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Maen Hussein,1 Marina Maglakelidze,2 Donald A Richards,3 Marielle Sabatini,4 Todd A Gersten,5 Keith Lerro,6 Ivan Sinielnikov,7 Alexander Spira,8,9 Yili Pritchett,10 Joyce M Antal,10 Rajesh Malik,10 J Thaddeus Beck11 1Florida Cancer Specialists, Leesburg, FL, USA; 2LLC Arensia Exploratory Medicine, Tbilisi, Georgia; 3Texas Oncology-Tyler, US Oncology Research, Tyler, TX, USA; 4Saint Leon Hospital, Bayonne, France; 5Florida Cancer Specialists, West Palm Beach, FL, USA; 6Regional Medical Oncology Center, Wilson, NC, USA; 7Volyn Regional Oncology Center, Lutsk, Ukraine; 8Virginia Cancer Specialists, Fairfax, VA, USA; 9US Oncology Research, The Woodlands, TX, USA; 10G1 Therapeutics, Inc., Research Triangle Park, NC, USA; 11Highlands Oncology Group, Fayetteville, AR, USACorrespondence: Maen HusseinFlorida Cancer Specialists, Leesburg, FL, USATel +1 352-787-9448Email mhussein@flcancer.comPurpose: Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression (CIM) by protecting hematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myeloprotection). Here, we investigated the myeloprotective effects of trilaciclib among patients at increased risk of CIM.Patients and Methods: Data were pooled from three randomized, double-blind, placebo-controlled, phase 2 clinical studies of trilaciclib administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Myeloprotective outcomes were evaluated in patient subgroups based on age (< 65 or ≥ 65 years), risk of chemotherapy-induced febrile neutropenia (FN), and risk of anemia or red blood cell (RBC) transfusions. For the FN and anemia analyses, risk factors were identified from published literature and used to classify patients into FN and anemia risk categories. Subgroup analysis based on age was also performed on patient reported outcome (PRO) measures.Results: In total, 123 patients received trilaciclib and 119 patients received placebo. Myeloprotective benefits of trilaciclib were observed regardless of age, with greater effects observed among patients aged ≥ 65 years. Across FN risk factors and categories, trilaciclib had beneficial effects on neutrophil-related endpoints vs placebo, with greater effects observed in patients at higher risk of FN. Effects on RBC-related endpoints favored trilaciclib vs placebo, regardless of anemia risk factors and categories. Improvements in PROs with trilaciclib were observed irrespective of age group, but with greater improvements and less deterioration from baseline observed in older patients.Conclusion: By both decreasing the incidence of CIM and improving quality of life, trilaciclib has the potential to allow patients receiving chemotherapy for ES-SCLC, including patients who are older or more vulnerable to CIM, to receive chemotherapy on schedule and at standard-of-care doses, and to improve the experience for patients receiving chemotherapy to treat ES-SCLC.Clinical Trial Numbers: NCT02499770; NCT03041311; NCT02514447.Keywords: trilaciclib, myelosuppression, myeloprotection, myelopreservation, chemotherapy, small cell lung cancer

In a guest editorial in this journal, Rahm Hallberg [Rahm Hallberg, I., 2006. Challenges for future nursing research: providing evidence for health-care practice. International Journal of Nursing Studies 43, 923-927] called for research which has greater explanatory power to determine the effectiveness of nursing interventions. In this paper we critique the suggestion made by the evidence-based nursing movement that randomisation per se is the principal route to better quality nursing research. In contrast, we evaluate the new CONSORT criteria for pragmatic RCTs, which assess the quality of strategies to reduce selection, performance, attrition and detection biases, allowing many different types of comparative studies to be covered by application of the checklist. We propose that randomisation alone is a necessary but insufficient strategy and that nursing researchers rise to Rahm Hallberg's challenge by adopting the extended criteria to assist in the critical appraisal, design and reporting of all experimental research in nursing. [ABSTRACT FROM AUTHOR]

BACKGROUND: LY293111 (LY) is a novel oral anticancer agent with leukotriene B4 receptor antagonist and peroxisome proliferator-activated receptor gamma agonist properties, producing promising results alone and in combination with gemcitabine in pancreatic cancer xenograft models. A phase I study proved that the combination (gemcitabine plus LY) is safe and well tolerated. PATIENTS AND METHODS: Chemotherapy-naive patients with histologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas were randomly assigned to gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and continuously administered LY 600 mg twice daily or gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and daily oral placebo. Arms were balanced for Eastern Cooperative Oncology Group performance status and disease stage. The primary end point was 6-month survival; secondary objectives include response rate (RR), progression-free survival, and overall survival. RESULTS: Six-month survival was not different between groups (P>0.2, 1-sided); progression-free survival and RR were not different (P>0.05, 2-sided). RR was also not impacted. LY did not increase grades 3-4 hematologic toxicities, but was associated with a trend toward more, grades 3-4 diarrhea. CONCLUSIONS: These results do not demonstrate any benefit to adding LY to gemcitabine in unpretreated patients with advanced pancreatic carcinoma. [ABSTRACT FROM AUTHOR]

The randomised controlled trial (RCT) is at the heart of the evidence-based medicine movement and by implication should also be central to evidence-based nursing. One objection to RCTs in nursing science is that nursing is too complex an activity to be subjected to a carefully controlled experimental paradigm. We suggest that this argument is false and use examples from complex interventions research in nursing and experimental laboratory methods to demonstrate that RCTs can bring much needed clarity to the search for nursing knowledge. [ABSTRACT FROM AUTHOR]

Although the primary cause of constrictive pericarditis is entirely different to that of restrictive cardiomyopathy, the two often present with very similar clinical findings. As such, making the distinction between the two is a diagnostic challenge. We report a case that highlights how tissue Doppler imaging may simplify the distinction between pericardial constriction and myocardial restriction. [ABSTRACT FROM AUTHOR]

