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Background: Combined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested., Methods and Results: We examined Sac/Val treatment in mice with mutation of the cGMP-dependent protein kinase I (PKGI)α leucine zipper domain, which is required for cGMP-PKGIα antiremodeling actions in vivo. Wild-type (WT) or PKG leucine zipper mutant (LZM) mice were exposed to 56-day left ventricular (LV) pressure overload by moderate (26G) transaortic constriction (TAC). At day 14 after TAC, mice were randomized to vehicle or Sac/Val by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by Sac/Val. Although LZM mice, but not WT, developed LV dilation after TAC, Sac/Val improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice., Conclusion: These findings indicate the beneficial effects of Sac/Val on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the Sac/Val effects on cardiac hypertrophy and on LV function suggests that signaling other than natriuretic peptide- cGMP-PKG mediates the therapeutic benefits of neprilysin inhibition in heart failure., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antibody-targeted nanoparticles have shown exceptional promise as delivery vehicles for anticancer drugs, although manufacturability challenges have hampered clinical progress. These include the potential for uncontrolled and random antibody conjugation, resulting in masked or inactive paratopes and unwanted Fc domain interactions. To circumvent these issues, we show that the interchain disulfide of cetuximab F(ab) may be selectively re-bridged with a strained alkyne handle, to permit 'click' coupling to azide-capped nanoparticles in a highly uniform and oriented manner. When compared to conventional carbodiimide chemistry, this conjugation approach leads to the generation of nanoparticles with a higher surface loading of cetuximab F(ab) and with markedly improved ability to bind to the target epidermal growth factor receptor. Moreover, we show that entrapment of a camptothecin payload within these nanoparticles can enhance drug targeting to antigen-expressing pancreatic cancer cells, resulting in superior cytotoxicity versus the conventional nanoformulation. Collectively, this work highlights the critical need to develop refined methods for the construction of targeted nanoparticles that will accelerate their clinical translation through improved performance and manufacturability.

Background: Necuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0-1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety., Results: One-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95-11.96) for necuparanib arm and 9.99 months (95% CI: 7.85-12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66-1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%)., Conclusion: The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243., Competing Interests: Conflict of interest statement E.M. O.’R. received research funding to MSK: Momenta Pharmaceuticals, Genentech, Roche, BMS, Celgene, MabVax Therapeutics, ActaBiologica, Parker Institute, AstraZeneca, Silenseed. She is a consulting/advisory to Cytomx, BioLineRx, Targovax, Celgene, Bayer, Loxo, Polaris, Merck, AstraZenica to Consulting/advisory. D.M. received research funding from Oncolytics and Merck and is a consultant/advisory to Amgen, Bayer, BMS, Eisai, EMD Serono, Exelexis, Genentech. T.B.S. is a consultant to Imugene, Immuneering, Bayer, Genentech, Incyte, Ipsen, Exelexis, Lilly, Astra-Zeneca, Merck and Array. M.R., J.M.R.: Momenta Pharmaceuticals (former employee). K.T.F. is Board of Directors at Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals; he is also in Corporate Advisory Board of X4 Pharmaceuticals, PIC Therapeutics, Scientific Advisory Board of Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome, and he is Consultant for Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Debiopharm. D.R.: Equity: MPM Capital, Acworth Pharmaceuticals, is on Advisory Board of MPM Capital, Oncorus, Gritstone Oncology, Maverick Therapeutics. Publishing: Johns Hopkins University Press, Uptodate McGraw Hill. All other authors have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims and Objectives: To systematically identify, appraise and synthesise patients', residents' and nurses' experiences of fundamental nursing care for nutrition, elimination, mobility and hygiene., Background: The evidence base for effective nursing behaviours to assist people with their fundamental care needs is sparse, hampering the development of effective interventions. Synthesising data on patients' and nurses' experiences of fundamentals of nursing care could contribute to the development of such an intervention., Methods: Systematic review and synthesis of qualitative data from qualitative studies on patients' and nurses' experiences of fundamental nursing care behaviours addressing peoples' nutrition, elimination, mobility and hygiene needs. We appraised study quality and relevance and used a narrative approach to data synthesis, fulfilling PRISMA criteria (Appendix S2)., Results: We identified 22,374 papers, and 47 met our inclusion criteria. Most papers were of low quality. Sixteen papers met our quality and relevance criteria and were included for synthesis. Papers were about nutrition (2) elimination (2), mobility (5), hygiene (5) and multiple care areas (2). We found nurses and patients report that fundamental nursing care practices involve strong leadership, collaborative partnerships with patients and cohesive organisational practices aligned to nursing care objectives and actions., Conclusions: To improve fundamental care and interventions suitable for testing may require attention to leadership, patient-nurse relationships and organisational coherence plus the fundamentals of care nursing interventions themselves., Relevance to Clinical Practice: More rigorous mixed methods research about fundamental nursing care is needed to inform nursing practice and improve patient's experience. Nursing interventions should include effective nurse leadership and nurse-patient collaboration and a focus on fundamental care by the host organisation., (© 2019 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Due to their homogeneity, tuneable properties, low cost and ease of manufacture, thermally induced phase separation (TIPS) polymeric microparticles are emerging as an exciting class of injectable device for the treatment of damaged tissue or complex diseases, such as cancer. However, relatively little work has explored enhancing surface functionalisation of this system. Herein, we present the functionalisation of TIPS microparticles with both small molecules and an antibody fragment of Herceptin™, via a heterobifunctional pyridazinedione linker capable of participating in SPAAC "click" chemistry, and compare it to the traditional method of preparing active-targeted microparticle systems, that is, physisorption of antibodies to the microparticle surface. Antigen-binding assays demonstrated that functionalisation of microparticles with Herceptin Fab, via a pyridazinedione linker, provided an enhanced avidity to HER2+ when compared to traditional physisorption methods.

Background: Relapse (the re-emergence of depression symptoms before full recovery) is common in depression and relapse prevention strategies are not well researched in primary care settings. Collaborative care is effective for treating acute phase depression but little is known about the use of relapse prevention strategies in collaborative care. We undertook a systematic review to identify and characterise relapse prevention strategies in the context of collaborative care., Methods: We searched for Randomised Controlled Trials (RCTs) of collaborative care for depression. In addition to published material, we obtained provider and patient manuals from authors to provide more detail on intervention content. We reported the extent to which collaborative care interventions addressed four relapse prevention components., Results: 93 RCTs were identified. 31 included a formal relapse prevention plan; 42 had proactive monitoring and follow-up after the acute phase; 39 reported strategies for optimising sustained medication adherence; and 20 of the trials reported psychological or psycho-educational treatments persisting beyond the acute phase or focussing on long-term health/relapse prevention. 30 (32.3%) did not report relapse prevention approaches., Limitations: We did not receive trial materials for approximately half of the trials, which limited our ability to identify relevant features of intervention content., Conclusion: Relapse is a significant risk amongst people treated for depression and interventions are needed that specifically address and minimise this risk. Given the advantages of collaborative care as a delivery system for depression care, there is scope for more consistency and increased effort to implement and evaluate relapse prevention strategies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019. Published by Elsevier B.V.)

Individuals with intellectual disabilities (IDs) - and specifically those with genetic disorders - are more prone to medical and psychological challenges that affect their sexual development, experiences, and fertility. In this review paper we first provide an overview of the biopsychosocial (BPS) model and then explain how the model can guide and improve the assessment and treatment of challenging sexual behaviors by persons with IDs. We discuss two genetic conditions - fragile X syndrome and 22q11.2 deletion syndrome - in case studies, showing how the BPS model can be used to assess and treat the sexual problems of individuals with various types of ID. We conclude with BPS-formulated treatment considerations in three key domains: biomedical treatment (e.g., medication side effects; stopping or changing medications), psychological treatment (e.g., providing psychological therapies), and socio-environmental interventions (e.g., providing socio-sexual education and staff training). Together, these treatment interventions can aid clinicians to prevent and/or treat problematic sexual behaviors of people with IDs., (© 2020 John Wiley & Sons, Ltd.)

Both the three-dimensional internal structure and elemental distribution of near-field radioactive fallout particulate material released during the March 2011 accident at the Fukushima Daiichi Nuclear Power Plant is analysed using combined high-resolution laboratory and synchrotron radiation x-ray techniques. Results from this study allow for the proposition of the likely formation mechanism of the particles, as well as the potential risks associated with their existence in the environment, and the likely implications for future planned reactor decommissioning. A suite of particles is analyzed from a locality 2 km from the north-western perimeter of the site - north of the primary contaminant plume in an area formerly attributed to being contaminated by fallout from reactor Unit 1. The particles are shown to exhibit significant structural similarities; being amorphous with a textured exterior, and containing inclusions of contrasting compositions, as well as an extensive internal void volume - bimodal in its size distribution. A heterogeneous distribution of the various elemental constituents is observed inside a representative particle, which also exhibited a Fukushima-derived radiocesium (134Cs, 135Cs and 137Cs) signature with negligible natural Cs. We consider the structure and composition of the particle to suggest it formed from materials associated with the reactor Unit 1 building explosion, with debris fragments embedded into the particles surface. Such a high void ratio, comparable to geological pumice, suggests such material formed during a rapid depressurisation and is potentially susceptible to fragmentation through attrition.

