across the UK via networking and snowball techniques. The stakeholders spanned local organisations (NHS commissioners, GPs, and academics), third sector and national organisations (Public Health England and The National Institute for Health and Care Excellence). We used the validated Hovmand "group model building" approach to engage stakeholders in a series of pre-piloted, structured, small group exercises. We then used Framework Analysis to analyse responses., Results: Fifteen stakeholders participated in workshop 1. Stakeholders identified continued financial and political support for the NHS Health Check Programme. However, many stakeholders highlighted issues concerning lack of data on processes and outcomes, variability in quality of delivery, and suboptimal public engagement. Stakeholders' hopes included maximising coverage, uptake, and referrals, and producing additional evidence on population health, equity, and economic impacts. Key model suggestions focused on developing good-practice template scenarios, analysis of broader prevention activities at local level, accessible local data, broader economic perspectives, and fit-for-purpose outputs., Conclusions: A shared understanding of current implementations of the NHS Health Check Programme was developed. Stakeholders demonstrated their commitment to the NHS Health Check Programme whilst highlighting the perceived requirements for enhancing the service and discussed how the modelling tool could be instrumental in this process. These suggestions for improvement informed subsequent workshops and model development.

Low loss, single mode, Ge-on-Si rib waveguides are used to demonstrated optical sensing in the molecular fingerprint region of the mid-infrared spectrum. Sensing is carried out using two spin-coated films, with strong absorption in the mid-infrared. These films are used to calibrate the modal overlap with an analyte, and therefore experimentally demonstrate the potential for Ge-on-Si waveguides for mid-infrared sensing applications. The results are compared to Fourier transform infrared spectroscopy measurements. The advantage of waveguide spectroscopy is demonstrated in terms of the increased optical interaction, and a new multi-path length approach is demonstrated to improve the dynamic range, which is not possible with conventional FTIR or attenuated total reflection (ATR) measurements. These results highlight the potential for Ge-on-Si as an integrated sensing platform for healthcare, pollution monitoring and defence applications.

The waveguide losses from a range of surface plasmon and double metal waveguides for Ge/Si 1-x Ge x THz quantum cascade laser gain media are investigated at 4.79 THz (62.6 μm wavelength). Double metal waveguides demonstrate lower losses than surface plasmonic guiding with minimum losses for a 10 μm thick active gain region with silver metal of 21 cm -1 at 300 K reducing to 14.5 cm -1 at 10 K. Losses for silicon foundry compatible metals including Al and Cu are also provided for comparison and to provide a guide for gain requirements to enable lasers to be fabricated in commercial silicon foundries. To allow these losses to be calculated for a range of designs, the complex refractive index of a range of nominally undoped Si 1-x Ge x with x = 0.7, 0.8 and 0.9 and doped Ge heterolayers were extracted from Fourier transform infrared spectroscopy measurements between 0.1 and 10 THz and from 300 K down to 10 K. The results demonstrate losses comparable to similar designs of GaAs/AlGaAs quantum cascade laser plasmon waveguides indicating that a gain threshold of 15.1 cm -1 and 23.8 cm -1 are required to produce a 4.79 THz Ge/SiGe THz laser at 10 K and 300 K, respectively, for 2 mm long double metal waveguide quantum cascade lasers with facet coatings.

A silicon nitride micro-ring resonator with a loaded Q factor of 1.4 × 10 6 at 780 nm wavelength is demonstrated on silicon substrates. This is due to the low propagation loss waveguides achieved by optimization of waveguide sidewall interactions and top cladding refractive index. Potential applications include laser frequency stabilization allowing for chip-scale atomic systems targeting the 87 Rb atomic transition at 780.24 nm. The temperature dependent wavelength shift of the micro-ring was determined to be 13.1 pm/K indicating that a minimum temperature stability of less than ±15 mK is required for such devices for wavelength locking applications. If a polyurethane acrylate top cladding of an optimized thickness is used then the micro-ring could effectively be athermal, resulting in reduced footprint, power consumption, and cost of potential devices.

Anticholinergic drugs are prescribed for a range of conditions including gastrointestinal disorders, overactive bladder, allergies, and depression. While in some circumstances anticholinergic effects are therapeutic, they also pose many undesired or adverse effects. The overall impact from concomitant use of multiple medications with anticholinergic properties is termed anticholinergic burden (ACB). Greater ACB is associated with increased risks of impaired physical and cognitive function, falls, cardiovascular events, and mortality. This has led to the development of interventions aimed at reducing ACB through the deprescribing of anticholinergic drugs. However, little is known about the implementation issues that may influence successful embedding and integration of such interventions into routine clinical practice. In this paper, we present the protocol for our systematic review that aims to identify the qualitative evidence for the barriers and facilitators to reduce ACB from the perspectives of patients, carers, and healthcare professionals. A comprehensive search strategy will be conducted across OVID Medline, EMBASE, PsycInfo, and CINAHL. The review will be conducted in accordance with ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) and has been registered with PROSPERO (Registration CRD42018109084). Normalization process theory (NPT) will be used to explore, understand, and explain qualitative data in relation to factors that act as barriers or facilitators to ACB reduction., (© 2019 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

