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Background: While primary care physicians (PCPs) play a key role in cancer detection, they can find cancer diagnosis challenging, and some patients have considerable delays between presentation and onward referral. Aim: To explore European PCPs’ experiences and views on cases where they considered that they had been slow to think of, or act on, a possible cancer diagnosis. Design & setting: A multicentre European qualitative study, based on an online survey with open-ended questions, asking PCPs for their narratives about cases when they had missed a diagnosis of cancer. Method: Using maximum variation sampling, PCPs in 23 European countries were asked to describe what happened in a case where they were slow to think of a cancer diagnosis, and for their views on why it happened. Thematic analysis was used to analyse the data. Results: A total of 158 PCPs completed the questionnaire. The main themes were as follows: patients’ descriptions did not suggest cancer; distracting factors reduced PCPs’ cancer suspicions; patients’ hesitancy delayed the diagnosis; system factors not facilitating timely diagnosis; PCPs felt that they had acted wrongly; and problems with communicating adequately. Conclusion: The study identified six overarching themes that need to be addressed. Doing so should reduce morbidity and mortality in the small proportion of patients who have a significant, avoidable delay in their cancer diagnosis. The ‘Swiss cheese’ model of accident causation showed how the themes related to each other.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic continues to affect the globe. After 18 months of the SARS-CoV-2 emergence, clinicians have clearly defined a subgroup of patients with lasting, disabling symptoms. While big strides have been made in understanding the acute phase of SARS-CoV-2 infection, the pathophysiology of long COVID is still largely unknown, and evidence-based, effective treatments for this condition remain unavailable. Objectives To evaluate the efficacy of 10 mg oral montelukast every 24 h versus placebo in improving quality of life associated with mild to moderate respiratory symptoms in patients with long COVID as measured with the COPD Assessment Test (CAT) questionnaire. The secondary objectives will evaluate the effect of montelukast versus placebo on improving exercise capacity, COVID-19 symptoms (asthenia, headache, mental confusion or brain fog, ageusia, and anosmia), oxygen desaturation during exertion, functional status, and mortality. Methods and analysis Phase III, randomized, double-blind clinical trial. We will include 18- to 80-year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow-up will finish 56 days after the start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting the treatment. The following are the secondary outcomes: (a) exercise capacity and oxygen saturation (1-min sit-to-stand test); (b) Post-COVID-19 Functional Status Scale; (c) other symptoms: asthenia, headache, mental confusion (brain fog), ageusia, and anosmia (Likert scale); (d) use of healthcare resources; (e) mortality; (f) sick leave duration in days; and (g) side effects of montelukast. Ethics and dissemination This study has been approved by the Clinical Research Ethics Committee of the IDIAPJGol (reference number 21/091-C). The trial results will be published in open access, peer-reviewed journals and explained in webinars to increase awareness and understanding about long COVID among primary health professionals. Trial registration ClinicalTrials.gov NCT04695704 . Registered on January 5, 2021. EudraCT number 2021-000605-24. Prospectively registered.

Abstract Background This study aimed to evaluate the effectiveness of a) a Multiple Health Behaviour Change (MHBC) intervention on reducing smoking, increasing physical activity and adherence to a Mediterranean dietary pattern in people aged 45–75 years compared to usual care; and b) an implementation strategy. Methods A cluster randomised effectiveness-implementation hybrid trial-type 2 with two parallel groups was conducted in 25 Spanish Primary Health Care (PHC) centres (3062 participants): 12 centres (1481 participants) were randomised to the intervention and 13 (1581 participants) to the control group (usual care). The intervention was based on the Transtheoretical Model and focused on all target behaviours using individual, group and community approaches. PHC professionals made it during routine care. The implementation strategy was based on the Consolidated Framework for Implementation Research (CFIR). Data were analysed using generalised linear mixed models, accounting for clustering. A mixed-methods data analysis was used to evaluate implementation outcomes (adoption, acceptability, appropriateness, feasibility and fidelity) and determinants of implementation success. Results 14.5% of participants in the intervention group and 8.9% in the usual care group showed a positive change in two or all the target behaviours. Intervention was more effective in promoting dietary behaviour change (31.9% vs 21.4%). The overall adoption rate by professionals was 48.7%. Early and final appropriateness were perceived by professionals as moderate. Early acceptability was high, whereas final acceptability was only moderate. Initial and final acceptability as perceived by the participants was high, and appropriateness moderate. Consent and recruitment rates were 82.0% and 65.5%, respectively, intervention uptake was 89.5% and completion rate 74.7%. The global value of the percentage of approaches with fidelity ≥50% was 16.7%. Eight CFIR constructs distinguished between high and low implementation, five corresponding to the Inner Setting domain. Conclusions Compared to usual care, the EIRA intervention was more effective in promoting MHBC and dietary behaviour change. Implementation outcomes were satisfactory except for the fidelity to the planned intervention, which was low. The organisational and structural contexts of the centres proved to be significant determinants of implementation effectiveness. Trial registration ClinicalTrials.gov , NCT03136211 . Registered 2 May 2017, “retrospectively registered”.