BACKGROUND: Collaborative care is an effective intervention for depression which includes both organizational and patient-level intervention components. The effect in the UK is unknown, as is whether cluster- or patient-randomization would be the most appropriate design for a Phase III clinical trial.MethodWe undertook a Phase II patient-level randomized controlled trial in primary care, nested within a cluster-randomized trial. Depressed participants were randomized to 'collaborative care' - case manager-coordinated medication support and brief psychological treatment, enhanced specialist and GP communication - or a usual care control. The primary outcome was symptoms of depression (PHQ-9). RESULTS: We recruited 114 participants, 41 to the intervention group, 38 to the patient randomized control group and 35 to the cluster-randomized control group. For the intervention compared to the cluster control the PHQ-9 effect size was 0.63 (95% CI 0.18-1.07). There was evidence of substantial contamination between intervention and patient-randomized control participants with less difference between the intervention group and patient-randomized control group (-2.99, 95% CI -7.56 to 1.58, p=0.186) than between the intervention and cluster-randomized control group (-4.64, 95% CI -7.93 to -1.35, p=0.008). The intra-class correlation coefficient for our primary outcome was 0.06 (95% CI 0.00-0.32). CONCLUSIONS: Collaborative care is a potentially powerful organizational intervention for improving depression treatment in UK primary care, the effect of which is probably partly mediated through the organizational aspects of the intervention. A large Phase III cluster-randomized trial is required to provide the most methodologically accurate test of these initial encouraging findings. [ABSTRACT FROM AUTHOR]

This paper's aim is to draw attention to the pitfalls that novice and, sometimes, experienced researchers fall into when undertaking quantitative data analysis in the health and social sciences, and to offer some guidance as to how such pitfalls might be avoided.Many health and social science students are routinely instructed that the procedure for undertaking data analysis in quantitative research is as follows: specify hypotheses; collect data and enter it into a computerised statistical package; run various statistical procedures; examine the computer outputs for p-values that are statistically significant. If significant differences are found, jubilation often exists because statistically significant results are deemed to be a clear indicator that something worthwhile (and publishable) has been discovered. This paper argues that this approach has two major oversights: a failure to explore the raw data prior to analysis and an overdependence on p-values. Both of these oversights are routinely present in much health and social-science research, and both create problems for scientific rigour.Researchers need to exercise caution ('look before you leap') and prudence ('don't put all your eggs in one basket') when undertaking quantitative data analyses. Caution demands that, prior to full data analysis, researchers employ procedures such as data cleaning, data screening and exploratory data analysis. Prudence demands that researchers see p-values for their true worth, which exists only within the context of statistical theory, confidence intervals, effect sizes and the absolute meaning of statistical significance. [ABSTRACT FROM AUTHOR]

Recent policy statements that address the quality of care provided by acute mental health services have highlighted an urgent need for specialist nurse education and training. However, examples of how to design and implement such training initiatives are sparse. Drawing on recent experience of developing an innovative training programme for acute psychiatric settings, this paper seeks to examine some of the key issues associated with current training provision for acute inpatient mental health workers. The methodological and practical concerns surrounding this type of initiative are discussed with the main aspects of programme content, service user participation, team training and organizational challenges being explored. Resulting from this work, several recommendations regarding the content, organization and delivery of future training initiatives are made. [ABSTRACT FROM AUTHOR]

Nursing attitudes towards acute mental health care: development of a measurement toolAim. This paper reports the development, piloting and validation of a tool to measure attitudes for use with nursing staff working in acute mental health care units. Background. The quality of care provided for service users in acute mental health care has come under both scrutiny and severe criticism. The attitudes of staff working in these environments have been cited as a contributory factor in poor care. No measure of attitudes specific to acute mental health has been reported. Methods. A 64-question measure was constructed and distributed to a sample of qualified and unqualified nurses drawn from seven mental health care units in the North of England. Exploratory factor analysis and a number of other statistical tests were performed to validate the questionnaire. Results. Preliminary analysis reduced the original 64 questions to 37. Five components were retained, accounting for 42% of the variance, and the five rotated factors were identified. The resultant 'Attitudes Towards Acute Mental Health Scale' (ATAMHS) achieved good internal reliability, with a Cronbach's alpha of 0.72. Conclusion. The construction and validation of the ATAMHS measure will enable improved understanding of the attitudes of nursing staff working in acute mental health care settings to occur. This measure is available for use in a clinical area of nursing in which attitude change is of fundamental importance for future development of care. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nurse telephone triage is a popular way of managing workload in primary care and has been shown to be as safe as general practitioner (GP)-delivered alternatives. No studies have tested a routine method of assessing the quality of decision-making by triage nurses in primary care. AIMS: The aim of this paper is to describe a study to evaluate accuracy and utility of audiotaping telephone consultations to assess the quality of decisions made by practice nurses triaging same day appointment requests in routine practice. METHOD: An observational study was carried out using external assessment by GPs and nurse practitioners of triage quality in 218 audiotaped nurse telephone triage consultations. RESULTS: There were high levels of agreement between triage nurses and assessors on identifying the presenting problem. However, there were only moderate levels of agreement between GPs and nurse assessors both on level of information sought (kappa = 0.434) and appropriateness of outcome (kappa = 0.614). Assessors rated information-gathering as poor in 19.3% of calls (95% confidence interval 14.6 to 25.0), and seven (3.2%) consultations were rated as potentially dangerous (95% confidence interval 1.6 to 6.5). A 1% sample of all consultations would have a probability of 0.48 of identifying unsafe consultations and 0.99 probability of identifying consultations with poor information-gathering. CONCLUSIONS: External assessment of triage quality may be of only moderate accuracy and reliability. Nonetheless, considerable information can be gleaned from assessing audiotapes to assess consultation quality. Even where nurses are generally highly skilled and competent, a 1% review of triage consultations would be sufficient to identify their information-gathering learning needs in relation to patients' presenting problems. Audio-taped consultations could be an important part of clinical governance strategies. [ABSTRACT FROM AUTHOR]

This study compares the effects of the nursing process and traditional care in a patient population where the environment, nurses, other multidisciplinary team members and the nursing model were the same for two patient groups. Both groups were nursed using traditional therapeutic community techniques. One group also received care using a nursing process approach. Patients in the nursing process group did not feel nurses were significantly more therapeutic nor were they more satisfied with their care. [ABSTRACT FROM AUTHOR]

1 The anti-hypertensive effects of labetalol have been compared and contrasted with other groups of anti-hypertensive drugs in this review of the published literature. 2 The data show that the pharmacological and haemodynamic profile of labetalol in man is distinctly different from that of other specific anti-hypertensive agents; namely the properties of competitive alpha-and beta-adrenoceptor blockade leading to haemodynamic effects of reduced blood pressure and peripheral vascular resistance with little accompanying changes in resting heart rate or cardiac output. 3 The anti-hypertensive effects of labetalol are dose related. In fixed dose comparative studies equivalent anti- hypertensive effects to those of labetalol have been shown for individual drugs of the beta-adrenoceptor-blocking and diuretic groups. In dose titration studies, equivalent anti-hypertensive effects at given doses of labetalol have been demonstrated for drugs of the following types: beta-adrenoceptor blockers, beta-blockers plus diuretics, methyldopa, adrenergic neurone blockers and the combination of beta-blockers plus a peripheral vasodilator. 4 Comparing side-effect liabilities, it is clear that quantitatively labetalol produces no greater burden of side-effects than drugs of the beta-adrenoceptor- blocking group. Qualitative differences, however, do exist; in particular, symptomatic postural hypotension is dose related and is more likely to occur when excessive doses (greater than 2 g daily) are used. [ABSTRACT FROM AUTHOR]