Competing Interests: Conflicts of interest: Dr. Aitken reports grants from The Farr Institute at The University of Manchester is supported by a 10-funder consortium led by the MRC (Grant No: MR/M501633/2), during the conduct of the study; Dr. Black reports grants from Farr Institute UK (MRC collaboration), grants from ESRC (ADRC-Scotland), during the conduct of the study; Dr Cunningham-Burley reports grants from Farr Institute UK (MRC collaboration (Grant No: MR/M501633/2), grants from ESRC (ADRC-Scotland), during the conduct of the study; Dr. Denegri reports non-financial support and other from National Institute for Health Research (NIHR), personal fees and non-financial support from University College London, personal fees from Google DeepMind Health, grants from Wellcome Trust, other from a wide range of engagements, speaking invitations and requests for advice consistent with my expertise some of which relates to the submitted work, outside the submitted work; Dr. Goddard reports grants from MRC, during the conduct of the study; Dr. Tully reports grants from The Farr Institute at The University of Manchester which is supported by a 10-funder consortium led by the MRC (Grant No: MR/M501633/2), during the conduct of the study; non-financial support from EuroRec Institute, non-financial support from BioData World Congress, outside the submitted work.

Competing Interests: Competing interestsThe BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: TQ and KG are supported by Stroke Association/ Chief Scientist Office Clinical Lectureships. SPM receives support from Institute for Evidence Based Medicine in Older Age. JKB is supported by the Scottish Clinical Research Excellence Development Scheme funded by NHS Education for Scotland. Further details of The BMJ policy on financial interests is here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests All authors contributed to researching the manuscript, drafting and editing and obtaining expert review from patients, carers and other stakeholders.

We demonstrate third harmonic generation in plasmonic antennas consisting of highly doped germanium grown on silicon substrates and designed to be resonant in the mid-infrared frequency range that is inaccessible with conventional nonlinear plasmonic materials. Owing to the near-field enhancement, the result is an ultrafast, subdiffraction, coherent light source with a wavelength tunable between 3 and 5 µm, and ideally overlapping with the fingerprint region of molecular vibrations. To observe the nonlinearity in this challenging spectral window, a high-power femtosecond laser system equipped with parametric frequency conversion in combination with an all-reflective confocal microscope setup is employed. We demonstrate spatially resolved maps of the linear scattering cross section and the nonlinear emission of single isolated antenna structures. A clear third-order power dependence as well as mid-infrared emission spectra prove the nonlinear nature of the light emission. Simulations support the observed resonance length of the double-rod antenna and demonstrate that the field enhancement inside the antenna material is responsible for the nonlinear frequency mixing., Competing Interests: The authors declare that they have no conflict of interest.

Germanium-on-silicon waveguides were modeled, fabricated and characterized at wavelengths ranging from 7.5 to 11 µm. Measured waveguide losses are below 5 dB/cm for both TE and TM polarization and reach values of ∼ 1 dB/cm for ≥ 10 µm wavelengths for the TE polarization. This work demonstrates experimentally for the first time that Ge-on-Si is a viable waveguide platform for sensing in the molecular fingerprint spectral region. Detailed modeling and analysis is presented to identify the various loss contributions, showing that with practical techniques losses below 1 dB/cm could be achieved across the full measurement range.

Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra- and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology. Here we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of β-catenin immunohistochemistry shows high levels of β-catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation., (Copyright © 2018. Published by Elsevier Inc.)

Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Measurements recorded over monitoring networks often possess spatial and temporal correlation inducing redundancies in the information provided. For river water quality monitoring in particular, flow-connected sites may likely provide similar information. This paper proposes a novel approach to principal components analysis to investigate reducing dimensionality for spatiotemporal flow-connected network data in order to identify common spatiotemporal patterns. The method is illustrated using monthly observations of total oxidized nitrogen for the Trent catchment area in England. Common patterns are revealed that are hidden when the river network structure and temporal correlation are not accounted for. Such patterns provide valuable information for the design of future sampling strategies.