Background: Current quantitative methods for personalising psychotherapies for depression are unlikely to be able to inform clinical decision-making for hundreds of years. Novel alternative methods to generate hypotheses for prospective testing are therefore required, and we showcase mixed methods as one such approach. By exploring patients' perspectives in depth, and integrating qualitative and quantitative data at the level of the individual, we may identify new potential psychosocial predictors of psychotherapy outcomes, potentially informing the personalisation of depression treatment in a shorter timeframe. Using Morita therapy (a Japanese psychotherapy) as an exemplar, we thus explored how Morita therapy recipients' views on treatment acceptability explain their adherence and response to treatment., Methods: The Morita trial incorporated a pilot randomised controlled trial of Morita therapy versus treatment as usual for depression, and post-treatment qualitative interviews. We recruited trial participants from general practice record searches in Devon, UK, and purposively sampled data from 16 participants for our mixed methods analysis. We developed typologies of participants' views from our qualitative themes, and integrated these with quantitative data on number of sessions attended and whether participants responded to treatment in a joint typologies and statistics display. We enriched our analysis using participant vignettes to demonstrate each typology., Results: We demonstrated that (1) participants who could identify with the principles of Morita therapy typically responded to treatment, regardless of how many sessions they attended, whilst those whose orientation towards treatment was incompatible with Morita therapy did not respond to treatment, again regardless of treatment adherence and (2) participants whose personal circumstances impeded their opportunity to engage in Morita therapy attended the fewest sessions, though still benefitted from treatment if the principles resonated with them., Conclusions: We identified new potential relationships between "orientation" and outcomes, and "opportunity" and adherence, which could not have been identified using existing non-integrative methods. This mixed methods approach warrants replication in future trials and with other psychotherapies to generate hypotheses, based on typologies (or profiles) of patients for whom a treatment is more or less likely to be suitable, to be tested in prospective trials., Trial Registration: Current Controlled Trials, ISRCTN17544090. Registered on 23 July 2015.

Objective: The International Learning Collaborative (ILC) is an organisation dedicated to understanding why fundamental care, the care required by all patients regardless of clinical condition, fails to be provided in healthcare systems globally. At its 11th annual meeting in 2019, nursing leaders from 11 countries, together with patient representatives, confirmed that patients' fundamental care needs are still being ignored and nurses are still afraid to 'speak up' when these care failures occur. While the ILC's efforts over the past decade have led to increased recognition of the importance of fundamental care, it is not enough. To generate practical, sustainable solutions, we need to substantially rethink fundamental care and its contribution to patient outcomes and experiences, staff well-being, safety and quality, and the economic viability of healthcare systems., Key Arguments: We present five propositions for radically transforming fundamental care delivery:Value: fundamental care must be foundational to all caring activities, systems and institutionsTalk: fundamental care must be explicitly articulated in all caring activities, systems and institutions.Do: fundamental care must be explicitly actioned and evaluated in all caring activities, systems and institutions.Own: fundamental care must be owned by each individual who delivers care, works in a system that is responsible for care or works in an institution whose mission is to deliver care., Research: fundamental care must undergo systematic and high-quality investigations to generate the evidence needed to inform care practices and shape health systems and education curricula., Conclusion: For radical transformation within health systems globally, we must move beyond nursing and ensure all members of the healthcare team-educators, students, consumers, clinicians, leaders, researchers, policy-makers and politicians-value, talk, do, own and research fundamental care. It is only through coordinated, collaborative effort that we will, and must, achieve real change., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

It is common to undertake qualitative research alongside randomised controlled trials (RCTs) when evaluating complex interventions. Researchers tend to analyse these datasets one by one and then consider their findings separately within the discussion section of the final report, rarely integrating quantitative and qualitative data or findings, and missing opportunities to combine data in order to add rigour, enabling thorough and more complete analysis, provide credibility to results, and generate further important insights about the intervention under evaluation. This paper reports on a 2 day expert meeting funded by the United Kingdom Medical Research Council Hubs for Trials Methodology Research with the aims to identify current strengths and weaknesses in the integration of quantitative and qualitative methods in clinical trials, establish the next steps required to provide the trials community with guidance on the integration of mixed methods in RCTs and set-up a network of individuals, groups and organisations willing to collaborate on related methodological activity. We summarise integration techniques and go beyond previous publications by highlighting the potential value of integration using three examples that are specific to RCTs. We suggest that applying mixed methods integration techniques to data or findings from studies involving both RCTs and qualitative research can yield insights that might be useful for understanding variation in outcomes, the mechanism by which interventions have an impact, and identifying ways of tailoring therapy to patient preference and type. Given a general lack of examples and knowledge of these techniques, researchers and funders will need future guidance on how to undertake and appraise them., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer., Methods: In this randomised, open-label, multicentre, phase 2 study, adult patients (aged ≥18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m 2 and intravenous carboplatin (area under the concentration-time curve 2 μg × h/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m 2 on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual., Findings: Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8·4 months (IQR 3·8-13·6) for group 1, 12·7 months (5·5-17·4) for group 2, and 12·9 months (6·7-16·8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0·8 day (SD 2·4) in group 1, 1·5 days (3·5) in group 2, and 1·0 day (2·6) in group 3 (group 3 vs group 1 one-sided adjusted p=0·70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0·70). Overall survival was 12·6 months (IQR 5·8-15·6) in group 1, 20·1 months (9·4-not reached) in group 2, and 17·8 months (8·8-not reached) in group 3 (group 3 vs group 1 two-sided p=0·0023). The most common treatment-emergent adverse events were anaemia (22 [73%] of 34), neutropenia (21 [70%]), and thrombocytopenia (18 [60%]) in group 1; neutropenia (27 [82%] of 33), thrombocytopenia (18 [55%]) and anaemia (17 [52%]) in group 2; and neutropenia (23 [66%] of 35), thrombocytopenia (22 [63%]), and nausea (17 [49%]) in group 3. There were no treatment-related deaths., Interpretation: No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted., Funding: G1 Therapeutics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity., Patients and Methods: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy., Results: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107)., Conclusion: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits., Clinical Trail Number: NCT02499770., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Objectives: Physical rehabilitation is a complex process, and trials of rehabilitation interventions are increasing in number but often report null results. This study aimed to establish treatment success rates in physical rehabilitation trials funded by the National Institute of Health Research Health Technology Assessment (NIHR HTA) programme and examine any relationship between treatment success and the quality of intervention development work undertaken., Design: This is a mixed methods study., Setting: This study was conducted in the UK., Methods: The NIHR HTA portfolio was searched for all completed definitive randomised controlled trials of physical rehabilitation interventions from inception to July 2016. Treatment success was categorised according to criteria developed by Djulbegovic and colleagues. Detailed textual data regarding any intervention development work were extracted from trial reports and supporting publications and informed the development of quality ratings. Mixed methods integrative analysis was undertaken to explore the relationship between quantitative and qualitative data using joint displays., Results: Fifteen trials were included in the review. Five reported a definitive finding, four of which were in favour of the 'new' intervention. Eight trials reported a true negative (no difference) outcome. Integrative analysis indicated those with lower quality intervention development work were less likely to report treatment success., Conclusions: Despite much effort and funding, most physical rehabilitation trials report equivocal findings. Greater focus on high quality intervention development may reduce the likelihood of a null result in the definitive trial, alongside high quality trial methods and conduct., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Herein we report the construction of a nanoparticle-based drug delivery system which targets a key regulator in tumour angiogenesis. We exploit a Variable New Antigen Receptor (VNAR) domain, conjugated using site-specific chemistry, to direct poly lactic acid-co-glycolic acid-polyethylene glycol (PLGA-PEG) nanoparticles to delta like canonical Notch ligand 4 (DLL4). The importance of site-specific chemistry is demonstrated.

Here we report the results of multiple analytical techniques on sub-mm particulate material derived from Unit 1 of the Fukushima Daiichi Nuclear Power Plant to provide a better understanding of the events that occurred and the environmental legacy. Through combined x-ray fluorescence and absorption contrast micro-focused x-ray tomography, entrapped U particulate are observed to exist around the exterior circumference of the highly porous Si-based particle. Further synchrotron radiation analysis of a number of these entrapped particles shows them to exist as UO 2 -identical to reactor fuel, with confirmation of their nuclear origin shown via mass spectrometry analysis. While unlikely to represent an environmental or health hazard, such assertions would likely change should break-up of the Si-containing bulk particle occur. However, more important to the long-term decommissioning of the reactors at the FDNPP (and environmental clean-upon), is the knowledge that core integrity of reactor Unit 1 was compromised with nuclear material existing outside of the reactors primary containment.