Melanoma is the most common form of cardiac metastases. Surgical excision has been shown to be an effective palliative measure. This requires detailed definition of cardiac anatomy in relation to the tumour. Two-dimensional (2D), three-dimensional (3D) transthoracic (TTE) and transoesophageal echocardiography (TEE), spiral computerised tomography (CT) and magnetic resonance imaging (MRI) have all been described in aiding surgical planning for excision of cardiac tumours. In this case report, 3D-TTE provided excellent anatomical definition for surgical planning of a large right atrial melanoma precluding the need for more invasive and expensive investigations. [ABSTRACT FROM AUTHOR]

Abstract Background Recent years have seen an increase in primary care workload, especially following the introduction of a new General Medical Services contract in 2004. Telephone triage and telephone consultation with patients seeking health care represent initiatives aimed at improving access to care. Some evidence suggests that such approaches may be feasible but conclusions regarding GP workload, cost, and patients’ experience of care, safety, and health status are equivocal. The ESTEEM trial aims to assess the clinical- and cost-effectiveness of nurse-led computer-supported telephone triage and GP-led telephone triage, compared to usual care, for patients requesting same-day consultations in general practice. Methods/design ESTEEM is a pragmatic, multi-centre cluster randomised clinical trial with patients randomised at practice level to usual care, computer decision-supported nurse triage, or GP-led triage. Following triage of 350–550 patients per practice we anticipate estimating and comparing total primary care workload (volume and time), the economic cost to the NHS, and patient experience of care, safety, and health status in the 4-week period following the index same-day consultation request across the three trial conditions. We will recruit all patients seeking a non-emergency same-day appointment in primary care. Patients aged 12.0–15.9 years and temporary residents will be excluded from the study. The primary outcome is the number of healthcare contacts taking place in the 4-week period following (and including) the index same-day consultation request. A range of secondary outcomes will be examined including patient flow, primary care NHS resource use, patients’ experience of care, safety, and health status. The estimated sample size required is 3,751 patients (11,253 total) in each of the three trial conditions, to detect a mean difference of 0.36 consultations per patient in the four week follow-up period between either intervention group and usual care 90% power, 5% alpha, and an estimated intracluster correlation coefficient ICC of 0.05. The primary analysis will be based on the intention-to-treat principle and take the form of a random effects regression analysis taking account of the hierarchical nature of the study design. Statistical models will allow for adjustment for practice level minimisation variables and patient-level baseline covariates shown to differ at baseline. Trial registration Current Controlled Trials ISCRTN20687662

Abstract Background In the United Kingdom, clinical guidelines recommend that services for depression and anxiety should be structured around a stepped care model, where patients receive treatment at different 'steps,' with the intensity of treatment (i.e., the amount and type) increasing at each step if they fail to benefit at previous steps. There are very limited data available on the implementation of this model, particularly on the intensity of psychological treatment at each step. Our objective was to describe patient pathways through stepped care services and the impact of this on patient flow and management. Methods We recorded service design features of four National Health Service sites implementing stepped care (e.g., the types of treatments available and their links with other treatments), together with the actual treatments received by individual patients and their transitions between different treatment steps. We computed the proportions of patients accessing, receiving, and transiting between the various steps and mapped these proportions visually to illustrate patient movement. Results We collected throughput data on 7,698 patients referred. Patient pathways were highly complex and very variable within and between sites. The ratio of low (e.g., self-help) to high-intensity (e.g., cognitive behaviour therapy) treatments delivered varied between sites from 22:1, through 2.1:1, 1.4:1 to 0.5:1. The numbers of patients allocated directly to high-intensity treatment varied from 3% to 45%. Rates of stepping up from low-intensity treatment to high-intensity treatment were less than 10%. Conclusions When services attempt to implement the recommendation for stepped care in the National Institute for Health and Clinical Excellence guidelines, there were significant differences in implementation and consequent high levels of variation in patient pathways. Evaluations driven by the principles of implementation science (such as targeted planning, defined implementation strategies, and clear activity specification around service organisation) are required to improve evidence on the most effective, efficient, and acceptable stepped care systems.

Abstract Background Integrating the best available evidence into program standards is essential if system-wide improvements in the delivery of community-based mental health services are to be achieved. Since the beginning of the Assertive Community Treatment (ACT) program movement, program standards have included a role for the community. In particular, ACT program standards have sought to ensure that members of the local community are involved in governance and that former clients participate in service delivery as "Peer Support Specialists". This paper reports on the extent to which ACT program standards related to community participation have been implemented and identifies barriers to full compliance. Methods Qualitative and quantitative data were collected through a telephone survey of ACT Program Coordinators in Ontario, Canada, using a census sample of the existing 66 ACT programs. A thematic approach to content analysis was used to analyze respondents' qualitative comments. Quantitative data were analyzed using SPSS 16.0 and included means, frequencies, independent t-tests and Pearson Correlations. Results An 85% response rate was achieved. Of the 33 program standards, the two that received the lowest perceived compliance ratings were the two standards directly concerning community participation. Specifically, the standard to have a functioning Community Advisory Body and the standard requiring the inclusion of a Peer Support Specialist. The three major themes that emerged from the survey data with respect to the barriers to fully implementing the Community Advisory Body were: external issues; standard related issues; and, organizational/structural related issues. The three major themes concerning barriers to implementing the Peer Support Specialist role were: human resource related issues; organizational/structural related issues; and, standard related issues. Conclusions The reasons for low compliance of ACT programs with community participation standards are complex and are tied to structural and human resources barriers (both internal and external to the ACT programs) as well as to the requirements of the standards themselves. In order for improvements to the mental health system to be achieved there is a need to identify and address these barriers. Failure to do so will result in less than optimal client, family and economic efficiency outcomes.