Abaloparatide is a novel, potent and selective activator of parathyroid hormone receptor 1 (PTHR1) under clinical development for the treatment of osteoporosis. We assessed the effect of 6 weeks of abaloparatide on bone mass, microarchitecture, quality and strength in ovariectomized (OVX) rats. After 8 weeks of post-surgical bone depletion (baseline), OVX rats (n = 20-21/group) received daily subcutaneous vehicle (OVX-Veh) or abaloparatide at 5 or 20 µg/kg. Sham-operated control rats (n = 24) received vehicle. Areal bone mineral density (aBMD) of the lumbar spine (L4), total femur and femur diaphysis was measured at baseline and after 6 weeks of treatment. Femur and vertebral bone architecture and mechanical properties were assessed at the end of the treatment phase. At baseline, OVX-Veh rats exhibited significantly lower aBMD relative to Sham controls. Treatment of OVX rats with abaloparatide at 5 or 20 µg/kg/day increased aBMD dose-dependently in the lumbar spine, total femur and femur diaphysis to levels exceeding OVX-Veh or Sham controls. The abaloparatide 5 and 20 µg/kg groups had improved trabecular microarchitecture relative to OVX vehicle, with trabecular BV/TV exceeding OVX-Veh control values by 57 and 78 % (respectively) at the lumbar spine, and by 145 and 270 % at the distal femur. Femur diaphyseal cortical volume and thickness were significantly greater in the abaloparatide 20 µg/kg group relative to OVX vehicle or Sham controls. Bone strength parameters of the femur diaphysis, femur neck and L4 vertebra were significantly improved in the OVX-ABL groups relative to OVX-Veh controls. Bone mass-strength relationships and estimated intrinsic strength properties suggested maintained or improved bone quality with abaloparatide. These data demonstrate skeletal restoration via abaloparatide treatment of osteopenic OVX rats, in association with improved trabecular microarchitecture, cortical geometry and bone strength at sites that have clinical relevance in patients with osteoporosis., Competing Interests: Authors H. B, K. G, J. D, C. N, M. S and G. H are current or former employees of Radius Health. Human and Animal Rights and Informed Consent All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

The aim of this study was to develop and evaluate a procedure for equine pudendal nerve block using a peripheral nerve locator. In the first experiment, six ponies were used to determine the relationship between elicited muscle contractions (anal, perineal or both) and nerves serving the perineal region (pudendal, caudorectal and perineal nerves) when methylene blue dye was injected using the electrolocation technique. This experiment showed that the pudendal nerve was approached effectively when both anal and perineal twitch were elicited during electrolocation. In a second experiment, seven Thoroughbred horses were used to evaluate the appropriate volume of anaesthetic solution for the nerve block. Immediately after euthanasia, lidocaine/methylene blue solution was injected after positive electrolocation. A stained segment of 2 cm or more of the nerve was considered effective and this was evaluated after dissection. Both 10 and 20 mL per injection site resulted in effective nerve staining. Finally, pudendal nerve block was performed and evaluated in 27 horses admitted for selected reproductive surgical procedures including perineoplasty, urethroplasty, clitorectomy in mares and penile examination, phallectomy and urethrostomy in geldings. Surgical time varied from several minutes to 3 h. The choice between lidocaine, mepivacaine or bupivacaine was based on the duration of analgesia required. In mares and males, a volume of 20 mL and 10 mL, respectively, was injected per site. The use of a peripheral nerve stimulator-guided pudendal nerve block is a feasible, safe and reliable alternative for both epidural and general anaesthesia, to provide peri-operative analgesia in clinical equine patients undergoing specific reproductive surgeries., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Ge on Si micro-disk, ring and racetrack cavities are fabricated and strained using silicon nitride stressor layers. Photoluminescence measurements demonstrate emission at wavelengths ≥ 2.3 μm, and the highest strained samples demonstrate in-plane, tensile strains of > 2 %, as measured by Raman spectroscopy. Strain analysis of the micro-disk structures demonstrate that shear strains are present in circular cavities, which can detrimentally effect the carrier concentration for direct band transitions. The advantages and disadvantages of each type of proposed cavity structure are discussed.

Purpose: Absence of contrast on contrast enhanced MRI (CEMRI) and reduction in uterine volume at 6 months post-uterine artery embolisation (UAE) currently indicate the successful disruption of the fibroid blood supply by UAE. This study assesses whether (1)H MR spectroscopy ((1)H MRS) can also indicate the success of UAE., Method: 20 patients with symptomatic fibroids were randomised 1:1 to undergo UAE with either Gelfoam or Embospheres. CEMRI and spectra (1.5 T) were acquired pre-, 24-h and 6 months post-UAE. LCModel was used to detect significant levels of choline, creatine and lactate in fibroid spectra. Uterine volumes were measured and paired t tests (p < 0.05) assessed volume reduction over time. Qualitative assessments of CEMRI were performed., Results: Choline was detected in 17/18 spectra pre-UAE, 12/14 at 24-h and 6/16 at 6 months post-UAE. Choline was not detected in the 7/7 spectra available for the Embospheres group at 6 months. These fibroids were non-enhancing on CEMRI and associated with a significant reduction in mean uterine volume at 6 months (mean/min/max 396.5/84.1/997.5 cm(3), p = 0.003). Choline was detected in 6/9 fibroid spectra available for the Gelfoam group at 6 months. Of these fibroids, four demonstrated persistent enhancement on CEMRI and two were non-enhancing. This group did not demonstrate significant uterine volume reduction (mean/min/max 117.2/-230.6/382.6 cm(3), p = 0.15). The negative minimum value indicates fibroid growth., Conclusions: This study has demonstrated the potential of (1)H MRS to provide an additional marker of the success of UAE.