Background: The health service delivery framework collaborative care is an effective intervention for depression. However, uncertainties remain about how to optimise its delivery at scale. Structured case management is a core component of collaborative care; its delivery via the telephone may improve access., Aims: To examine using meta-regression if telephone delivered case management diminishes the clinical effectiveness of collaborative care on depressive symptoms and anti-depressant use relative to face-to-face delivery methods., Methods: Randomised controlled trials were eligible if they included collaborative care interventions for adults with depression identified using self-report measures or diagnostic interviews and reported depression outcomes. Sociodemographics, intervention characteristics, depressive symptoms, and anti-depressant use were extracted. Random effects univariable and multivariable meta-regression analyses were used to examine the moderating effect of telephone delivered case-management on outcomes., Results: Ninety-four trials were identified comprising of 103 comparisons across 24, 132 participants with depression outcomes and 67 comparisons from 15,367 participants with anti-depressant use outcomes. Telephone delivered case management did not diminish the effects of collaborative care on depressive symptoms (β = -0.01, 95% CI -0.12 to 0.10; p = 0.86). Telephone delivered case management decreased anti-depressant medication use (relative risk 0.76, 95% CI 0.63 to 0.92; p = 0.005); this effect remained when assessed simultaneously alongside other study-level moderators of collaborative care., Conclusion: Using remote platforms such as the telephone to deliver case management may be a feasible way to implement collaborative care with no loss of effectiveness on depressive symptoms. However, adherence to anti-depressant medication may decrease when telephone case management is used., Competing Interests: The authors have declared that no competing interests exist.

Objective: To explore the views of UK-based recipients of Morita Therapy (MT) on the acceptability of MT., Design: Qualitative study nested within a pilot randomised controlled trial of MT (a Japanese psychological therapy largely unknown in the UK) versus treatment as usual, using post-treatment semistructured interviews analysed with a framework approach., Setting and Participants: Participants who received MT as part of the Morita Trial, recruited for the trial from General Practice record searches in Devon, UK. Data from 16 participants were purposively sampled for analysis., Results: We identified five themes which, together, form a model of how different participants viewed and experienced MT. Overall, MT was perceived as acceptable by many participants who emphasised the value of the approach, often in comparison to other treatments they had tried. These participants highlighted how accepting and allowing difficulties as natural phenomena and shifting attention from symptoms to external factors had facilitated symptom reduction and a sense of empowerment. We found that how participants understood and related to the principles of MT, in light of their expectations of treatment, was significantly tied to the extent to which MT was perceived as acceptable. Our findings also highlighted the distinction between MT in principle and practice, with participants noting challenges of engaging with the process of therapy such as fear and discomfort around rest, needing sufficient support from the therapist and others, and the commitment of treatment., Conclusions: People in the UK can accept the premise of MT, and consider the approach beneficial and novel. Therefore, proceeding to a large-scale trial of MT is appropriate with minor modifications to our clinical protocol. Participants' expectations and understandings of treatment play a key role in acceptability, and future research may investigate these potential moderators of acceptability in MT., Trial Registration Numberc: ISRCTN17544090; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Transverse aortic constriction (TAC) is a well-established model of pressure overload-induced cardiac hypertrophy and failure in mice. The degree of constriction "tightness" dictates the TAC severity and is determined by the gauge (G) of needle used. Though many reports use the TAC model, few studies have directly compared the range of resulting phenotypes. In this study adult male mice were randomized to receive TAC surgery with varying degrees of tightness: mild (25G), moderate (26G) or severe (27G) for 4 weeks, alongside sham-operated controls. Weekly echocardiography and terminal haemodynamic measurements determined cardiac remodelling and function. All TAC models induced significant, severity-dependent left ventricular hypertrophy and diastolic dysfunction compared to sham mice. Mice subjected to 26G TAC additionally exhibited mild systolic dysfunction and cardiac fibrosis, whereas mice in the 27G TAC group had more severe systolic and diastolic dysfunction, severe cardiac fibrosis, and were more likely to display features of heart failure, such as elevated plasma BNP. We also observed renal atrophy in 27G TAC mice, in the absence of renal structural, functional or gene expression changes. 25G, 26G and 27G TAC produced different responses in terms of cardiac structure and function. These distinct phenotypes may be useful in different preclinical settings.

In this article we ask our profession to consider whether something is rotten at the core of modern nursing. We will use our own experiences as patients, together with published literature, to ask questions of our profession in perpetrating what one of our colleagues recently, and with great embarrassment, referred to as 'shitty nursing'. Our intention is most certainly not to offend any readers, for this term has been used in literature for more than one hundred years to describe bad situations, including those where events or people's behaviour are of a low standard. Our intention instead, is to challenge ourselves, the profession and you the reader by raising a measured debate which seems at present to be missing within the profession. We examine the potential idea that poor nursing care may not be the exception, but horrifyingly, may be the new normal. We are particularly concerned that patients' fundamental care needs may be falling into an ever widening gap between assistant and registered nurses. Whilst we acknowledge the potential causes of poor nursing care, causes that are often cited by nurses themselves, we come to the conclusion that a mature profession including clinicians, educators, administrators, researchers and regulators cannot continually blame contextual factors for its failings. A mature profession with an intact contract between itself and society must shoulder some of the responsibility for its own problems. We do suggest a way forward, including a mix of reconciliation, refocus and research, underpinned by what we argue is a much needed dose of professional humility. Readers may take us to task for potentially overstating the problem, ignoring non-nursing drivers, and downplaying other significant factors. You may think that there is much in nursing to glory in. However, we make no apology for presenting our views. Our lived experiences tell us something different. As professional nurses our main aim is to ensure that our adverse experiences as patients are statistical anomalies, and our future encounters with nursing care represent all that we know to be excellent in our profession. We leave you to judge and comment., (Copyright © 2018. Published by Elsevier Ltd.)

Introduction: Although diabetes distress is found to be associated with decreased glycaemic control among adults with type 1 diabetes, the psychological and emotional impact of living with the condition is often not recognised and often under-reported in diabetes care. Therefore, regular assessment of diabetes distress is recommended. Assessment of diabetes distress using patient-reported outcome measures (PROMs) in clinical practice has the potential to enhance care for people with diabetes by identifying problems and improving patient-clinician communication. In this study protocol, we describe a pilot randomised controlled trial (RCT) aiming to test the feasibility of all components of an empowerment-based intervention using PROMs as dialogue support in clinical diabetes consultations, and to address the uncertainties associated with running a fully powered evaluation study., Methods and Analysis: We will undertake a two-arm pilot RCT of an intervention using the Problem Areas In Diabetes (PAID) scale in clinical diabetes consultations in order to conclude whether a fully powered trial is appropriate and/or feasible. The study will also include qualitative indepth interviews with participants and healthcare providers. Our objectives are to (1) evaluate the recruitment procedures and attrition rates; (2) evaluate the performance of the randomisation procedure; (3) evaluate the participants' mean scores on the outcome measures before and after the intervention; (4) evaluate if the intervention consultations are acceptable and feasible; and (5) explore patients' and healthcare providers' experiences with the use of PAID as dialogue support and empowerment-based communication skills in clinical diabetes consultations. The quantitative data analysis includes descriptive statistics (frequencies, percentages, means, SD and CI). For the qualitative data, we will perform thematic analysis., Ethics and Dissemination: Ethical approval has been obtained from the Western Norway Regional Committee for Medical and Health Research Ethics (2017/1506/REC west). We will present the findings from the study phases at national and international conferences and submit manuscripts to peer-reviewed journals and popular science journals., Trial Registration Number: NCT03471104; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH 2 -terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3 -/- ) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3 -/- mice subjected to chronic left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with MLK3 +/+ littermates ( n = 8). LV mass, pathological markers of hypertrophy ( Nppa, Nppb), and cardiomyocyte size were elevated in MLK3 -/- TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3 -/- TAC hearts. In adult rat cardiomyocytes, pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. These data demonstrate that MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK, which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.