Abstract Background Depression accounts for the greatest burden of disease among all mental health problems, and is expected to become the second-highest amongst all general health problems by 2020. By the age of 75, 1 in 7 older people meet formal diagnostic criteria for depression. Efforts to ameliorate the burden of illness and personal suffering associated with depression in older people have focussed on those with more severe depressive syndromes. Less attention has been paid to those with mild disorders/sub-threshold depressive syndromes but these patients also suffer impairments in their quality of life and level of functioning. Methods/Design The CASPER study has been designed to assemble an epidemiological cohort of people over 75 years of age (the CASPER cohort), from which we will identify those eligible to participate in a trial of collaborative care for sub-threshold depression (the CASPER trial). We aim to undertake a pragmatic randomised controlled multi-centre trial evaluating the effectiveness and cost-effectiveness of collaborative care; a low intensity psychological intervention in addition to usual general practitioner care versus usual general practitioner care alone. General practitioners from practices based in the North of England will be asked to identify potentially eligible patients over the age of 75 years. Patients will be sent a letter inviting them to participate in the study. We aim to recruit approximately 540 participants for the CASPER trial. A diagnostic interview will be carried out to ascertain trial eligibility with the major depressive episode module of the Mini International Neuropsychiatric Interview (M.I.N.I.), eligible participants randomised to either the intervention or usual care. The primary outcome will be measured with the Patient Health Questionnaire-9 (PHQ-9) and additional quality of life measures will be collected. Data will be collected at baseline, 4 and 12 months for both trial and cohort participants. Trial Registration ISRCTN: ISRCTN02202951

Abstract Background Prediction of the location of culprit lesions responsible for ST-segment elevation myocardial infarctions may allow for prevention of these events. A retrospective analysis of coronary artery motion (CAM) was performed on coronary angiograms of 20 patients who subsequently had ST-segment elevation myocardial infarction treated by primary or rescue angioplasty and an equal number of age and sex matched controls with normal angiograms. Findings There was no statistically significant difference between the frequency of CAM types of the ST-segment elevation acute myocardial infarction and control patients (p = 0.97). The compression type of CAM is more frequent in the proximal and mid segments of all three coronary arteries. No statistically significant difference was found when the frequency of the compression type of CAM was compared between the ST-segment elevation acute myocardial infarction and control patients for the individual coronary artery segments (p = 0.59). Conclusion The proportion of the compression type of coronary artery motion for individual artery segments is not different between patients who have subsequent ST-segment elevation myocardial infarctions and normal controls.

Abstract Background There is a considerable evidence base for 'collaborative care' as a method to improve quality of care for depression, but an acknowledged gap between efficacy and implementation. This study utilises the Normalisation Process Model (NPM) to inform the process of implementation of collaborative care in both a future full-scale trial, and the wider health economy. Methods Application of the NPM to qualitative data collected in both focus groups and one-to-one interviews before and after an exploratory randomised controlled trial of a collaborative model of care for depression. Results Findings are presented as they relate to the four factors of the NPM (interactional workability, relational integration, skill-set workability, and contextual integration) and a number of necessary tasks are identified. Using the model, it was possible to observe that predictions about necessary work to implement collaborative care that could be made from analysis of the pre-trial data relating to the four different factors of the NPM were indeed borne out in the post-trial data. However, additional insights were gained from the post-trial interview participants who, unlike those interviewed before the trial, had direct experience of a novel intervention. The professional freedom enjoyed by more senior mental health workers may work both for and against normalisation of collaborative care as those who wish to adopt new ways of working have the freedom to change their practice but are not obliged to do so. Conclusions The NPM provides a useful structure for both guiding and analysing the process by which an intervention is optimized for testing in a larger scale trial or for subsequent full-scale implementation.

Abstract Background Comprising of both organisational and patient level components, collaborative care is a potentially powerful intervention for improving depression treatment in UK primary Care. However, as previous models have been developed and evaluated in the United States, it is necessary to establish the effect of collaborative care in the UK in order to determine whether this innovative treatment model can replicate benefits for patients outside the US. This Phase III trial was preceded by a Phase II patient level RCT, following the MRC Complex Intervention Framework. Methods/Design A multi-centre controlled trial with cluster-randomised allocation of GP practices. GP practices will be randomised to usual care control or to "collaborative care" - a combination of case manager coordinated support and brief psychological treatment, enhanced specialist and GP communication. The primary outcome will be symptoms of depression as assessed by the PHQ-9. Discussion If collaborative care is demonstrated to be effective we will have evidence to enable the NHS to substantially improve the organisation of depressed patients in primary care, and to assist primary care providers to deliver a model of enhanced depression care which is both effective and acceptable to patients. Trial Registration Number ISRCTN32829227

Abstract Background Current guidelines for the management of depression suggest the use of guided self-help for patients with mild to moderate disorders. However, there is little consensus concerning the optimal form and delivery of this intervention. To develop acceptable and effective interventions, a phased process has been proposed, using a modelling phase to examine and develop an intervention prior to preliminary testing in an exploratory trial. This paper (a) describes the modelling phase used to develop a guided self-help intervention for depression in primary care and (b) reports data from an exploratory randomised trial of the intervention. Methods A guided self-help intervention was developed following a modelling phase which involved a systematic review, meta synthesis and a consensus process. The intervention was then tested in an exploratory randomised controlled trial by examining (a) fidelity using analysis of taped guided self-help sessions (b) acceptability to patients and professionals through qualitative interviews (c) effectiveness through estimation of the intervention effect size. Results Fifty eight patients were recruited to the exploratory trial. Seven professionals and nine patients were interviewed, and 22 tapes of sessions analysed for fidelity. Generally, fidelity to the intervention protocol was high, and the professionals delivered the majority of the specific components (with the exception of the use of feedback). Acceptability to both professionals and patients was also high. The effect size of the intervention on outcomes was small, and in line with previous analyses showing the modest effect of guided self-help in primary care. However, the sample size was small and confidence intervals around the effectiveness estimate were wide. Conclusion The general principles of the modelling phase adopted in this study are designed to draw on a range of evidence, potentially providing an intervention that is evidence-based, patient-centred and acceptable to professionals. However, the pilot outcome data did not suggest that the intervention developed was particularly effective. The advantages and disadvantages of the general methods used in the modelling phase are discussed, and possible reasons for the failure to demonstrate a larger effect in this particular case are outlined.