Confining the entire population to a lockdown after the outbreak of SARS-CoV-2 was an unprecedented measure designed to protect the health of those living in Spain. The objective of the present study is to assess the evolution of mental health and psychological wellbeing during lockdown. To do this, we carried out a longitudinal study, via an online survey over the eight weeks of lockdown (weekly assessments). Sociodemographic variables were recorded, along with data related to COVID-19, psychological wellbeing (anxiety, depression, psychotropic drugs, consultations made to improve mood or anxiety), life satisfaction, and self-perceived health. A total of 681 individuals participated in the study, 76.8% were women; the mean age was 43 years old (SD = 12.7). Initially, high scores were reported for anxiety, depression, and the number of consultations to improve mood, but these decreased significantly over the study period. The reverse seems to be true for life satisfaction, perceived good health, and intake of psychotropic drugs. We also identified groups whose psychological wellbeing was more susceptible to the effects of lockdown. Women, those worried about their jobs after the pandemic, and those afraid of being infected were the most affected individuals. More generally, after the initial negative effect on psychological wellbeing, various indicators improved over the lockdown period.

Abstract The multi-domain transcriptional coactivators CBP/p300 integrate a multitude of signaling inputs, interacting with more than 400 proteins via one or more of their globular domains. While CBP/p300 function is typically considered in terms of these structured domains, about half of the protein consists of intrinsically disordered regions (IDRs) of varying length. However, these IDRs have only been thought of as linkers that allow flexible spatial arrangement of the structured domains, but recent studies have shown that similar IDRs mediate specific and critical interactions in other proteins. To examine the roles of IDRs in CBP, we performed yeast-two-hybrid screenings of placenta and lung cancer cDNA libraries, which demonstrated that the long IDR linking the KIX domain and bromodomain of CBP (termed ID3) can potentially bind to several proteins. The RNA-binding Zinc-finger protein 106 (ZFP106) detected in both libraries was identified as a novel substrate for CBP-mediated acetylation. Nuclear magnetic resonance (NMR) spectroscopy combined with cross-linking experiments and competition-binding assays showed that the fully disordered isolated ID3 transiently interacts with an IDR of ZFP106 in a fashion that disorder of both regions is maintained. These findings demonstrate that beside the linking function, ID3 can also interact with acetylation substrates of CBP.

Protein quantification is essential in a great variety of biochemical assays, yet the inherent systematic errors associated with the concentration determination of intrinsically disordered proteins (IDPs) using classical methods are hardly appreciated. Routinely used assays for protein quantification, such as the Bradford assay or ultraviolet absorbance at 280 nm, usually seriously misestimate the concentrations of IDPs due to their distinct and variable amino acid composition. Therefore, dependable method(s) have to be worked out/adopted for this task. By comparison to elemental analysis as the gold standard, we show through the example of four globular proteins and nine IDPs that the ninhydrin assay and the commercial QubitTM Protein Assay provide reliable data on IDP quantity. However, as IDPs can show extreme variation in amino acid composition and physical features not necessarily covered by our examples, even these techniques should only be used for IDPs following standardization. The far-reaching implications of these simple observations are demonstrated through two examples: (i) circular dichroism spectrum deconvolution, and (ii) receptor-ligand affinity determination. These actual comparative examples illustrate the potential errors that can be incorporated into the biophysical parameters of IDPs, due to systematic misestimation of their concentration. This leads to inaccurate description of IDP functions.

Recent advances in NMR methodology and techniques allow the structural investigation of biomolecules of increasing size with atomic resolution. NMR spectroscopy is especially well-suited for the study of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) which are in general highly flexible and do not have a well-defined secondary or tertiary structure under functional conditions. In the last decade, the important role of IDPs in many essential cellular processes has become more evident as the lack of a stable tertiary structure of many protagonists in signal transduction, transcription regulation and cell-cycle regulation has been discovered. The growing demand for structural data of IDPs required the development and adaption of methods such as 13C-direct detected experiments, paramagnetic relaxation enhancements (PREs) or residual dipolar couplings (RDCs) for the study of ‘unstructured’ molecules in vitro and in-cell. The information obtained by NMR can be processed with novel computational tools to generate conformational ensembles that visualize the conformations IDPs sample under functional conditions. Here, we address NMR experiments and strategies that enable the generation of detailed structural models of IDPs.

AbstractObjective Diagnosis of cancer is challenging in primary care due to the low incidence of cancer cases in primary care practice. A prolonged diagnostic interval may be due to doctor, patient or system factors, or may be due to the characteristics of the cancer itself. The objective of this study was to learn from Primary Care Physicians’ (PCP) experiences of incidents when they had failed to think of, or act on, a cancer diagnosis.Design A qualitative, online survey eliciting PCP narratives. Thematic analysis was used to analyse the data.Setting and subjects A primary care study, with narratives from 159 PCPs in 23 European countries.Main outcome measures PCPs’ narratives on the question ‘If you saw this patient with cancer presenting in the same way today, what would you do differently?Results The main themes identified were: thinking broadly; improvement in communication and clinical management; use of other available resources and ‘I wouldn’t do anything differently’.Conclusion (Implications) To achieve more timely cancer diagnosis, PCPs need to provide a long-term, holistic and active approach with effective communication, and to ensure shared decision-making, follow-up and continuing re-assessment of the patients’ clinical conditions.