The field of targeted therapeutics has benefitted immeasurably from the development of high-affinity antibodies. These important ligands have facilitated the development of effective therapies, particularly when conjugated to potent cytotoxic payloads i.e. in antibody-drug conjugates (ADCs). The success of ADCs is evidenced by rapid adoption within the pharmaceuticals community; many major companies have dedicated ADC research programmes. However, despite the advantages, the field of ADCs has failed to live up to its full potential. Studies have emerged suggesting that traditional IgG scaffolds may not be the optimal format for targeted payload delivery. In response, the protein engineering community has begun to explore alternative high-binding protein scaffolds as antibody mimics. In this short review I will summarise the generation, modification, and application of emerging antibody fragments and synthetic antibody mimics, with a focus on their use as drug carriers. The review aims to highlight the advantages of antibody mimics, and how they could be employed to overcome the issues and limitations of traditional ADCs., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Plutonium and radiocaesium are hazardous contaminants released by the Fukushima Daiichi nuclear power plant (FDNPP) disaster and their distribution in the environment requires careful characterisation using isotopic information. Comprehensive spatial survey of 134 Cs and 137 Cs has been conducted on a regular basis since the accident, but the dataset for 135 Cs/ 137 Cs atom ratios and trace isotopic analysis of Pu remains limited because of analytical challenges. We have developed a combined chemical procedure to separate Pu and Cs for isotopic analysis of environmental samples from contaminated catchments. Ultra-trace analyses reveal a FDNPP Pu signature in environmental samples, some from further afield than previously reported. For two samples, we attribute the dominant source of Pu to Reactor Unit 3. We review the mechanisms responsible for an emergent spatial pattern in 134,135 Cs/ 137 Cs in areas northwest (high 134 Cs/ 137 Cs, low 135 Cs/ 137 Cs) and southwest (low 134 Cs/ 137 Cs, high 135 Cs/ 137 Cs) of FDNPP. Several samples exhibit consistent 134,135 Cs/ 137 Cs values that are significantly different from those deposited on plant specimens collected in previous works. A complex spatial pattern of Pu and Cs isotopic signature is apparent. To confidently attribute the sources of mixed fallout material, future studies must focus on analysis of individual FDNPP-derived particles.

Background: European research in nursing has been criticized as overwhelmingly descriptive, wasteful and with little relevance to clinical practice. This second triennial review follows our previous review of articles published in 2010, to determine whether the situation has changed., Objective: To identify, appraise, and synthesize reports of European nursing research published during 2013 in the top 20 nursing research journals., Methods: Systematic review with descriptive results synthesis., Results: We identified 2,220 reports, of which 254, from 19 European countries, were eligible for analysis; 215 (84.7%) were primary research, 36 (14.2%) secondary research, and three (1.2%) mixed primary and secondary. Forty-eight (18.9%) of studies were experimental: 24 (9.4%) randomized controlled trials, 11 (4.3%) experiments without randomization, and 13 (5.1%) experiments without control group. A total of 106 (41.7%) articles were observational: 85 (33.5%) qualitative research. The majority (158; 62.2%) were from outpatient and secondary care hospital settings. One hundred and sixty-five (65.0%) articles reported nursing intervention studies: 77 (30.3%) independent interventions, 77 (30.3%) interdependent, and 11 (4.3%) dependent. This represents a slight increase in experimental studies compared with our previous review (18.9% vs. 11.7%). The quality of reporting remained very poor., Linking Evidence to Action: European research in nursing remains overwhelmingly descriptive. We call on nursing researchers globally to raise the level of evidence and, therefore, the quality of care and patient outcomes. We urge them to replicate our study in their regions, diagnose reasons for the lack of appropriate research, identify solutions, and implement a deliberate, targeted, and systematic global effort to increase the number of experimental, high quality, and relevant studies into nursing interventions. We also call on journal editors to mandate an improvement in the standards of research reporting in nursing journals., (© 2018 The Authors. Worldviews on Evidence-Based Nursing published by Wiley Periodicals, Inc. on behalf of Sigma Theta Tau International The Honor Society of Nursing.)

Purpose: This single-arm, open-label phase II study evaluated the safety and efficacy of taselisib (GDC-0032) plus fulvestrant in postmenopausal women with locally advanced or metastatic HER2-negative, hormone receptor (HR)-positive breast cancer. Patients and Methods: Patients received 6-mg oral taselisib capsules daily plus intramuscular fulvestrant (500 mg) until disease progression or unacceptable toxicity. Tumor tissue (if available) was centrally evaluated for PIK3CA mutations. Adverse events (AE) were recorded using NCI-CTCAE v4.0. Tumor response was investigator-determined using RECIST v1.1. Results: Median treatment duration was 4.6 (range: 0.9-40.5) months. All patients experienced ≥1 AE, 30 (50.0%) had grade ≥3 AEs, and 19 (31.7%) experienced 35 serious AEs. Forty-seven of 60 patients had evaluable tissue for central PIK3CA mutation testing [20 had mutations, 27 had no mutation detected (MND)]. In patients with baseline measurable disease, clinical activity was observed in tumors with PIK3CA mutations [best confirmed response rate: 38.5% (5/13; 95% CI, 13.9-68.4); clinical benefit rate (CBR): 38.5% (5/13; 95% CI, 13.9-68.4)], PIK3CA -MND [best confirmed response rate: 14.3% (3/21; 95% CI, 3.0-36.3); CBR: 23.8% (5/21; 95% CI, 8.2-47.2)], and unknown PIK3CA mutation status [best confirmed response rate: 20.0% (2/10; 95% CI, 2.5-55.6); CBR: 30.0% (3/10; 95% CI, 6.7-65.2)]. Conclusions: Taselisib plus fulvestrant had clinical activity irrespective of PIK3CA mutation status, with numerically higher objective response rate and CBR in patients with PIK3CA -mutated (vs. -MND) locally advanced or metastatic HER2-negative, HR-positive breast cancer. No new safety signals were reported. A confirmatory phase III trial is ongoing. Clin Cancer Res; 24(18); 4380-7. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objective: To address uncertainties prior to conducting a fully powered randomised controlled trial of Morita Therapy plus treatment as usual (TAU) versus TAU alone, or to determine that such a trial is not appropriate and/or feasible., Design: Pilot parallel group randomised controlled feasibility trial., Setting and Participants: Participants aged ≥18 years with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV major depressive disorder, with or without DSM-IV anxiety disorder(s), recruited from general practice record searches in Devon, UK., Interventions: We randomised participants on a 1:1 basis stratified by symptom severity, concealing allocation using a secure independent web-based system, to receive TAU (control) or 8-12 sessions of Morita Therapy, a Japanese psychological therapy, plus TAU (intervention)., Outcomes: Rates of recruitment, retention and treatment adherence; variance and estimated between-group differences in follow-up scores (on the Patient Health Questionnaire 9 (PHQ-9) (depressive symptoms); Generalised Anxiety Disorder Questionnaire 7 (anxiety symptoms); Short Form 36 Health Survey Questionnaire/Work and Social Adjustment Scale (quality of life); Morita Attitudinal Scale for Arugamama (attitudes)) and their correlation with baseline scores., Results: We recruited 68 participants, 5.1% (95% CI 3.4% to 6.6%) of those invited (34 control; 34 intervention); 64/68 (94%; 95% CI 88.3% to 99.7%) provided 4-month follow-up data. Participants had a mean age of 49 years and mean PHQ-9 score of 16.8; 61% were female. Twenty-four of 34 (70.6%) adhered to the minimum treatment dose. The follow-up PHQ-9 (future primary outcome measure) pooled SD was 6.4 (95% CI 5.5 to 7.8); the magnitude of correlation between baseline and follow-up PHQ-9 scores was 0.42 (95% CI 0.19 to 0.61). Of the participants, 66.7% and 30.0% recovered in the intervention and control groups, respectively; 66.7% and 13.3% responded to treatment in the intervention and control groups, respectively., Conclusions: A large-scale trial of Morita Therapy would require 133 participants per group and is feasible with minor modifications to the pilot trial protocol. Morita Therapy shows promise in treating depression and may provide patients with a distinct alternative to current treatments., Trial Registration Number: ISRCTN17544090; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2., Methods: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed., Results: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%)., Conclusions: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.

Aims and Objectives: To determine the effects of nursing interventions for people's nutrition, elimination, mobility and hygiene needs., Background: Patient experience of health care is sensitive to nursing quality. A refocus on fundamental nursing care is undermined by lack of evidence of effectiveness for interventions in core areas such as elimination, nutrition, mobility and hygiene., Design: Systematic review., Methods: We searched for and included experimental studies on interventions by professionally qualified and unregistered nurses that addressed participants' nutrition, elimination, mobility and hygiene needs. We extracted data on scope, quality and results of studies followed by descriptive narrative synthesis of included study outcomes using a novel form of harvest plots., Results: We included 149 studies, 35 nutrition, 56 elimination, 16 mobility, 39 hygiene and three addressing two or more areas simultaneously (67 randomised controlled trials, 32 non-randomised controlled trials and 50 uncontrolled trials). Studies into interventions on participant self-management of nutrition (n = 25), oral health (n = 26), catheter care (n = 23) and self-management of elimination (n = 21) were the most prevalent. Most studies focussed their outcomes on observational or physiological measures, with very few collecting patient-reported outcomes, such as quality of life, experience or self-reported symptoms. All but 13 studies were of low quality and at significant risk of bias. The majority of studies did not define primary outcomes, included multiple measures of identical concepts, used inappropriate analyses and did not conform to standard reporting quality criteria., Conclusions: The current evidence for fundamental nursing care interventions is sparse, of poor quality and unfit to provide evidence-based guidance to practising nurses., Relevance to Clinical Practice: Researchers in nursing internationally should now undertake a programme of work to produce evidence for clinical practice in the fundamentals of care that is reliable, replicable and robust., (© 2017 The Authors. Journal of Clinical Nursing Published by John Wiley & Sons Ltd.)