Abstract Background Access to psychotherapy is limited by psychopathology (e.g. agoraphobia), physical disability, occupational or social constraints and/or residency in under-served areas. For these populations, interventions delivered via remote communication technologies (e.g. telephone, internet) may be more appropriate. However, there are concerns that such delivery may influence the therapeutic relationship and thus reduce therapy effectiveness. This review aimed to determine the clinical effectiveness of remotely communicated, therapist-delivered psychotherapy. Methods Systematic review (including electronic database searching and correspondence with authors) of randomised trials of individual remote psychotherapy. Electronic databases searched included MEDLINE (1966–2006), PsycInfo (1967–2006), EMBASE (1980–2006) and CINAHL databases (1982–2006). The Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDAN-CTR). All searches were conducted to include studies with a publication date to July 2006. Results Thirteen studies were identified, ten assessing psychotherapy by telephone, two by internet and one by videoconference. Pooled effect sizes for remote therapy versus control conditions were 0.44 for depression (95%CI 0.29 to 0.59, 7 comparisons, n = 726) and 1.15 for anxiety-related disorders (95%CI 0.81 to 1.49, 3 comparisons, n = 168). There were few comparisons of remote versus face-to-face psychotherapy. Conclusion Remote therapy has the potential to overcome some of the barriers to conventional psychological therapy services. Telephone-based interventions are a particularly popular research focus and as a means of therapeutic communication may confer specific advantages in terms of their widespread availability and ease of operation. However, the available evidence is limited in quantity and quality. More rigorous trials are required to confirm these preliminary estimates of effectiveness. Future research priorities should include overcoming the methodological shortcomings of published work by conducting large-scale trials that incorporate both clinical outcome and more process-orientated measures.

Aims: The aim of this study is to determine the prevalence of impaired awareness of hypoglycaemia (IAH) and examine risk factors for IAH in adults with type 1 diabetes., Methods: We conducted a population-based registry study of 10,202 adults (≥18 years) with type 1 diabetes using data from the Norwegian Diabetes Register for Adults. The registry used the 1-item Gold scale, measuring hypoglycaemia symptom awareness. We calculated the overall prevalence of IAH (Gold score ≥4) (95% CI) and prevalence for subgroups based on demographic and clinical variables. We estimated IAH prevalence based on continuous scales of age, diabetes duration and HbA 1c using predicted probabilities from generalised additive logistic regression models. Finally, we quantified the associations of selected variables on IAH prevalence using log-binomial regression models., Results: Overall, 18.0% reported IAH (95% CI 17.2, 18.7). The prevalence increased linearly with the participants' age, whereas the associations of diabetes duration and HbA 1c with IAH were non-linear with higher prevalence in both lower and higher tails of their distributions. Multiple severe hypoglycaemic events, female sex, age ≥ 65 years, diabetes duration ≤4 years or ≥ 30 years, multiple DKA events and CGM use were associated with higher risk for IAH. HbA 1c 65-74 mmol/mol (8.1-8.9%) was associated with lower risk for IAH., Conclusions: In this nationwide study, the IAH prevalence was 18.0%. Multiple hypoglycaemic events, female sex and diabetes duration were identified as important risk factors for IAH. Study findings highlight the complexity of self-reported hypoglycaemia symptom awareness and emphasise the importance of routinely addressing symptom awareness in diabetes follow-up., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Relapse of depression is common and contributes to the overall associated morbidity and burden. We lack evidence-based tools to estimate an individual's risk of relapse after treatment in primary care, which may help us more effectively target relapse prevention., Objective: The objective was to develop and validate a prognostic model to predict risk of relapse of depression in primary care., Methods: Multilevel logistic regression models were developed, using individual participant data from seven primary care-based studies (n=1244), to predict relapse of depression. The model was internally validated using bootstrapping, and generalisability was explored using internal-external cross-validation., Findings: Residual depressive symptoms (OR: 1.13 (95% CI: 1.07 to 1.20), p<0.001) and baseline depression severity (OR: 1.07 (1.04 to 1.11), p<0.001) were associated with relapse. The validated model had low discrimination (C-statistic 0.60 (0.55-0.65)) and miscalibration concerns (calibration slope 0.81 (0.31-1.31)). On secondary analysis, being in a relationship was associated with reduced risk of relapse (OR: 0.43 (0.28-0.67), p<0.001); this remained statistically significant after correction for multiple significance testing., Conclusions: We could not predict risk of depression relapse with sufficient accuracy in primary care data, using routinely recorded measures. Relationship status warrants further research to explore its role as a prognostic factor for relapse., Clinical Implications: Until we can accurately stratify patients according to risk of relapse, a universal approach to relapse prevention may be most beneficial, either during acute-phase treatment or post remission. Where possible, this could be guided by the presence or absence of known prognostic factors (eg, residual depressive symptoms) and targeted towards these., Trial Registration Number: NCT04666662., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. Published by BMJ.)

Electrochemical paper-based microfluidics has attracted much attention due to the promise of transforming point-of-care diagnostics by facilitating quantitative analysis with low-cost and portable analyzers. Such devices harness capillary flow to transport samples and reagents, enabling bioassays to be executed passively. Despite exciting demonstrations of capillary-driven electrochemical tests, conventional methods for fabricating electrodes on paper impede capillary flow, limit fluidic pathways, and constrain accessible device architectures. This account reviews recent developments in paper-based electroanalytical devices and offers perspective by revisiting key milestones in lateral flow tests and paper-based microfluidics engineering. The study highlights the benefits associated with electrochemical sensing and discusses how the detection modality can be leveraged to unlock novel functionalities. Particular focus is given to electrofluidic platforms that embed electrodes into paper for enhanced biosensing applications. Together, these innovations pave the way for diagnostic technologies that offer portability, quantitative analysis, and seamless integration with digital healthcare, all without compromising the simplicity of commercially available rapid diagnostic tests., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

C lustered R egularly I nterspaced S hort P alindromic R epeats- C RISPR- A ssociated P rotein (CRISPR-Cas) systems have evolved several mechanisms to specifically target foreign DNA. These properties have made them attractive as biosensors. The primary drawback associated with contemporary CRISPR-Cas biosensors is their weak signaling capacity, which is typically compensated for by coupling the CRISPR-Cas systems to nucleic acid amplification. An alternative strategy to improve signaling capacity is to engineer the reporter, i.e., design new signal-generating substrates for Cas proteins. Unfortunately, due to their reliance on custom synthesis, most of these engineered reporter substrates are inaccessible to many researchers. Herein, we investigate a substrate based on a fluorescein (FAM)-tetramethylrhodamine (TAMRA) Förster resonant energy-transfer (FRET) pair that functions as a seamless "drop-in" replacement for existing reporters, without the need to change any other aspect of a CRISPR-Cas12a-based assay. The reporter is readily available and employs FRET to produce two signals upon cleavage by Cas12a. The use of both signals in a ratiometric manner provides for improved assay performance and a decreased time-to-result for several CRISPR-Cas12a assays when compared to a traditional FAM-Black Hole Quencher (BHQ) quench-based reporter. We comprehensively characterize this reporter to better understand the reasons for the improved signaling capacity and benchmark it against the current standard CRISPR-Cas reporter. Finally, to showcase the real-world utility of the reporter, we employ it in a R ecombinase P olymerase A mplification (RPA)-CRISPR-Cas12a D NA E ndonuclease- T arget e d C RISPR T rans R eporter (DETECTR) assay to detect Human papillomavirus in patient-derived samples.

