It is important that the process goes quickly, isn't it?” A qualitative multi-country study of colorectal or lung cancer patients’ narratives of the timeliness of diagnosis and quality of care

Purpose: The emphasis on early diagnosis to improve cancer survival has been a key factor in the development of cancer pathways across Europe. The aim of this analysis was to explore how the emphasis on early diagnosis and timely treatment is reflected in patient's accounts of care, from the first suspicion of colorectal or lung cancer to their treatment in Denmark, England and Sweden. Method: We recruited 155 patients in Denmark, England and Sweden who were within six months of being diagnosed with lung or colorectal cancer. Data were collected via semi-structured narrative interviews and analysed using a thematic approach. Results: Participants’ accounts of quality of care were closely related to how quickly (or not) diagnosis, treatment and/or healthcare processes went. Kinetic metaphors as a description of care (such as treadmill) could be interpreted positively as participants were willing to forgo some degree of control and accept disruption to their lives to ensure more timely care. Drawing on wider cultural expectations of the benefits of diagnosing and treating cancer quickly, some participants were concerned that the waiting times between interventions might allow time for the cancer to grow. Conclusions: Initiatives emphasising the timeliness of diagnosis and treatment are reflected in the ways some patients experience their care. However, these accounts were open to further contextualisation about what speed of healthcare processes meant for evaluating the quality of their care. Healthcare professionals could therefore be an important patient resource in providing reassurance and support about the timeliness of diagnosis or treatment

Patients' initial steps to cancer diagnosis in Denmark, England and Sweden: what can a qualitative, cross-country comparison of narrative interviews tell us about potentially modifiable factors?

OBJECTIVES: To illuminate patterns observed in International Cancer Benchmarking Programme studies by extending understanding of the various influences on presentation and referral with cancer symptoms. DESIGN: Cross-country comparison of Denmark, England and Sweden with qualitative analysis of in-depth interview accounts of the prediagnostic process in lung or bowel cancer. PARTICIPANTS: 155 women and men, aged between 35 and 86 years old, diagnosed with lung or bowel cancer in 6 months before interview. SETTING: Participants recruited through primary and secondary care, social media and word of mouth. Interviews collected by social scientists or nurse researchers during 2015, mainly in participants' homes. RESULTS: Participants reported difficulties in interpreting diffuse bodily sensations and symptoms and deciding when to consult. There were examples of swift referrals by primary care professionals in all three countries. In all countries, participants described difficulty deciding if and when to consult, highlighting concerns about access to general practitioner appointments and overstretched primary care services, although this appears less prominent in the Swedish data. It was not unusual for there to be more than one consultation before referral and we noted two distinct patterns of repeated consultation: (1) situations where the participant left the primary care consultation with a plan of action about what should happen next; (2) participants were unclear about under which conditions to return to the doctors. This second pattern sometimes extended over many weeks during which patients described uncertainty, and sometimes frustration, about if and when they should return and whether there were any other feasible investigations. The latter pattern appeared more evident in the interviews in England and Denmark than Sweden. CONCLUSION: We suggest that if clear action plans, as part of safety netting, were routinely used in primary care consultations then uncertainty, false reassurance and the inefficiency and distress of multiple consultations could be reduced

An early warning risk prediction tool (RECAP-V1) for patients diagnosed with COVID-19: the protocol for a statistical analysis plan