Aims and Objectives: To investigate the components of the Amalgamation of Marginal Gains (AMG) performance system to identify a set of principles that can be built into an innovative fundamental nursing care protocol., Background: Nursing is urged to refocus on its fundamental care activities, but little evidence exists to guide practising nurses. Fundamental care is a combination of many small behaviours aimed at meeting a person's care needs. AMG is a successful system of performance management that focusses on small (or marginal) gains, and might provide a new delivery framework for fundamental nursing care., Design: Qualitative interview study., Methods: We undertook in-depth interviews with healthcare and sports professionals experienced in AMG. We analysed data using open coding in a framework analysis, and then interrogated the data using Normalisation Process Theory (NPT). We triangulated findings with AMG literature to develop an intervention logic model., Results: We interviewed 20 AMG practitioners. AMG processes were as follows: focusing on many details to optimise performance, identification of marginal gains using different sources, understanding current versus optimum performance, monitoring at micro and macro level and strong leadership. Elements of normalisation were as follows: whole team belief in AMG to improve performance, a collective desire for excellence using evidence-based actions, whole team engagement to identify choose and implement changes, and individual and group responsibility for monitoring performance., Conclusions: We have elicited the processes described by AMG innovators in health care and sport and have mapped the normalisation potential and work required to embed such a system into nursing practice., Relevance to Clinical Practice: The development of our logic model based on AMG and NPT may provide a practical framework for improving fundamental nursing care and is ripe for further development and testing in clinical trials., (© 2017 The Authors Journal of Clinical Nursing Published by John Wiley & Sons Ltd.)

Background: Around 19% of people screened by UK cardiac rehabilitation programmes report having moderate or severe symptoms of depression. These individuals are at an increased risk of cardiac mortality and morbidity, reduced quality of life and increased use of health resources compared with their non-depressed counterparts. Maximising psychological health is a goal of cardiac rehabilitation, but psychological care is patchy., Objective(s): To examine the feasibility and acceptability of embedding enhanced psychological care (EPC) within cardiac rehabilitation, we tested the feasibility of developing/implementing EPC and documented the key uncertainties associated with undertaking a definitive evaluation., Design: A two-stage multimethods study; a feasibility study and a qualitative evaluation, followed by an external pilot cluster randomised controlled trial (RCT) with a nested qualitative study., Setting: UK comprehensive cardiac rehabilitation teams., Participants: Adults eligible for cardiac rehabilitation following an acute coronary syndrome with new-onset depressive symptoms on initial nurse assessment. Patients who had received treatment for depression in the preceding 6 months were excluded., Interventions: The EPC intervention comprised nurse-led mental health-care co-ordination and behavioural activation within cardiac rehabilitation. The comparator was usual cardiac rehabilitation care., Main Outcome Measures: Measures at baseline, and at the 5- (feasibility and pilot) and 8-month follow-ups (pilot only). Process measures related to cardiac team and patient recruitment, and participant retention. Outcomes included depressive symptoms, cardiac mortality and morbidity, anxiety, health-related quality of life and service resource use. Interviews explored participant and nurses' views and experiences., Results: Between September 2014 and May 2015, five nurses from four teams recruited participants into the feasibility study. Of the 203 patients screened, 30 were eligible and nine took part (the target was 20 participants). At interview, participants and nurses gave valuable insights into the EPC intervention design and delivery. Although acceptable, the EPC delivery was challenging for nurses (e.g. the ability to allocate sufficient time within existing workloads) and the intervention was modified accordingly. Between December 2014 and February 2015, 8 out of 20 teams approached agreed to participate in the pilot RCT [five were randomised to the EPC arm and three were randomised to the usual-care (UC) arm]. Of the 614 patients screened, 55 were eligible and 29 took part (the target was 43 participants). At baseline, the trial arms were well matched for sex and ethnicity, although the EPC arm participants were younger, from more deprived areas and had higher depression scores than the UC participants. A total of 27 out of 29 participants were followed up at 5 months. Interviews with 18 participants (12 in the EPC arm and six in the UC arm) and seven nurses who delivered EPC identified that both groups acknowledged the importance of receiving psychological support embedded within routine cardiac rehabilitation. For those experiencing/delivering EPC, the intervention was broadly acceptable, albeit challenging to deliver within existing care., Limitations: Both the feasibility and the pilot studies encountered significant challenges in recruiting patients, which limited the power of the pilot study analyses., Conclusions: Cardiac rehabilitation nurses can be trained to deliver EPC. Although valued by both patients and nurses, organisational and workload constraints were significant barriers to implementation in participating teams, suggesting that future research may require a modified approach to intervention delivery within current service arrangements. We obtained important data informing definitive research regarding participant recruitment and retention, and optimal methods of data collection., Future Research: Consideration should be given to the delivery of EPC by dedicated mental health practitioners, working closely with cardiac rehabilitation services., Trial Registration: Current Controlled Trials ISRCTN34701576., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 30. See the NIHR Journals Library website for further project information., Competing Interests: Rob Anderson contributes to the work of the National Institute for Health Research (NIHR) Health Services and Delivery Research (HSDR) programme as an unpaid member of their funding advisory panel (a researcher-led funding stream). Rod S Taylor is the chairperson of the NIHR HSDR researcher-led panel, a member of the Health Technology Assessment (HTA) Efficient Study Designs Board, the NIHR Priority Research Advisory Methodology Group, the HTA General Board, the HTA Themed Call, the Core Group of Methodological Experts for the NIHR Programme Grants for Applied Research programme and the HSDR Commissioning Board (commissioned and researcher led). Willem Kuyken receives royalties from the publication of Kuyken W, Padesky CA, Dudley R, Collaborative Case Conceptualization, New York, NY: Guildford Press; 2011, outside the submitted work.

Background: Around 17% of people attending UK cardiac rehabilitation programmes have depression. Optimising psychological wellbeing is a rehabilitation goal, but provision of psychological care is limited. We developed and piloted an Enhanced Psychological Care (EPC) intervention embedded within cardiac rehabilitation, aiming to test key areas of uncertainty to inform the design of a definitive randomised controlled trial (RCT) and economic evaluation., Methods: An external pilot randomised controlled trial (RCT) randomised eight cardiac rehabilitation teams (clusters) to either usual care of cardiac rehabilitation provision (UC), or EPC in addition to UC. EPC comprised mental health care coordination and patient-led behavioural activation with nurse support. Adults eligible for cardiac rehabilitation following an acute coronary syndrome and identified with new-onset depressive symptoms during an initial nurse assessment were eligible. Measures were performed at baseline and 5- and 8-month follow-ups and compared between EPC and UC. Team and participant recruitment and retention rates, and participant outcomes (clinical events, depression, anxiety, health-related quality of life, patient experiences, and resource use) were assessed., Results: Eight out of twenty teams were recruited and randomised. Of 614 patients screened, 55 were eligible and 29 took part (5%, 95% CI 3 to 7% of those screened), with 15 patient participants cluster randomised to EPC and 14 to UC. Nurse records revealed that 8/15 participants received the maximum number of EPC sessions offered; and 4/15 received no sessions. Seven out of fifteen EPC participants were referred to another NHS psychological service compared to none in UC. We followed up 27/29 participants at 5 months and 17/21 at 8 months. The mean difference (EPC minus UC) in depressive symptoms (Beck Depression Inventory) at follow-up (adjusting for baseline score) was 1.7 (95% CI - 3.8 to 7.3; N = 26) at 5 months and 4.4 (95% CI - 1.4 to 10.2; N = 17) at 8 months., Discussion: While valued by patients and nurses, organisational and workload constraints are significant barriers to EPC implementation. There remains a need to develop and test new models of psychological care within cardiac rehabilitation. Our study offers important data to inform the design of future trials of similar interventions., Trial Registration: ISRCTN34701576 . Registered on 29 May 2014. Funding details: UK NIHR HTA Programme (project 12/189/09).

Background: In recent years there has been much emphasis on 'research waste' caused by poor question selection, insufficient attention to previous research results, and avoidable weakness in research design, conduct and analysis. Little attention has been paid to the effect of inadequate development of interventions before proceeding to a full clinical trial., Objective: We therefore propose to enrich the development phase of the MRC Framework by adding crucial elements to improve the likelihood of success and enhance the fit with clinical practice METHODS: Based on existing intervention development guidance and synthesis, a comprehensive iterative intervention development approach is proposed. Examples from published reports are presented to illustrate the methodology that can be applied within each element to enhance the intervention design., Results: A comprehensive iterative approach is presented by combining the elements of the MRC Framework development phase with essential elements from existing guidance including: problem identification, the systematic identification of evidence, identification or development of theory, determination of needs, the examination of current practice and context, modelling the process and expected outcomes leading to final element: the intervention design. All elements are drawn from existing models to provide intervention developers with a greater chance of producing an intervention that is well adopted, effective and fitted to the context., Conclusion: This comprehensive approach of developing interventions will strengthen the internal and external validity, minimize research waste and add value to health care research. In complex interventions in health care research, flaws in the development process immediately impact the chances of success. Knowledge regarding the causal mechanisms and interactions within the intended clinical context is needed to develop interventions that fit daily practice and are beneficial for the end-user., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Due to their exquisite cysteine-selectivity, excellent stability, and ability to functionally rebridge disulfide bonds, dibromopyridazinediones are emerging as an exciting new class of bioconjugation reagents, particularly in the field of antibody conjugation. Despite this, relatively little work has been performed on the optimisation of their synthesis and subsequent reaction with immunoglobulins. Herein we present a novel synthetic route towards functionalised dibromopyridazinediones, proceeding via an isolatable dibromopyridazinedione-NHS ester. Reaction of this activated intermediate with a variety of amines produces functional dibromopyridazinediones in good to excellent yields. The disulfide rebridging capacity of these reagents was optimised on the clinically relevant IgG1 trastuzumab, resulting in a general method which allows for the generation of site-selectively modified native trastuzumab with over 90% homogeneity (no disulfide scrambling) without the need for protein engineering or enzymatic conjugation.