Paper-based rapid diagnostic tests (RDTs) are an essential component of modern healthcare, particularly for the management of infectious diseases. Despite their utility, these capillary-driven RDTs are compromised by high failure rates, primarily caused by user error. This limits their utility in complex assays that require multiple user operations. Here, we demonstrate how this issue can be directly addressed through continuous electrochemical monitoring of reagent flow inside an RDT using embedded graphenized electrodes. Our method relies on applying short voltage pulses and measuring variations in capacitive discharge currents to precisely determine the flow times of injected samples and reagents. This information is reported to the user, guiding them through the testing process, highlighting failure cases and ultimately decreasing errors. Significantly, the same electrodes can be used to quantify electrochemical signals from immunoassays, providing an integrated solution for both monitoring assays and reporting results. We demonstrate the applicability of this approach in a serology test for the detection of anti-SARS-CoV-2 IgG in clinical serum samples. This method paves the way towards "smart" RDTs able to continuously monitor the testing process and improve the robustness of point-of-care diagnostics.

Background: Public contribution in research can lead to the design and conduct of more feasible and relevant research. However, our understanding of the acceptability and feasibility of public contribution and the evidence base regarding its impact in low- and middle-income countries (LMICs) is limited., Methods: In this study protocol, we describe a mixed-method examination of public contribution activities in the GuardiansCan project. The GuardiansCan project aims to respond to Tanzanian guardians' poor adherence to children's follow-up care after treatment for acute lymphoblastic leukemia (ALL) with the help of Mobile Health technology. We aim to: (1) involve guardians of children treated for ALL as Guardians Advisory Board (GAB) members in the managing and undertaking, analysis and interpretation, and dissemination phases of the GuardiansCan project; and (2) examine the acceptability, feasibility, and perceived impact of GAB members' contribution to the GuardiansCan project from the perspective of the GAB members and public contribution coordinators. We will recruit six to eight guardians of children treated for ALL to the GAB. We will hold workshops where GAB members contribute to all project phases. Using impact logs, we will record GAB workshop activities and the perceived impact of these activities. We will interview GAB members and public contribution coordinators 6 months after establishing the GAB, and at the end of each study within the project, to examine the acceptability, feasibility, and perceived impact of public contribution activities., Discussion: We expect GAB contribution to increase project quality and relevance, and inform how to best embed public contribution in research in LMICs., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Due to their ability to selectively target pathogen-specific nucleic acids, CRISPR-Cas systems are increasingly being employed as diagnostic tools. "One-pot" assays that combine nucleic acid amplification and CRISPR-Cas systems (NAAT-CRISPR-Cas) in a single step have emerged as one of the most popular CRISPR-Cas biosensing formats. However, operational simplicity comes at a cost, with one-pot assays typically being less sensitive than corresponding two-step NAAT-CRISPR-Cas assays and often failing to detect targets at low concentrations. It is thought that these performance reductions result from the competition between the two enzymatic processes driving the assay, namely, Cas-mediated cis -cleavage and polymerase-mediated amplification of the target DNA. Herein, we describe a novel one-pot RPA-Cas12a assay that circumvents this issue by leveraging in situ complexation of the target-specific sgRNA and Cas12a to purposefully limit the concentration of active Cas12a during the early stages of the assay. Using a clinically relevant assay against a DNA target for HPV-16, we show how this in situ format reduces competition between target cleavage and amplification and engenders significant improvements in detection limit when compared to the traditional one-pot assay format, even in patient-derived samples. Finally, to gain further insight into the assay, we use experimental data to formulate a mechanistic model describing the competition between the Cas enzyme and nucleic acid amplification. These findings suggest that purposefully limiting cis -cleavage rates of Cas proteins is a viable strategy for improving the performance of one-pot NAAT-CRISPR-Cas assays.

Affinity protein-oligonucleotide conjugates are increasingly being explored as diagnostic and therapeutic tools. Despite growing interest, these probes are typically constructed using outdated, non-selective chemistries, and little has been done to investigate how conjugation to oligonucleotides influences the function of affinity proteins. Herein, we report a novel site-selective conjugation method for furnishing affinity protein-oligonucleotide conjugates in a 93% yield within fifteen minutes. Using SPR, we explore how the choice of affinity protein, conjugation strategy, and DNA length impact target binding and reveal the deleterious effects of non-specific conjugation methods. Furthermore, we show that these adverse effects can be minimised by employing our site-selective conjugation strategy, leading to improved performance in an immuno-PCR assay. Finally, we investigate the interactions between affinity protein-oligonucleotide conjugates and live cells, demonstrating the benefits of site-selective conjugation. This work provides critical insight into the importance of conjugation strategy when constructing affinity protein-oligonucleotide conjugates., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aim: To evaluate the impact of usual care plus a fundamental nursing care guideline compared to usual care only for patients in hospital with COVID-19 on patient experience, care quality, functional ability, treatment outcomes, nurses' moral distress, patient health-related quality of life and cost-effectiveness., Design: Parallel two-arm, cluster-level randomized controlled trial., Methods: Between 18th January and 20th December 2021, we recruited (i) adults aged 18 years and over with COVID-19, excluding those invasively ventilated, admitted for at least three days or nights in UK Hospital Trusts; (ii) nurses caring for them. We randomly assigned hospitals to use a fundamental nursing care guideline and usual care or usual care only. Our patient-reported co-primary outcomes were the Relational Aspects of Care Questionnaire and four scales from the Quality from the Patient Perspective Questionnaire. We undertook intention-to-treat analyses., Results: We randomized 15 clusters and recruited 581 patient and 418 nurse participants. Primary outcome data were available for 570-572 (98.1%-98.5%) patient participants in 14 clusters. We found no evidence of between-group differences on any patient, nurse or economic outcomes. We found between-group differences over time, in favour of the intervention, for three of our five co-primary outcomes, and a significant interaction on one primary patient outcome for ethnicity (white British vs. other) and allocated group in favour of the intervention for the 'other' ethnicity subgroup., Conclusion: We did not detect an overall difference in patient experience for a fundamental nursing care guideline compared to usual care. We have indications the guideline may have aided sustaining good practice over time and had a more positive impact on non-white British patients' experience of care., Implications for the Profession And/or Patient Care: We cannot recommend the wholescale implementation of our guideline into routine nursing practice. Further intervention development, feasibility, pilot and evaluation studies are required., Impact: Fundamental nursing care drives patient experience but is severely impacted in pandemics. Our guideline was not superior to usual care, albeit it may sustain good practice and have a positive impact on non-white British patients' experience of care., Reporting Method: CONSORT and CONSERVE., Patient or Public Contribution: Patients with experience of hospitalization with COVID-19 were involved in guideline development and writing, trial management and interpretation of findings., (© 2023 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