Background: Since the start of the Covid-19 pandemic efforts have been made to develop early warning risk scores to help clinicians decide which patient is likely to deteriorate and require hospitalisation. The RECAP (Remote COVID Assessment in Primary Care) study investigates the predictive risk of hospitalisation, deterioration, and death of patients with confirmed COVID-19, based on a set of parameters chosen through a Delphi process done by clinicians. The study aims to use rich data collected remotely through the use of electronic data templates integrated in the electronic health systems of a number of general practices across the UK to construct accurate predictive models that will use pre-existing conditions and monitoring data of a patient’s clinical parameters such as blood oxygen saturation to make reliable predictions as to the patient’s risk of hospital admission, deterioration, and death. Objective: We outline the statistical methods to build the prediction model to be used in the prioritisation of patients in the primary care setting. The statistical analysis plan for the RECAP study includes as primary outcome the development and validation of the RECAP-V1 prediction model. Such prediction model will be adapted as a three-category risk score split into red (high risk), amber (medium risk), and green (low risk) for any patient with suspected covid-19. The model will predict risk of deterioration, hospitalisation, and death. Methods: After the data has been collected, we will assess the degree of missingness and use a combination of traditional data imputation using multiple imputation by chained equations, as well as more novel machine learning approaches to impute the missing data for the final analysis. For predictive model development we will use multiple logistic regressions to construct the model on a training dataset, as well as validating the model on an independent dataset. The model will also be applied for multiple different datasets to assess both its performance in different patient groups, and applicability for different methods of data collection. Results: As of 5th of May 2021 we have recruited 2280 patients for the main dataset for model development, as well as a further 1741 patients for the validation dataset. Final analysis will commence as soon as data for 2880 are collected. Conclusions: We believe that the methodology for the development of the RECAP V1 prediction model as well as the risk score will provide clinicians with a statistically robust tool to help prioritise Covid-19 patients. Clinical Trial: Trial registration number: NCT0443504

Active surveillance of acute paediatric hospitalisations demonstrates the impact of vaccination programmes and informs vaccine policy in Canada and Australia

Sentinel surveillance of acute hospitalisations in response to infectious disease emergencies such as the 2009 influenza A(H1N1)pdm09 pandemic is well described, but recognition of its potential to supplement routine public health surveillance and provide scalability for emergency responses has been limited. We summarise the achievements of two national paediatric hospital surveillance networks relevant to vaccine programmes and emerging infectious diseases in Canada (Canadian Immunization Monitoring Program Active; IMPACT from 1991) and Australia (Paediatric Active Enhanced Disease Surveillance; PAEDS from 2007) and discuss opportunities and challenges in applying their model to other contexts. Both networks were established to enhance capacity to measure vaccine preventable disease burden, vaccine programme impact, and safety, with their scope occasionally being increased with emerging infectious diseases' surveillance. Their active surveillance has increased data accuracy and utility for syndromic conditions (e.g. encephalitis), pathogen-specific diseases (e.g. pertussis, rotavirus, influenza), and adverse events following immunisation (e.g. febrile seizure), enabled correlation of biological specimens with clinical context and supported responses to emerging infections (e.g. pandemic influenza, parechovirus, COVID-19). The demonstrated long-term value of continuous, rather than incident-related, operation of these networks in strengthening routine surveillance, bridging research gaps, and providing scalable public health response, supports their applicability to other countries.Karina A Top, Kristine Macartney, Julie A Bettinger, Ben Tan, Christopher C Blyth, Helen S Marshall ... et al. (on behalf of the IMPACT and PAEDS investigators

Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1

International audienceMutations in the PTEN-induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser 65) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1-dependent phosphorylation targets in HEK (human embry-onic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub-family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser 111) in response to PINK1 activation. Using phospho-specific antibodies raised against Ser 111 of each of the Rabs, we demonstrate that Rab Ser 111 phosphoryla-tion occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient-derived fibroblasts stimulated by mitochondrial depolari-sation. We provide evidence that Rab8A GTPase Ser 111 phosphory-lation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser 111 phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser 65. We further show mechanistically that phosphorylation at Ser 111 significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/ 8B/13 at Ser 111 may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase-mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease

The histone binding capacity of SPT2 controls chromatin structure and function in Metazoa

Histone chaperones control nucleosome density and chromatin structure. In yeast, the H3-H4 chaperone Spt2 controls histone deposition at active genes but its roles in metazoan chromatin structure and organismal physiology are not known. Here we identify the Caenorhabditis elegans ortholog of SPT2 (CeSPT-2) and show that its ability to bind histones H3-H4 is important for germline development and transgenerational epigenetic gene silencing, and that spt-2 null mutants display signatures of a global stress response. Genome-wide profiling showed that CeSPT-2 binds to a range of highly expressed genes, and we find that spt-2 mutants have increased chromatin accessibility at a subset of these loci. We also show that SPT2 influences chromatin structure and controls the levels of soluble and chromatin-bound H3.3 in human cells. Our work reveals roles for SPT2 in controlling chromatin structure and function in Metazoa.</p