Paper-based lateral flow immunoassays (LFIAs) are one of the most widely used point-of-care (PoC) devices; however, their application in early disease diagnostics is often limited due to insufficient sensitivity for the requisite sample sizes and the short time frames of PoC testing. To address this, we developed a serum-stable, nanoparticle catalyst-labeled LFIA with a sensitivity surpassing that of both current commercial and published sensitivities for paper-based detection of p24, one of the earliest and most conserved biomarkers of HIV. We report the synthesis and characterization of porous platinum core-shell nanocatalysts (PtNCs), which show high catalytic activity when exposed to complex human blood serum samples. We explored the application of antibody-functionalized PtNCs with strategically and orthogonally modified nanobodies with high affinity and specificity toward p24 and established the key larger nanoparticle size regimes needed for efficient amplification and performance in LFIA. Harnessing the catalytic amplification of PtNCs enabled naked-eye detection of p24 spiked into sera in the low femtomolar range (ca. 0.8 pg·mL -1 ) and the detection of acute-phase HIV in clinical human plasma samples in under 20 min. This provides a versatile absorbance-based and rapid LFIA with sensitivity capable of significantly reducing the HIV acute phase detection window. This diagnostic may be readily adapted for detection of other biomolecules as an ultrasensitive screening tool for infectious and noncommunicable diseases and can be capitalized upon in PoC settings for early disease detection.

Background: Mouse models of heart disease are extensively employed. The echocardiographic characterization of contractile function is usually focused on systolic function with fewer studies assessing diastolic function. Furthermore, the applicability of diverse echocardiographic parameters of diastolic function that are commonly used in humans has not been extensively evaluated in different pathophysiological models in mice., Methods and Results: We used high resolution echocardiography to evaluate parameters of diastolic function in mouse models of chronic pressure overload (aortic constriction), volume overload (aorto-caval shunt), heart failure with preserved ejection fraction (HFpEF; DOCA-salt hypertension), and acute sarcoplasmic reticulum dysfunction induced by thapsigargin - all known to exhibit diastolic dysfunction. Left atrial area increased in all three chronic models while mitral E/A was difficult to quantify at high heart rates. Isovolumic relaxation time (IVRT) and Doppler E/E' increased significantly and the peak longitudinal strain rate during early filling (peak reverse longitudinal strain rate) decreased significantly after aortic constriction, with the changes being proportional to the magnitude of hypertrophy. In the HFpEF model, reverse longitudinal strain rate decreased significantly but changes in IVRT and E/E' were non-significant, consistent with less severe dysfunction. With volume overload, there was a significant increase in reverse longitudinal strain rate and decrease in IVRT, indicating a restrictive physiology. Acute thapsigargin treatment caused significant prolongation of IVRT and decrease in reverse longitudinal strain rate., Conclusion: These results indicate that the combined measurement of left atrial area plus reverse longitudinal strain rate and/or IVRT provide an excellent overall assessment of diastolic function in the diseased mouse heart, allowing distinction between different types of pathophysiology., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mechanistic understanding of the control of vesicle motion from within a secretory cell to the site of exocytosis remains incomplete. In this work, we have used total internal reflection (TIRF) microscopy to examine the mobility of secretory vesicles at the plasma membrane. Under resting conditions, we found vesicles showed little lateral mobility. Anchoring of vesicles in this membrane proximal compartment could be disrupted with latrunculin A, indicating an apparent actin dependent process. A candidate intermediary between vesicles and the actin skeleton is the actin binding protein scinderin. Co-transfection of an shRNA construct against scinderin blocked secretion, and also increased the mobility of vesicles in the membrane-proximal section of the cell, indicating a dual role for scinderin in secretion; tethering vesicles to the cytoskeleton, as well as liberating them following stimulation through the previously described calcium dependent actin severing activity. Analysis of lipid dependence indicates that scinderin exhibits calcium dependent binding to phosphatidyl-inositol monophosphate, providing a possible mechanism for vesicle binding., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Interventions aiming to coordinate services for the community-based dementia population vary in components, organisation and implementation. In this review we aimed to investigate the views of stakeholders on the key components of community-based interventions coordinating care in dementia., Methods: We searched four databases from inception to June 2015; Medline, The Cochrane Library, EMBASE and PsycINFO, this was aided by a search of four grey literature databases, and backward and forward citation tracking of included papers. Title and abstract screening was followed by a full text screen by two independent reviewers, and quality was assessed using the CASP appraisal tool. We then conducted thematic synthesis on extracted data., Results: A total of seven papers from five independent studies were included in the review, and encompassed the views of over 100 participants from three countries. Through thematic synthesis we identified 32 initial codes that were grouped into 5 second-order themes: (1) case manager had four associated codes and described preferences for the case manager personal and professional attributes, including a sound knowledge in dementia and availability of local services; (2) communication had five associated codes and emphasized the importance stakeholders placed on multichannel communication with service users, as well as between multidisciplinary teams and across organisations; (3) intervention had 11 associated codes which focused primarily on the practicalities of implementation such as the contact type and frequency between case managers and service users, and the importance of case manager training and service evaluation; (4) resources had five associated codes which outlined stakeholder views on the required resources for coordinating interventions and potential overlap with existing resources, as well as arising issues when available resources do not meet those required for successful implementation; and (5) support had seven associated codes that reflect the importance that was placed on the support network around the case manager and the investment of professionals involved directly in care as well as the wider professional network., Conclusion: The synthesis of relevant qualitative studies has shown how various stakeholder groups considered dementia care coordination interventions to be acceptable, useful and appropriate for dementia care, and have clear preferences for components, implementation methods and settings of these interventions. By incorporating stakeholders' perspectives and preferences when planning and developing coordinating interventions we may increase the likelihood of successful implementation and patient benefits.

Background: Interventions aiming to coordinate services for the community-based dementia population vary in components, organisation and implementation. In this review we aimed to evaluate the effectiveness of community-based care coordinating interventions on health outcomes and investigate whether specific components of interventions influence their effects., Methods: We searched four databases from inception to April 2017: Medline, The Cochrane Library, EMBASE and PsycINFO. This was aided by a search of four grey literature databases, and backward and forward citation tracking of included papers. Title and abstract screening was followed by a full text screen by two independent reviewers, and quality was assessed using the CASP appraisal tool. We then conducted meta-analyses and subgroup analyses., Results: A total of 14 randomised controlled trials (RCTs) involving 10,372 participants were included in the review. Altogether we carried out 12 meta-analyses and 19 subgroup analyses. Meta-analyses found coordinating interventions showed a statistically significant improvement in both patient behaviour measured using the Neuropsychiatric Inventory (NPI) (mean difference (MD) = -9.5; 95% confidence interval (CI): -18.1 to -1.0; p = 0.03; number of studies (n) = 4; I 2  = 88%) and caregiver burden (standardised mean difference (SMD) = -0.54; 95% CI: -1.01 to -0.07; p = 0.02; n = 5, I 2  = 92%) compared to the control group. Subgroup analyses found interventions using a case manager with a nursing background showed a greater positive effect on caregiver quality of life than those that used case managers from other professional backgrounds (SMD = 0.94 versus 0.03, respectively; p < 0.001). Interventions that did not provide supervision for the case managers showed greater effectiveness for reducing the percentage of patients that are institutionalised compared to those that provided supervision (odds ratio (OR) = 0.27 versus 0.96 respectively; p = 0.02). There was little evidence of effects on other outcomes, or that other intervention components modify the intervention effects., Conclusion: Results show that coordinating interventions in dementia care has a positive impact on some outcomes, namely patient behaviour and caregiver burden, but the evidence is inconsistent and results were not strong enough to draw definitive conclusions on general effectiveness. With the rising prevalence of dementia, effective complex interventions will be necessary to provide high quality and effective care for patients, and facilitate collaboration of health, social and third sector services.