Semiconducting polymer nanoparticles (SPNs) are explored for applications in cancer theranostics because of their high absorption coefficients, photostability, and biocompatibility. However, SPNs are susceptible to aggregation and protein fouling in physiological conditions, which can be detrimental for in vivo applications. Here, a method for achieving colloidally stable and low-fouling SPNs is described by grafting poly(ethylene glycol) (PEG) onto the backbone of the fluorescent semiconducting polymer, poly(9,9'-dioctylfluorene-5-fluoro-2,1,3-benzothiadiazole), in a simple one-step substitution reaction, postpolymerization. Further, by utilizing azide-functionalized PEG, anti-human epidermal growth factor receptor 2 (HER2) antibodies, antibody fragments, or affibodies are site-specifically "clicked" onto the SPN surface, which allows the functionalized SPNs to specifically target HER2-positive cancer cells. In vivo, the PEGylated SPNs are found to have excellent circulation efficiencies in zebrafish embryos for up to seven days postinjection. SPNs functionalized with affibodies are then shown to be able to target HER2 expressing cancer cells in a zebrafish xenograft model. The covalent PEGylated SPN system described herein shows great potential for cancer theranostics., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Objective: To estimate diabetes distress prevalence and associations with demographic and clinical variables among adults with type 1 diabetes in Norway., Research Design and Methods: In this nationwide population-based registry study, the 20-item Problem Areas in Diabetes (PAID-20) questionnaire was sent to 16,255 adults with type 1 diabetes. Linear regression models examined associations of demographic and clinical variables with distress., Results: In total, 10,186 individuals (62.7%) completed the PAID-20, with a mean score of 25.4 (SD 18.4) and 21.7% reporting high distress. Respondents endorsed worrying about the future and complications as the most problematic item (23.0%). Female sex, younger age, non-European origin, primary education only, unemployment, smoking, continuous glucose monitoring use, more symptomatic hypoglycemia, reduced foot sensitivity, treated retinopathy, and higher HbA1c were associated with higher distress., Conclusions: Diabetes distress is common among adults with type 1 diabetes and associated with clinically relevant factors, underlining that regular care should include efforts to identify and address distress., (© 2023 by the American Diabetes Association.)

With an ageing population and improved treatments people live longer with their chronic diseases, and primary care clinics face more costly and difficult-to-treat multimorbid patients. To meet these challenges, current guidelines for the management of type 2 diabetes suggest that an interprofessional team should collaborate to enhance the delivery of worthwhile self-management support interventions. In this study, we aimed to evaluate the effects of an empowerment-based interprofessional follow-up intervention in people with type 2 diabetes in primary care on patient-reported outcomes, biomarkers and weight, and to explore the experiences of patients attending the intervention. We invited patients during regular visits to their general practitioners. The 12-month intervention included 1) empowerment-based counselling; 2) a standardized medical report. The control group received consultations with physicians only. The primary outcome was the Patient Activation Measure, a patient-reported measure assessing individual knowledge, skills, and confidence integral to managing one's health and healthcare. After the trial we conducted qualitative interviews. We observed no difference in the primary outcome scores. On secondary outcomes we found a significant between-group intervention effect in favor of the intervention group, with mean differences in glycemic control after 12 months (B [95% CI] = -8.6 [-17.1, -0.1] mmol/l; p = 0.045), and significant within-group changes of weight (B [95% CI] = -1.8 kg [-3.3, -0.3]; p = 0.02) and waist circumference (B [95% CI] = -3.9 cm [-7.3, -0.6]; p = 0.02). The qualitative data showed that the intervention opened patients' eyes for reflections and greater awareness, but they needed time to take on actions. The patients emphasized that the intervention gave rise to other insights and a greater understanding of their health challenges. We suggest testing the intervention among patients with larger disease burden and a more expressed motivation for change., Competing Interests: KIB has received research support from Astra Zeneca, Bayer, Boehringer Ingelheim, Lilly, MSD, Novo Nordisk, Roche, Sanofi and Sysmex Norway, AH has received honoraria for speaking at meetings from Novo Nordisk and Abbot. IH has received honoraria for speaking at meetings from Novo Nordisk. The other authors have no relevant competing interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Graue et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The development of low-cost, disposable electrochemical sensors is an essential step in moving traditionally inaccessible quantitative diagnostic assays toward the point of need. However, a major remaining limitation of current technologies is the reliance on standardized reference electrode materials. Integrating these reference electrodes considerably restricts the choice of the electrode substrate and drastically increases the fabrication costs. Herein, we demonstrate that adoption of two-electrode detection systems can circumvent these limitations and allow for the development of low-cost, paper-based devices. We showcase the power of this approach by developing a continuous flow assay for urinary creatinine enabled by an embedded graphenic two-electrode detector. The detection system not only simplifies sensor fabrication and readout hardware but also provides a robust sensing performance with high detection efficiencies. In addition to enabling high-throughput analysis of clinical urine samples, our two-electrode sensors provide unprecedented insights into the fundamental mechanism of the ferricyanide-mediated creatinine reaction. Finally, we developed a simplified circuitry to drive the detector. This forms the basis of a smart reader that guides the user through the measurement process. This study showcases the potential of affordable capillary-driven cartridges for clinical analysis within primary care settings.

Background: Cancer is a leading cause of death during childhood and in low- and middle-income countries survival rates can be as low as 20%. A leading reason for low childhood cancer survival rates in low- and middle-income countries such as Tanzania is treatment abandonment. Contributing factors include poor communication between health care providers and children's guardians, insufficient cancer knowledge, and psychological distress., Objective: Our aim is to respond to Tanzanian guardians' poor adherence to children's follow-up care after treatment for acute lymphoblastic leukemia with the help of mobile health (mHealth) technology. Our goal is to increase guardians' adherence to children's medications and follow-up visits and to decrease their psychological distress., Methods: Following the Medical Research Council framework for developing and evaluating complex interventions, we will undertake the GuardiansCan project in an iterative phased approach to develop an mHealth intervention for subsequent testing. Public contribution activities will be implemented throughout via the establishment of a Guardians Advisory Board consisting of guardians of children with acute lymphoblastic leukemia. We will examine the acceptability, feasibility, and perceived impact of Guardians Advisory Board activities via an impact log and semistructured interviews (study I). In phase 1 (intervention development) we will explore guardians' needs and preferences for the provision of follow-up care reminders, information, and emotional support using focus group discussions and photovoice (study II). We will then co-design the mHealth intervention with guardians, health care professionals, and technology experts using participatory action research (study III). In phase 2 (feasibility), we will examine clinical, methodological, and procedural uncertainties associated with the intervention and study procedures to prepare for the design and conduct of a future definitive randomized controlled trial using a single-arm pre-post mixed methods feasibility study (study IV)., Results: Data collection for the GuardiansCan project is anticipated to take 3 years. We plan to commence study I by recruiting Guardians Advisory Board members in the autumn of 2023., Conclusions: By systematically following the intervention development and feasibility phases of the Medical Research Council Framework, and working alongside an advisory board of guardians, we intend to develop an acceptable, culturally appropriate, feasible, and relevant mHealth intervention with the potential to increase guardians' adherence to children's follow-up care after treatment of acute lymphoblastic leukemia, leading to a positive impact on children's health and chances to survive, and reducing distress for guardians., International Registered Report Identifier (irrid): PRR1-10.2196/48799., (©Faraja S Chiwanga, Joanne Woodford, Golden M Masika, David A Richards, Victor Savi, Louise von Essen. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 02.08.2023.)

Background: Patient activation refers to patients' knowledge, confidence, skills, ability, beliefs, and willingness to manage their health and healthcare. Patient activation is an essential component of self-management and identifying patient activation levels will identify people at risk for health decline at an earlier stage. We aimed to explore patient activation in among adults attending general practice by (1) investigating differences in patient activation according to characteristics and markers of health-related behaviour; (2) examining the associations of quality of life and satisfaction with health with patient activation; and (3) comparing patient activation between persons with or without type 2 diabetes (T2D) and with or without elevated T2D risk., Methods: We performed a cross-sectional study and recruited 1,173 adult patients from four Norwegian general practices between May to December 2019. The participants completed a questionnaire containing sociodemographic and clinical variables, the Patient Activation Measure (PAM-13), the quality of life and satisfaction with health items from the WHO Quality of Life-BREF, three questions about exercise (regularity, intensity and exercise time), the Finnish Diabetes Risk Score (FINDRISC) and Body Mass Index. We tested differences between groups and associations using Chi-squared tests, Fisher's exact tests, t-tests, one-way ANOVAs and Spearman's rho tests., Results: The sample's mean PAM-13 score was 69.8 (0-100) (SD 14.8). In the total population, we found that participants reporting higher patient activation scores also reported more favourable health-related behaviours (exercise and healthy eating). We found positive correlations between the PAM-13 scores and, respectively, the quality of life score and the satisfaction with health score. We found no differences in patient activation between people with or without T2D and those with or without elevated T2D risk., Conclusions: We found that higher patient activation was associated with favourable health-related behaviours, a better quality of life and better satisfaction with health among adults attending four general practices in Norway. Assessing patient activation has the potential to help general practitioners identify patients who might benefit from closer follow-up in advance of negative health outcomes., (© 2023. The Author(s).)

Microfluidic paper-based analytical devices (µPADs) are indispensable tools for disease diagnostics. The integration of electronic components into µPADs enables new device functionalities and facilitates the development of complex quantitative assays. Unfortunately, current electrode fabrication methods often hinder capillary flow, considerably restricting µPAD design architectures. Here, laser-induced graphenization is presented as an approach to fabricate porous electrodes embedded into cellulose paper. The resulting electrodes not only have high conductivity and electrochemical activity, but also retain wetting properties for capillary transport. Paper-based electrofluidics, including a lateral flow device for injection analysis of alkaline phosphatase in serum and a vertical flow device for quantitative detection of HPV16 with a CRISPR-based assay are demonstrated. It is expected that this platform will streamline the development of diagnostic devices that combine the operational simplicity of colorimetric lateral flow tests with the added benefits and possibilities offered by electronic signaling., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Introduction: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity., Methods: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) from CPI. The primary end point was objective response rate (ORR); secondary objectives included safety and secondary efficacy end points., Results: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naive patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naive. The median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naive, respectively; the median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naive patients; median follow-up 20.4 mo). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naive patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction or interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action., Conclusions: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination exhibited antitumor activity and encouraged survival in CPI-experienced patients with nonsquamous NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is a progressive disease associated with a high burden of symptoms, high morbidity and mortality, and low quality of life (QoL). This study aimed to evaluate the feasibility and potential outcomes of a novel multicomponent complex intervention, to inform a future full-scale randomized controlled trial (RCT) in Switzerland., Methods: We conducted a pilot RCT at a secondary care hospital for people with HF hospitalized due to decompensated HF or with a history of HF decompensation over the past 6 months. We randomized 1:1; usual care for the control (CG) and intervention group (IG) who received the intervention as well as usual care. Feasibility measures included patient recruitment rate, study nurse time, study attrition, the number and duration of consultations, intervention acceptability and intervention fidelity. Patient-reported outcomes included HF-specific self-care and HF-related health status (KCCQ-12) at 3 months follow-up. Clinical outcomes were all-cause mortality, hospitalization and days spent in hospital., Results: We recruited 60 persons with HF (age mean = 75.7 years, ± 8.9) over a 62-week period, requiring 1011 h of study nurse time. Recruitment rate was 46.15%; study attrition rate was 31.7%. Follow-up included 2.14 (mean, ± 0.97) visits per patient lasting a total of 166.96 min (mean, ± 72.55), and 3.1 (mean, ± 1.7) additional telephone contacts. Intervention acceptability was high. Mean intervention fidelity was 0.71. We found a 20-point difference in mean self-care management change from baseline to 3 months in favour of the IG (Cohens' d = 0.59). Small effect sizes for KCCQ-12 variables; less IG participants worsened in health status compared to CG participants. Five deaths occurred (IG = 3, CG = 2). There were 13 (IG) and 18 (CG) all-cause hospital admissions; participants spent 8.90 (median, IQR = 9.70, IG) and 15.38 (median, IQR = 18.41, CG) days in hospital. A subsequent full-scale effectiveness trial would require 304 (for a mono-centric trial) and 751 participants (for a ten-centre trial) for HF-related QoL (effect size = 0.3; power = 0.80, alpha = 0.05)., Conclusion: We found the intervention, research methods and outcomes were feasible and acceptable. We propose increasing intervention fidelity strategies for a full-scale trial., Trial Registration: ISRCTN10151805 , retrospectively registered 04/10/2019., (© 2023. The Author(s).)