Background: Depression in older adults is common and is associated with poor quality of life, increased morbidity and early mortality, and increased health and social care use. Collaborative care, a low-intensity intervention for depression that is shown to be effective in working-age adults, has not yet been evaluated in older people with depression who are managed in UK primary care. The CollAborative care for Screen-Positive EldeRs (CASPER) plus trial fills the evidence gap identified by the most recent guidelines on depression management., Objectives: To establish the clinical effectiveness and cost-effectiveness of collaborative care for older adults with major depressive disorder in primary care., Design: A pragmatic, multicentred, two-arm, parallel, individually randomised controlled trial with embedded qualitative study. Participants were automatically randomised by computer, by the York Trials Unit Randomisation Service, on a 1 : 1 basis using simple unstratified randomisation after informed consent and baseline measures were collected. Blinding was not possible., Setting: Sixty-nine general practices in the north of England., Participants: A total of 485 participants aged ≥ 65 years with major depressive disorder., Interventions: A low-intensity intervention of collaborative care, including behavioural activation, delivered by a case manager for an average of six sessions over 7-8 weeks, alongside usual general practitioner (GP) care. The control arm received only usual GP care., Main Outcome Measures: The primary outcome measure was Patient Health Questionnaire-9 items score at 4 months post randomisation. Secondary outcome measures included depression severity and caseness at 12 and 18 months, the EuroQol-5 Dimensions, Short Form questionnaire-12 items, Patient Health Questionnaire-15 items, Generalised Anxiety Disorder-7 items, Connor-Davidson Resilience Scale-2 items, a medication questionnaire, objective data and adverse events. Participants were followed up at 12 and 18 months., Results: In total, 485 participants were randomised (collaborative care, n  = 249; usual care, n  = 236), with 390 participants (80%: collaborative care, 75%; usual care, 86%) followed up at 4 months, 358 participants (74%: collaborative care, 70%; usual care, 78%) followed up at 12 months and 344 participants (71%: collaborative care, 67%; usual care, 75%) followed up at 18 months. A total of 415 participants were included in primary analysis (collaborative care, n  = 198; usual care, n  = 217), which revealed a statistically significant effect in favour of collaborative care at the primary end point at 4 months [8.98 vs. 10.90 score points, mean difference 1.92 score points, 95% confidence interval (CI) 0.85 to 2.99 score points; p   <  0.001], equivalent to a standard effect size of 0.34. However, treatment differences were not maintained in the longer term (at 12 months: 0.19 score points, 95% CI -0.92 to 1.29 score points; p  = 0.741; at 18 months: < 0.01 score points, 95% CI -1.12 to 1.12 score points; p  = 0.997). The study recorded details of all serious adverse events (SAEs), which consisted of 'unscheduled hospitalisation', 'other medically important condition' and 'death'. No SAEs were related to the intervention. Collaborative care showed a small but non-significant increase in quality-adjusted life-years (QALYs) over the 18-month period, with a higher cost. Overall, the mean cost per incremental QALY for collaborative care compared with usual care was £26,016; however, for participants attending six or more sessions, collaborative care appears to represent better value for money (£9876/QALY)., Limitations: Study limitations are identified at different stages: design (blinding unfeasible, potential contamination), process (relatively low overall consent rate, differential attrition/retention rates) and analysis (no baseline health-care resource cost or secondary/social care data)., Conclusion: Collaborative care was effective for older people with case-level depression across a range of outcomes in the short term though the reduction in depression severity was not maintained over the longer term of 12 or 18 months. Participants who received six or more sessions of collaborative care did benefit substantially more than those who received fewer treatment sessions but this difference was not statistically significant., Future Work Recommendations: Recommendations for future research include investigating the longer-term effect of the intervention. Depression is a recurrent disorder and it would be useful to assess its impact on relapse and the prevention of future case-level depression., Trial Registration: Current Controlled Trials ISRCTN45842879., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 21, No. 67. See the NIHR Journals Library website for further project information.

Determination of 135 Cs/ 137 Cs atom ratios has the potential to be a powerful tool for nuclear forensics and monitoring environmental processes. We present optimized chemical separation techniques and thermal ionization mass spectrometry (TIMS) protocols to obtain precise 135 Cs/ 137 Cs atom ratios for a range of environmental sample types. We use a combination of double AMP-PAN separation and Sr-spec resin column purification to yield excellent separation from the alkali metals (Rb separation factor > 600), which normally suppress ionization of Cs. A range of emission activators for the ionization of Cs were evaluated and glucose solution yielded the optimal combination of a stable Cs + beam, minimal low-temperature polyatomic interferences and improved ionization efficiency. Mass-spectrometric determination of low abundance 135 Cs and 137 Cs is compromised by the presence of a very large 133 Cs + beam, which may be scattered and cause significant spectral interferences. These are explored using multi-static Faraday cup - ion counter methods and a range of energy filter settings. The method is evaluated using environmental samples and standards from regions affected by fallout from Chernobyl (IAEA-330) and Fukushima nuclear disasters. Where the intensity of 133 Cs + is large relative to 135 Cs + and 137 Cs + (< 30cps), minor polyatomic interferences need to be considered. In the absence of a standard with 135, 137 Cs/ 133 Cs < 1 × 10 -8 , we explored the reproducibility of 135 Cs/ 137 Cs atom ratios at these high dynamic ranges and extremely low abundance ( 137 Cs ≈ 12 fg g -1 ) for sediments from an estuarine setting in SW England, UK., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this paper is to showcase best practice in intervention development by illustrating a systematic, iterative, person-based approach to optimising intervention acceptability and feasibility, as applied to the cross-cultural adaptation of Morita therapy for depression and anxiety., Methods: We developed the UK Morita therapy outpatient protocol over four stages integrating literature synthesis and qualitative research. Firstly, we conducted in-depth interviews combining qualitative and cognitive interviewing techniques, utilising vignettes of Morita therapy being delivered and analysed using Framework analysis to investigate potential patients and therapists' perceptions of Morita therapy. Secondly, we developed qualitative themes into recommendations for optimising Morita therapy and synthesised Morita therapy literature in line with these to develop a draft protocol. Thirdly, we conducted repeat interviews with therapists to investigate their views of the protocol. Finally, we responded to these qualitative themes through protocol modification and tailoring our therapist training programme., Results: As a consequence of literature describing Morita therapy and participants' perceptions of the approach, we developed both a therapy protocol and therapist training programme which were fit for purpose in proceeding to a UK-based Morita therapy feasibility study. As per our key qualitative findings and resulting recommendations, we structured our protocol according to the four-phased model of Morita therapy, included detailed guidance and warning points, and supported therapists in managing patients' expectations of the approach., Conclusions: Our systematic approach towards optimising intervention acceptability and feasibility prioritises the perspectives of those who will deliver and receive the intervention. Thus, we both showcase best practice in intervention development and demonstrate the application of this process to the careful cross-cultural adaptation of an intervention in which balancing both optimisation of and adherence to the approach are key. This presentation of a generalisable process in a transparent and replicable manner will be of interest to those both developing and evaluating complex interventions in the future.

Objective: To explore patients' and nurses' views on the feasibility and acceptability of providing psychological care within cardiac rehabilitation services., Design: In-depth interviews analysed thematically., Participants: 18 patients and 7 cardiac nurses taking part in a pilot trial (CADENCE) of an enhanced psychological care intervention delivered within cardiac rehabilitation programmes by nurses to patients with symptoms of depression., Setting: Cardiac services based in the South West of England and the East Midlands, UK., Results: Patients and nurses viewed psychological support as central to good cardiac rehabilitation. Patients' accounts highlighted the significant and immediate adverse effect a cardiac event can have on an individual's mental well-being. They also showed that patients valued nurses attending to both their mental and physical health, and felt this was essential to their overall recovery. Nurses were committed to providing psychological support, believed it benefited patients, and advocated for this support to be delivered within cardiac rehabilitation programmes rather than within a parallel healthcare service. However, nurses were time-constrained and found it challenging to provide psychological care within their existing workloads., Conclusions: Both patients and nurses highly value psychological support being delivered within cardiac rehabilitation programmes but resource constraints raise barriers to implementation. Consideration, therefore, should be given to alternative forms of delivery which do not rely solely on nurses to enable patients to receive psychological support during cardiac rehabilitation., Trial Registration Number: ISCTRN34701576., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Arterial hypertension continues to be a major health burden. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. Oxidants induce an interprotein disulfide in PKG Iα (protein kinase G Iα) at C42, which is associated with its targeting and activation, resulting in vasodilation and blood pressure lowering. Consequently, we developed an assay and screened for electrophilic drugs that activate PKG Iα by selectively targeting C42, as such compounds have potential as novel antihypertensives with a mechanism of action that differs from current therapies. In this way, a drug that we termed G1 was identified, which targets C42 of PKG Iα to induce vasodilation of isolated resistance blood vessels and blood pressure lowering in a mouse model of angiotensin II-induced hypertension. In contrast, these antihypertensive effects were deficient in angiotensin II-induced hypertensive C42S PKG Iα knockin mice. These transgenic mice were engineered to have the reactive cysteinyl thiol replaced with a hydroxyl so that it cannot react with endogenous vasodilatory oxidants or electrophiles such as drug G1. These studies, therefore, provide validation of PKG Iα C42 as the target of G1, as well as proof-of-principle for a new class of antihypertensive drugs that have potential for further development for clinical use in humans., (© 2017 The Authors.)

The successful development of targeted nanotherapeutics is contingent upon the conjugation of therapeutic nanoparticles to target-specific ligands, with particular emphasis being placed on antibody-based ligands. Thus, new methods that enable the covalent and precise installation of targeting antibodies to nanoparticle surfaces are greatly desired, especially those which do not rely on costly and time-consuming antibody engineering techniques. Herein we present a novel method for the highly controlled and oriented covalent conjugation of non-engineered antibody F(ab) fragments to PLGA-PEG nanoparticles using disulfide-selective pyridazinedione linkers and strain-promoted alkyne-azide click chemistry. Exemplification of this method with trastuzumab and cetuximab showed significant improvements in both conjugation efficiency and antigen binding capability, when compared to commonly employed strategies for antibody-nanoparticle construction. This new approach paves the way for the development of antibody-targeted nanomedicines with improved paratope availability, reproducibility and uniformity to enhance both biological activity and ease of manufacture.

Background: Depression is a common, debilitating and costly disorder. The best-evidenced psychological therapy - cognitive-behavioural therapy (CBT) - is complex and costly. A simpler therapy, behavioural activation (BA), may be an effective alternative., Objectives: To determine the clinical effectiveness and cost-effectiveness of BA compared with CBT for depressed adults at 12 and 18 months' follow-up, and to investigate the processes of treatments., Design: Randomised controlled, non-inferiority trial stratified by depression severity, antidepressant use and recruitment site, with embedded process evaluation; and randomisation by remote computer-generated allocation., Setting: Three community mental health services in England., Participants: Adults aged ≥ 18 years with major depressive disorder (MDD) recruited from primary care and psychological therapy services., Interventions: BA delivered by NHS junior mental health workers (MHWs); CBT by NHS psychological therapists., Outcomes: Primary: depression severity (as measured via the Patient Health Questionnaire-9; PHQ-9) at 12 months. Secondary: MDD status; number of depression-free days; anxiety (as measured via the Generalised Anxiety Disorder-7); health-related quality of life (as measured via the Short Form questionnaire-36 items) at 6, 12 and 18 months; and PHQ-9 at 6 and 18 months, all collected by assessors blinded to treatment allocation. Non-inferiority margin was 1.9 PHQ-9 points. We undertook intention-to-treat (ITT) and per protocol (PP) analyses. We explored cost-effectiveness by collecting direct treatment and other health- and social-care costs and calculating quality-adjusted life-years (QALYs) using the EuroQol-5 Dimensions, three-level version, at 18 months., Results: We recruited 440 participants (BA, n  = 221; CBT, n  = 219); 175 (79%) BA and 189 (86%) CBT participants provided ITT data and 135 (61%) BA and 151 (69%) CBT participants provided PP data. At 12 months we found that BA was non-inferior to CBT {ITT: CBT 8.4 PHQ-9 points [standard deviation (SD) 7.5 PHQ-9 points], BA 8.4 PHQ-9 points (SD 7.0 PHQ-9 points), mean difference 0.1 PHQ-9 points, 95% confidence interval (CI) -1.3 to 1.5 PHQ-9 points, p  = 0.89; PP: CBT 7.9 PHQ-9 points (SD 7.3 PHQ-9 points), BA 7.8 PHQ-9 points (SD 6.5 PHQ-9 points), mean difference 0.0 PHQ-9 points, 95% CI -1.5 to 1.6 PHQ-9 points, p  = 0.99}. We found no differences in secondary outcomes. We found a significant difference in mean intervention costs (BA, £975; CBT, £1235; p  < 0.001), but no differences in non-intervention (hospital, community health, social care and medication costs) or total (non-intervention plus intervention) costs. Costs were lower and QALY outcomes better in the BA group, generating an incremental cost-effectiveness ratio of -£6865. The probability of BA being cost-effective compared with CBT was almost 80% at the National Institute for Health and Care Excellence's preferred willingness-to-pay threshold of £20,000-30,000 per QALY. There were no trial-related adverse events., Limitations: In this pragmatic trial many depressed participants in both groups were also taking antidepressant medication, although most had been doing so for a considerable time before entering the trial. Around one-third of participants chose not to complete a PP dose of treatment, a finding common in both psychotherapy trials and routine practice., Conclusions: We found that BA is as effective as CBT, more cost-effective and can be delivered by MHWs with no professional training in psychological therapies., Future Work: Settings and countries with a paucity of professionally qualified psychological therapists, might choose to investigate the delivery of effective psychological therapy for depression without the need to develop an extensive and costly professional infrastructure., Trial Registration: Current Controlled Trials ISRCTN27473954., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 21, No. 46. See the NIHR Journals Library website for further project information.

Shape of change, sudden gains and depression spikes were examined in an online 12-session Behavioral Activation (BA) treatment for depression. Client and therapist factors related to sudden gains were examined to investigate processes associated with outcome., Methods: Participants were postpartum Women with Major Depressive Disorder (n=42) who received online BA supported in 30-minute telephone sessions by a mental health worker. Depression symptoms were assessed at each session and number of sessions completed were recorded by the online program. Therapist records were rated for client stressful life event and therapist concrete focus. A quadratic pattern provided the best fit with the data; a cubic pattern was a poor fit. Sudden gains, but not depression spikes, predicted lower depression scores at 17-week outcome. Women who had higher baseline social functioning, did not experience a stressful life event during therapy, and completed more online modules, but not more telephone sessions, were more likely to have a sudden gain. A concrete therapist focus was associated with sudden gains. These results extend research on trajectories of change and sudden gains to an online BA treatment and to postpartum depression, and suggest important client and therapist factors associated with sudden gains., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting ( t ½ ≥7 hours) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo., Methods: The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the αAnalogue on angiotensin II-induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis, Western blot, and histology., Results: The angiotensin II-induced hypertension was attenuated by cotreatment with the αAnalogue (50 nmol·kg -1 ·d -1 , SC, at a dose selected for lack of long-term hypotensive effects at baseline). The αAnalogue protected against vascular, renal, and cardiac dysfunction, characterized by reduced hypertrophy and biomarkers of fibrosis, remodeling, inflammation, and oxidative stress. In a separate study, the αAnalogue reversed angiotensin II-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart failure. It preserved heart function, assessed by echocardiography, while protecting against adverse cardiac remodeling and apoptosis. Moreover, treatment with the αAnalogue was well tolerated with neither signs of desensitization nor behavioral changes., Conclusions: These findings, in 2 distinct models, provide the first evidence for the therapeutic potential of a stabilized αAnalogue, by mediating (1) antihypertensive effects, (2) attenuating cardiac remodeling, and (3) increasing angiogenesis and cell survival to protect against and limit damage associated with the progression of cardiovascular diseases. This indicates the therapeutic potential of the CGRP pathway and the possibility that this injectable CGRP analogue may be effective in cardiac disease., (© 2017 The Authors.)

Background: Hypertension caused by increased renin-angiotensin system activation is associated with elevated reactive oxygen species production. Previous studies implicate NADPH oxidase (Nox) proteins as important reactive oxygen species sources during renin-angiotensin system activation, with different Nox isoforms being potentially involved. Among these, Nox2 is expressed in multiple cell types, including endothelial cells, fibroblasts, immune cells, and microglia. Blood pressure (BP) is regulated at the central nervous system, renal, and vascular levels, but the cell-specific role of Nox2 in BP regulation is unknown., Methods: We generated a novel mouse model with a floxed Nox2 gene and used Tie2-Cre, LysM Cre, or Cdh5-CreERT2 driver lines to develop cell-specific models of Nox2 perturbation to investigate its role in BP regulation., Results: Unexpectedly, Nox2 deletion in myeloid but not endothelial cells resulted in a significant reduction in basal BP. Both Tie2-CreNox2 knockout (KO) mice (in which Nox2 was deficient in both endothelial cells and myeloid cells) and LysM CreNox2KO mice (in which Nox2 was deficient in myeloid cells) had significantly lower BP than littermate controls, whereas basal BP was unaltered in Cdh5-CreERT2 Nox2KO mice (in which Nox2 is deficient only in endothelial cells). The lower BP was attributable to an increased NO bioavailability that dynamically dilated resistance vessels in vivo under basal conditions without a change in renal function. Myeloid-specific Nox2 deletion had no effect on angiotensin II-induced hypertension, which, however, was blunted in Tie2-CreNox2KO mice, along with preservation of endothelium-dependent relaxation during angiotensin II stimulation., Conclusions: We identify a hitherto unrecognized modulation of basal BP by myeloid cell Nox2, whereas endothelial cell Nox2 regulates angiotensin II-induced hypertension. These results identify distinct cell-specific roles for Nox2 in BP regulation., (© 2017 The Authors.)